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National Guideline Alliance (UK). Pancreatic cancer in adults: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2018 Feb. (NICE Guideline, No. 85.)
11.1. Management of locally advanced pancreatic cancer
Review question: What is the most effective treatment (chemotherapy, chemoradiotherapy, radiotherapy, combination of chemotherapy and chemoradiotherapy, biological therapies or other local therapies) for adults with newly diagnosed or recurrent unresectable locally advanced non-metastatic pancreatic cancer?
11.1.1. Introduction
Approximately 30-40% of the people present with locally advanced pancreatic cancer, which is unresectable, but without evidence of metastatic spread. Unlike people with borderline resectable disease, people with locally advanced pancreatic cancer can sometimes be downstaged to resectability with chemotherapy or chemoradiotherapy. They comprise a distinct subset of advanced disease, as the overall survival is significantly better than for people with metastatic disease (10-12 months versus 5-6 months).
Competing risks of locoregional progression versus systemic progression influence overall prognosis in this patient group. In addition to overall survival, management of local symptoms are an important consideration. Autopsy series suggest that about a third of these people die with local progression alone without evidence of metastatic spread. Both systemic therapy alone or in combination with loco-regional therapy (radiotherapy) has been widely used, but the optimal treatment strategy, particularly the role of radiation therapy, remains controversial.
Guidance is needed on what is the most effective treatment for people with locally advanced pancreatic cancer.
11.1.1.1. Review protocol summary
The review protocol summary used for this question can be found in Table 157. Full details of the review protocol can be found in Appendix C.
Table 157
Clinical review protocol summary for the review of most effective treatment of locally advanced, non-metastatic pancreatic cancer.
11.1.2. Description of Clinical Evidence
Eighteen studies were included in the review: ten phase III RCTs (Cantore et al. 2005; Chauffert et al. 2008; Chung et al. 2004; Cohen et al. 2005; Hammel et al. 2016; Herman et al. 2013; Li et al. 2003; Loehrer et al. 2011; Shinchi et al. 2002; Sunamura et al. 2004), seven phase II RCTs including five studies (Heinemann et al. 2013; Hurt et al. 2015; Hurt et al. 2017; Khan et al. 2016; Mukherjee et al. 2013; Rich et al. 2012; Wilkowski et al. 2009) and 1 prospective cohort study (Cantore et al. 2012). A summary of the included studies is presented in Table 158.
Three RCTs (n=175) compared different chemoradiotherapy (CRT) regimens (gemcitabine based CRT versus paclitaxel-based CRT (Chung et al. 2004); gemcitabine-based CRT versus 5FU-based CRT (Li et al. 2003); gemcitabine/cisplatin-based CRT versus 5FU-based CRT (Wilkowski et al. 2009) in patients with locally advanced pancreatic cancer.
Two phase II RCTs (n=127) compared different CRT regimens after induction chemotherapy: gemcitabine-CRT versus capecitabine-CRT after induction chemotherapy (Mukherjee et al. 2013; Hurt et al. 2015); capecitabine-CRT + cetuximab versus capecitabine-CRT alone after induction chemotherapy (Khan et al. 2016) for patients with locally advanced pancreatic cancer.
One RCT (n=31) evaluated whether 5FU-based CRT affected the length and quality of survival in patients with locally advanced pancreatic cancer (Shinchi et al. 2002).
One RCT (n=95) compared gemcitabine/cisplatin-based CRT against the same CRT regimen followed by a sequential full-dose of gemcitabine and cisplatin in patients with locally advanced pancreatic cancer (Wilkowski et al. 2009).
One RCT (n=195) compared the effect of gemcitabine/paclitaxel-based CRT [low-dose gemcitabine plus paclitaxel and concurrent radiation] against the same CRT regimen followed by R115777 [a farnesyl transferase inhibitor] in patients with locally advanced pancreatic cancer (Rich et al. 2012).
One RCT (n=304) compared CRT + TNFerade with CRT alone in patients with locally advanced pancreatic cancer (Herman et al. 2013).
Two RCTs (n=182) compared CRT with chemotherapy in patients with locally advanced pancreatic cancer. One trial compared an intensified induction phase with CRT, followed by maintenance gemcitabine with gemcitabine alone (Chauffert et al. 2008); the other trial examined whether CRT improves survival or provides additional benefit compared with gemcitabine-based chemotherapy alone (Loehrer et al. 2011).
One phase III RCT (n=268) compared chemoradiotherapy with chemotherapy alone (after 4 months of gemcitabine-based induction chemotherapy in patients with locally advanced pancreatic cancer controlled (Hammel et al. 2016 - 2nd randomization).
One RCT (n=105) compared CRT (using 5FU and mytomycin C) against radiotherapy alone in patients with locally advanced pancreatic cancer (Cohen et al. 2005).
Two RCTs (n=617) compared the effect of different chemotherapy regimens in patients with locally advanced pancreatic cancer. One trial evaluated the FLEC regimen (5-fluoruracil + leucovorin + epirubicin + carboplatin) compared with the gold standard chemothreapy (Cantore et al. 2005); the other trial compared gemcitabine-based chemotherapy against gemcitabine+erlonitib based chemotherapy.
One RCT (n=95) compared the urokinase plasminogen activator (uPA) inhibitor upmostat in combination with gemcitabine-based chemotherapy against gemcitabine-based chemotherapy alone in locally advanced pancreatic cancer (Heinemann et al. 2013).
One RCT (n=48) compared radiotherapy plus a novel radiosensitiser (PR-350) against radiotherapy plus placebo in patients with locally advanced pancreatic cancer (Sunamura et al. 2004).
One observational study (n=107) compared giving radiofrequency ablation as a primary treatment against giving radiofrequency ablation after another primary treatment in patients with locally advanced pancreatic cancer (Cantore et al. 2012).
The Cochrane Collaboration’s ‘Risk of bias’ tool was used for assessing risk of bias of randomised trials, the Newcastle-Ottawa Scale (NOS) was used for assessing the risk of bias of non-randomised studies (i.e. prospective cohort studies).
Further information about the search strategy can be found in Appendix D. See study selection flow chart in Appendix E, forest plots in Appendix H, GRADE tables in Appendix I, study evidence tables in Appendix F and list of excluded studies in Appendix G.
11.1.3. Summary of included studies
A summary of the studies that were included in this review is presented in Table 158.
Table 158
Summary of included studies.
11.1.4. Clinical evidence profile
The clinical evidence profiles for this review question are presented in Table 159 to Table 176.
Table 159
Summary clinical evidence profile for gemcitabine-based chemoradiotherapy versus paclitaxel-based chemoradiotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 160
Summary clinical evidence profile for gemcitabine-based chemoradiotherapy versus 5FU-based chemoradiotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 161
Summary clinical evidence profile for gemcitabine/Cisplatin-based chemoradiotherapy versus 5FU-based chemoradiotherapy in adults unresectable non-metastatic locally advanced pancreatic cancer.
Table 162
Summary clinical evidence profile for gemcitabine-chemoradiotherapy after induction chemotherapy versus capecitabine-chemoradiotherapy after induction chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 163
Summary clinical evidence profile for capecitabine-chemoradiotherapy + cetuximab versus capecitabine-chemoradiotherapy alone after induction chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 164
Summary clinical evidence profile for chemoradiotherapy versus best supportive care in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 165
Summary clinical evidence profile for chemoradiotherapy followed by chemotherapy versus chemoradiotherapy alone in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 166
Summary clinical evidence profile for chemoradiotherapy + R115777 versus chemoradiotherapy alone in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 167
Summary clinical evidence profile for chemoradiotherapy + TNFerade versus chemoradiotherapy alone in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 168
Summary clinical evidence profile for chemoradiotherapy versus chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 169
Summary clinical evidence profile chemoradiotherapy versus chemotherapy followed by maintenance chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 170
Summary clinical evidence profile for chemoradiotherapy versus chemotherapy after chemotherapy induction therapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 171
Summary clinical evidence profile for chemoradiotherapy versus radiotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 172
Summary clinical evidence profile for gemcitabine+erlonitib-based chemotherapy versus gemcitabine-based chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 173
Summary clinical evidence profile for FLEC-based chemotherapy versus gemcitabine-based chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 174
Summary clinical evidence profile for gemcitabine-based chemotherapy + upmostat versus gemcitabine-based chemotherapy alone in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 175
Summary clinical evidence profile for radiotherapy + PR-350 radiosensitiser versus radiotherapy + placebo in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Table 176
Summary clinical evidence profile for radiofrequency ablation as primary treatment versus radiofrequency ablation after other primary treatments in adults with unresectable non-metastatic locally advanced pancreatic cancer.
11.1.5. Economic evidence
11.1.5.1. Systematic literature review
A literature review of published cost effectiveness analyses did not identify any relevant studies for this topic.
11.1.5.2. Economic modelling
As there were potential implications for resource use associated with making recommendations in this area and it was deemed a high economic priority by the committee a network meta-analysis (NMA) and economic model was developed to aid in making recommendations in this area. The full methods and results of the NMA and economic model can be found in Chapter 13.
11.1.5.3. Overview of methods
A NMA was developed to consider the effectiveness of treatments for unresectable locally advanced non-metastatic pancreatic cancer (LAPC). The NMA includes all studies, identified by the accompanying clinical evidence review, which are phase II or phase III randomised comparative trials that compared treatments which fit into the broad groups of:
- chemotherapy,
- chemoradiotherapy,
- combination of chemotherapy and chemoradiotherapy,
- radiotherapy
- biological therapies
with another treatment or to placebo, best supportive care or no treatment. Only studies published in the year 2000 or later were included in the NMA. Studies were excluded from the NMA if they included cancers other than pancreatic cancer or included populations that had both locally advanced and metastatic disease and the locally advanced group were not analysed and reported separately. Studies which considered a previously treated patient group with responding or stable disease were also excluded from the NMA, unless they were randomised before receiving treatment.
The systematic review identified 9 trials involving 1294 patients considering 12 different treatments which were eligible for inclusion in the NMA. From the evidence reported it was decided that 1 primary NMA considering overall survival (OS) could be created as this outcome was reported by or could be derived from all trials. Two secondary NMAs were created looking at progression-free survival and objective response. As these outcomes were not reported by all trials not all studies could be included in these secondary NMAs. All three NMAs had gemcitabine as the reference treatment. Outcomes were reported in terms of a hazard ratio for overall survival and progression-free survival and in absolute terms and odds ratio for objective response.
Results from the NMAs were used to inform an economic model again comparing the cost effectiveness of treatments for unresectable LAPC. The model was a partitioned survival analysis considering three states ‘alive and not progressed’, ‘alive and progressed’ and ‘death’. The economic evaluation considered all treatments included in the primary NMA apart from best supportive care, TNFerade and Upamostat. FOLFIRINOX was also added as part of a secondary economic analysis despite no evidence being identified which matched the inclusion criteria for it to be included in any of the NMAs or the clinical evidence review. The clinical inputs for this intervention were informed by 1 systematic review and patient level meta-analysis. The study identified 13 studies of 653 patients, 355 of which had LAPC. A secondary analysis was included in the economic model to compare a change in treatment for disease which had not progressed. Three interventions were considered for this economic model. This covered all interventions that were investigated in studies which were solely excluded from the NMA on account of being in people with responding or stable disease. The model was configured so that change in treatment happened 12 weeks into the model.
The main outcome of the economic model was incremental cost per QALY compared to the base case strategy. A NHS and PSS perspective was taken. The model had a time horizon of three years which was deemed sufficient to capture the lifetime of the vast majority of the cohort. All health outcomes were discounted at a rate of 3.5% per annum in line with the NICE guidelines manual.
All chemotherapy and radiotherapy were costed in line with the trial protocols identified in the accompanying clinical evidence review. All patients in the cohort were assumed to complete the regimens as per the trial protocols. Given the relatively low life expectancy of the model cohort, the high probability of progression and the potential for serious adverse events this assumption was likely to be an unrealistic assumption. However it was likely to bias against interventions with the lower adverse events and higher overall survival and progression-free survival i.e. the more clinically effective interventions.
The cost of chemotherapy drugs were taken from the Drugs and Pharmaceutical Electronic Market Information Tool (eMIT). Where the cost of the chemotherapy regimens were not available on eMIT the drugs were costed using the BNF (BNF 72). The costs of drug procurement and administration were based on NHS reference costs. Radiotherapy and surgery were also costed using NHS reference costs. For radiotherapy, the model cohort were assumed to complete the regimen specified in the trial protocols. The cost of surgery was estimated assuming a probability of complications of 39.6%.
No UK costs were identified for the specific adverse events considered by the economic model. In the absence of this evidence it was assumed that the adverse events could be treated during one face-to-face consultant follow-up meeting and was costed as such using NHS reference costs. Only one cost was assumed for any combination of the four considered adverse events. Again this assumption was likely to bias against the more effective treatments.
Each of these health states were given a quality of life weighting based on those reported in a previous economic evaluation of LAPC. This study used expert opinion to estimate a utility weight of 0.68 for patients without progressed disease. Based on a review of the literature a detriment of 0.12 was estimated for disease progression. This gave an estimate of 0.56 for patients with progressed disease. These estimates were considered low quality and were therefore given a wide range during PSA. In the base case analysis no quality of life detriment was assigned to adverse events as these were considered to be straight forward to treat and would only occur for a short period.
11.1.5.4. Results of the NMA and economic model
The studies included in the NMA had a serious risk of bias and the quality of inputs for the model ranged from very low to good quality across all outcomes and comparisons, with most of the evidence being of low quality. The NMAs for progression-free survival and objective response had very wide credible intervals and all crossed the line of no effect therefore it was difficult to conclude anything based solely on these. In all three analyses only one treatment, chemoradiotherapy with gemcitabine, reported a hazard ratio or odds ratio, which had a 95% credible interval that did not pass the line of no effect. This effect would have been completely driven by 1 trial, Loehrer et al. 2012. The estimated hazard ratios and credible intervals compared to gemcitabine for the treatments in the overall survival NMA are reported in Table 177. Results of all other NMAs are reported in Chapter 13.
Table 177
Estimated Hazard Ratios and Credible Intervals for overall survival compared to gemcitabine.
For the economic model in the primary base case analysis, considering only interventions included in the NMA, chemoradiotherapy with gemcitabine came out as the preferred option with an incremental net monetary benefit (INMB) of £786 when a £20,000 per QALY willingness to pay was assumed. Full results of the primary base case analysis are shown in Table 178.
Table 178
Primary Base Case Analysis Results.
Considerable uncertainty around this conclusion was identified during probabilistic sensitivity analysis with only a 14% probability of chemoradiotherapy with gemcitabine being the most cost effective therapy at a £20,000 per QALY willingness to pay. Chemoradiotherapy with gemcitabine and cisplatin becomes the preferred treatment option at the £20,000 per QALY threshold with a 24% chance of being the preferred option. Chemoradiotherapy with gemcitabine, the preferred choice in the deterministic analysis now has a 16% probability of being the most cost effective option. Gemcitabine alone had a 17% probability of being the preferred option in this scenario. As the only monotherapy in the analysis this corresponds to an 83% probability that some form of combination therapy is the most cost effective option. Again the plateauing lines for all interventions suggests there is significant uncertainty around the clinical inputs for the model. This suggests that interventions were likely to be cost effective if the regimens were effective at NICE’s conventional thresholds. It was also acknowledged that there may be scope to consider a higher £50,000 per QALY threshold given the potential benefits and short life expectancy of the interventions and population. The use of either a £20,000 or £50,000 threshold did not alter the conclusions of the model.
When FOLFIRINOX was considered this regimen came out as the preferred option with an INMB of £5,992 compared to gemcitabine alone at a willingness to pay of £20,000 per QALY. During probabilistic sensitivity analysis FOLFIRINOX had a >40% chance of being the preferred option compared to all other regimens for all willingness to pay per QALY above £15,000. During this analysis gemcitabine alone has a 3% and zero probability of being cost effective for a willingness to pay per QALY of £20,000 and £50,000 respectively. Again, this strongly suggests that a combination therapy approach is almost certainly the most cost effective treatment option.
The secondary analysis around the use of chemoradiotherapy in stable and responding patients predicted that the use of chemoradiotherapy with capecitabine in this patient population would be cost effective. Again this result was robust to sensitivity analysis.
11.1.5.5. Conclusions
Of the interventions considered in the NMA, chemoradiotherapy with gemcitabine was the preferred option in the deterministic results but chemoradiotherapy with gemcitabine and cisplatin was the preferred option in the largest number of iterations in the PSA. However, it never had a greater than 25% probability compared to all other interventions at a willingness to pay per QALY values of £20,000 and £50,000 respectively. It was therefore again difficult to strongly conclude for any intervention to be the preferred option from this group. The economic model suggested that gemcitabine alone was unlikely to be the preferred option for any conventionally used willingness to pay threshold suggesting that a form combination therapy.
FOLFIRINOX was the preferred option in the when included in the analysis and in over 40% of the iterations of the probabilistic sensitivity analysis. However, despite its prevalent usage for treatment of LAPC across England no direct, randomised comparative evidence was identified for this intervention. The comparability of FOLFIRINOX to other interventions considered in the NMA and economic model is not strong. Whilst FOLFIRINOX was robust to the probabilistic sensitivity analysis, as the overall survival and progression-free survival for FOLFIRINOX were reduced closer to those of other interventions in the NMA, the strength of this conclusion was largely reduced. Comparative randomised evidence comparing FOLFIRINOX with other interventions in the NMA, would increase the comparability of this intervention and the strength of any conclusions drawn. Additional randomised clinical trials which would strengthen and increase the power of the NMA would likely reduce this uncertainty and increase the strength of any recommendations made from the model.
It is difficult to draw comparisons between the NMA and economic model above with the economic model used in Guidance on the use of gemcitabine for the treatment of pancreatic cancer (TA25). The cost effectiveness evidence for TA25 compared 5-FU chemotherapy with gemcitabine chemotherapy. The two economic evaluations for this technology assessment were largely based around 1 RCT (Burris et al. 1997) comparing gemcitabine monotherapy to 5-FU monotherapy in patients with either locally advanced or metastatic pancreatic cancer. The models submitted estimated a cost per QALY for gemcitabine compared to 5-FU of between £7,200 and £18,700. Given that 5-FU monotherapy was not a comparison considered in the NMA and economic model above, due to an absence of identified trials, direct comparisons of results could not be made. The costs of gemcitabine are also now likely to be much reduced compared to those considered in TA25 given that the treatment is now ‘off patent’ for this condition.
Despite the TA25 models not being strictly comparable to the economic model above the most pertinent difference is that gemcitabine monotherapy is now very unlikely to be the preferred option with the PSA estimating an almost 0% probability of being cost effective.
