The role of reoperation for glioblastoma multiforme (GBM) recurrence is currently unknown. However, multiple studies have indicated that survival and quality of life are improved with a repeat operation at the time of disease recurrence. Prognosis is likely interdependent on several factors, including age, functional status, initial resection status, disease location, and surgical efficacy. However, there are significant data indicating no survival benefit for reoperation 1).
Patients with suspected recurrent glioblastoma (GBM) have undergone cranial radiotherapy and likely systemic chemotherapy, both of which suppress immune system functioning 2) and increase the chances of wound dehiscence and consequent infection. Patients with known GBM also are imaged frequently and many recurrences are radiographic in nature only, without obvious mass effect or clinical progression; surgical resection may not be needed as often to relieve symptoms related to mass effect, as is the case for surgery in the newly diagnosed GBM setting. With the demonstrably increased risk associated with surgery in the recurrent setting, we owe it to our patients, and to ourselves, to fully evaluate whether tumor debulking carries a meaningful clinical benefit 3).
Higher level evidence is required before re-operation of recurrent glioblastoma can be recommended as standard treatment for defined patient and tumour criteria.
Repeat surgery is not recommended for patients with the involvement of critical structures. Controversial practice sustains with implantation of biodegradable chemotherapy wafers containing carmustine. 5).
Nieder et al. found that median survival on re-resection ranged from 14 to 50 weeks, though the role of re-resection by itself remains unclear because most patients receive postoperative chemoradiotherapy. 6)
Current indications for reoperation include new focal neurological deficits, tumor mass effect resulting in signs and symptoms of increased intracranial pressure, increased seizure frequency, and radiographic evidence of tumor progression with or without accompanying changes in clinical status. Existing evidence indicates that age should not be an absolute contraindication to reoperation. A time interval of at least 6 months between operations and favorable performance status (KPS score >70) are predictors of improved survival after reoperation. Extent of resection (EOR) at reoperation appears to be an important determinant of improved survival, even in patients with subtotal resection (STR) at the time of initial operation. Although fraught with patient selection bias, mounting evidence suggests a survival benefit in patients receiving gross total resection (GTR) at recurrence compared with a lesser degree of resection. Additional reoperations beyond the first reoperation may add to overall survival and should be considered in patients with a favorable KPS score at the time of recurrence, regardless of symptomatology 7)
Repeat cytoreductive surgery is recommended in symptomatic patients with locally recurrent or progressive malignant glioma. The median survival in these patient diagnosed with glioblastoma is expected to range from 6 to 17 months following a second procedure. It is recommended that the following preoperative factors be considered when evaluating a patient for repeat operation: location of recurrence in eloquent/critical brain regions, Karnofsky Performance Status and tumor volume. 8).
DIRECTOR trial. This prospective randomized multicenter study evaluated the effect of 2 different dose-intensified temozolomide regimens at first recurrence of glioblastoma.
They analyzed prospectively collected clinical, molecular, and imaging data from the DIRECTOR cohort (n = 105). Imaging data were available from 87 patients. Volumetric analysis was performed based on gadolinium (Gd) enhancement on magnetic resonance imaging and correlated with progression-free survival (PFS) and overall survival (OS). Proportional hazards models were applied to obtain prognostic factors.
Seventy-one of 105 patients received surgery at recurrence. Prognostic factors such as age (P = .358), O-methylguanine-DNA methyltransferase (MGMT) promoter methylation (P = .965), IDH-1 mutation (P = .724), Karnofsky performance score (P = .880), or steroid intake before randomization (P = .950 were balanced between patients with and without reoperation. Mean tumor volumes at study entry were smaller in patients who had received surgery than in patients without (3.0 cm [range 0-37] vs 6.8 cm [range 1-23], P < .001). The outcomes in patients with/without surgery at recurrence were similar for PFS (2.0 months vs 1.9 months, P = .1974) and OS (9.2 months vs 9.4 months, P = .9538). Among patients who underwent reoperation, postsurgery imaging was available in 59 cases. In these patients, complete resection of Gd-enhancing tumor (n = 39) vs residual detection of Gd enhancement (n = 20) was associated with significantly improved OS (11.5 months [95% CI 9.3-15.1] vs 6.7 months [95% CI 5.2-9.5], P = .006).
