Abstract

Unlike newly diagnosed glioblastoma, no clear or widely accepted standard of care is available for patients with a recurrence. A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogression, pseudoresponse, or radionecrosis. Based on parameters like tumor location and volume, patient’s performance status, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient. The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a recurrent glioblastoma can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserve the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies.

Introduction

Maximal safe debulking surgery is well accepted as the mainstay treatment for newly diagnosed glioblastoma (GBM), and postoperative radiochemotherapy was determined in 2005 as the standard of care (SOC) by a pivotal phase 3 randomized trial by the European Organisation for the Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) (1, 2). According to this trial, adult patients, up to the age of 70, with newly diagnosed GBM are being treated with 6 weeks of radiotherapy with concomitant temozolomide chemotherapy, followed by six adjuvant cycles of adjuvant temozolomide. However, despite multimodal therapy, prognosis for GBM patients remains poor with a median progression-free survival (PFS) of only 6.9 months, median overall survival (OS) of 14.6 months, and a 5-year survival rate of 9.8%. The low PFS is also reflected in the fact that less than 50% of patients completed the six cycles of adjuvant temozolomide in the EORTC–NCIC trial.

Notwithstanding intense preclinical research and clinical trials, standard therapy has not changed over the past decade. New agents with promising results in Phase 1 and/or Phase 2 trials, for example, the Vascular Endothelial Growth Factor-A (VEGF-A) Inhibitor bevacizumab or the integrin inhibitor Cilengitide, failed to improve survival in randomized phase 3 trials (3, 4). Moreover, in an effort to optimize the current chemotherapy, a dose-dense schedule of adjuvant temozolomide did not lead to improved survival (5). Recurrence, regrowth of tumor after a period of complete remission or stable disease, is universal. Unlike the well-defined treatment schedule in the newly diagnosed setting, no standard therapy exists for recurrent GBM. Treatment options in the recurrent setting include reoperation, re-irradiation, rechallenge temozolomide, or nitrosourea chemotherapy (e.g., lomustin [CCNU]), bevacizumab, or combinations of therapies (6). Given the absence of SOC, inclusion in clinical trials is optional upon recurrence. Whichever therapy is given, prognosis at recurrence is grim, with median survival in recent years estimated to be about 9 months and only one-third of patients alive after 1 year (7). Eventually, GBM will recur and lead to progressive neurological deterioration and death. Preserving quality of life (QoL) for as long as possible, therefore, becomes a priority in this palliative oncological setting.

Radiological Diagnosis of a Recurrence in Clinical Practice

During follow-up of GBM patients, most oncologists will perform an MRI scan every 2–3 months, or earlier upon clinical deterioration (8). This regular MRI scan will detect many recurrences in the early phase, often in asymptomatic patients. However, interpretation of these follow-up MRI scans can be challenging in the context of possible appearance of contrast enhancement due to radionecrosis or pseudoprogression in patients treated with radiotherapy and chemotherapy. Pseudoprogression is thought to occur in up to 50% of patients during the first 3–6 months after radiotherapy, whereas radionecrosis can occur up to several years after treatment and does not spontaneously regress without treatment (9). As much as 15% of samples after reoperation showed only radionecrosis but no viable tumor in a series by Azoulay et al. (10). Moreover, bevacizumab, which is often used to treat recurrent GBM, compromises interpretation of follow-up MRIs as it normalizes leaky tumor vasculature and hence decreases T1 gadolinium enhancement and peritumoral edema (11, 12), sometimes resulting in only a pseudoresponse. To assess progressive disease, it is therefore recommended to use the recent Response Assessment in Neuro-Oncology (RANO) criteria that include evaluation of corticosteroid use, T2/FLAIR images, and restricted parameters to determine progressive disease during the first 3 months after radiochemotherapy, instead of the classical MacDonald criteria (13).