This however is compared to regimens that were not considered by TA25. However, interventions that have a component of gemcitabine, in particular chemoradiation with gemcitabine, perform favourably in the economic model.
11.1.6. Evidence Statements for pair-wise comparisons
11.1.6.1. Different chemoradiotherapy regimens
Objective Response
Very low quality evidence from 1 phase III RCT (n=46) showed no clinically important difference between gemcitabine-based chemoradiotherapy (CRT) and paclitaxel-based chemoradiotherapy about the relative probability of objective response rate (CR + PR) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.55 (95% CI 0.15-1.92), where RR higher than 1 favours the gemcitabine-based CRT group.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
Very low quality evidence from 1 phase III RCT (n=46) showed no clinically important difference between gemcitabine-based CRT and paclitaxel-based CRT on survival rates in adults with unresectable non-metastatic locally advanced pancreatic cancer: HR=0.98 (95% CI 0.52-1.85), where RR higher than 1 favours the GEM-based CRT group.
Adverse Events
Very low and low quality evidence from 1 phase III RCT (n=46) showed no clinically important difference between gemcitabine-based CRT and paclitaxel-based CRT about the relative risk of grade 3/4 toxicities (including haematological and non-haematological) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 1.09 (95% CI 0.36-3.27) and RR 1.96 (95% CI 1.18-3.28) respectively, where RR higher than 1 favours the paclitaxel-based CRT group.
Very low and low quality evidence from 1 open label phase III RCT (n=34) showed no clinically important difference between gemcitabine-based CRT and 5FU-based CRT about the relative risk of grade 3/4 toxicities (including nausea, vomiting, anorexia, anaemia, neutropenia, thrombocytopenia and GI bleeding) in adults with unresectable non-metastatic locally advanced pancreatic cancer (relative effect not estimable).
Low quality evidence from 1 multicentre phase II RCT (n=60) showed a clinical important difference favouring 5FU-based CRT in drug-related grade 3/4 toxicities (leukocytopenia and thrombocytopenia) compared to gemcitabine/cisplatin-based CRT in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 14.97 (95% CI 2.12-105.82) and RR 14.97 (95% CI 2.12-105.82) respectively.
Very low quality evidence from 1 multicentre phase II RCT (n=60) showed no clinically important difference between 5FU-CRT and gemcitabine/cisplatin-CRT about the relative risk of grade 3/4 toxicities (including non-haematological, lower GI tract, upper GI tract, anaemia) in adults with unresectable non-metastatic locally advanced pancreatic cancer (relative effect not estimable).
Health Related Quality of Life
Low quality evidence from 1 open label phase III RCT (n=34) showed a clinically important difference favouring gemcitabine-based CRT on global quality of life scores compared to 5FU-based CRT in adults with unresectable non-metastatic locally advanced pancreatic cancer: MD = 9.00 (95% CI 6.98-11.03).
Pain control
Very low quality evidence from 1 open label phase III RCT (n=34) showed a clinically important difference favouring gemcitabine-based CRT on pain control compared to 5FU-based CRT in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 6.22 (95% CI 0.86-45.25).
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.2. Different chemoradiotherapy regimens after induction chemotherapy
Objective Response
Very low quality evidence from 1 open label phase II RCT (n=71) showed no clinically important difference between gemcitabine-CRT and capecitabine-CRT after induction chemotherapy on the relative probability of objective response rate (CR + PR) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.85 (95% CI 0.35-2.10), where RR higher than 1 favours the GEM-CRT group.
Very low quality evidence from 1 Phase II RCT (n=13) showed no clinically important difference between CRT + cetuximab and CRT alone after induction chemotherapy on the relative probability of objective response rate (CR + PR) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.50 (95% CI 0.06-4.15), where RR higher than 1 favours the CRT + cetuximab group.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
Moderate quality evidence from 1 open label phase II RCT (n=72) showed no clinically important difference between gemcitabine-CRT and capecitabine-CRT after induction chemotherapy on time to progression rates in adults with unresectable non-metastatic locally advanced pancreatic cancer: HR=0.60 (95% CI 0.32-1.12), where HR higher than 1 favours the gemcitabine-CRT arm.
Overall Survival
Moderate quality evidence from 1 open label phase II RCT (n=72) indicates that capecitabine-CRT after induction chemotherapy is associated with a clinically important difference in overall survival compared to gemcitabine-CRT after induction chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer: HR=0.39 (95% CI 0.18-0.85)
Low quality evidence from 1 phase II RCT (n=13) showed no clinically important difference between CRT + cetuximab and CRT alone after induction chemotherapy on survival rates in adults with unresectable non-metastatic locally advanced pancreatic cancer (relative effect not estimable).
Adverse Events
Very low and low quality evidence from 1 open label phase II RCT (n=72) showed no clinically important difference between gemcitabine-CRT and capecitabine-CRT after induction chemotherapy on the relative risk of grade 3/4 toxicities (including haematological and non-haematological toxicities) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 13.46 (95% CI 0.8-227.22) and 2.24 (95% CI 0.77-6.48) respectively, where RR less than 1 favours the gemcitabine-CRT arm.
Very low and low quality evidence from 1 phase II RCT (n=13) showed no clinically important difference between CRT + cetuximab and CRT alone after induction chemotherapy on relative risk of grade 3/4 toxicities (including hyponatremia, fatigue and abdominal pain) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.33 (95% CI 0.02-6.86) for all outcomes, where RR less than 1 favours the CRT + cetuximab group.
Health Related Quality of Life
Low quality evidence from 1 open label phase II RCT (n=48) showed no clinically important difference between gemcitabine-CRT and capecitabine-CRT after induction chemotherapy on the improvement of quality of life (measured as mean of the EORTC QLQ-C30) in adults with unresectable non-metastatic locally advanced pancreatic cancer (relative effect not estimable).
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.3. Chemoradiotherapy versus best supportive care
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
No evidence was identified to inform this outcome.
Health Related Quality of Life
Low quality evidence from 1 phase III RCT (n=31) indicates a clinically important difference favouring CRT on global quality of life scores (measured as mean of the Karnofsky performance status) compared to best supportive care [no CRT] in adults with unresectable non-metastatic locally advanced pancreatic cancer: MD = 11.60 (95% CI 6.61-15.69).
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.4. Chemoradiotherapy versus chemoradiotherapy followed by chemotherapy
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
Low quality evidence from 1 multicentre phase II RCT (n=56) showed a clinically important difference favouring CRT [5FU-CRT] on the relative risk of drug-related grade 3/4 toxicities (leukocytopenia and thrombocytopenia) compared to CRT followed by chemotherapy [gemcitabine/cisplatin-CRT followed by gemcitabine chemotherapy] in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 18.26 (95% CI 2.60-128.02) and 10.74 (95% CI 1.47-78.39) respectively, where RR less than 1 favours the CRT followed by chemotherapy arm.
Very low quality evidence from 1 multicentre phase II RCT (n=56) showed no clinically important difference between CRT [5FU-CRT] and CRT followed by chemotherapy [gemcitabine/cisplatin-CRT followed by gemcitabine chemotherapy] on the relative risk of grade 3/4 toxicities (including non-haematological, lower GI tract, upper GI tract, anaemia) in adults with unresectable non-metastatic locally advanced pancreatic cancer.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.5. Chemoradiotherapy + R115777 versus chemoradiotherapy alone
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
Moderate quality evidence from 1 phase II RCT (n=185) showed no clinically important difference between CRT+R115777 and CRT alone in survival rates after induction chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer (relative effect not estimable).
Adverse Events
Very low and low quality evidence from 1 phase II RCT (n=185) showed no clinically important difference between CRT+R115777 and CRT alone on the relative risk of grade 3/4 toxicities (including allergy/immunology, blood/bone marrow, cardiovascular, coagulation, constitutional, endocrine, and gastrointestinal) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.65 (95% CI 0.11-3.77); RR 1.39 (95% CI 0.96-2.0); RR 2.26 (95% CI 0.6-8.47); RR 0.32 (95% CI 0.01-7.82); RR 1.69 (95% CI 0.75-3.84); RR 0.32 (95% CI 0.01-7.82); and RR 1.12 (95% CI 0.77-1.63) respectively, where RR less than 1 favours the CRT+R115777 arm.
No grade 3/4 toxicities were reported for the following outcomes in both intervention groups: auditory/hearing, cardiovascular (arrhythmia), dermatology/skin, and ocular/visual/renal/genitourinary.
Moderate quality evidence from 1 phase II RCT (n=185) suggests a clinically important difference favouring CRT+R115777 on the relative risk of drug-related grade 3/4 toxicities (haemorrhage) compared to CRT alone: RR 0.06 (95% CI 0.02-0.26).
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.6. Chemoradiotherapy + TNFerade versus chemoradiotherapy alone
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
Very low quality evidence from 1 open label phase III RCT (n=304) showed no clinically important difference between CRT + TNFerade and CRT alone on the relative risk of grade 3/4 toxicities (including gastrointestinal, haematological, and non-gastrointestinal/haematological) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 1.64 (95% CI 0.85-3.16); RR 0.90 (95% CI 0.64-1.28); and RR 1.51 (95% CI 0.67-3.41) respectively, where RR less than 1 favours the CRT + TNFerade arm.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.7. Chemoradiotherapy versus chemotherapy
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
Low quality evidence from 1 phase III RCT (n=71) showed a clinically important difference favouring CRT on the relative risk of drug-related grade 3/4 toxicities (fatigue) compared to chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 5.66 (95% CI 1.35-33.68)
Very low quality evidence from 1 phase III RCT (n=71) showed no clinically important difference between CRT and chemotherapy on the relative risk of grade 3/4 toxicities (including haemoglobin, leukocytes, neutrophils, nausea, vomiting, hypokalaemia, and anorexia) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 3.09 (95% CI 0.67-14.25); RR 2.26 (95% CI 0.88-5.83); RR 1.12 (95% CI 0.60-2.09); RR 3.43 (95% CI 1.03-11.40); RR 3.09 (95% CI 0.91-10.44); RR 2.06 (95% CI 0.40-10.51); and RR 6.18 (95% CI 0.78-48.64) respectively, where RR less than 1 favours the CRT arm.
Health Related Quality of Life
Low and very low quality evidence from 1 phase III RCT (n=71) showed a clinically important difference favouring CRT on the improvement of global quality of life scores compared to chemotherapy at 6 weeks follow-up in adults with unresectable non-metastatic locally advanced pancreatic cancer: MD = −12.20 (95% CI −17.98 to −6.42, measured as mean difference of changes from baseline).
The same study showed no clinically important difference between CRT and chemotherapy on the improvement in global quality of life scores (measured as mean difference of changes from baseline) at 16 week and 9 month follow-up in adults with unresectable non-metastatic locally advanced pancreatic cancer: MD = −3.30 (95% CI −9.08 to 2.48) and 2.70 (95% CI - 3.08 to 8.48), where MD less than 1 favours the GEM-CRT arm.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.8. Chemotherapy versus chemoradiotherapy after induction chemotherapy
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
Moderate quality evidence from 1 open label phase III RCT (n=368) showed no clinically important difference between chemotherapy and CRT after induction chemotherapy on time to progression rates in adults with unresectable non-metastatic locally advanced pancreatic cancer: HR=0.78 (95% CI 0.61-1.00), where HR higher than 1 favours the CT arm.
Overall Survival
Moderate quality evidence from 1 open label phase III RCT (n=368) showed no clinically important difference between chemotherapy and CRT after induction chemotherapy on overall survival rates in adults with unresectable non-metastatic locally advanced pancreatic cancer: HR=1.03 (95% CI 0.79-1.14), where HR higher than 1 favours the CT arm.
Adverse Events
Very low and low quality evidence from 1 open label phase III RCT (n=368) showed no clinically important difference between chemotherapy and CRT after induction chemotherapy on the relative risk of grade 3/4 toxicities (including haematological and non-haematological) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR = 2.93 (95% CI 0.97-8.87) and 0.94 (95% CI 0.56-1.58), where RR less than 1 favours the CRT arm.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.9. Chemoradiotherapy versus radiotherapy
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
Very low quality evidence from 1 open label phase III RCT (n=114) showed no clinically important difference between CRT and radiotherapy on the relative risk of grade 3/4 toxicities (including gastrointestinal, vomiting, infection, skin, mucous, neurologic, genitourinary, hematologic, liver, constipation, cardiac, and fever) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.32 (95% CI 0.01-7.72); RR 0.72 (95% CI 0.17-3.08); RR 2.89 (95% CI 0.12-69.47); RR 4.82 (95% CI 0.24-98.13); RR 3.85 (95% CI 0.45-33.38); RR 0.96 (95% CI 0.06-15.01); RR 2.70 (95% CI 1.04-6.97); RR 0.39 (95% CI 0.08-1.90) and RR 1.93 (95% CI 0.18-20.63) respectively, where RR less than 1 favours the CRT arm.
No grade 3/4 toxicities were reported for the following outcomes in both intervention groups: diarrhoea, haemorrhage, and respiratory system.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.10. Different chemotherapy regimens
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
Very low quality evidence from 1 open label phase III RCT (n=443) showed no clinically important difference between the gemcitabine chemotherapy and gemcitabine/erlotinib chemotherapy on the relative risk of grade 3/4 toxicities (including haematological and non-haematological) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR = 1.17 (95% CI 0.91-1.5) and 1.01 (95% CI 0.8-1.27) respectively, where RR less than 1 favours the gemcitabine/erlotinib chemotherapy arm.
Low quality evidence from 1 phase III RCT (n=138) showed a clinically important difference favouring gemcitabine chemotherapy on drug-related grade 3/4 toxicities (including leukopenia, vomiting, diarrhoea, anaemia, thrombocytopenia, fever, microsites, and gastrointestinal bleeding) compared to FLEC chemotherapy in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR = 2.14 (95% CI 1.29-3.55).
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.11. Gemcitabine- based chemotherapy + upmostat versus gemcitabine-based chemotherapy alone
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
No evidence was identified to inform this outcome.
Adverse Events
Very low and low quality evidence from 1 open label phase II RCT (n=95) showed no clinically important difference between gemcitabine-based chemotherapy and gemcitabine-based chemotherapy + upmostat on the relative risk of grade 3/4 toxicities (any type) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR = 1.31 (95% CI 0.78-2.19)- 200mg upmostat and RR 1.54 (95% CI 0.96-2.74)- 400mg upmostat, where RR less than 1 favours the gemcitabine-based chemotherapy + upmostat arm.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.12. Radiotherapy + PR-350 Radiosensitiser versus Radiotherapy + Placebo
Objective Response
Very low quality evidence from 1 double-blind phase III RCT (n=48) showed no clinically important difference between radiotherapy + PR-350 and radiotherapy + placebo on the relative probability of objective response rate (CR + PR) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 2.18 (95% CI 0.88-5.41), where RR higher than 1 favours the radiotherapy + PR-350 group.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
Low quality evidence from 1 double-blind phase III RCT (n=48) showed no clinically important difference between radiotherapy + PR-350 and radiotherapy + placebo on survival rates in adults with unresectable non-metastatic locally advanced pancreatic cancer (relative effect not estimable).
Adverse Events
Very low quality evidence from 1 double-blind phase III RCT (n=48) showed no clinically important difference between radiotherapy + PR-350 and radiotherapy + placebo on the relative risk of grade 3/4 toxicities (including any type) in adults with unresectable non-metastatic locally advanced pancreatic cancer: RR 0.38 (95% CI 0.02-8.80), where RR higher than 1 favours the radiotherapy + PR-350 group.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.6.13. Radiofrequency ablation (RFA) as primary treatment versus RFA after other primary treatments
Objective Response
No evidence was identified to inform this outcome.
Resection rate
No evidence was identified to inform this outcome.
Progression Free Survival
No evidence was identified to inform this outcome.
Overall Survival
Low quality evidence from 1 prospective cohort study (n=107) indicates a clinical important difference favouring RFA as primary treatment on overall survival compared to RFA following any other primary treatment (relative effect not estimable).
Adverse Events
No evidence was identified to inform this outcome.
Health Related Quality of Life
No evidence was identified to inform this outcome.
Pain control
No evidence was identified to inform this outcome.
Patient experience and PROMS
No evidence was identified to inform this outcome.
11.1.7. Recommendations
- 50.
Offer systemic combination chemotherapy to people with locally advanced pancreatic cancer who are well enough to tolerate it.
- 51.
Consider gemcitabine for people with locally advanced pancreatic cancer who are not well enough to tolerate combination chemotherapy.
- 52.
When using chemoradiotherapy, consider capecitabine as the radiosensitiser.
11.1.8. Evidence to recommendations
11.1.8.1. Relative value placed on the outcomes considered
Overall survival, progression free survival, objective response, resection rate, adverse events, health related quality of life, pain control, patient experience and PROMS were considered to be the critical outcomes for this question. Objective response was reported by eleven studies, progression free survival was reported by nine studies and overall survival was reported by sixteen studies.
11.1.8.2. Quality of evidence
Network meta-analysis (NMA)
Given the variation in practice for this topic and the potential for a significant resource impact from any recommendations, a network meta-analysis (NMA) was developed to help inform recommendations.
All identified phase III and phase II randomised clinical trials in pure locally advanced pancreatic cancer populations were considered in the network meta-analysis as long as the intervention in a given trial was also considered by another study and could therefore form part of the network. Studies where the patient group had received induction chemotherapy and were randomised only if they had responding or stable disease, were excluded. Three NMAs were built based on the outcomes of overall survival, progression free survival and objective response with gemcitabine monotherapy being used as the reference standard. The committee noted that most of the studies included in the NMA had a serious risk of bias and that the quality of inputs for the economic model ranged from very low to good quality across all outcomes and comparisons, with most of the evidence being of low quality.
The committee noted that the results of the NMA for progression free survival and objective response had very wide credible intervals and all crossed the line of no effect. They therefore agreed that no conclusions could be drawn from these outcomes.
The committee also noted that the results of the NMA for overall survival had 1 intervention, chemoradiotherapy with Gemcitabine, for which the 95% credible intervals did not pass the line of no effect (HR=1). They also noted that 1 RCT (Loehrer 2011) which was identified as having a serious risk of bias was independently driving the results of the NMA in this way. All other credible intervals crossed 1, although the credible intervals were much narrower than for the other NMAs. The committee agreed that the NMA considering overall survival would be somewhat useful for informing recommendations, but they noted great uncertainty and that caution in interpreting results was needed.
