Results

Suzanne Belinson; Ryan Chopra; Yoojung Yang; Veena Shankaran; Naomi Aronson

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Belinson S, Chopra R, Yang Y, et al. Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Dec. (Comparative Effectiveness Reviews, No. 93.)

This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer [Internet].

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Results

In this chapter, we present the results of our systematic review of the literature and synthesis of the extracted data on outcomes on the effectiveness and comparative effectiveness of local hepatic therapy for unresectable CRC metastases to the liver. The Key Questions (KQs) for this review are: KQ1 (effectiveness) and KQ2 (harms) of local hepatic therapy for unresectable CRC metastases to the liver in patients whose disease is refractory to systemic chemotherapy and who have no or minimal extrahepatic disease; and KQ3 (effectiveness) and KQ4 (harms) of local hepatic therapy for unresectable CRC metastases to the liver in patients who are also receiving systemic chemotherapy and have no extrahepatic disease.

We first describe the results of our literature searches and then present the results for KQ1 and KQ2, which include a list of key points, an overview of the included literature, and a detailed synthesis of the data. This is followed by the same for KQ3 and KQ4. We identified 937 nonduplicate titles or abstracts with potential relevance, and of these, 189 proceeded to full-text review (Figure 3). Thirty-one articles were included in the review, including one hand-searched article and five articles from gray literature identified through other sources (the American Society of Clinical Oncology, American Society of Clinical Oncology Gastrointestinal Cancers, Surgical Society of Oncology, and Radiosurgical Society). The 31 arms represent 30 distinct studies: 1 RCT, 12 prospective case series, and 17 retrospective case series. Twenty-three studies pertain to KQ1, 23 studies to KQ2, 7 studies to KQ3, and 7 studies to KQ4.

Figure 3

PRISMA diagram for identified published literature.

Results of Literature Searches

Of the 937 records identified through the literature search, we excluded 913 at various stages of screening and included 24 records.⁶³^–⁸⁶ We included one hand-searched article,⁸⁷ two published studies from scientific information packets,⁸⁸^,⁸⁹ and three articles from conference abstracts.⁹⁰^–⁹² A total of 30 articles were included in this report: 29 case-series and one RCT⁸⁷ for which a single arm was abstracted as a case series. This RCT compared RFA with systemic chemotherapy to systemic chemotherapy alone. The scope of the review was liver-directed therapy versus liver-directed therapy. Systemic chemotherapy alone was not a relevant intervention or comparator for this review. Only the RFA combined with systemic chemotherapy arm was abstracted and included in this report as it is relevant for KQ3 and KQ4.

The PRISMA diagram (Figure 3) depicts the flow of search screening and study selection.⁵³ A list of full-text studies with reason for exclusion is presented in Appendix F.

Our searches of various gray literature sources yielded five published studies that we added to the articles identified in the search of publications databases and that were included in the analyses presented in this evidence review.⁸⁸^–⁹²

We evaluated the results of the gray literature search as follows:

Regulatory information: The search yielded six results, but no new studies were identified from this source.
Clinical trial registries (ClinicalTrials.gov): The search yielded 259 clinical trials; we excluded 219 trials during the title and abstract screen. Twenty-five of the remaining 40 trials were excluded. Among the 15 trials remaining, 2 contained too little information to make a conclusion about their relevance to the KQs of this report. Of the remaining 13 studies, three had been terminated, seven were ongoing or recruiting, and three had been completed. We found no publications for the three completed trials. All terminated studies cited low recruitment as the reason for study termination.
Abstracts and conference papers: The search yielded 174 citations, and we excluded 132 during the title and abstract screen. Of the remaining 42 items, two were duplicates and 37 did not meet inclusion criteria after full-text review. The three remaining references met all inclusion criteria and were included in this report.⁹⁰^–⁹²
Manufacturer database: Scientific information packets were received from Accuray (manufacturers of the CyberKnife^® SBRT system) and SIRTEX (manufacturers of the Yttrium-90–infused SIR-Spheres microspheres). The submissions consisted of 55 published references, listings of clinical trials, or conference abstracts. Of the 55 references, we excluded 53 during the abstract and title screen. The remaining two references met the inclusion criterion and were included in this report.⁸⁸^,⁸⁹

Overview of the Literature

Thirty-one arms within 30 studies met our inclusion criteria and addressed local hepatic therapy for unresectable CRC metastases to the liver. Nine studies were conducted in the United States, four in Italy, four in Germany, three in Australia, three in Japan, two in the United Kingdom, two in Korea, and one study each in France, the Netherlands, and Turkey (Table 4). The number of patients in each study ranged from 6 to 140.