Surgery at first recurrence of glioblastoma seems to improve outcome if complete resection of Gd-enhancing tumor volume is feasible 9).
In a cohort of 204 patients with de novo glioblastoma, 49 (24%) received reoperation at recurrence. The median overall survival in the reoperation group was 20.1 months compared with 9.0 months in the nonreoperation group (P = .001). Reoperation was associated with longer overall survival in our total population (hazard ratio, 0.646; 95% confidence interval, 0.543-0.922; P = .016) but subject to selection bias. Subgroup analyses excluding patients unlikely to be considered for reoperation suggested a much less significant effect of reoperation on survival, which warrants further study with larger cohorts. Factors at initial surgery predictive for reoperation were younger age, smaller tumor size, initial extent of resection ≥50%, shorter inpatient stay, and maximal initial adjuvant therapy. When unfavorable patient characteristics are excluded, reoperation is not an independent predictor of survival.
Patients undergoing reoperation have favorable prognostic characteristics, which may be responsible for the survival difference observed. We recommend that a large clinical registry be developed to better aid consistent and homogenous data collection 10).
Consecutive adult patients operated on for de novo GB at a single institution from 2006 to 2011 were reviewed. Clinical, radiographic and molecular data of 141 patients diagnosed of recurrent disease were assessed. Reasons for recurrence therapy and therapy modalities were reviewed. Univariate analysis was used to analyze differences in parameters of patients operated on at recurrence and those not. Impact of re-operation on survival was evaluated by the Kaplan-Meier method and Log-rank test.
53 (38%) patients were selected for repeat surgery upon recurrent disease, this was followed by either chemotherapy (CT) (40%), radiotherapy (8%) or both (49%). 57 (40%) patients received CT alone, which was the most frequent mono-second-line therapy opted for. Most frequent indications for repeat-surgery were maximum possible tumor resection mass reduction and symptom relief (62% and 21%, respectively). Univariate analysis of re-operated vs. not operated patients, showed significant differences for age (p=0.0001*) and Karnofsky Performance status (KPS) >70 at both primary and repeat tumor resection (p=0.013* and 0.0001*, respectively). The operated group had a significantly lower Charlson-comorbidity-index≤3 (p=0.004*) and larger tumor size (p=0.0001*). Complication risk at recurrence was not significantly different between groups (p=0.069). However, patients chosen for repeat surgery had significantly less complications at index surgery (p=0.006*). Median time from recurrence to death was 11 months (range, 1-33 months) for operated patients as opposed to 5 months (range, 0-22 months) for not operated patients. The former survived significantly longer; 19 months compared to 13 months for those not operated upon (p=0.002*).
The study depicts that patients eligible for repeat-surgery at GB recurrence are characterized by a KPS>70% before primary and repeat-surgery, Charlson-comorbidity-index≤3, large tumor size and young age. These well-selected patients survive significantly longer after repeat-surgery without being at a higher complication risk in comparison to patients not operated upon 11).
Sughrue et al. present outcomes in 104 patients undergoing repeat surgery for focally recurrent glioblastoma with at least 95% resection and adjuvant treatment at most recent prior surgery. In addition to common variables, they provide data regarding the period of progression free survival (PFS) following an aggressive lesionectomy for focally recurrent primary glioblastoma (T2) and the time the tumor took to recur since the previous surgery (T1). They term the ratio T1/T2 the relative aggressivity index (RAI).
The median PFS was 7.8 months, 6.0 months, and 4.8 months following the second, third, and fourth-sixth craniotomies, respectively. Importantly, there was a wide range of outcomes, with time to postoperative recurrence ranging from 1 to 24 months in this group. Analysis showed no meaningful relationship between T1 and T2, meaning that previous PFS is entirely unable to predict the PFS that another surgery will provide the patient.
Repeat surgery for glioblastoma is beneficial in many cases, however this is hard to predict preoperatively. Often, surgery can provide the patient with a good period of disease freedom, but this is variable and in general it is not possible to reliably predict who these patients are 12).
In a multicenter retrospective-design study, patients with primary glioblastomas undergoing repeat resections for recurrent tumors were evaluated for factors affecting survival. Age, Karnofsky performance status (KPS), extent of resection (EOR), tumor location, and complications were assessed.