Usually this would mean making a weaker recommendation, but the committee agreed that because a very high proportion of people with locally advanced disease will go on to develop metastatic disease unless they have treatment, a stronger recommendation should be made. The committee also noted that chemotherapy used in the identified studies would no longer be considered standard for either metastatic or locally advanced pancreatic cancer. There were no randomised clinical trials of FOLFIRINOX, which is frequently offered as standard of care, so it was not possible for this intervention to be included in the NMA. It was agreed that FOLFIRINOX should be investigated as a secondary economic analysis instead. The clinical data for FOLFIRINOX came from Suker 2016, which was a non-comparative patient level meta-analysis of 13 studies. The committee noted that this is a lower level of evidence than the RCT data on other interventions that went into the NMA, so used caution when interpreting the results. The committee noted that FOLFIRINOX is only suitable for fit patients.
Pairwise comparison
Pairwise comparisons were conducted for outcomes in the review question that were not covered by the NMA. Pairwise comparisons were also conducted for studies which did not meet the inclusion criteria for the NMA. The evidence for the outcomes of pairwise comparisons ranged from very low to moderate quality across all outcomes and comparisons, with most of the evidence being either very low or low quality. The committee noted that the overall trend being reported by the evidence was that more chemotherapy (in the form of combination regimens) was associated with more adverse events.
Very little evidence was found on ablative therapies so the committee agreed not to make any recommendations for clinical practice about this intervention. They did not recommend further research on any of the ablative therapies investigated in this question as they did not think they were a priority for research funding.
11.1.8.3. Consideration of clinical benefits and harms
Based on the results of the NMA and economic analysis the committee agreed that combination chemotherapy was more clinically effective than monotherapy in terms of overall survival and the most cost effective option.
The health economic analysis showed FOLFIRINOX was cost effective but there was uncertainty about the clinical data used to inform the model. Therefore they agreed not to make a specific recommendation on FOLFIRINOX but noted that the offer of combination chemotherapy allowed FOLFIRINOX to be considered. Given the potential toxicity with combination chemotherapy and difficulty for less fit patients to tolerate it, the committee also recommended gemcitabine as an option for people who are unlikely to tolerate combination therapy.
The committee noted that consolidation chemoradiotherapy was relatively safe, improved local control and may be cost effective but that survival was not superior to chemotherapy alone. Therefore they agreed that they were unable to make a specific recommendation on the use of consolidation chemoradiotherapy. Based on data from pairwise comparisons that there was improved overall survival and less haematological toxicity with capecitabine-based chemoradiotherapy compared with gemcitabine-based chemoradiotherapy, the committee agreed to recommend capecitabine as the radiosensitiser for people in whom the decision to offer chemoradiotherapy has been made.
11.1.8.4. Consideration of economic benefits and harms
The estimates and distributions from the NMA were used to inform a bespoke economic model. The committee raised concerns that there were important elements for this topic not considered by the NMA, most notably the role of chemoradiotherapy in patients with stable and responding disease and the use of FOLFIRINOX (for which no randomised evidence was identified and thus was excluded from the NMA). Two secondary economic analyses were therefore performed to consider these.
In the primary base case analysis, considering only interventions included in the NMA, chemoradiotherapy with gemcitabine came out as the preferred option with an incremental net monetary benefit (INMB) of £786 when a £20,000 per QALY willingness to pay was assumed. However, considerable uncertainty around this conclusion was identified during probabilistic sensitivity analysis with only a 14% probability of being the most cost effective therapy at a £20,000 per QALY willingness to pay. Above a willingness to pay of £10,000 per QALY there was never more than a few percentage difference in being the preferred option between the top four therapies. It was therefore difficult for the committee to conclude which regimen was most cost effective.
When FOLFIRINOX was considered, this regimen came out as the preferred option with an INMB of £5,992 compared to gemcitabine alone. During probabilistic sensitivity analysis FOLFIRINOX had a >40% chance of being the preferred option compared to all other regimens for all willingness to pay per QALY above £15,000. The committee noted that this was based on observational data and that the likely associated biases would mean that inputs into the economic model would overestimate the true effectiveness of FOLFIRINOX. However, these results were robust to deterministic sensitivity analyses which reduced the effectiveness of FOLFIRINOX. The committee therefore agreed, based on the results of the economic model that whilst FOLFIRINOX appeared to be cost effective, the clinical data was very weak and therefore did not make a recommendation for this intervention.
The secondary analysis around the use of chemoradiotherapy in stable and responding patients predicted that the use of chemoradiotherapy with capecitabine in this patient population would be cost effective. Again this result was robust to sensitivity analysis. The committee noted that from the clinical evidence that whilst consolidation chemoradiotherapy appeared to be relatively safe and improve local control, that survival was not superior to chemotherapy alone. Therefore they agreed that they were unable to make a specific recommendation on the use of consolidation chemoradiotherapy.
It was also acknowledged by the committee that most of the uncertainty in the model was driven by clinical factors with the lines of the cost-effectiveness acceptability curve running almost horizontal for values above a willingness to pay of £15,000 per QALY. This suggested that interventions were likely to be cost effective if the regimens were effective at NICE’s conventional thresholds. It was also acknowledged that there may be scope to consider a higher £50,000 per QALY threshold given the potential benefits and short life expectancy of the interventions and population. Whilst the use of either a £20,000 or £50,000 threshold did not alter the conclusions, it does strengthen the argument that the recommendations made around the model are cost effective.
The committee agreed that there was unlikely to be any significant resource impact as a result of the recommendations made since the interventions are already widely used as treatment in this patient group.
11.1.8.5. Other considerations
The committee noted that there was existing NICE Interventional Procedure guidance on the use of irreversible electroporation for treating pancreatic cancer (IPG579). It concluded that current evidence on its safety and efficacy is inadequate in quantity and quality, and therefore recommended that this procedure should only be used in the context of research. Consequently this intervention was not investigated by this guideline and the committee were not able to make any recommendations on it.
11.1.9. References
- Cantore M, Fiorentini G, Luppi G et al. (2004) Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology. Journal of Chemotherapy 16(6): 589–94 [PubMed: 15700852]
- Cantore M, Girelli R, Mambrini A et al. (2012) Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma. British Journal of Surgery 99(8): 1083–8 [PubMed: 22648697]
- Chauffert B, Mornex F, Bonnetain F et al. (2008) Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer Definitive results of the 2000-01 FFCD/SFRO study. Annals of Oncology 19(9): 1592–9 [PubMed: 18467316]
- Chung HW, Bang SM, Park SW et al. (2004) A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer. International Journal of Radiation*Oncology*Biology* Physics 60(5): 1494–501 [PubMed: 15590180]
- Cohen SJ, Dobelbower R Jr et al. (2005) A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. International Journal of Radiation*Oncology*Biology* Physics 62(5): 1345–50 [PubMed: 16029791]
- Hammel P, Huguet F, van Laethem JL et al. (2016) Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 315(17): 1844–53 [PubMed: 27139057]
- Heinemann V, Ebert MP, Laubender RP et al. (2013) Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer. British Journal of Cancer 108(4): 766–70 [PMC free article: PMC3590684] [PubMed: 23412098]
- Herman JM, Wild AT, Wang H et al. (2013) Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results. Journal of Clinical Oncology 31(7): 886–94 [PMC free article: PMC4820756] [PubMed: 23341531]
- Hurt CN, Mukherjee S, Bridgewater J et al. (2015) Health-Related Quality of Life in SCALOP, a Randomized Phase 2 Trial Comparing Chemoradiation Therapy Regimens in Locally Advanced Pancreatic Cancer. International Journal of Radiation*Oncology*Biology*Physics. 93(4): 810–8 [PMC free article: PMC4627359] [PubMed: 26530749]
- Hurt CN, Falk S, Crosby T et al. (2017) Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-chemoradiation for locally advanced pancreatic cancer. British Journal of Cancer 116(10): 1264–1270 [PMC free article: PMC5482737] [PubMed: 28376080]
- Khan K, Cunningham D, Peckitt C et al. (2016) miR-21 expression and clinical outcome in locally advanced pancreatic cancer: exploratory analysis of the pancreatic cancer Erbitux, radiotherapy and UFT (PERU) trial. Oncotarget 7(11): 12672–81 [PMC free article: PMC4914313] [PubMed: 26862857]
- Li CP, Chao Y, Chi KH et al. (2003) Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. International Journal of Radiation*Oncology*Biology*Physics 57(1): 98–104 [PubMed: 12909221]
- Loehrer PJ Sr, Feng Y, Cardenes H et al. (2011) Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. Journal of Clinical Oncology 29(31): 4105–12 [PMC free article: PMC3525836] [PubMed: 21969502]
- Mukherjee S, Hurt CN, Bridgewater J et al. (2013) Gemcitabine-or capecitabine-chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncology 14(4): 317–26 [PMC free article: PMC3620899] [PubMed: 23474363]
- Rich TA, Winter K, Safran H et al. (2012) Weekly paclitaxel, gemcitabine, and external irradiation followed by randomized farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer. OncoTargets and Therapy 5: 161–70 [PMC free article: PMC3430391] [PubMed: 22977306]
- Shinchi H, Takao S, Noma H et al. (2002) Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. International Journal of Radiation*Oncolology*Biology*Physics 53(1): 146–50 [PubMed: 12007953]
- Sunamura M, Karasawa K, Okamoto A et al. & PR-350 study group (2004) Phase III trial of radiosensitiser PR-350 combined with intraoperative radiotherapy for the treatment of locally advanced pancreatic cancer. Pancreas 28(3): 330–4 [PubMed: 15084982]
- Wilkowski R, Boeck S, Ostermaier S et al. (2009) Chemoradiotherapy with concurrent gemcitabine and cisplatin with or without sequential chemotherapy with gemcitabine/cisplatin vs chemoradiotherapy with concurrent 5-fluorouracil in patients with locally advanced pancreatic cancer--a multi-centre randomised phase II study. British Journal of Cancer 101(11): 1853–9 [PMC free article: PMC2788265] [PubMed: 19904268]
11.2. Management of metastatic pancreatic cancer
Review question: What are the most effective interventions for adults with newly diagnosed or recurrent metastatic pancreatic cancer (Chemotherapy, surgery, radiotherapy)?
11.2.1. Introduction
At presentation, the majority of pancreatic cancer patients have locally advanced or metastatic disease. The prognosis of those with metastatic pancreatic cancer is measured in months, which may be extended, albeit to a limited extent by systemic chemotherapy. Pancreatic cancer frequently affects older people and metastatic disease is associated with multiple problems, including pain, weight loss, anorexia, cachexia, jaundice, nausea, vomiting, altered bowel habit, dyspepsia, mood disturbance and depression and increased risk of thromboembolic events.
Despite recent advances in chemotherapy, with interventions such as FOLFIRNOX and other combination regimes providing a prolonged median survival, the prognosis for people diagnosed with metastatic pancreatic cancer remains poor and any subsequent treatment is deemed palliative (for example not curative). People with metastatic pancreatic cancer may experience distressing symptoms that require ongoing and specialist support. In respect of this, it is important that people diagnosed with metastatic pancreatic cancer have their physical and psychological needs assessed at the time of diagnosis. General and specialist palliative care services have an important role in introducing the person with pancreatic cancer, and their family if applicable, to a range of services and support available to ease the burden of physical and psychological distress through the trajectory of their cancer diagnosis towards end of life. If a person presents with end stage metastatic disease with a poor performance status and no treatment can be offered to them, the support of specialist palliative care is essential.
Individuals with significant comorbidities or poor performance status due to advancing disease may not tolerate chemotherapy. For those people fit for treatment, various single agent and combination chemotherapy regimens are in routine use, few of which have undergone NICE technology appraisal. Those interventions where there is existing NICE technology appraisal guidance will not be reviewed here, paclitaxel as albumin-bound nanoparticles in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA476, 2017) and pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine (TA440, 2017).
Metastatic disease results in a significant symptom burden for the individual which requires active management to achieve symptom control, with the intention of improving quality of life, patient and family experience. Radiotherapy with or without chemotherapy has been used to reduce local tumour volume (including at the coeliac plexus) with the intention of improving pain control. Pharmacological interventions including analgesia, antiemetics, pancreatic enzyme replacement, blood sugar management, corticosteroid and other hormonal agents as well as anticoagulants play a role in symptom management and may influence overall outcomes. An area of current uncertainty is whether isolated metastases can be effectively targeted by surgery or local ablative techniques.
While most randomised trials have focussed on evaluating first line chemotherapy, there is uncertainty regarding the role of second line chemotherapy in a subgroup of people who are sufficiently fit to receive it.
Guidance is needed on the most effective interventions for people with metastatic pancreatic cancer.
11.2.1.1. Review protocol summary
The review protocol summary used for this question can be found in Table 179. Full details of the review protocol can be found in Appendix C.
Table 179
Clinical review protocol summary for review of management of metastatic pancreatic cancer.
11.2.2. Description of Clinical Evidence
Thirty-nine phase II/III RCTs and 1 network-meta analysis of 23 RCTs (Gresham et al. 2014) were included in this review. A summary of the studies included in pairwise comparisons is presented in Table 180. A summary of the studies included in the NMA is presented in Table 181.
Two RCTs were found that compared chemotherapy with chemoimmunotherapy in adults with advanced/metastatic pancreatic cancer (Middleton et al. 2014; Wang et al. 2013). One of the studies assessed the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy as first-line therapy in adults with advanced/metastatic pancreatic cancer (Middleton et al. 2014). The other study compared S-1 combined with cytokine-induced killer cells (CIK) with S-1 only in adults with advanced/metastatic pancreatic cancer who had previously received gemcitabine-based therapy (Wang et al. 2013).
A total of 15 RCTs (Bernhard et al. 2008; Burris et al. 1997; Chao et al. 2013; Deplanque et al. 2015; Eckhardt et al. 2009; Fuchs et al. 2015; Gourgou-Bourgade et al. 2013; Irigoyen et al. 2017; Lee et al. 2017; Kindler et al. 2010; Moinpour et al. 2010; Rougier et al. 2013; Sudo et al. 2014; Ueno et al. 2013; Yamaue et al. 2015) and 1 NMA (Gresham et al. 2014) of 23 RCTs (Abou-Alfa et al. 2006; Berlin et al. 2002; Bramhall et al. 2002; Colucci et al. 2010; Conroy et al. 2011; Cunningham et al. 2009; Gonçalves et al. 2012; Heinemann et al. 2006; Heinemann et al. 2012; Herrmann et al. 2007; Kindler et al. 2011; Louvet et al. 2005; Moore et al. 2007; Oettle et al. 2005; Philip et al. 2010; Poplin et al. 2006; Reni et al. 2005; Riess et al. 2005; Rocha Lima et al. 2004; Stathopoulos et al. 2006; Van-Cutsem et al. 2004; Van-Cutsem et al. 2009; Von-Hoff et al. 2013) were found that compared gemcitabine with other chemotherapy regimens. Ten of the 15 RCTs included in this review were in a mixed population that included adults with either locally advanced or metastatic pancreatic cancer, whilst the remaining 5 were in adults with metastatic pancreatic cancer only (Chao et al. 2013; Fuchs et al. 2015; Gourgou-Bourgade et al. 2013; Irigoyen et al. 2017; Rougier et al. 2013). The majority of the studies in the NMA by Gresham et al. 2014 included adults with either locally advanced or metastatic pancreatic cancer. A summary of the characteristics of the 15 included RCTs studies are presented in Table 180, whilst a summary of the characteristics of the 23 RCTs in the included NMA of Gresham et al. 2014 are presented in Table 181.
Data were extracted from the NMA for overall survival only. Data on response rate, progression-free survival, adverse events, and health-related quality of life were extracted from the original studies included in the NMA (pairwise evidence review). The NMA included a study (Von Hoff et al. 2013) that is part of a NICE TA evaluation of nab-Paclitaxel plus Gemcitabine; TA476 [see NICE 2017]). Although the results of this study were included in the NMA - to increase its precision and decrease heterogeneity - it was excluded from the pairwise comparisons presented to the committee (and hence its decision making).
Three RCTs were found that compared gemcitabine with novel gemcitabine-based treatments in adults with locally advanced or metastatic pancreatic cancer (Middleton et al. 2017; Moore et al. 2003; Smith et al. 2003).
One RCT was identified that compared a low-dose gemctiabine infusion with a standard-dose gemcitabine infusion in adults with locally advanced or metastatic pancreatic cancer (Sakamoto et al. 2006).
Four RCTs were found that compared 5-FU with combination 5-FU in adults with metastatic pancreatic cancer (Cullinan et al. 1985; Cullinan et al. 1990; Ducreux et al. 2002; Maisey et al. 2002). Two of these studies were in adults with metastatic pancreatic cancer (Cullinan et al. 1985; Maisey et al. 2002), whilst two of them were in adults with locally advanced or metastatic pancreatic cancer (Cullinan et al. 1990; Ducreux et al. 2002).
Two RCTs, which were both in adults with locally advanced or metastatic pancreatic cancer, compared first-line combination 5-FU with other chemotherapy regimens (Bukowski et al. 1983; Oster et al. 1986). One of the studies compared FAM (a combination of 5-FU, Adriamycin [Doxorubicin], and Mitomycin) with FSM (a combination of 5-FU, Streptozotocin, and Mitomycin) (Oster et al. 1986); whilst the other study compared FSM with MF (a combination of Mitomycin C and 5-FU) (Bukowski et al. 1983).
Three RCTs were found that compared regional intra-arterial chemotherapy (RIAC) with systemic chemotherapy in adults with locally advanced or metastatic pancreatic cancer (Aigner et al. 1998; Cantore et al. 2004; Ji et al. 2003).
Two RCTs were found that compared a combination of chemotherapy and a prophylactic anticoagulant with chemotherapy only in adults with locally advanced or metastatic pancreatic cancer. One study compared a combination of gemcitabine and weight-adjusted dalteparin (WAD) with gemcitabine only (Maraveyas et al. 2012), whilst 1 study compared a combination of first-line chemotherapy and prophylactic enoxaparin with chemotherapy only (Pelzer et al. 2015).
One RCT was found that compared second-line glufosfamide with best supportive care (BSC) in adults with metastatic pancreatic cancer (Ciuleanu et al. 2009).
Six RCTs were found that compared two types of second-line chemotherapy with 1 another in adults with locally advanced or metastatic pancreatic cancer who had previously received gemcitabine-based chemotherapy (Azmy et al. 2013; Dahan et al. 2010; Gill et al. 2016; Heinemann et al. 2012; Oettle et al. 2014; Ulrich-Pur et al. 2003).
The ISPOR checklist was used for the quality assessment of the NMA (Jansen et al. 2014), whilst the GRADE tool was used for assessing risk of bias and overall quality of the phase II/III RCTs.
Further information about the search strategy can be found in Appendix D. See study selection flow chart in Appendix E, forest plots in Appendix H, GRADE tables in Appendix I, study evidence tables in Appendix F and list of excluded studies in Appendix G.
11.2.3. Summary of included studies
A summary of the studies that were included in this review is presented in Table 180.
Table 180
Summary table of included RCT studies.