Table 4

Characteristics of studies included in this review by intervention.

All 30 studies had clearly defined questions and well-described interventions, used validated outcome measures, and had conclusions that were supported by the data. Studies varied on how well they described the study population, how well they described their results, and acknowledgement of sponsorship and funding. Fifteen studies did not have well-described patient populations,⁶³^,⁶⁵^,⁶⁷^,⁷⁰^,⁷⁴^,⁷⁸^,⁷⁹^,⁸¹^,⁸³^–⁸⁶^,⁸⁸^,⁸⁹^,⁹¹ and three studies lacked well-described results.⁶⁷^,⁷⁰^,⁷⁴

Fifteen studies were rated as good quality,⁶⁴^,⁶⁶^,⁶⁸^,⁶⁹^,⁷¹^–⁷³^,⁷⁵^–⁷⁷^,⁸⁰^,⁸²^,⁸⁷^,⁹⁰^,⁹² 12 studies as fair quality,⁵⁷^,⁶³^,⁶⁵^,⁷⁸^,⁷⁹^,⁸¹^,⁸⁴^–⁸⁶^,⁸⁸^,⁸⁹^,⁹¹ and three as poor quality.⁶⁷^,⁷⁰^,⁷⁴

Key Questions 1 and 2. Effectiveness and Harms of Therapies in Patients Refractory to Systemic Chemotherapy

KQs 1 and 2 focus on the comparative effectiveness (KQ1) and harms (KQ2) of the various local hepatic therapies in patients with unresectable colorectal cancer (CRC) metastases to the liver and who have minimal evidence of extrahepatic disease and whose disease is refractory to systemic therapy (i.e., are not eligible to receive systemic chemotherapy).

Key Points

The evidence is insufficient to draw conclusions about overall survival, quality of life, or adverse events. Due to the absence of comparative data, we are limited in drawing conclusions regarding the efficacy and effectiveness of these interventions. Risk of bias is a primary concern in observational studies. Intended effects are likely to be biased by preferential prescribing of the intervention based on the patients’ prognosis.
All studies were case series. Carey and Boden quality rankings were converted into AHRQ “good,” “fair,” and “poor” ratings. Eleven studies were rated as good quality,⁶⁶^,⁶⁸^,⁶⁹^,⁷¹^,⁷³^,⁷⁵^–⁷⁷^,⁸²^,⁹⁰^,⁹² nine studies as fair quality,⁶³^,⁶⁵^,⁷⁸^,⁸³^,⁸⁴^,⁸⁶^,⁸⁸^,⁸⁹^,⁹¹ and three as poor quality.⁶⁷^,⁷⁰^,⁷⁴
The assessment of applicability of the study findings to clinical practice is limited by the poor characterization of the patient populations (e.g., number and size of metastases, performance status) and variability in the delivery of the interventions (e.g., surgical approach, dose and drugs delivered).