When there is a clear relapse or high suspicion of a (symptomatic) recurrence for which new treatment has to be initiated, a neurosurgeon should always be consulted to assess whether the patient is suitable for a repeat surgery. In general, it is estimated that only about 25% of patients can be considered for repeat surgery (6). Certainly, in the case in which clinical symptoms are due to mass effect, surgery remains the only treatment strategy that can drastically and rapidly decrease tumor load and possible symptoms. This can alleviate symptoms such as headache and (more rapidly) reduce the need for steroids to decrease peritumoral edema (14, 15). On the other hand a reoperation exposes patients to a risk of new temporary or permanent neurological deficits, general surgical and/or anesthesiological risks, and, at least temporarily, exclusion from other second-line treatments. Moreover, the oncological effect remains controversial (16).

Most recurrences appear locally in or close to the resection cavity of the first surgery (14). In a study by Brandes et al. on 79 patients with a recurrent GBM after initial treatment with standard therapy, almost 80% of recurrences occurred inside or at the margin of the radiotherapy field, where radiotherapy was administered at the contrast-enhancing mass with a margin of 2–3 cm (17). Rapp et al. reported on 97 recurrent GBM patients and found pure local recurrences in 79.3%, and combined local and distant recurrences in another 10.3% of patients (18). Obviously, diffuse, multifocal recurrences or deep infiltrative lesions are not surgical indications, contrary to a local well-circumscribed lesion. However, many patients will present with a local but poorly delineated lesion, for which a surgical indication cannot be advocated based on radiology alone.

Clinical Outcome after Surgery for Recurrent GBM

INHERENT SELECTION BIAS LEADS TO BETTER OUTCOME IN SURGICALLY TREATED RECURRENT PATIENTS

No randomized trials exist that randomize patients for surgery in the relapse setting, and most reported surgical series in recurrent GBM are retrospective (15). An overview of selected surgical outcome series is given in Table 1. Several authors have reported better outcome after surgery for recurrent GBM, compared to control nonsurgical populations. However, we have to take into account that these reports inherently suffer from selection bias, as patients who are selected for reoperation usually tend to be younger and have a better Karnofsky Performance Scale (KPS), and hence belong to a more favorable prognostic group (19). Azoulay et al. compared 68 reoperated patients with a matched cohort of nonsurgically treated recurrent GBM patients, based on initial extent of resection (EOR) and subventricular zone involvement (10). Median OS in the surgical subgroup was 9.6 months versus 5.3 months in the nonsurgical group, which was statistically significant. They concluded that reoperation, combined with additional rescue therapies, can induce prolonged survival in recurrent GBM. Chen et al. described 65 recurrent GBM patients, of whom 20 were reoperated. Median OS after recurrence in the surgical group was statistically higher with 13.5 months versus 5.8 months in the nonsurgical group (20). However, KPS at recurrence was also significantly higher in the surgical group, and 77.8% of the nonsurgical group received only palliative therapy. Tully et al. described 204 GBM patients of whom 24% were reoperated at recurrence, and they found a significantly improved survival of 20.1 months in reoperated patients compared to 9.0 months in recurrent patients who were treated nonsurgically (21). In their series, reoperated patients were younger, had a smaller initial tumor diameter, and were more likely to have an initial EOR of ≥50% at first resection. Moreover, reoperated patients had a significantly higher percentage of completion of adjuvant therapy (79.6% vs. 35.9%). To compensate for this selection bias, patients that were a priori unlikely to be selected for reoperation based on age or performance scale were excluded in a subgroup analysis. A much less significant, though still present, advantage for the surgical group was found at first recurrence, but not anymore at second recurrence. Moreover, reoperation was no longer an independent predictor of OS in a multivariate analysis. The authors suggested that the improved OS in the surgical group might be more of a reflection of favorable patient characteristics than surgery itself. Chaichana et al. showed a survival benefit resulting from repeat resections using a multivariate analysis and case control evaluation to correct for selection bias (22). In their series, median survival was 6.8 months for patients that had one resection versus 26.6 months for patients that underwent four resections. Very often, a more favorable course of disease and pattern of recurrence render these patients eligible for reoperation rather than vice versa (Figure 1).