Table 181
Summary of studies included in Gresham et al. 2014 Network Meta-Analysis.
11.2.4. Clinical evidence profile
The clinical evidence profiles for this review question are presented in Table 182 to Table 214.
11.2.4.1. Chemotherapy versus chemoimmunotherapy
11.2.4.1.1. First-line chemotherapy with sequential or concurrent immunotherapy versus chemotherapy
Table 182
Summary clinical evidence profile for first-line chemotherapy with sequential or concurrent immunotherapy versus chemotherapy in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.1.2. Second-line chemoimmunotherapy versus chemotherapy
Table 183
Summary clinical evidence profile for second-line chemoimmunotherapy versus chemotherapy in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.2. Gemcitabine versus other chemotherapy
11.2.4.2.1. Adults with metastatic pancreatic cancer
Table 184
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Response rate, overall survival and progression-free survival).
Table 185
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events).
Table 186
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Health-related quality of life).
Table 187
Summary clinical evidence profile for gemcitabine and gemcitabine, erlotinib and capecitabine erlotinib versus.
11.2.4.2.2. Adults with locally advanced or metastatic pancreatic cancer
Table 188
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Response rate).
Table 189
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Progression-free survival, overall survival).
Table 190
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events - nausea/vomiting).
Table 191
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events - diarrhoea).
Table 192
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events - fatigue).
Table 193
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events - neutropenia).
Table 194
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events - thrombocytopenia).
Table 195
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Adverse events - leucopenia).
Table 196
Summary clinical evidence profile for gemcitabine versus other chemotherapy (Health-related quality of life).
Table 197
Summary clinical evidence profile for gemcitabine and erlotinib versus gemcitabine, erlotinib and bevacizumab.
Table 198
Summary clinical evidence profile for gemcitabine and erlotinib versus capecitabine and erlotinib.
11.2.4.3. Gemcitabine versus novel agents
Table 199
Summary clinical evidence profile for gemcitabine versus BAY 12-9566/ ZD9331 in adults with locally advanced or metastatic pancreatic cancer.
Table 200
Summary clinical evidence profile for gemcitabine and placebo versus gemcitabine and vandetanib in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.4. Standard-dose versus low-dose gemcitabine
Table 201
Summary clinical evidence profile for standard-dose versus low-dose gemcitabine in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.5. 5-FU versus combination 5-FU
Table 202
Summary clinical evidence profile for 5-FU versus combination 5-FU in adults with metastatic pancreatic cancer.
Table 203
Summary clinical evidence profile for 5-FU versus combination 5-FU in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.6. Combination 5-FU (FSM) versus other chemotherapy
Table 204
Summary clinical evidence profile for combination 5-FU (FSM) versus other chemotherapy regimens in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.7. Intra-arterial chemotherapy versus systemic chemotherapy
Table 205
Summary clinical evidence profile for intra-arterial chemotherapy versus systemic chemotherapy in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.8. Chemotherapy versus chemotherapy and prophylactic anticoagulant
Table 206
Summary clinical evidence profile for gemcitabine versus gemcitabine and weight-adjusted dalteparin in adults with locally advanced or metastatic pancreatic cancer.
Table 207
Summary clinical evidence profile for gemcitabine and enoxaparin versus gemcitabine in adults with locally advanced or metastatic pancreatic cancer.
11.2.4.9. Second-line chemotherapy versus best supportive care
Table 208
Summary clinical evidence profile for second-line chemotherapy versus best supportive care.
11.2.4.10. Second-line chemotherapy versus other chemotherapy regimens
Table 209
Summary clinical evidence profile for LV5FU2-CDDP then gemcitabine versus gemcitabine then LV5FU2-CDDP in adults with metastatic pancreatic cancer.
Table 210
Summary clinical evidence profile for irinotecan and raltitrexed versus raltitrexed in adults with metastatic pancreatic cancer.
Table 211
Summary clinical evidence profile for Oxaliplatin and 5-FU versus bolus 5-FU and bolus folinic acid in adults with locally advanced or metastatic pancreatic cancer.
Table 212
Summary clinical evidence profile for mFOLFOX6 versus 5-FU and folinic acid in adults with locally advanced or metastatic pancreatic cancer.
Table 213
Summary clinical evidence profile for capecitabine and erlotinib then gemcitabine versus gemcitabine and erlotinib then capecitabine in adults with locally advanced or metastatic pancreatic cancer.
Table 214
Summary clinical evidence profile for 5-FU and folinic acid versus oxaliplatin and 5-FU in adults with locally advanced or metastatic pancreatic cancer.
11.2.5. Economic evidence
11.2.5.1. Systematic literature review
Two studies (Tam et al. 2013, Attard et al. 2014) were included in the review of published economic evidence for this topic. Both papers reported cost-utility studies of chemotherapy interventions in people with metastatic pancreatic cancer from a Canadian health payer perspective and reported outcomes in terms of cost (Canadian dollars) per QALY. Both studies used gemcitabine chemotherapy as the base case compared to FOLFIRINOX. Tam 2013 also included gemcitabine with the addition of capecitabine and gemcitabine with the addition of erlotinib in their analysis. Effectiveness data to inform both economic models were based on phase III randomised trials and the same trial was used to inform the effectiveness of FOLFIRINOX and gemcitabine in both studies. Tam 2013 used a cost year of 2010 compared to Attard 2014 which used a cost year of 2013. Both studies were deemed partially applicable to the decision problem that we are evaluating. This is because they did not take a NHS+PSS perspective.
Potentially serious limitations were identified with both studies. There were potential conflicts of interest with the studies either being funded by, or the authors having received funding from a manufacturer of 1 of the interventions considered. Both studies performed probabilistic sensitivity analyses although these were inadequately reported with descriptions of the distributions missing.
The base cases in Tam 2013 and Attard 2014 suggested an ICER of CA$133,184 and CA$57,858 for FOLFIRINOX compared to gemcitabine. This discrepancy can largely be explained by Tam 2013 having an upper limit for the number of cycles of FOLFIRINOX, a more detailed costing and used a different method for estimating quality of life weightings.
Deterministic sensitivity analysis suggested these results were robust to alternative clinical assumptions. Probabilistic sensitivity analyses suggested that in Tam 2013, FOLFIRNOX had a less than 5% chance of being cost effective compared to gemcitabine under the conventionally held Canadian willingness to pay threshold of CA$100,000. Alternatively, Attard 2014 reported an 85% chance of being cost effective at the same WTP threshold. This again can be accounted for by the more favourable assumptions towards FOLFIRINOX in Attard 2014.
References to all included studies and evidence tables for all economic evaluations included in the systematic literature review of the economic evidence are presented in Appendix L. Economic evidence profiles of these studies are presented in Appendix K.
11.2.6. Evidence statements
11.2.6.1. Chemotherapy versus chemoimmunotherapy
11.2.6.1.1. First-line chemotherapy and sequential/concurrent immunotherapy versus chemotherapy
Response rate
Very low quality evidence from 1 multicentre phase III RCT (n=1062) showed no clinically important difference between 1st-line chemotherapy with sequential GV1001, first-line chemotherapy with concurrent GV1001 and first-line chemotherapy alone about the relative probability of objective response rate (CR + PR) in adults with locally advanced or metastatic pancreatic cancer: RR 0.98 (95% CI 0.58-1.67- sequential group) and RR 1.13 (95% CI 0.68-1.88 - concurrent group), where RR less than 1 favours the chemotherapy alone arm.
Progression-free survival
Low quality evidence from 1 multicentre phase III RCT (n=712) showed no clinically important difference between first-line chemotherapy with concurrent GV1001 and first-line chemotherapy alone in time to progression rates in adults with locally advanced or metastatic pancreatic cancer: HR 1.00 (95% CI 0.84-1.19), where HR higher than 1 favours the chemotherapy alone arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=708) showed that there is a clinically important difference favouring first-line chemotherapy alone on PFS rates when compared with first-line chemotherapy plus sequential GV1001 in adults with locally advanced or metastatic pancreatic cancer: HR 1.5 (95% CI 1.26-1.79)
Overall Survival
Low quality evidence from 1 multicentre phase III RCT (n=712) showed no clinically important difference between first-line chemotherapy with concurrent GV1001 and first-line chemotherapy alone in overall survival rates in adults with locally advanced or metastatic pancreatic cancer: HR 1.05 (95% CI 0.85-1.29), where HR higher than 1 favours the chemotherapy alone arm.
Low quality evidence from 1 multicentre phase III RCT (n=708) showed no clinically important difference between first-line chemotherapy with sequential GV1001 and first-line chemotherapy alone in overall survival rates in adults with locally advanced or metastatic pancreatic cancer: HR 1.19 (95% CI 0.97-1.48), where HR higher than 1 favours the chemotherapy alone arm.
Adverse Events
Very low and low quality evidence from 1 multicentre phase III RCT (n=1062) showed no clinically important difference between first-line chemotherapy with sequential GV1001, first-line chemotherapy with concurrent GV1001 and first-line chemotherapy alone about the relative risk of grade 3/4/5 toxicities (including nausea, vomiting, diarrhoea, fatigue, neutropenia, and pain) in adults with locally advanced or metastatic pancreatic cancer.
Health-related quality of life
Low quality evidence from 1 multicentre phase III RCT (n=1062) showed no clinically important difference between first-line chemotherapy with sequential GV1001, first-line chemotherapy with concurrent GV1001 and first-line chemotherapy alone on the improvement of quality of life (measured as mean of the EORTC QLQ-C30) in adults with locally advanced or metastatic pancreatic cancer.
11.2.6.1.2. Second-line chemoimmunotherapy versus chemotherapy
Response rate
Very low quality evidence from 1 phase III RCT (n=58) showed no clinically important difference between chemotherapy + concurrent ICT [CIK - Cytokine-induced killer cells] and chemotherapy as second-line treatments on the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.07 (95% CI 0.16-7.1), where RR less than 1 favours the chemotherapy alone arm.
Progression-free survival
Very low quality evidence from 1 phase III RCT (n=58) showed no clinically important difference between chemotherapy + concurrent ICT [CIK - Cytokine-induced killer cells] and chemotherapy alone as second-line treatments on progression-free survival in adults with locally advanced/metastatic pancreatic cancer (relative effect not estimable).
Overall Survival
Very low quality evidence from 1 phase III RCT (n=58) showed no clinically important difference between chemotherapy + concurrent ICT [CIK - Cytokine-induced killer cells] and chemotherapy alone as second-line treatments on survival rates in adults with locally advanced/metastatic pancreatic cancer (relative effect not estimable).
Adverse Events
Very low quality evidence from 1 phase III RCT (n=58) showed no clinically important difference between chemotherapy + concurrent ICT [CIK - Cytokine-induced killer cells] and chemotherapy alone as second-line treatments on the relative risk of grade 3/4 toxicities (including neutropenia, nausea/vomiting, diarrhoea, and fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.07 (95% CI 0.07-16.32), RR 0.36 (95% CI 0.02-8.4), RR 1.07 (95% CI 0.16-7.1), and RR 0.36 (95% CI 0.02-8.4) where RR less than 1 favours the chemotherapy + concurrent ICT arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.2. Gemcitabine versus other chemotherapy
11.2.6.2.1. In adults with metastatic disease
Response rate
High quality evidence from 1 multicentre phase III RCT (n=342) showed that there is a clinically important difference favouring gemcitabine single-agent on objective response rate (CR + PR) compared to FOLFIRINOX in adult with metastatic pancreatic cancer: RR 3.38 (95% CI 2.01-5.65).
Very low quality evidence from a meta-analysis of 2 phase III RCTs (n=425) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adult with metastatic pancreatic cancer: RR 1.25 (95% CI 0.73-2.12), where RR higher less 1 favours the gemcitabine arm.
Moderate quality evidence from 1 phase III RCT (n=619) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and in the gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adult with metastatic pancreatic cancer: RR 1.58 (95% CI 1.04-2.39), where RR less than 1 favours the gemcitabine arm.
Moderate quality evidence from 1 phase III RCT (n=464) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adult with metastatic pancreatic cancer: RR 1.44 (95% CI 0.87-2.39), where RR less than 1 favours the gemcitabine arm.
Moderate quality evidence from 1 phase III RCT (n=607) showed no clinically important difference between gemcitabine + erlotinib + bevacizumab group and gemcitabine + erlotinib about the relative probability of objective response rate (CR + PR) in adult with metastatic pancreatic cancer: RR 1.57 (95% CI 0.98-2.53), where RR less than 1 favours the gemcitabine + erlotinib arm.
Low quality evidence from 1 phase IIb RCT (n=120) showed no clinically important difference between gemcitabine + capecitabine + erlotinib group and gemcitabine + erlotinib about the relative probability of objective response rate (CR + PR) in adult with metastatic pancreatic cancer: RR 1.18 (95% CI 0.58-2.43), where RR higher than 1 favours the gemcitabine + erlotinib + capecitabine arm.
Progression-free survival
High quality evidence from 1 multicentre phase III RCT (n=342) showed that there is a clinically important difference favouring FOLFIRINOX in PFS compared to gemcitabine single-agent in adult with metastatic pancreatic cancer: HR 0.47 (95% CI 0.32-0.69)
Moderate quality evidence from 1 phase III RCT (n=411) showed no clinically important difference between gemcitabine + Aflibercept and gemcitabine single-agent in PFS rates in adult with metastatic pancreatic cancer: HR 1.02 (95% CI 0.83-1.25), where HR less than 1 favours the gemcitabine + Aflibercept arm.
Low quality evidence from 1 phase III RCT (n=375) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent in PFS rates in adult with metastatic pancreatic cancer: HR 0.97 (95% CI 0.8-1.18), where HR less than 1 favours the gemcitabine + Cisplatin arm.
Moderate quality evidence from 1 phase III RCT (n=619) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent in PFS rates in adult with metastatic pancreatic cancer: HR 1 (95% CI 0.84-1.19), where HR less than 1 favours the gemcitabine + Ganitumab arm.
Moderate quality evidence from 1 phase III RCT (n=464) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent in PFS rates in adult with metastatic pancreatic cancer: HR 0.97 (95% CI 0.77-1.22), where HR less than 1 favours the gemcitabine + Ganitumab arm.
Moderate 1.35) quality evidence from 1 phase III RCT (n=707) showed that there is a clinically important difference favouring gemcitabine + erlotinib + bevacizumab in PFS compared to gemcitabine + erlotinib in adult with metastatic pancreatic cancer: HR 0.73 (95% CI 0.61-0.87).
Low quality evidence from 1 phase IIb RCT (n=120) showed no clinically important difference between gemcitabine + capecitabine + erlotinib and gemcitabine + erlotinib in PFS rates in adult with metastatic pancreatic cancer: HR 0.88 (95% CI 0.58-1.34), where HR less than 1 favours the gemcitabine + erlotinib + capecitabine arm.
Overall Survival
Moderate quality evidence from 1 phase III RCT (n=411) showed no clinically important difference between gemcitabine + Aflibercept and gemcitabine single-agent in overall survival in adult with metastatic pancreatic cancer: HR 1.17 (95% CI 0.92-1.49), where HR less than 1 favours the gemcitabine + Aflibercept arm.
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=425) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent in overall survival in adult with metastatic pancreatic cancer: HR 0.92 (95% CI 0.76-1.11), where HR less than 1 favours the gemcitabine + Cisplatin arm.
Moderate quality evidence from 1 phase III RCT (n=619) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent in overall survival in adult with metastatic pancreatic cancer: HR 1 (95% CI 0.82-1.22), where HR less than 1 favours the gemcitabine + Ganitumab arm.
Moderate quality evidence from 1 phase III RCT (n=464) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent in overall survival in adult with metastatic pancreatic cancer: HR 0.97 (95% CI 0.76-1.24), where HR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase IIb RCT (n=120) showed no clinically important difference between gemcitabine + capecitabine + erlotinib and gemcitabine + erlotinib in overall survival in adult with metastatic pancreatic cancer: HR 1.09 (95% CI 0.72-1.65), where HR less than 1 favours the gemcitabine + erlotinib + capecitabine arm.
Adverse Events
a) Grade 3/4 toxicities: diarrhoea
High quality evidence from 1 multicentre phase III RCT (n=342) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) compared to FOLFIRINOX in adult with metastatic pancreatic cancer: RR 7.17 (95% CI 2.18-23.58)
Low quality evidence from 1 phase III RCT (n=541 patients: 270) showed no clinically important difference between gemcitabine + Aflibercept and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adult with metastatic pancreatic cancer: RR 1 (95% CI 0.2-4.93), where RR less than 1 favours the gemcitabine + Aflibercept arm.
Very low quality evidence from a meta-analysis of 2 phase III RCTs (n=421) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adult with metastatic pancreatic cancer: RR 0.34 (95% CI 0.04-3.23), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Low quality evidence from 1 phase III RCT (n=632) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adult with metastatic pancreatic cancer: RR 3.02 (95% CI 0.32-28.87), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=477) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adult with metastatic pancreatic cancer: RR 3.96 (95% CI 0.36-43.37), where RR less than 1 favours the gemcitabine + Ganitumab arm.
b) Grade 3/4 toxicities: fatigue
Moderate quality evidence from 1 multicentre phase III RCT (n=334) showed no clinically important difference between FOLFIRINOX and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adult with metastatic pancreatic cancer: RR 1.33 (95% CI 0.87-2.04), where RR less than 1 favours the FOLFIRINOX arm.
Very low quality evidence from 1 phase III RCT (n=375) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adult with metastatic pancreatic cancer: RR 1.69 (95% CI 0.63-4.57), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Low quality evidence from 1 phase III RCT (n=632) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adult with metastatic pancreatic cancer: RR 1.59 (95% CI 0.79-3.23), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=477) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adult with metastatic pancreatic cancer: RR 1.32 (95% CI 0.55-1.17), where RR less than 1 favours the gemcitabine + Ganitumab arm.
c) Grade 3/4 toxicities: Neutropenia
High quality evidence from 1 Multicentre phase III RCT (n=331) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) compared to FOLFIRINOX in adult with metastatic pancreatic cancer: RR 2.18 (95% CI 1.56-3.06)
Moderate quality evidence from 1 phase III RCT (n=541) showed no clinically important difference between gemcitabine + Aflibercept and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adult with metastatic pancreatic cancer: RR 1.27 (95% CI 0.96-1.67), where RR less than 1 favours the gemcitabine + Aflibercept arm.
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=421) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adult with metastatic pancreatic cancer: RR 1.84 (95% CI 1.21-2.8), where RR less than 1 favours the gemcitabine + Cisplatin arm.