Description of Included Studies

Twenty-three case series⁶³^,⁶⁵^–⁷¹^,⁷³^–⁷⁸^,⁸²^–⁸⁴^,⁸⁶^,⁸⁸^–⁹² met inclusion criteria to address KQ1 and KQ2. Of the 23 case series, nine were prospective⁶⁶^,⁶⁷^,⁷⁰^,⁷³^–⁷⁶^,⁷⁸^,⁸⁸ and 14 were retrospective.⁶³^,⁶⁵^,⁶⁸^,⁶⁹^,⁷¹^,⁷⁷^,⁸²^–⁸⁴^,⁸⁶^,⁸⁹^–⁹² The total number of patients for whom data were abstracted from the 23 studies was 932. Three studies included patients treated with TACE with DEB;⁶⁷^,⁷⁵^,⁹⁰ and two articles reported on TACE alone;⁶³^,⁶⁸ three on SBRT;⁷¹^,⁸²^,⁸⁸ thirteen on RE;⁶⁵^,⁶⁶^,⁶⁸^,⁷⁰^,⁷³^,⁷⁶^–⁷⁸^,⁸⁴^,⁸⁶^,⁸⁹^,⁹¹^,⁹³ two on HAI,⁸³^,⁹² and one on RFA.⁶⁹ All studies initiated treatment in patients after January 1, 2000, except for the study by Albert and colleagues²¹ on TACE. We included this study because it reported on relatively large numbers of patients treated, and analyses showed no differences in outcomes before and after 2000. Table 5 shows the summary of the study and patient characteristics, including number of patients enrolled, study design, intervention period, and intervention, and patient demographics.

Table 5

Local hepatic therapies for CRC metastases to the liver: Summary of study characteristics KQ1 and KQ2.

Patients ranged in age from 30 to 91 years, but they were generally in their late 50s or early 60s. Thirteen studies reported rates of previous resection that ranged from 2.6 to 83.5 percent.⁶³^,⁶⁴^,⁶⁶^,⁶⁸^–⁷⁰^,⁷⁵^,⁸²^,⁸⁴^,⁸⁸^,⁸⁹^,⁹¹^,⁹² Five studies reported median ECOG scores of 0–1, with a range of 0–3.⁶⁶^,⁶⁷^,⁷³^,⁷⁵^,⁷⁷ In all but two studies,⁷²^,⁸¹ patients had been treated with prior lines of systemic chemotherapy, and 11 studies reported patient experience with prior local hepatic therapy.⁶³^,⁶⁸^–⁷⁰^,⁷⁵^,⁷⁸^,⁸²^,⁸⁴^,⁸⁸^,⁸⁹^,⁹¹ Lines of previous systemic chemotherapy are presented in Appendix D.

The included evidence is clinically diverse with respect to the number of patients undergoing previous resection and local hepatic therapy. Variations are also present in the treatments—in terms of the drugs or dosage—within a given intervention.

Data on tumor characteristics were inconsistently reported across studies and are detailed in Table 6. Synchronous or metachronous disease status was reported in eight studies and synchronous disease ranged from 17 to 73 percent.⁶⁶^,⁶⁸^,⁷¹^,⁷⁵^,⁸³^,⁹¹^,⁹²^,⁹⁴ Bilobar or unilobar disease was reported in six studies and bilobar disease ranged from 66.7 to 95.1 percent.⁶⁵^,⁶⁶^,⁶⁸^,⁷³^,⁷⁶^,⁸⁶ Eight studies reported liver involvement, but used nonuniform measurements.⁶⁵^,⁶⁷^,⁷⁰^,⁷³^,⁷⁵^–⁷⁷^,⁹⁰ Four studies reported mean or median number of hepatic lesions.⁶⁹^,⁷¹^,⁷⁵^,⁸² Six studies reported the mean size of hepatic lesions, which ranged from 2.9 to 12cm.⁶⁶^,⁶⁸^,⁶⁹^,⁸²^,⁹⁰^,⁹⁴ Presence of extrahepatic metastases were reported by five studies and ranged from 33 to 81 percent of patients.⁶³^,⁶⁶^,⁶⁸^,⁹¹^,⁹² Although extrahepatic disease was reported by these studies, the patients were all described as having liver-dominant disease (i.e., majority of the disease is confined to the liver).

Table 6

Local hepatic therapies for CRC metastases to the liver: Summary of tumor characteristics KQ1 and KQ2.