TABLE 1

Selected Surgical Series Reporting Outcomes after Reoperation for Recurrent GBM.

Figure 1

A 57-year-old lady was diagnosed with a left occipital glioblastoma (A), for which a total resection was performed (B). She was treated with standard radiotherapy, temozolomide chemotherapy, and experimental dendritic cell vaccination. An asymptomatic (more...)

On the other hand several authors did not find a survival advantage for surgery. Franceschi et al. reported outcomes of a retrospective study on 232 recurrent GBM patients of whom 102 were treated with reoperation and chemotherapy, and compared these patients with 130 recurrent patients who were treated only with chemotherapy. They did not find a survival advantage in the reoperation group (23). In a large prospective registry database, including >1000 patients treated from 1997 to 2010, Nava et al. did not find better survival after recurrence in patients that underwent a reoperation. However, this study did not provide data on patient stratification at recurrence or EOR (7).

Extent of Resection in the Recurrent Glioblastoma

Surgical Risks and Complications at Reoperation

In 1987, Ammirati et al. reported an early mortality rate of 1.4% and surgical morbidity of 16% per procedure. In their series on reoperated malignant glioma patients, they found that 46% of patients improved on performance scale after surgery but also found worsening in 25% of patients. Harsh et al. had a 5.1% mortality and 7.7% morbidity (25). Sipos and Afra found a 3.4% mortality rate in 60 reoperated GBM patients (40). In their series, patients with a lower preoperative KPs were more likely to deteriorate postoperatively. In a series of 20 reoperated GBM patients, Mandl et al. found a mortality of 15%, and permanent neurological morbidity of 15% (41). Moreover, 40% of patients had a worse KPS postoperatively. More recently, in a series of 503 reoperated patients, Ringel et al. found a nonneurological complication rate of 7.4% (30). New neurological deficits appeared in 16.8% of patients, of which 9.2% were transient and 7.6% were permanent. The authors concluded that complications in reoperations are higher than in primary surgery, but the increase is rather small, and the overall complication rate stayed fairly small. D’Amico et al. published a retrospective study of 28 patients aged ≥65 years operated for recurrent GBM (31). In their study, no postoperative mortality was seen after reoperation, and the overall complication rate in reoperated patients was 17.9% at first surgery and 25.8% at reoperation. This difference was not statistically significant, and the authors concluded that age itself should not exclude patients from repeat surgeries. In summary, combined mortality and morbidity rates of repeat surgery can be estimated to be around 12–30%. This should always be taken into account, as the goal of surgery in recurrent GBM is essentially prolonging survival with good QoL.

Beyond Cytoreduction: Additional Benefits of Surgery

Conclusion

No prospective randomized trials directly evaluating the effect of reoperation for recurrent GBM have been published, and almost all available outcome data in surgical series are blurred by the inherent selection bias of patients with a high performance score and local recurrences. However, literature provides some evidence for an oncological advantage when a high EOR (or a CRET) can be obtained. This judgment needs to be made by a multidisciplinary oncological team with oncological neurosurgeons. Besides a cytoreductive effect, surgery can have an important role in obtaining tissue. Given the future expected importance of subclassification of glioblastoma and/or detection of specific druggable mutations, surgery probably will remain an important treatment strategy in the recurrent setting.

Conflict of interest: Dr. S. De Vleeschouwer organizes Gliolan (5-ALA) training sessions for neurosurgeons, for which a fee is received from Medac GmbH.

Copyright and permission statement: To the best of our knowledge, the materials included in this chapter do not violate copyright laws. All original sources have been appropriately acknowledged and/or referenced. Where relevant, appropriate permissions have been obtained from the original copyright holder(s).

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Doi: http://dx​.doi.org/10​.15586/codon.glioblastoma.2017.ch14