High quality evidence from 1 phase III RCT (n=632) showed that there is a clinically important difference favouring gemcitabine + Ganitumab [12 mg/kg] on the relative risk of drug-related grade 3/4 toxicities (neutropenia) compared to gemcitabine single-agent in adult with metastatic pancreatic cancer: RR 0.48 (95% CI 0.32-0.71)
High quality evidence from 1 phase III RCT (n=477) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) compared to those treated with gemcitabine + Ganitumab [20 mg/kg] in adult with metastatic pancreatic cancer: RR 2.26 (95% CI 1.72-2.97)
Low quality evidence from 1 phase III RCT (n=583) showed no clinically important difference between gemcitabine + erlotinib + bevacizumab and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adult with metastatic pancreatic cancer: RR 0.97 (95% CI 0.68-1.39), where RR less than 1 favours the gemcitabine + erlotinib arm.
d) Grade 3/4 toxicities: Nausea/vomiting
Moderate quality evidence from 1 multicentre phase III RCT (n=335) showed no clinically important difference between FOLFIRINOX and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adult with metastatic pancreatic cancer: RR 1.75 (95% CI 0.94-3.26), where RR less than 1 favours the FOLFIRINOX arm.
Moderate quality evidence from 1 phase III RCT (n=541) showed no clinically important difference between gemcitabine + Aflibercept and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adult with metastatic pancreatic cancer: RR 2.11 (95% CI 1.01-4.39), where RR less than 1 favours the gemcitabine + Aflibercept arm.
Very low quality evidence from a meta-analysis of 2 phase III RCTs (n=421) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adult with metastatic pancreatic cancer: RR 1.83 (95% CI 0.54-6.2), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Low quality evidence from 1 phase III RCT (n=632) showed no clinically important between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adult with metastatic pancreatic cancer: RR 0.96 (95% CI 0.52-1.76), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=477) showed no clinically important difference between Ganitumab [20 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adult with metastatic pancreatic cancer: RR 0.5 (95% CI 0.19-1.3), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=583) showed no clinically important difference between gemcitabine + erlotinib + bevacizumab and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adult with metastatic pancreatic cancer: RR 1.54 (95% CI 0.86-2.79), where RR less than 1 favours the gemcitabine + erlotinib arm.
e) Grade 3/4 toxicities: Thrombocytopenia
Moderate quality evidence from 1 multicentre phase III RCT (n=333) showed no clinically important difference between FOLFIRINOX and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adult with metastatic pancreatic cancer: RR 2.55 (95% CI 1.01-6.4), where RR less than 1 favours the FOLFIRINOX arm.
Moderate quality evidence from 1 phase III RCT (n=541) showed no clinically important difference between gemcitabine + Aflibercept and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adult with metastatic pancreatic cancer: RR 1.77 (95% CI 1-3.13), where RR less than 1 favours the gemcitabine + Aflibercept arm.
Moderate quality evidence from a meta-analysis of 2 phase III RCTs (n=421) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Thrombocytopenia) compared to gemcitabine + Cisplatin: RR 3.2 (95% CI 1.67-6.14), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Low quality evidence from 1 phase III RCT (n=632) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adult with metastatic pancreatic cancer: RR 1.29 (95% CI 0.75-2.24), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=477) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adult with metastatic pancreatic cancer: RR 1.13 (95% CI 0.57-2.24), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=583) showed no clinically important difference between gemcitabine + erlotinib + bevacizumab and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adult with metastatic pancreatic cancer: RR 1.31 (95% CI 0.72-2.40), where RR less than 1 favours the gemcitabine + erlotinib arm.
f) Grade 3/4 toxicities: Leucopoenia
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=421) suggests not significant differences between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adult with metastatic pancreatic cancer: RR 1.89 (95% CI 0.9-3.98)
Low quality evidence from 1 phase III RCT (n=632) showed no clinically important difference between gemcitabine + Ganitumab [12 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adult with metastatic pancreatic cancer: RR 1.68 (95% CI 0.74-3.78), where RR less than 1 favours the gemcitabine + Ganitumab arm.
Low quality evidence from 1 phase III RCT (n=477) showed no clinically important difference between gemcitabine + Ganitumab [20 mg/kg] and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adult with metastatic pancreatic cancer: RR 0.88 (95% CI 0.28-2.82), where RR less than 1 favours the gemcitabine + Ganitumab arm.
g) Grade 3/4 toxicities: Any
Low quality evidence from 1 phase IIb RCT (n=118) showed no clinically important difference between gemcitabine + capecitabine + erlotinib and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (including asthenia, diarrhoea, neutropenia, reduced appetite, thrombocytopenia, nausea, anaemia, rash, constipation, mucositis, vomiting, pyrexia, elevated GGT, hand - foot syndrome, and peripheral oedema): RR 1.28 (95% CI 0.97-1.68), where RR less than 1 favours the gemcitabine + erlotinib + capecitabine arm.
Health-related quality of life
High quality evidence from 1 multicentre phase III RCT (n=320) showed that there is a clinically important difference favouring gemcitabine single-agent on quality of life scores (global health status, measured as mean of the QLQ-C30 questionnaire) compared to FOLFINOROX at the end of the treatment (6 months) in adult with metastatic pancreatic cancer: RR 0.39 (95% CI 0.21-0.72)
High to low quality evidence from 1 multicentre phase III RCT (n=320) showed that there is a clinically important difference favouring gemcitabine single-agent on quality of life scores (including social functioning, role functioning, and financial difficulties - measured as mean of the QLQ-C30) compared to FOLFINOROX at the end of the treatment (6 months) in adult with metastatic pancreatic cancer.
Moderate and low quality evidence from 1 multicentre phase III RCT (n=333) showed no clinically important difference between FOLFIRINOX and gemcitabine single-agent at the end of the treatment (6 months) on the improvement of quality of life in physical functioning, emotional functioning, cognitive functioning, fatigue, nausea/vomiting, pain, dyspnoea, insomnia, loss of appetite, constipation and diarrhoea (measured as mean of the QLQ-C30) in adult with metastatic pancreatic cancer.
11.2.6.2.2. In adults with locally advanced and metastatic pancreatic cancer
Response rate
Low quality evidence from 1 multicentre phase III RCT (n=126) showed no clinically important difference between 5-FU single agent and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.14 (95% CI 0.01-2.71), where RR less than 1 favours the gemcitabine arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=489) showed that there is a clinically important difference favouring S-1 chemotherapy about the relative probability of objective response rate compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 1.58 (95% CI 1.06-2.36)
Very low quality evidence from 1 multicentre phase III RCT (n=322) showed no clinically important difference between gemcitabine + 5-FU and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.24 (95% CI 0.53-2.91), where RR less than 1 favours the gemcitabine arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib group and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 3.03 (95% CI 0.99-9.29), where RR less than 1 favours the gemcitabine arm.
Low quality evidence from 1 multicentre phase III RCT (n=602) showed no clinically important difference between gemcitabine + Bevacizumab and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.29 (95% CI 0.82-2.02), where RR less than 1 1 favours the gemcitabine arm.
Low quality evidence from a meta-analysis of 3 multicentre phase III RCTs (n=1050) showed that there is a clinically important difference favouring gemcitabine + Capecitabine about the relative probability of objective response rate (CR + PR) compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 1.70 (95% CI 1.27-2.27)
Very low quality evidence from 1 multicentre phase III RCT (n=660) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.22 (95% CI 0.72-2.08), where RR less than 1 1 favours the gemcitabine arm.
Very low quality evidence from 1 multicentre phase III RCT (n=195) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.24 (95% CI 0.51-3.00), where RR less than 1 1 favours the gemcitabine arm.
Moderate quality evidence from 1 phase III RCT (n=99) showed that there is a clinically important difference favouring PEFG about the relative probability of objective response rate (CR + PR) compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 4.52 (95% CI 1.67-12.27)
Very low quality evidence from 1 multicentre phase III RCT (n=349) showed no clinically important difference between gemcitabine + Exatecan and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.33 (95% CI 0.57-3.07), where RR less than 1 favours the gemcitabine arm.
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=490) showed that there is a clinically important difference favouring gemcitabine + Irinotecan chemotherapy about the relative probability of objective response rate (CR + PR) compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 2.50 (95% CI 1.43-4.39).
Low quality evidence from 1 phase III RCT (n=319) showed no clinically important difference between gemcitabine + Marimastat and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.78 (95% CI 0.37-1.65), where RR less than 1 favours the gemcitabine arm.
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=313) showed that there is a clinically important difference favouring gemcitabine + Oxaliplatin chemotherapy about the relative probability of objective response rate (CR + PR) compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 1.55 (95% CI 1.01-2.38).
Moderate quality evidence from 1 multicentre phase III RCT (n=565) showed that there is a clinically important difference favouring gemcitabine + Pemetrexed chemotherapy about the relative probability of objective response rate (CR + PR) compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 2.09 (95% CI 1.26-3.47).
Low quality evidence from 1 phase III RCT (n=104) showed no clinically important difference between gemcitabine + Sorafenib and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.54 (95% CI 0.22-1.33), where RR less than 1 favours the gemcitabine arm.
Low quality evidence from 1 phase III RCT (n=688) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.73 (95% CI 0.42-1.26), where RR less than 1 favours the gemcitabine arm.
High quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=584) showed that there is a clinically important difference favouring gemcitabine + S-1 chemotherapy about the relative probability of objective response rate (CR + PR) compared to gemcitabine alone in adults with locally advanced/metastatic pancreatic cancer: RR 2.33 (95% CI 1.62-3.34).
Moderate quality evidence from 1 phase III RCT (n=274) showed that there is a clinically important difference favouring gemcitabine + erlotinib chemotherapy about the relative probability of objective response rate (CR + PR) compared to Capecitabine + erlotinib in adults with locally advanced/metastatic pancreatic cancer: RR 2.88 (95% CI 1.27-6.52).
Progression free survival
Moderate quality evidence from 1 multicentre phase III RCT (n=489) showed no clinically important difference between S-1 single agent and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.09 (95% CI 0.9-1.32), where HR less than 1 favours the S-1 arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=322) showed that there is a clinically important difference favouring gemcitabine + 5-FU in PFS rates compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.77 (95% CI 0.62-0.96)
Moderate quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.01 (95% CI 0.78-1.30), where HR less than 1 favours the gemcitabine + Axitanib arm.
Moderate quality evidence from a meta-analysis of 3 multicentre phase III RCTs (n=1050) showed that there is a clinically important difference favouring gemcitabine + Capecitabine in PFS rates compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.80 (95% CI 0.72-0.90)
Moderate quality evidence from 1 multicentre phase III RCT (n=602) showed no clinically important difference between gemcitabine + Bevacizumab and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.96 (95% CI 0.81-1.15), where HR less than 1 favours the gemcitabine + Bevacizumab arm.
Low quality evidence from 1 multicentre phase III RCT (n=660) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.07 (95% CI 0.93-1.23), where HR less than 1 favours the gemcitabine + Cetuximab arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=195) showed that there is a clinically important difference favouring gemcitabine + Cisplatin in PFS rates compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.69 (95% CI 0.50-0.95)
Moderate quality evidence from 1 phase III RCT (n=99) showed that there is a clinically important difference favouring PEFG in PFS rates compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.51 (95% CI 0.33-0.78)
High quality evidence from 1 multicentre phase III RCT (n=569) showed that there is a clinically important difference favouring gemcitabine + Erlotinib in PFS rates compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.77 (95% CI 0.65-0.92)
Moderate quality evidence from 1 multicentre phase III RCT (n=360) showed no clinically important difference between gemcitabine + Irinotecan and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.98 (95% CI 0.77-1.25), where HR less than 1 favours the gemcitabine + Irinotecan arm.
Moderate quality evidence from 1 phase III RCT (n=319) showed no clinically important difference between gemcitabine + Marimastat and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.95 (95% CI 0.73-1.23), where HR less than 1 favours the gemcitabine + Marimastat arm.
Moderate quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=313) showed that there is a clinically important difference favouring gemcitabine + Oxaliplatin in PFS rates when compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.83 (95% CI 0.72-0.97)
Moderate quality evidence from 1 phase III RCT (n=104) showed no clinically important difference between gemcitabine + Sorafenib and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.04 (95% CI 0.70-1.55), where HR less than 1 favours the gemcitabine + Sorafenib arm.
Moderate quality evidence from 1 phase III RCT (n=688) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.03 (95% CI 0.87-1.22), where HR less than 1 favours the gemcitabine + Tipifarnib arm.
High quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=584) showed that there is a clinically important difference favouring gemcitabine + S-1 group in PFS rates when compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 0.65 (95% CI 0.57-0.75)
Overall survival
High quality evidence from a network meta-analysis of 23 phase III RCTs involving 9.989 patients with locally advanced/metastatic pancreatic cancer showed that there is a clinically important difference favouring FOLFIRINOX, PEFG, gemcitabine + erlotinib+/-bevacizumab, gemcitabine+capecitabine, and gemcitabine+oxaliplatin in OS when compared to gemcitabine single-agent and several other gemcitabine-based chemotherapy treatments in adults with locally advanced/metastatic PC.
High quality evidence from 1 multicentre phase III RCT (n=126) showed that there is a clinically important difference favouring gemcitabine single-agent chemotherapy in long-term survival compared with the 5-FU single-agent in adults with locally advanced/metastatic pancreatic cancer: HR 1.75 (95% CI 1.21-0.2.54)
Moderate quality evidence from 1 multicentre phase III RCT (n=489) showed no clinically important difference between S-1 single agent and gemcitabine single-agent in long-term survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.96 (95% CI 0.71-1.30), where HR less than 1 favours the S-1 arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=602) showed no clinically important difference between gemcitabine + Bevacizumab and gemcitabine single-agent in long-term survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.96 (95% CI 0.81-1.15), where HR less than 1 favours the gemcitabine + Bevacizumab arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=159) showed no clinically important difference between gemcitabine + elpamotide and gemcitabine single-agent in long-term survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.87 (95% CI 0.49-1.56), where HR less than 1 favours the gemcitabine + elpamotide arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=602) showed no clinically important difference between gemcitabine + masitinib and gemcitabine single-agent in long-term survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.89 (95% CI 0.70-1.13), where HR less than 1 favours the gemcitabine + masitinib arm.
Moderate quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=584) showed no clinically important difference between gemcitabine + S-1 and gemcitabine single-agent in long-term survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.89 (95% CI 0.74-1.08), where HR less than 1 favours the gemcitabine + S-1 arm.
Adverse Events
a) Grade 3/4 toxicities: Nausea/Vomiting
Low quality evidence from 1 multicentre phase III RCT (n=126) showed no clinically important difference between 5-FU single agent and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 0.38 (95% CI 0.1-1.35), where RR less than 1 favours the 5-FU arm.
Very low quality evidence from 1 multicentre phase III RCT (n=545) showed no clinically important difference between S-1 single agent and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.29 (95% CI 0.49-3.42), where RR less than 1 favours the S-1 arm.
Very low quality evidence from 1 multicentre phase III RCT (n=316) showed no clinically important difference between gemcitabine + 5-FU and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 0.79 (95% CI 0.42-1.50), where RR less than 1 favours the gemcitabine + 5-FU arm.
Low quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine+ Axitanib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.40 (95% CI 0.78-2.52), where RR less than 1 favours the gemcitabine + Axitanib arm.
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=1017) showed no clinically important difference between gemcitabine + Capecitabine and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.20 (95% CI 0.83-1.74), where RR less than 1 favours the gemcitabine + Capecitabine arm.
Low quality evidence from 1 multicentre phase III RCT (n=726) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.71 (95% CI 0.99-2.95), where RR less than 1 favours the gemcitabine + Cetuximab arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=195) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Nausea/vomiting) compared to gemcitabine + Cisplatin in adults with locally advanced/metastatic pancreatic cancer: RR 3.63 (95% CI 1.54-8.56)
Low quality evidence from 1 multicentre phase III RCT (n=153) showed no clinically important difference between gemcitabine + elpamotide and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 0.53 (95% CI 0.08-3.66), where RR less than 1 favours the gemcitabine + elpamotide arm.
Very low quality evidence from 1 multicentre phase III RCT (n=325) showed no clinically important difference between gemcitabine + Exatecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.56 (95% CI 0.70-3.46), where RR less than 1 favours the gemcitabine + Exatecan arm.
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=472) showed no clinically important difference between gemcitabine + Irinotecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.60 (95% CI 1.09-2.33), where RR less than 1 favours the gemcitabine + Irinotecan arm.
Moderate quality evidence from 1 phase III RCT (n=319) showed no clinically important difference between gemcitabine + Marimastat and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 0.50 (95% CI 0.27-0.92), where RR less than 1 favours the gemcitabine + Marimastat arm.
Moderate evidence [GRADE] from a meta-analysis of 2 multicentre phase III RCTs (n=840) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Nausea/vomiting) compared to gemcitabine + Oxaliplatin in adults with locally advanced/metastatic pancreatic cancer: RR 2.77 (95% CI 1.81-4.25)
Very low quality evidence from 1 multicentre phase III RCT (n=546) showed no clinically important difference between gemcitabine + Pemetrexed and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1 (95% CI 0.53-1.88), where RR less than 1 favours the gemcitabine + Pemetrexed arm.
Moderate quality evidence from a meta-analysis of 2 phase III RCTs (n=915) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 0.75 (95% CI 0.55-1.01), where RR less than 1 favours the gemcitabine + Tipifarnib arm.
High quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=636) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Nausea/vomiting) compared to gemcitabine + S-1 in adults with locally advanced/metastatic pancreatic cancer: RR 2.99 (95% CI 1.49-5.99)
Moderate quality evidence from 1 phase III RCT (n=256) showed no clinically important difference between Capecitabine + erlotinib and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 15.98 (95% CI 0.93-273.93), where RR less than 1 favours the gemcitabine + erlotinib
b) Grade 3/4 toxicities: diarrhoea
Low quality evidence from 1 multicentre phase III RCT (n=126) showed no clinically important difference between5-FU single-agent and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 3 (95% CI 0.32-28.07), where RR less than 1 favours the 5-FU arm.
High quality evidence from 1 multicentre phase III RCT (n=545) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) compared to S-1 single-agent in adults with locally advanced/metastatic pancreatic cancer: RR 5.02 (95% CI 1.47-17.14)
Very low quality evidence from 1 multicentre phase III RCT (n=316) showed no clinically important difference between gemcitabine + 5-FU and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 2.5 (95% CI 0.8-7.8), where RR less than 1 favours the gemcitabine + 5-FU arm.
Low quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 0.81 (95% CI 0. 22-2.98), where RR less than 1 favours the gemcitabine + Axitanib arm.
Low quality evidence from 1 multicentre phase III RCT (n=602) showed no clinically important difference between gemcitabine + Bevacizumab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 1 (95% CI 0.22-2.98), where RR less than 1 favours the gemcitabine + Bevacizumab arm.