Detailed Synthesis

Table 7 displays the outcomes reported. All studies reported overall survival. All studies reported on adverse events, but four studies aggregated these events by multiple primary cancer sites, which did not permit us to extract CRC-specific adverse events.⁶⁹^,⁷⁰^,⁷⁷^,⁷⁸ Eight studies also reported progression-free survival.⁶³^,⁶⁵^,⁶⁶^,⁷¹^,⁷⁵^,⁹⁰^,⁹²^,⁹³ Three studies reported on both liver-specific progression-free survival and overall progression-free survival;⁶³^,⁷⁵^,⁹² no studies reported on liver-specific progression-free survival alone; and the remaining five studies reported overall progression-free survival alone.⁶⁵^,⁶⁶^,⁷¹^,⁷⁴^,⁹⁰ Jakobs et al. (2006)⁶⁹ attempted to calculate the time to recurrence statistic but were unable to do so because of the low rate of recurrence (18%). Two studies reported on length of stay,⁶³^,⁶⁷ and two studies reported on quality of life.⁶⁶^,⁶⁷ We report data on individual outcomes, except for results on overall progression-free survival and liver-specific progression-free survival, which are located in Appendix D.

Table 7

Outcomes reported for Key Questions 1 and 2.

Overall Survival

All studies reported on outcomes related to overall survival (Table 8, which is organized by intervention). One RFA study by Jakobs et al. (2006)⁶⁹ did not report mean or median survival measures, but did report 1-, 2-, and 3-year survival rates of 96 percent, 71 percent, and 68 percent, respectively, from the time of study treatment. Three studies in our report used TACE with DEB. Median survival was reported by two⁷⁵^,⁹⁰ studies and ranged from 19 to 25 months from study treatment. Florentini et al. (2007) reported only a 1-year survival rate of 61 percent.⁶⁷ Two studies reported on TACE alone.⁶³^,⁶⁸ Both studies reported median survival from time of diagnosis of liver metastases, which ranged from 26.3 to 27 months. Thirteen studies of RE with Yttrium-90 were included in this review.⁶⁵^,⁶⁶^,⁶⁸^,⁷⁰^,⁷³^,⁷⁴^,⁷⁶^–⁷⁸^,⁸⁴^,⁸⁶^,⁸⁹^,⁹¹ One of these studies involved systemic chemotherapy in addition to RE and is therefore not presented in this summary of results.³⁰ Eight studies reported survival from study treatment; median survival ranged from 4 to 15.2 months.⁷⁰^,⁷³^,⁷⁷^,⁷⁸^,⁸⁴^,⁸⁶^,⁸⁹^,⁹¹ One of these studies⁸⁴ did not reach median survival at a follow up of 3 years. Three studies reported survival starting from diagnosis of liver metastases, which ranged from 31 to 34.6 months.⁶⁶^,⁶⁸^,⁷⁶ Two studies did not indicate the time point from which survival was measured.⁶⁵^,⁷⁴ HAI was used in two studies in our review,⁸³^,⁹² and reported median survival from the start of study treatment as 6.7 and 9.7 months.⁸³^,⁹² Three studies reported SBRT in this review and all defined survival from time of study treatment.⁷¹^,⁸²^,⁸⁸ Median survival values reported in two studies were 17 and 25 months.⁷¹^,⁸⁸ The third SBRT study only reported 1- and 2-year survival rates of 95 percent and 58 percent, respectively.⁸²

Table 8

Local hepatic therapies for CRC metastases to the liver: Outcomes related to overall survival KQ1 and KQ2.

Direct comparisons of overall survival cannot be made from the published data because there are no comparative studies and the studies measured survival from different starting points (i.e., time of diagnosis or time of treatment).

Quality of Life

Two studies reported on quality of life.⁶⁶^,⁶⁷ Cosimelli and colleagues used a battery of questionnaires to assess both cancer and disease-specific quality of life (The European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ] C30, EORTC QLQ C38, and EORTC QLQ LMC-21).⁶⁶ They also assessed anxiety and depression (Hamilton Rating Scale for Depression [HAM-D]) and patient satisfaction (EORTC QLQ SAT-32). They reported quality of life measures on 14 of 50 enrolled subjects. The study authors provided no insight as to why only 14 of the participants had available data on quality of life. Six weeks after treatment, the quality of life of 14 patients treated with RE was not adversely affected, and patients’ anxiety levels were significantly reduced from pretreatment levels. No significant difference was observed in depression score pre- and post-treatment. In a study of chemoembolization with irinotecan-eluting beads, Fiorentini and colleagues stated that 18 of 20 patients reported improvement in quality of life post-treatment.⁴¹ They used the Edmonton Symptom Assessment System in this study, but only reported qualitatively that these patients had improved without providing any metrics.