Very low quality evidence from a meta-analysis of 3 multicentre phase III RCTs (n=1017) showed no clinically important difference between gemcitabine + Capecitabine and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 1.53 (95% CI 0.80-2.91), where RR less than 1 favours the gemcitabine + Capecitabine arm.
Very low quality evidence from 1 multicentre phase III RCT (n=716) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 1.09 (95% CI 0.45-2.66), where RR less than 1 favours the gemcitabine + Cetuximab arm.
Very low quality evidence from 1 multicentre phase III RCT (n=195) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 0.59 (95% CI 0.15-2.42), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Low quality evidence from 1 multicentre phase III RCT (n=562) showed no clinically important difference between gemcitabine + Erlotinib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 2.98 (95% CI 0.61-14.63), where RR less than 1 favours the gemcitabine + Erlotinib arm.
Very low quality evidence from 1 multicentre phase III RCT (n=325) showed no clinically important difference between gemcitabine + Exatecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 1.87 (95% CI 0.17-20.41), where RR less than 1 favours the gemcitabine + Exatecan arm.
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=472) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) compared to gemcitabine + Irinotecan in adults with locally advanced/metastatic pancreatic cancer: RR 6.92 (95% CI 2.71-17.67)
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=840) showed no clinically important difference between gemcitabine + Oxaliplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 2.50 (95% CI 1.22-5.11), where RR less than 1 favours the gemcitabine + Oxaliplatin arm.
Low quality evidence from 1 multicentre phase III RCT (n=546) showed no clinically important difference between gemcitabine + Pemetrexed and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 4 (95% CI 0.86-18.67), where RR less than 1 favours the gemcitabine + Pemetrexed arm.
Low quality evidence from 1 phase III RCT (n=102) showed no clinically important difference between gemcitabine + Sorafenib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 0.69 (95% CI 0.12-3.98), where RR less than 1 favours the gemcitabine + Sorafenib arm.
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=915) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 1.34 (95% CI 0.60-3.02), where RR less than 1 favours the gemcitabine + Tipifarnib arm.
Moderate quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=636) showed no clinically important difference between gemcitabine + S-1 and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 2.59 (95% CI 0.94-7.14), where RR less than 1 favours the gemcitabine + S-1 arm.
Moderate quality evidence from 1 phase III RCT (n=256) showed no clinically important difference between Capecitabine + erlotinib and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 0.55 (95% CI 0.22-1.35), where RR less than 1 favours the gemcitabine + erlotinib arm.
c) Grade 3/4 toxicities in adults with locally advanced/metastatic pancreatic cancer: 11 Fatigue
Moderate quality evidence from 1 multicentre phase III RCT (n=545) showed no clinically important difference between S-1 single agent and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.81 (95% CI 0.85-3.84), where RR less than 1 favours the S-1 arm.
Low quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.3 (95% CI 0.75-2.25), where RR less than 1 favours the gemcitabine + Axitanib arm.
Low quality evidence from 1 multicentre phase III RCT (n=716) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.11 (95% CI 0.82-1.5), where RR less than 1 favours the gemcitabine + Cetuximab arm.
Low quality evidence from 1 multicentre phase III RCT (n=362) showed no clinically important difference between gemcitabine + Erlotinib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 0.99 (95% CI 0.49-1.99), where RR less than 1 favours the gemcitabine + Erlotinib arm.
Very low quality evidence from 1 multicentre phase III RCT (n=325) showed no clinically important difference between gemcitabine + Exatecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 2.62 (95% CI 0.96-7.10), where RR less than 1 favours the gemcitabine + Exatecan arm.
Very low quality evidence from 1 multicentre phase III RCT (n=342) showed no clinically important difference between gemcitabine + Irinotecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.09 (95% CI 0.67-1.77), where RR less than 1 favours the gemcitabine + Irinotecan arm.
Low quality evidence from 1 phase III RCT (n=319) showed no clinically important difference between gemcitabine + Marimastat and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.98 (95% CI 0.83-4.74), where RR less than 1 favours the gemcitabine + Marimastat arm.
Low quality evidence from 1 multicentre phase III RCT (n=527) showed no clinically important difference between gemcitabine + Oxaliplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 0.90 (95% CI 0.63-1.30), where RR less than 1 favours the gemcitabine + Oxaliplatin arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=546) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) compared to gemcitabine + Pemetrexed in adults with locally advanced/metastatic pancreatic cancer: RR 2.28 (95% CI 1.34-3.86)
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=915) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 0.91 (95% CI 0.65-1.27), where RR less than 1 favours the gemcitabine + Tipifarnib arm.
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=636) showed no clinically important difference between gemcitabine + S-1 and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (fatigue) in adults with locally advanced/metastatic pancreatic cancer: RR 1.19 (95% CI 0.55-2.57), where RR less than 1 favours the gemcitabine + S-1 arm.
d) Grade 3/4 toxicities: Neutropenia
High quality evidence from 1 multicentre phase III RCT (n=126) showed that there is a clinically important difference favouring 5-FU single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: RR 0.19 (95% CI 0.06-0.61)
High quality evidence from 1 multicentre phase III RCT (n=545) showed that there is a clinically important difference favouring S-1 single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: RR 0.22 (95% CI 0.14-0.32)
Low quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.34 (95% CI 0.01-8.23), where RR less than 1 favours the gemcitabine + Axitanib arm.
Low quality evidence from 1 multicentre phase III RCT (n=530) showed no clinically important difference between gemcitabine + Bevacizumab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.08 (95% CI 0.68-1.73), where RR less than 1 favours the gemcitabine + Bevacizumab arm.
Low quality evidence from a meta-analysis of 3 multicentre phase III RCTs (n=1017) showed no clinically important difference between gemcitabine + Capecitabine and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) in patients treated with gemcitabine compared to those treated with gemcitabine + Capecitabine in adults with locally advanced/metastatic pancreatic cancer: RR 1.44 (95% CI 1.15-1.81)
Very low quality evidence from 1 multicentre phase III RCT (n=716) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.97 (95% CI 0.75-1.26), where RR less than 1 favours the gemcitabine + Cetuximab arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=159) showed no clinically important difference between gemcitabine + elpamotide and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.85 (95% CI 0.62-1.16), where RR less than 1 favours the gemcitabine + elpamotide arm.
Low quality evidence from 1 multicentre phase III RCT (n=325) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) compared to in adults with locally advanced/metastatic pancreatic cancer: RR 2.07 (95% CI 1.33-3.22)
Low quality evidence from 1 multicentre phase III RCT (n=130) showed no clinically important difference between gemcitabine + Irinotecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.70 (95% CI 0.85-3.37), where RR less than 1 favours the gemcitabine + Irinotecan arm.
Very low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=840) showed no clinically important difference between gemcitabine + Oxaliplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.86 (95% CI 0.69-1.09), where RR less than 1 favours the gemcitabine + Oxaliplatin arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=546) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) compared to gemcitabine + Pemetrexed in adults with locally advanced/metastatic pancreatic cancer: RR 3.51 (95% CI 2.51-4.92)
Low quality evidence from 1 phase III RCT (n=102) showed no clinically important difference between gemcitabine + Sorafenib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.9 (95% CI 0.48-1.70), where RR less than 1 favours the gemcitabine + Sorafenib arm.
Moderate quality evidence from a meta-analysis of 2 phase III RCTs (n=915) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.26 (95% CI 1.07-1.5), where RR less than 1 favours the gemcitabine + Tipifarnib arm.
High quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=636) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Neutropenia) compared to gemcitabine + S-1 in adults with locally advanced/metastatic pancreatic cancer: RR 1.57 (95% CI 1.33-1.86)
e) Grade 3/4 toxicities: Thrombocytopenia
Low quality evidence from 1 multicentre phase III RCT (n=320) showed no clinically important difference between gemcitabine+ 5-FU and gemcitabine single-agent gemcitabine compared to those treated with gemcitabine + 5-FU: RR 1.81 (95% CI 1.04-3.15), where RR less than 1 favours the gemcitabine + 5-FU arm.
Low quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.34 (95% CI 0.01-8.23), where RR less than 1 favours the gemcitabine + Axitanib arm.
Low quality evidence from 1 multicentre phase III RCT (n=540) showed no clinically important difference between gemcitabine + Bevacizumab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.95 (95% CI 0.43-2.08), where RR less than 1 favours the gemcitabine + Bevacizumab arm.
Very low quality evidence from a meta-analysis of 3 multicentre phase III RCTs (n=1017) showed no clinically important difference between gemcitabine + Capecitabine and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.14 (95% CI 0.72-1.82), where RR less than 1 favours the gemcitabine + Capecitabine arm.
Low quality evidence from 1 multicentre phase III RCT (n=195) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.4 (95% CI 0.13-1.22), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Low quality evidence from 1 multicentre phase III RCT (n=153) showed no clinically important difference between gemcitabine + elpamotide and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.99 (95% CI 0.45-2.19), where RR less than 1 favours the gemcitabine + elpamotide arm.
Low quality evidence from 1 multicentre phase III RCT (n=325) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Thrombocytopenia) compared to gemcitabine + Exatecan in adults with locally advanced/metastatic pancreatic cancer: RR 3.47 (95% CI 1.55-7.77)
Very low quality evidence from 1 multicentre phase III RCT (n=130) showed no clinically important difference between gemcitabine + Irinotecan and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 8.15 (95% CI 0.43-154.64), where RR less than 1 favours the gemcitabine + Irinotecan arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=313) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Thrombocytopenia) compared to gemcitabine + Oxaliplatin in adults with locally advanced/metastatic pancreatic cancer: RR 4.37 (95% CI 1.7-11.25), where RR less than 1 favours the gemcitabine + Oxaliplatin arm
High quality evidence from 1 multicentre phase III RCT (n=546) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Thrombocytopenia) compared to gemcitabine + Pemetrexed in adults with locally advanced/metastatic pancreatic cancer: RR 2.88 (95% CI 1.70-4.88)
Low quality evidence from 1 phase III RCT (n=102) showed no clinically important difference between gemcitabine + Sorafenib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.52 (95% CI 0.14-1.97), where RR less than 1 favours the gemcitabine + Sorafenib arm.
Moderate quality evidence from a meta-analysis of 2 phase III RCTs (n=915) showed no clinically important difference between gemcitabine + Tipifarnib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.22 (95% CI 0.89-1.66), where RR less than 1 favours the gemcitabine + Tipifarnib arm.
High quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=636) showed that there is a clinically important difference favouring gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (Thrombocytopenia) compared to gemcitabine + S-1 in adults with locally advanced/metastatic pancreatic cancer: RR 3.4 (95% CI 1.33-8.7)
Low quality evidence from 1 phase III RCT (n=256) showed no clinically important difference between Capecitabine + erlotinib and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 5.17 (95% CI 1.17-22.85), where RR less than 1 favours the gemcitabine + erlotinib arm
f) Grade 3/4 toxicities: Leucopoenia
High quality evidence from 1 multicentre phase III RCT (n=545) showed that there is a clinically important difference favouring S-1 single-agent on the relative risk of drug-related grade 3/4 toxicities (Leucopoenia) compared to gemcitabine single-agent in adults with locally advanced/metastatic pancreatic cancer: RR 0.2 (95% CI 0.1-0.38)
Low quality evidence from 1 multicentre phase III RCT (n=316) showed no clinically important difference between gemcitabine + 5-FU and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.81 (95% CI 1.03-3.2), where RR less than 1 favours the gemcitabine + 5-FU arm.
High quality evidence from 1 multicentre phase III RCT (n=613) showed no clinically important difference between gemcitabine + Axitanib and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: no drug-related grade 3/4 toxicities (Leucopoenia) were reported.
Low quality evidence from 1 multicentre phase III RCT (n=716) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.76 (95% CI 0.51-1.11), where RR less than 1 favours the gemcitabine + Cetuximab arm.
Very low quality evidence from 1 multicentre phase III RCT (n=195) showed no clinically important difference between gemcitabine + Cisplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.24 (95% CI 0.51-3), where RR less than 1 favours the gemcitabine + Cisplatin arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=153) showed no clinically important difference between gemcitabine + elpamotide and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.71 (95% CI 0.47-1.09), where RR less than 1 favours the gemcitabine + elpamotide arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=527) showed no clinically important difference between gemcitabine + Oxaliplatin and gemcitabine single-agent on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.76 (95% CI 0.5-1.17), where RR less than 1 favours the gemcitabine + Oxaliplatin arm.
Moderate quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=636) showed no clinically important difference between gemcitabine + S-1 and gemcitabine single-agent between patients treated with gemcitabine compared to those treated with gemcitabine + S-1 on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.76 (95% CI 1.09-2.84), where RR less than 1 favours the gemcitabine + S-1 arm.
Low quality evidence from 1 phase III RCT (n=256) showed no clinically important difference between Capecitabine + erlotinib and gemcitabine + erlotinib on the relative risk of drug-related grade 3/4 toxicities (leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 15.98 (95% CI 0.93-273.93), where RR less than 1 favours the gemcitabine + erlotinib arm
Health-related quality of life
Low quality evidence from a meta-analysis of 2 multicentre phase III RCTs (n=319) showed no clinically important difference between gemcitabine + Capecitabine and gemcitabine single-agent on the improvement of quality of life in physical well-being, mood, pain, tiredness, functional performance, coping effort, and treatment burden (measured as mean of the linear-analogue self-assessment [LASA] indicators) in adults with locally advanced/metastatic pancreatic cancer at 6 months follow-up.
Low quality evidence from 1 multicentre phase III RCT (n=540) showed no clinically important difference between gemcitabine + Cetuximab and gemcitabine single-agent group at 5, 13, and 17 weeks follow-up on the improvement of quality of life in emotional well-being (measured as mean of the linear-analogue self-assessment [LASA] indicators) in adults with locally advanced/metastatic pancreatic cancer.
Moderate low quality evidence from 1 multicentre phase III RCT (n=195) showed that there is a clinically important difference favouring gemcitabine + Cisplatin on quality of life (measured as mean of the Spitzer 5-Item Index) compared to gemcitabine alone at the end of treatment in adults with locally advanced/metastatic pancreatic cancer: MD −0.40 (95% CI −0.66 to - 0.14)
Very low and low quality evidence from 1 phase III RCT (n=46) indicates showed no clinically important difference between PEFG and gemcitabine single-agent on the relative probability of improving quality of life in adults with locally advanced/metastatic pancreatic cancer at 6 months follow-up (measured as mean of the number of patients with a clinically significant improvement QLQ-C30).
11.2.6.3. Gemcitabine versus novel agents
Response rate
Low quality evidence from 1 multicentre phase II RCT (n=142) showed no clinically important difference between gemcitabine + novel agents [vandetanib] and gemcitabine + placebo about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.08 (95% CI 0.47-2.50), where RR less than 1 favours the gemcitabine + vandenitab arm.
Very low quality evidence from 1 multicentre phase III RCT (n=277) showed no clinically important difference between novel agents [BAY 12-9566] and gemcitabine single-agent chemotherapy for patients treated with the BAY 12-9566 when compared to those who received gemcitabine about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.18 (95% CI 0.02-1.45), where RR less than 1 favours the gemcitabine single-agent chemotherapy arm.
Very low quality evidence from 1 multicentre phase III RCT (n=55) showed no clinically important difference between novel agents [ZD9331] and gemcitabine single-agent chemotherapy for patients treated with the ZD9331 when compared to those who received gemcitabine about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.42 (95% CI 0.04-4.33), where RR less than 1 favours the gemcitabine single-agent chemotherapy arm.
Progression-free survival
Moderate quality evidence from 1 multicentre phase II RCT (n=142) showed no clinically important difference between gemcitabine + novel agents [vandetanib] and gemcitabine + placebo in progression-free survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.11 (95% CI 0.87-1.41), where HR less than 1 favours the gemcitabine + placebo arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=277) showed that there is a clinically important difference favouring gemcitabine single-agent chemotherapy in progression-free survival rates when compared with the BAY 12-9566: HR 0.53 (95% CI 0.41-0.68)
Overall Survival
Moderate quality evidence from 1 Multi multicentre phase RCT (n=142) showed no clinically important difference between gemcitabine + novel agents [vandetanib] and gemcitabine + placebo in overall survival in adults with locally advanced/metastatic pancreatic cancer: HR 1.21 (95% CI 0.96-1.53), where HR less than 1 favours the gemcitabine + vandenitab arm.
Moderate quality evidence from 1 multicentre phase III RCT (n=277) showed that there is a clinically important difference favouring gemcitabine single-agent chemotherapy in overall survival rates compared to BAY 12-9566 in adults with locally advanced/metastatic pancreatic cancer: HR 0.57 (95% CI 0.44-0.74), where HR less than 1 favours the gemcitabine single-agent chemotherapy arm.
Adverse Events
Moderate quality evidence from 1 multicentre phase II RCT (n=142) showed no clinically important difference between gemcitabine + novel agents [vandetanib] and gemcitabine + placebo about the relative risk of grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 1.55 (95% CI 1.02-2.35), where RR less than 1 favours the gemcitabine + vandenitab arm
Low quality evidence from 1 multicentre phase II RCT (n=142) showed no clinically important difference between gemcitabine + novel agents [vandetanib] and gemcitabine + placebo about the relative risk of grade 3/4 toxicities (including thrombocytopenia, fatigue, leucopenia, hypertension, ALT increased, hyponatraemia, ALP increased, lethargy, lymphocyte count decreased, diarrhoea, blood bilirubin increased, and abdominal pain) in adults with locally advanced/metastatic pancreatic cancer.
Very low quality evidence from 1 multicentre phase III RCT (n=277) showed no clinically important difference between novel agents [BAY 12-9566] and gemcitabine single-agent chemotherapy the relative risk of grade 3/4 toxicities (including nausea, vomiting, and diarrhoea) in adults with locally advanced/metastatic pancreatic cancer.
Very low quality evidence from 1 multicentre phase III RCT (n=55) showed no clinically important difference between novel agents [ZD9331] and gemcitabine single-agent chemotherapy about the relative risk of grade 3/4 toxicities (including nausea, vomiting, diarrhoea, fatigue, and neutropenia) in adults with locally advanced/metastatic pancreatic cancer.
Health-related quality of life
Moderate quality evidence from 1 multicentre phase III RCT (n=277) showed that there is a clinically important difference favouring novel agents [BAY 12-9566] on global quality of life and several functional domains: including physical, role and cognitive (measured as mean of the EORTC QLQ C-30) compared to gemcitabine single-agent chemotherapy in adults with locally advanced/metastatic pancreatic cancer at 8 weeks follow-up.