Length of Stay

Mean length of stay was reported by two studies⁶³^,⁶⁷ of TACE and ranged from 1.3 to 3 days. No direct comparisons can be made based on the published studies.

Time to Progression

Time to progression was not reported in any of the included studies.

Local Recurrence

Outcomes related to local recurrence are summarized in Table 9. In this report, local recurrence is defined as recurrence of the liver metastases in the area previously treated. This constitutes a treatment failure or failure to treat the entire lesion and is considered an adverse event. One RFA study reported a local recurrence rate of 18 percent.⁶⁹ Local recurrence was also reported in two studies of SBRT, both of which reported a rate of 33.3 percent.⁷¹^,⁸⁸

Table 9

Local hepatic therapies for unresectable CRC metastases to the liver: Adverse events KQ1 and KQ2.

Adverse Events

Twenty-four studies reported on adverse events with varying levels of detail and are presented in Table 9 by intervention. One TACE study reported a patient who developed a hepatic abscess.⁶⁷ Liver failure was reported in three studies, two on RE⁶⁵^,⁶⁶ and one⁷⁵ on TACE with DEB intervention. Two studies—one on TACE⁶³ and one on RE⁷⁶—reported elevated alkaline phosphatase levels. Elevated bilirubin was reported in five studies, one on TACE with DEB⁹⁰, one on TACE⁶³, two on RE⁷⁶^,⁹¹, and one on HAI⁹². Elevated transaminase levels were reported in one RE article,⁷⁶ which also reported elevated bilirubin and alkaline phosphatase. Although these results from liver function tests could point to disease progression, in the time period following a local hepatic therapy they are more likely to reflect an adverse effect of the treatment. Only Aliberti et al. reported liver function test results immediately after treatment.⁹⁰ Other liver function tests were evaluated as acute or late toxicity⁷⁶^,⁹¹ or were not reported⁶³^,⁹² at the time adverse events were evaluated. Two authors indicated that liver function toxicity was likely a result of progressive disease or biliary obstruction.⁷⁶^,⁹¹ One TACE with DEB study reported one death from myocardial infarction⁷⁵ and one TACE study reported a 30-day morality rate of 3.6 percent.⁶³ A description of rare adverse events is included in Table 9. No study reported on injury to adjacent organs, hepatic hemorrhage, or steatohepatitis.

Multivariate Analyses

Univariate or multivariate analyses of prognostic factors for overall survival including, but not limited to, ECOG score, presence of extrahepatic disease, and treatment response, were variously reported in six case series⁶³^,⁷³^,⁷⁶^,⁷⁸^,⁹¹^,⁹² of local hepatic therapies. All analyses reported on overall survival as the dependent variable.

Among the patient or tumor characteristics found to be associated with improved overall survival were the following: ECOG status (0 vs. ≥1 and in another study 0 or 1 vs. ≥2), performance status (0 or 1 vs. ≥ 2), number of extrahepatic metastases sites (0 or 1 vs. ≥2), number of lines of previous chemotherapy (0–1 vs. ≥ 2), performance status (0 or 1 vs. ≥ 2), carcinoembryonic antigen response (Yes, No), and Response Evaluation Criteria in Solid Tumors (RECIST).

Key Questions 3 and 4

Key Questions 3 and 4 focus on the comparative effectiveness (KQ3) and harms (KQ4) of the various local hepatic therapies in patients who are receiving local hepatic therapy as an adjunct to systemic therapy for unresectable CRC metastases to the liver and who have no evidence of extrahepatic disease.