Moderate quality evidence from 1 multicentre phase III RCT (n=277) showed that there is a clinically important difference favouring novel agents [BAY 12-9566] on perceived symptom burden: including fatigue, pain and constipation (measured as mean of the EORTC QLQ C-30) compared to gemcitabine single-agent chemotherapy in adults with locally advanced/metastatic pancreatic cancer at 8 weeks follow-up
Low quality evidence from 1 multicentre phase III RCT (n=277) showed no clinically important difference between novel agents [BAY 12-9566] and gemcitabine single-agent chemotherapy in quality of life: including emotional and social functional domains; and nausea, dyspnoea, insomnia, diarrhoea, and financial perceived symptom burden (measured as mean of the EORTC QLQ C-30) in adults with locally advanced/metastatic pancreatic cancer at 8 weeks follow-up.
11.2.6.4. Standard-dose gemcitabine versus low-dose
Response rate
Very low quality evidence from 1 phase III RCT (n=21) showed no clinically important difference between gemcitabine infusion at a standard dose and gemcitabine infusion at a low dose chemotherapy about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.91 (95% CI 0.16-5.3) where RR higher than 1 favours the standard dose arm.
Progression-free survival
No evidence was identified to inform this outcome.
Overall Survival
Moderate quality evidence from 1 phase III RCT (n=21) showed no clinically important difference in between survival rates gemcitabine infusion at a standard dose and gemcitabine infusion at a low dose chemotherapy in adults with locally advanced/metastatic pancreatic cancer.
Adverse Events
Very low quality evidence from 1 phase III RCT (n=21) showed no clinically important difference between gemcitabine infusion at a standard dose and gemcitabine infusion at a low dose chemotherapy about the relative risk of grade 3/4 toxicities (including neutropenia, anaemia, thrombocytopenia, general fatigue, nausea/vomiting, and diarrhoea) in adults with locally advanced/metastatic pancreatic cancer.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.5. 5-FU versus combination 5-FU
11.2.6.5.1. In adults with metastatic disease
Response rate
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=319) showed that there is a clinically important difference favouring 5-FU combination chemotherapy on objective response rate (CR + PR) compared to 5-FU single-agent chemotherapy in adults with metastatic pancreatic cancer: RR 8.62 (95% CI 1.57-47.22)
Very low quality evidence from 1 phase III RCT (n=123) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy [5-FU + doxorubicin + cisplatin] in objective response rate (CR + PR) in adults with metastatic pancreatic cancer: RR 2.17 (95% CI 0.2-23.31), where RR higher than 1 favours the 5-FU combination arm.
Very low quality evidence from 1 phase III RCT (n=196) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy [5-FU + cisplatin] in objective response rate (CR + PR) in adults with metastatic pancreatic cancer: RR 21 (95% CI 1.25-353.49), where RR higher than 1 favours the 5-FU combination arm.
Progression-free survival
Low quality evidence from 1 phase III RCT (n=196) showed that there is a clinically important difference favouring 5-FU + cisplatin chemotherapy in progression-free survival rates compared to 5-FU single-agent chemotherapy in adults with metastatic pancreatic cancer: HR 0.55 (95% CI 0.41-0.74)
Overall Survival
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=319) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy in overall survival rates in adults with metastatic pancreatic cancer: HR 0.97 (95% CI 0.79-1.2), where HR less than 1 favours the 5-FU combination arm.
Adverse Events
Very low quality evidence from 1 phase III RCT (n=123) showed that there is a clinically important difference favouring 5-FU single-agent chemotherapy on the relative risk of grade 3/4 toxicities (nausea) compared to 5-FU + doxorubicin + cisplatin in adults with metastatic pancreatic cancer: RR 4.70 (95% CI 1.51-10.91)
Moderate quality evidence from a meta-analysis of III phase III RCTs (n=319) showed that there is a clinically important difference favouring 5-FU combination chemotherapy on the relative risk of grade 3/4 toxicities (vomiting) compared to 5-FU single-agent chemotherapy in adults with metastatic pancreatic cancer: RR 3.75 (95% CI 1.73-7.32)
Very low quality evidence from 1 phase III RCT (n=123) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy [5-FU + doxorubicin + cisplatin] about the relative risk of grade 3/4 toxicities (vomiting) in adults with metastatic pancreatic cancer: RR 3.25 (95% CI 0.94-8.78), where RR higher than 1 favours the 5-FU single-agent arm.
Moderate quality evidence from 1 phase III RCT (n=196) showed that there is a clinically important difference favouring 5-FU combination [5-FU + cisplatin] chemotherapy on the relative risk of grade 3/4 toxicities (vomiting) compared to 5-FU single-agent chemotherapy in adults with metastatic pancreatic cancer: RR 4.12 (95% CI 1.49-9.52)
Very low quality evidence from 1 phase III RCT (n=196) showed no clinically important difference between 5-FU single-agent chemotherapy group & 98 in the 5-FU combination chemotherapy [5-FU + cisplatin] about the relative risk of grade 3/4 toxicities diarrhoea between intervention groups in adults with metastatic pancreatic cancer: RR 2.57 (95% CI 0.51-11.15), where RR higher than 1 favours the 5-FU single-agent arm.
Very low quality evidence from 1 phase III RCT (n=123) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy [5-FU + doxorubicin + cisplatin] about the relative risk of grade 3/4 toxicities (leucopoenia) in adults with metastatic pancreatic cancer: RR 1.68 (95% CI 1.11-2.23), where RR higher than 1 favours the 5-FU single-agent arm.
Very low quality evidence from a meta-analysis of 2 phase III RCTs (n=320) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy about the relative risk of grade 3/4 toxicities (stomatitis) in adults with metastatic pancreatic cancer: RR 1.2 (95% CI 0.6-2.27), where RR higher than 1 favours the 5-FU single-agent arm.
Very low quality evidence from 1 phase III RCT (n=123) showed no clinically important difference between 5-FU single-agent chemotherapy and 5-FU combination chemotherapy [5-FU + doxorubicin + cisplatin] about the relative risk of grade 3/4 toxicities (stomatitis) in adults with metastatic pancreatic cancer: RR 0.36 (95% CI 0.09-1.22), where RR higher than 1 favours the 5-FU single-agent arm.
Low quality evidence from 1 phase III RCT (n=197) showed no clinically important difference 5-FU single-agent chemotherapy and 5-FU combination chemotherapy [5-FU + cisplatin] about the relative risk of grade 3/4 toxicities (stomatitis) in adults with metastatic pancreatic cancer: RR 2.68 (95% CI 1.01-6.23), where RR higher than 1 favours the 5-FU single-agent arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.5.2. In adults with locally advanced and metastatic pancreatic cancer
Response rate
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=220) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy in objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.7 (95% CI 0.88-3.3), where RR higher than 1 favours the 5-FU combination arm.
Very low quality evidence from 1 phase III RCT (n=23) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy [5-FU + doxorubicin + mitomycin] on objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.26 (95% CI 0.03-2.11), where RR higher than 1 favours the 5-FU combination arm.
Moderate quality evidence from 1 phase III RCT (n=197) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy [5-FU + mitomycin] the 5-FU combination chemotherapy when compared to those who received 5-FU chemotherapy alone objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 2.28 (95% CI 1.08-4.83), where RR higher than 1 favours the 5-FU combination arm.
Progression-free survival
Moderate quality evidence from 1 phase III RCT (n=197) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy [5-FU + mitomycin] on progression-free survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 0.81 (95% CI 0.62-1.06), where HR less than 1 favours the 5-FU combination arm.
Overall Survival
Low quality evidence from a meta-analysis of 2 phase III RCTs (n=220) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy on overall survival in adults with locally advanced/metastatic pancreatic cancer: HR 0.97 (95% CI 0.79-1.20), where HR less than 1 favours the 5-FU combination arm.
Adverse Events
Low quality evidence from 1 phase III RCT (n=197) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy [5-FU + mitomycin] about the relative risk of grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 1.05 (95% CI 0.31-3.52) where RR higher than 1 favours the 5-FU combination arm.
Low quality evidence from 1 phase III RCT (n=197) showed no clinically important difference between 5-FU single-agent and 5-FU combination chemotherapy [5-FU + mitomycin] about the relative risk of grade 3/4 toxicities (neutropenia) in adults with locally advanced/metastatic pancreatic cancer: RR 7.34 (95% CI 0.38-140.36) where RR higher than 1 favours the 5-FU combination arm.
Low quality evidence from 1 phase III RCT (n=209) showed no clinically important difference between about the relative risk of grade 3/4 toxicities (stomatitis) 5-FU single-agent and 5-FU combination chemotherapy [5-FU + mitomycin] in adults with locally advanced/metastatic pancreatic cancer: RR 1.44 (95% CI 0.60-3.44) where RR higher than 1 favours the 5-FU combination arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.6. Combination 5-FU (FSM) versus other chemotherapy
Response rate
Very low quality evidence from 1 phase III RCT (n=184) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FAM chemotherapy [5-FU + Adriamycin + mitomycin] about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.32 (95% CI 0.09-1.14), where RR higher than 1 favours the FSM arm.
Low quality evidence from 1 phase III RCT (n=140) showed that there is a clinically important difference favouring FSM group [5-FU+ streptozotocin + mitomycin] in objective response rate (CR + PR) compared to FM chemotherapy [5-FU + mitomycin] in adults with locally advanced/metastatic pancreatic cancer: RR 3.8 (95% CI 1.5-9.61)
Progression-free survival
No evidence was identified to inform this outcome.
Overall Survival
Low quality evidence from 1 phase III RCT (n=184) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FAM chemotherapy [5-FU + Adriamycin + mitomycin] in overall survival rates.
Low quality evidence from 1 phase III RCT (n=140) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FM [5-FU + mitomycin] chemotherapy in overall survival rates.
Adverse Events
Very low quality evidence from 1 phase III RCT (n=140) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FM [5-FU + mitomycin] chemotherapy about the relative risk of drug-related grade 3/4 toxicities (diarrhoea) in adults with locally advanced/metastatic pancreatic cancer: RR 0.50 (95% CI 0.05-5.39) where RR less than 1 favours the FSM arm.
Very low quality evidence from 1 phase III RCT (n=184) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FAM chemotherapy [5-FU + Adriamycin + mitomycin] about the relative risk of drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.20 (95% CI 0.59-2.41) where RR less than 1 favours the FSM arm.
Very low quality evidence from 1 phase III RCT (n=140) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FM [5-FU + mitomycin] chemotherapy about drug-related grade 3/4 toxicities (nausea/vomiting) in adults with locally advanced/metastatic pancreatic cancer: RR 1.61 (95% CI 0.99-2.62), where RR less than 1 favours the FSM arm.
Very low quality evidence from 1 phase III RCT (n=184) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FAM chemotherapy [5-FU + Adriamycin + mitomycin] on the relative risk of drug-related grade 3/4 toxicities (leukopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.48 (95% CI 0.26-0.90), where RR less than 1 favours the FSM arm.
Very low quality evidence from 1 phase III RCT (n=140) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FM [5-FU + mitomycin] chemotherapy in the relative risk of drug-related grade 3/4 toxicities (leukopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.82 (95% CI 0.36-1.85) where RR less than 1 favours the FSM arm.
Very low quality evidence from 1 phase III RCT (n=184) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FAM chemotherapy [5-FU + Adriamycin + mitomycin] on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.58 (95% CI 0.36-0.93), where RR less than 1 favours the FSM arm
Very low quality evidence from 1 phase III RCT (n=140) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FM [5-FU + mitomycin] chemotherapy in the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.62 (95% CI 0.31-1.28) where RR less than 1 favours the FSM arm.
Very low quality evidence from 1 phase III RCT (n=140) showed no clinically important difference between FSM [5-FU+ streptozotocin + mitomycin] and FM [5-FU + mitomycin] chemotherapy in the relative risk of drug-related deaths in adults with locally advanced/metastatic pancreatic cancer: RR 0.25 (95% CI 0.03-2.18) where RR less than 1 favours the FSM arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.7. Intra-arterial chemotherapy versus systemic chemotherapy
Response rate
Low quality evidence from a meta-analysis of 3 phase III RCTs (n=181) showed that there is a clinically important difference favouring intra-arterial chemotherapy on objective response rate (CR + PR) compared to systemic chemotherapy in adults with locally advanced/metastatic pancreatic cancer: RR 2.76 (95% CI 1.23-6.18)
Progression-free survival
No evidence was identified to inform this outcome.
Overall Survival
Low quality evidence from 1 phase III RCT (n=138) showed no clinically important difference between intra-arterial and systemic chemotherapy in overall survival rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.02 (95% CI 0.63-1.66), where HR less than 1 intra-arterial chemotherapy arm.
Adverse Events
Moderate quality evidence from 1 phase III RCT (n=138) showed that there is a clinically important difference favouring intra-arterial chemotherapy on the relative risk of drug-related grade 3/4 toxicities (thrombocytopenia) compared to systemic chemotherapy in adults with locally advanced/metastatic pancreatic cancer: RR 16.04 (95% CI 2.20-117.24)
Low and very low quality evidence from 1 phase III RCT (n=138) showed no clinically important difference between the intra-arterial and systemic chemotherapy about the relative risk of drug-related grade 3/4 toxicities (including nausea/vomiting, diarrhoea, and leucopoenia) in adults with locally advanced/metastatic pancreatic cancer: RR 0.13 (95% CI 0.01-2.56), RR 0.19 (95% CI 0.01-3.86), and RR 2.64 (95% CI 1.01-6.94); where RR less than 1 favours the intra-arterial chemotherapy arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.8. Chemotherapy versus chemotherapy and prophylactic anticoagulant
Response rate
No evidence was identified to inform this outcome.
Progression-free survival
Low quality evidence from 1 multicentre phase III RCT (n=312) showed no clinically important difference between gemcitabine combined with enoxaparin and gemcitabine only on progression-free survival in adults with locally advanced or metastatic pancreatic cancer: HR 1.06 (95% CI 0.84-1.34), where HR less than 1 favours the gemcitabine + enoxaparin arm.
Overall Survival
Moderate quality evidence from 1 phase IIb RCT (n=121) showed no clinically important difference between gemcitabine with weight-adjusted dalteparin and gemcitabine only on overall survival in adults with locally advanced or metastatic pancreatic cancer.
Low quality evidence from 1 phase III RCT (n=312) showed no clinically important difference between gemcitabine combined with enoxaparin and gemcitabine only on overall survival in adults with locally advanced or metastatic pancreatic cancer: HR 1.10 (95% CI 0.87-1.39), where HR less than 1 favours the gemcitabine + enoxaparin arm.
Adverse Events
Very low quality evidence from 1 phase IIb RCT (n=116) showed no clinically important difference between gemcitabine with weight-adjusted dalteparin and gemcitabine only on drug-related Grade 3/4 haematological impairment (RR 0.87 [95% CI 0.55-1.37]) and hepatic functional impairment (RR 1.09 [95% CI 0.64-1.86]) in adults with locally advanced or metastatic pancreatic cancer, where RR less than 1 favours the gemcitabine and weight-adjusted dalteparin arm.
Moderate quality evidence from 1 phase IIb RCT (n=123) showed no clinically important difference between gemcitabine combined with weight-adjusted dalteparin and gemcitabine only on vascular thromboembolism in adults with locally advanced or metastatic pancreatic cancer: RR 0.39 (95% CI 0.18-0.85), where RR less than 1 favours the gemcitabine and weight-adjusted dalteparin arm.
Very low and low quality evidence from 1 multicentre phase III RCT (n=312) showed no clinically important difference between gemcitabine combined with enoxaparin and gemcitabine only on symptomatic VTE (RR 0.43 [95% CI 0.21-0.88]) and major haemorrhages (RR 1.24 [95% CI 0.56-2.73]) in adults with locally advanced or metastatic pancreatic cancer, where RR less than 1 favours the gemcitabine and weight-adjusted dalteparin arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.8.1. Second-line chemotherapy versus best supportive care
Response rate
No evidence was identified to inform this outcome.
Progression-free survival
Low quality evidence from 1 multicentre phase III RCT (n=303) showed no clinically important difference between second-line chemotherapy and best supportive care on progression-free survival in adults with metastatic pancreatic cancer: HR 0.76 (95% CI 0.57-1.01), where HR less than 1 favours the chemotherapy arm.
Overall Survival
Low quality evidence from 1 multicentre phase III RCT (n=303) showed no clinically important difference between second-line chemotherapy and best supportive care on overall survival in adults with metastatic pancreatic cancer: HR 0.85 (95% CI 0.66-1.09), where HR less than 1 favours the chemotherapy arm.
Adverse Events
Very quality evidence from 1 multicentre phase III RCT (n=286) showed no clinically important difference between second-line chemotherapy and best supportive care on Grade 3, 4 or 5 toxicities (including asthenia/fatigue, abdominal pain, anaemia, vomiting, nausea, deep vein thrombosis, renal failure, hyperbilirubinemia, and leukopenia) in adults with metastatic pancreatic cancer: RR 1.12 (95% CI 0.51-2.46), RR 0.87 (95% CI 0.4-1.88), RR 2.4 (95% CI 0.63-9.1), RR 3.6 (95% CI 0.76-17.03), RR 3.09 (95% CI 0.63-15.03), RR 5.14 (95% CI 0.61-43.46), RR 11.31 (95% CI 0.63-202.65), RR 2.06 (95% CI 0.38-11.05), and RR 9.25 (95% CI 0.5-170.31), where RR less than 1 favours the chemotherapy arm.
Health-related quality of life
No evidence was identified to inform this outcome.
11.2.6.8.2. Second-line chemotherapy versus other chemotherapy
In adults with metastatic disease
Response rate
Low quality evidence from 1 multicentre phase III RCT (n=202) showed no clinically important difference between LV5FU2-CDDP followed by gemcitabine single-agent [LV5FU2-CDDP/Gem] and gemcitabine single-agent followed by LV5FU2-CDDP [Gem/LV5FU2-CDDP] about the relative probability of objective response rate (CR + PR) in adults with metastatic pancreatic cancer: RR 0.85 (95% CI 0.49-1.47), where RR higher than 1 favours the LV5FU2-CDDP/Gem arm.
Very low quality evidence from 1 multicentre phase III RCT (n=38) showed no clinically important difference between irinotecan + raltitrexed and raltitrexed single-agent as second-line chemotherapy about the relative probability of objective response rate (CR + PR) in adults with metastatic pancreatic cancer: RR 0.14 (95% CI 0.01-2.59), where RR higher than 1 favours the irinotecan + raltitrexed arm.
Progression-free survival
Moderate quality evidence from 1 multicentre phase III RCT (n=202) showed no clinically important difference between LV5FU2-CDDP followed by gemcitabine single-agent [LV5FU2-CDDP/Gem] and gemcitabine single-agent followed by LV5FU2-CDDP [Gem/LV5FU2-CDDP] in PFS rates between intervention groups in adults with metastatic pancreatic cancer: HR 1.06 (95% CI 0.80-1.40), where HR less than 1 favours the LV5FU2-CDDP/Gem arm.
Overall Survival
Moderate quality evidence from 1 multicentre phase III RCT (n=202) showed no clinically important difference between LV5FU2-CDDP followed by gemcitabine single-agent [LV5FU2-CDDP/Gem] and gemcitabine single-agent followed by LV5FU2-CDDP [Gem/LV5FU2-CDDP] in long-term survival rates in adults with metastatic pancreatic cancer: HR 1.06 (95% CI 0.80-1.40), where HR less than 1 favours the LV5FU2-CDDP/Gem arm.
Adverse Events
Low quality evidence from 1 multicentre phase III RCT (n=202) showed no clinically important difference between LV5FU2-CDDP followed by gemcitabine single-agent [LV5FU2-CDDP/Gem] and gemcitabine single-agent followed by LV5FU2-CDDP [Gem/LV5FU2-CDDP] about the relative risk of drug-related grade 3/4 toxicities (including nausea/vomiting) in adults with metastatic pancreatic cancer: RR 0.92 (95% CI 0.47-1.80), where RR less than 1 favours the LV5FU2-CDDP/Gem arm.
Very low quality evidence from 1 multicentre phase III RCT (n=38) showed no clinically important difference between irinotecan + raltitrexed and raltitrexed single-agent as second-line chemotherapy about the relative risk of drug-related grade 3/4 toxicities in adults with metastatic pancreatic cancer, including leukocytopenia (RR 1.25 [95% CI 0.4-3.95]), neutropenia (RR 1.33 [95% CI 0.34-5.17]), nausea/vomiting (RR 1.0 [95% CI 0.07-14.85]), and diarrhoea (RR 1.0 [95% CI 0.16-6.38]), where RR less than 1 favours the raltitrexed alone arm. (There were no cases of thrombocytopenia, stomatitis, and fatigue).
Health-related quality of life
No evidence was identified to inform this outcome.
In adults with locally advanced and metastatic pancreatic cancer
Response rate
Very low quality evidence from 1 phase III RCT (n=110) showed no clinically important difference between the oxaliplatin + 5-FU and folinic acid + 5-FU second-line chemotherapy in adults with locally advanced/metastatic pancreatic cancer: RR 1.5 (95% CI 0.27-8.19), where RR higher than 1 favours the oxaliplatin + 5-FU arm.
Very low quality evidence from 1 multicentre phase III RCT (n=274) showed no clinically important difference between gemcitabine + erlotinib followed by capecitabine [Gem+E/Cap] and capecitabine + erlotinib followed by gemcitabine [Cap+E/ Gem] second-line chemotherapy about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 0.49 (95% CI 0.1-2.29), where RR higher than 1 favours the Gem+E/Cap arm.
Very low quality evidence from 1 phase III RCT (n=108) showed no clinically important difference between 5-FU + folinic acid + oxaliplatin [mFOLFOX6] and folinic acid/5-FU second-line chemotherapy about the relative probability of objective response rate (CR + PR) in adults with locally advanced/metastatic pancreatic cancer: RR 1.4 (95% CI 0.47-4.14), where RR higher than 1 favours the mFOLFOX6 arm.
Progression-free Survival
Low quality evidence from 1 phase III RCT (n=110) showed no clinically important difference between oxaliplatin + 5-FU and folinic acid + 5-FU second-line chemotherapy in PFS rates in adults with locally advanced/metastatic pancreatic cancer.
Low quality evidence from 1 multicentre phase III RCT (n=168) showed that there is a clinically important difference favouring OFF is associated with a marked improvement in PFS when compared with FF in adults with locally advanced/metastatic pancreatic cancer: HR 0.68 (95% CI 0.49-0.94), where HR less than 1 favours the OFF group.
Moderate quality evidence from 1 phase III RCT (n=108) showed no clinically important difference between 5-FU + folinic acid + oxaliplatin [mFOLFOX6] and folinic acid/5-FU second-line chemotherapy in PFS rates in adults with locally advanced/metastatic pancreatic cancer: HR 1.00 (95% CI 0.66-1.52), where HR less than 1 favours the mFOLFOX6 arm.
Overall Survival
Low quality evidence from 1 phase III RCT (n=110) showed no clinically important difference between oxaliplatin + 5-FU and folinic acid + 5-FU second-line chemotherapy in survival rates in adults with locally advanced/metastatic pancreatic cancer.
Moderate quality evidence from 1 multicentre phase III RCT (n=168) showed that there is a clinically important difference favouring oxaliplatin + 5-FU group [OFF] second-line chemotherapy in overall survival compared to FA + 5-FU group ff second-line chemotherapy in adults with locally advanced/metastatic pancreatic cancer: HR 0.66 (95% CI 0.48-0.91), where HR less than 1 favours the OFF group.
Low quality evidence from 1 multicentre phase III RCT (n=274) showed no clinically important difference between gemcitabine + erlotinib followed by capecitabine [Gem+E/Cap] and capecitabine + erlotinib followed by gemcitabine [Cap+E/ Gem] second-line chemotherapy in survival rates.
Moderate quality evidence from 1 phase III RCT (n=108) showed that there is a clinically important difference favouring folinic acid/5-FU second-line chemotherapy in overall survival compared to 5-FU + folinic acid + oxaliplatin [mFOLFOX6] second-line chemotherapy in adults with locally advanced/metastatic pancreatic cancer: HR 1.78 (95% CI 1.08-2.93), where HR less than 1 favours the mFOLFOX6 arm.
Adverse Events
Very low quality evidence from 1 phase III RCT (n=110) showed no clinically important difference between oxaliplatin + 5-FU and folinic acid + 5-FU second-line chemotherapy about the relative risk of drug-related grade 3/4 toxicities (including nausea/vomiting, diarrhoea, stomatitis and haematological -neutropenia, anaemia, thrombocytopenia).
Low quality evidence from 1 multicentre phase III RCT (n=168) showed no clinically important difference between oxaliplatin + 5-FU [OFF] and FA + 5-FU group ff second-line chemotherapy about the relative risk of drug-related grade 3/4 toxicities (including anaemia, nausea/emesis, paresthesia, pain, leucopoenia, thrombocytopenia, and diarrhoea).
Very low quality evidence from 1 multicentre phase III RCT (n=274) showed no clinically important difference between gemcitabine + erlotinib followed by capecitabine [Gem+E/Cap] and capecitabine + erlotinib followed by gemcitabine [Cap+E/ Gem] second-line chemotherapy about the relative risk of drug-related grade 3/4 toxicities (including nausea/vomiting, leucopoenia, thrombocytopenia, and diarrhoea).
Low to very low quality evidence from 1 phase III RCT (n=102) showed no clinically important difference between 5-FU + folinic acid + oxaliplatin [mFOLFOX6] and folinic acid/5-FU second-line chemotherapy about the relative risk of drug-related grade 3/4 toxicities (including febrile neutropenia, fatigue, thrombocytopenia, dehydration, pulmonary embolism, vomiting, hypokalaemia, and peripheral neuropathy).
Moderate quality evidence from 1 phase III RCT (n=102) showed that there is a clinically important difference favouring 5-FU + folinic acid + oxaliplatin [mFOLFOX6] second-line chemotherapy on the relative risk of drug-related grade 3/4 toxicities (neutropenia) compared to folinic acid/5-FU in adults with locally advanced/metastatic pancreatic cancer: RR 8.65 (95% CI 2.10-35.72)
Health-related quality of life
Very low quality evidence from 1 phase III RCT (n=108) showed no clinically important difference between 5-FU + folinic acid + oxaliplatin [mFOLFOX6] and folinic acid/5-FU second-line chemotherapy in health related quality of life in adults with locally advanced/metastatic pancreatic cancer.
11.2.7. Recommendations
First-line treatment
- 53.
Offer FOLFIRINOX4 to people with metastatic pancreatic cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
- 54.
Consider gemcitabine combination therapy5 for people who are not well enough to tolerate FOLFIRINOX. For guidance on combination therapy with gemcitabine and nab–paclitaxel, see the NICE technology appraisal guidance on paclitaxel as albumin-bound nanoparticles with gemcitabine for untreated metastatic pancreatic cancer.
- 55.
Offer gemcitabine to people who are not well enough to tolerate combination chemotherapy.
Second-line treatment
Venous thromboembolism prophylaxis
The updated NICE guideline on venous thromboembolism will cover venous thromboembolism prophylaxis for people with pancreatic cancer. This guideline is due to be published in March 2018, and the draft recommendations are available now.
11.2.8. Evidence to recommendations
11.2.8.1. Relative value placed on the outcomes considered
Response rate, progression free survival, overall survival, adverse events, heal th related quality of life, patient experience, PROMS and symptom control were considered the critical outcomes for this question.
Overall survival and adverse events were reported by all studies. Response rate was reported for all studies except 1. Health related quality of life and progression free survival were reported only by some studies. The outcomes of patient experience/patient reported outcome measures and symptom control were not reported by any studies.
11.2.8.2. Quality of evidence
The quality of the evidence was assessed by GRADE and the Cochrane risk of bias checklist. AMSTAR was used for assessing the methodological quality of systematic reviews.
The quality of the outcomes for the comparisons identified by this review were as follows:
- Chemotherapy versus immunochemotherapy for second line treatment - very low.
- 5-FU combination chemotherapy versus other chemotherapy regimens – ranged from very low to low
- Second-line chemotherapy versus other chemotherapy regimens for metastatic disease – ranged from very low to low
- Gemcitabine versus novel agents – ranged from very low to moderate
- 5-FU alone versus 5-FU combination chemotherapy (both metastatic and locally advanced disease) – ranged from very low to moderate
- Second-line chemotherapy versus other chemotherapy regimens for mixed metastatic and locally advanced disease – ranged from low to moderate
- Chemotherapy versus immunochemotherapy for first line treatment - ranged from low to moderate quality.
- Chemotherapy (second-line) versus best supportive care – ranged from low to moderate
- Standard-dose versus low-dose gemcitabine – ranged from low to moderate
- Intra-arterial chemotherapy versus systemic chemotherapy – ranged from low to moderate
- Chemotherapy versus prophylactic anticoagulation + chemotherapy – ranged from low to moderate
- Gemcitabine versus other chemotherapy regimens for locally advanced disease - ranged from very low to high.
- Gemcitabine versus other chemotherapy regimens for metastatic disease - ranged from low to high
A substantial number of studies in the evidence base included mixed locally advanced and metastatic cancer populations, but did not report the subgroups separately. Given that there is a continuum between locally advanced and metastatic disease, the committee agreed it was appropriate to use evidence with mixed populations to base their recommendations on. However, during their discussions the committee applied more weight to those studies that had exclusively metastatic populations or had reported metastatic populations separately.
The committee noted that no RCT evidence was identified which evaluated surgical resection of metastases in people with pancreatic cancer. The committee therefore agreed to recommend further research in this area, as the role of surgery in managing metastatic pancreatic cancer is a common question asked by patients.
11.2.8.3. Consideration of clinical benefits and harms
First line treatment
The committee noted that high quality evidence from a network meta-analysis of 23 RCTs had shown improvements in overall survival with the use of FOLFIRINOX in people with metastatic disease and ECOG performance status 0-1. They also noted the potential for increased toxicity with FOLFIRINOX chemotherapy, and that its use was contraindicated for people with significantly impaired liver function. However, the committee agreed that the benefits in overall survival from this intervention outweighed the potential side effects experienced by those fitter people receiving it and made a strong recommendation for its use in the appropriate subgroup of people reported by the PRODIGE4/ACCORD11 trial.
Given the potential for toxicity with FOLFIRINOX, the committee agreed to make additional recommendations that covered first line treatment for those people who would be unlikely to tolerate FOLFIRINOX. They noted that the evidence for both gemcitabine combination therapy and gemcitabine monotherapy had shown improved overall survival and progression free survival in people with metastatic disease. Whilst the survival advantage for gemcitabine combination therapy was larger compared with monotherapy, this needed to be balanced against the potential for increased side effects and a recognition that some patients were not sufficiently fit to tolerate combination chemotherapy. Gemcitabine monotherapy is remarkably well tolerated, even in relatively unfit people. The committee therefore agreed to make a weaker recommendation on gemcitabine combination and monotherapy as the balance between the benefits and harms was less certain.
It was not possible, based on the evidence, to determine the optimal gemcitabine combination therapy as several were shown to have some benefits. Therefore the committee did not recommend a particular regimen.
The committee noted that the potential benefits of the recommendations made could be improvements in overall survival, progression free survival and quality of life. The potential harms were considered to be side effects from chemotherapy. The committee agreed that the potential benefits of offering chemotherapy outweighed the harms of not doing so.
Second line treatment
The committee noted, based on the evidence, that oxaliplatin-based chemotherapy had shown improved progression-free survival when given second line. However the results for overall survival were inconsistent, with 1 study showing a statistically significant benefit on overall survival whilst another showed no difference. The committee therefore agreed it was only possible to make a weak recommendation for this intervention.
Based on their clinical knowledge and experience the committee also agreed to recommend gemcitabine or gemcitabine-based chemotherapy as second line treatment for those people who progress on first line FOLFIRINOX. The committee noted that 80% of patients treated in the PRODIG4/ACCORD11 trial of first line FOLFIRINOX received gemcitabine or gemcitabine-based combination chemotherapy second line, and that they had based their first line treatment recommendations on results of this clinical trial. It is also the current standard of care.
Based on their knowledge and experience, the committee noted that treatment options for metastatic disease are currently very limited and second line treatment is often not considered as an option due to the poor prognosis of the disease. These factors generate an impression of futility which has a significant negative psychological impact on people with pancreatic cancer. The committee considered that making recommendations for second line treatment would help promote the active treatment of people with metastatic disease thereby helping to alleviate some of this psychological impact. They noted that other more tangible benefits could be improvements in overall survival, progression free survival and quality of life. The potential harms of the recommendations made were considered to be side effects from chemotherapy. The committee agreed that the potential benefits outweighed the harms of treatment.
11.2.8.4. Consideration of economic benefits and harms
The economic evidence review identified two previous economic evaluations for this topic both from a Canadian public healthcare payer perspective. Both studies compared FOLFIRINOX to gemcitabine in a metastatic population with 1 study also comparing gemcitabine in combination with erlotinib and gemcitabine in combination with capecitabine.
Whilst both studies reported broadly similar incremental improvements in health of approximately 0.25 QALYs, when comparing FOLFIRNOX to gemcitabine the reported lifetime incremental costs were double in 1 study compared to the other. These resulted in the studies concluding differently as to the cost effectiveness of FOLFIRINOX from a Canadian perspective. The committee acknowledged that the study that concluded that FOLFIRINOX was not cost effective incorporated the more realistic assumptions. They also noted that FOLFIRINOX was significantly more expensive in Canada (approximately by a factor of 10) where the oxaliplatin component is still on patent.
The committee acknowledged the low applicability of the studies given the differing perspective to that used by NICE although they agreed that the QALY values reported were believable in a NHS setting and were in line with the evidence from the clinical evidence review. With the lower costs associated with using FOLFIRINOX in a NHS setting it was strongly thought that FOLFIRINOX would be cost effective from a NHS+PSS perspective compared to gemcitabine alone. It was also noted that FOLFIRINOX is currently standard of care for eligible people and that this recommendation would be cost neutral.
Both gemcitabine with capecitabine and gemcitabine with erlotinib were health improving and more costly than gemcitabine alone. Given that the increase in QALYs were lower in this group compared to FOLFIRINOX, the committee found it more difficult to generalise these results to an NHS setting. Whilst the committee thought combination therapies were health improving compared to gemcitabine alone it would also be cost increasing through increased use of additional chemotherapies - although the committee did not think this cost would be significant. It was difficult to draw any conclusions from the evidence identified about cost effectiveness from a NHS+PSS perspective and a weaker recommendation was made around combination therapies.
No published economic evidence was identified for the other interventions in the review question. The committee agreed that recommendations for second line treatment would probably cause an increase in costs as the current standard of care was best supportive care. Given the relatively short life expectancy and limited number of people receiving second line treatment it was felt that any cost increases were unlikely to be significant.
11.2.8.5. Other considerations
The committee were aware that there was existing NICE guidance on the use of paclitaxel as albumin-bound nanoparticles in combination with gemcitabine for previously untreated metastatic pancreatic cancer (TA476, 2017) and pegylated liposomal irinotecan for treating pancreatic cancer after gemcitabine (TA440, 2017), in metastatic pancreatic cancer. Consequently and in line with NICE processes, the committee did not investigate the use of nab-paclitaxel or liposomal irinotecan in this population or make any recommendations on these interventions. Committee members also noted that the venous thromboembolism in over 16s is in the process of being updated (to be published in March 2018) and contains a new recommendation related to pancreatic cancer. The committee cross-referenced to TA476 (related to gemcitabine combinations for first line treatment) and noted in the recommendation section that the venous thromboemobolism guideline is being updated with a link to the version that is in consultation. They did not cross-refer to TA440 because it does not recommend the use of pegulated liposomal irinotecan and the committee decided that a cross-reference would therefore not be appropriate.
11.2.9. Research recommendation
- 8.
A randomised phase II feasibility study should be undertaken comparing surgery/ablative treatment (in combination with chemotherapy) against chemotherapy in people with hepatic oligometastatic potentially resectable pancreatic cancer.
The role of surgery in controlling metastatic pancreatic cancer is of considerable interest. Debulking surgery is established in some other forms of advanced cancer and, combined with chemotherapy, helps to prolong life. No RCT evidence exists which evaluates the role of surgical resection of metastatic pancreatic cancer and compares it against standard non-surgical treatment. More data in this area my enable recommendations to be made about this intervention. Outcomes of interest are feasibility of recruitment, recurrence/progression free survival, quality of life and PROMS.
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11.2.10.1. Included studies in Gresham et al., 2014 (n=23)
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Footnotes
- 4
Although this use is common in UK clinical practice, at the time of publication (January 2018) FOLFIRINOX did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- 5
Although this use is common in UK clinical practice, at the time of publication (January 2018) many gemcitabine combination therapies did not have a UK marketing authorisation covering the first-line treatment of adults with metastatic pancreatic cancer. The prescriber should follow relevant professional guidance, taking full responsibility for the decision to prescribe. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- 6
Although this use is common in UK clinical practice, at the time of publication (January 2018) oxaliplatin-based chemotherapy did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- 7
Although this use is common in UK clinical practice, at the time of publication (January 2018) gemcitabine-based chemotherapy did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- Management of unresectable pancreatic cancer - Pancreatic cancer in adults: diag...Management of unresectable pancreatic cancer - Pancreatic cancer in adults: diagnosis and management
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