Five hundred and three patients (initially diagnosed between 2006 and 2010) undergoing resections for recurrent glioblastoma at 20 institutions were included in the study. The patients' median overall survival after initial diagnosis was 25.0 months and 11.9 months after first re-resection. The following parameters were found to influence survival significantly after first re-resection: preoperative and postoperative KPS, EOR of first re-resection, and chemotherapy after first re-resection. The rate of permanent new deficits after first re-resection was 8%.
The present study supports the view that surgical resections of recurrent glioblastomas may help to prolong patient survival at an acceptable complication rate 13).
Forty patients were included in a study. Median age was 58 years and median KPS score was 80. Average tumor volume was 5.5 cm(3). A radiologically confirmed complete resection was achieved in 29 patients (72.5 %). Median follow-up was 18.8 months, and median survival after re-resection was 13.5 months. Only complete removal of contrast enhancing tumor was significantly correlated with survival after re-resection according to multivariate analysis. There was a statistical trend for KPS score influencing survival. In contrast, time between first diagnosis and tumor-recurrence, tumor volume at recurrence, MGMT status and MSM score were not significantly correlated with survival after second surgery. In the event of tumor recurrence, patients in good clinical condition with recurrent GBM amenable to complete resection should thus not be withheld second surgery as a treatment option 14).
170 consecutive patients with recurrent supratentorial glioblastomas treated at the Barrow Neurological Institute from 2001 to 2011. All patients previously had a de novo glioblastoma and following their initial resection received standard temozolomide and fractionated radiotherapy.
The mean clinical follow-up was 22.6 months and no patient was lost to follow-up. At the time of recurrence, the median preoperative tumor volume was 26.1 cm(3). Following re-resection, median postoperative tumor volume was 3.1 cm(3), equating to an 87.4% extent of resection (EOR). The median overall survival was 19.0 months, with a median progression-free survival following re-resection of 5.2 months. Using Cox proportional hazards analysis, the variables of age, Karnofsky Performance Scale (KPS) score, and EOR were predictive of survival following repeat resection (p = 0.0001). Interestingly, a significant survival advantage was noted with as little as 80% EOR. Recursive partitioning analysis validated these findings and provided additional risk stratification at the highest levels of EOR. Overall, at 7 days after surgery, a deterioration in the NIH stroke scale score by 1 point or more was observed in 39.1% of patients with EOR ≥ 80% as compared with 16.7% for those with EOR < 80% (p = 0.0049). This disparity in neurological morbidity, however, did not endure beyond 30 days postoperatively (p = 0.1279).
For recurrent glioblastomas, an improvement in overall survival can be attained beyond an 80% EOR. This survival benefit must be balanced against the risk of neurological morbidity, which does increase with more aggressive cytoreduction, but only in the early postoperative period. Interestingly, this putative EOR threshold closely approximates that reported for newly diagnosed glioblastomas, suggesting that for a subset of patients, the survival benefit of microsurgical resection does not diminish despite biological progression 15).
Multiple resections were performed in 107 patients. Fifty-two patients had initial GTR, of whom 31 (60%) had GTR at recurrence, with a median survival of 20.4 months (standard error [SE] 1.0 months), and 21 (40%) had STR at recurrence, with a median survival of 18.4 months (SE 0.5 months) (difference not statistically significant). Initial STR was performed in 55 patients, of whom 26 (47%) had GTR at recurrence, with a median survival of 19.0 months (SE 1.2 months), and 29 (53%) had STR, with a median survival of 15.9 months (SE 1.2 months) (p = 0.004). A Cox proportional hazards model was constructed demonstrating that age (HR 1.03, p = 0.004), KPS score at recurrence (HR 2.4, p = 0.02), and EOR at repeat resection (HR 0.62, p = 0.02) were independent predictors of survival. Extent of initial resection was not a statistically significant factor (p = 0.13) when repeat EOR was included in the model, suggesting that GTR at second craniotomy could overcome the effect of an initial STR. CONCLUSIONS: Extent of resection at recurrence is an important predictor of overall survival. If GTR is achieved at recurrence, overall survival is maximized regardless of initial EOR, suggesting that patients with initial STR may benefit from surgery with a GTR at recurrence 16).
Forty-six patients underwent second resections during the study period. The actuarial rate of the second resections was 15% of the patients 1 year after diagnosis and 31% 2 years after diagnosis. Younger age (P = 0.01) and more extensive initial resection (P = 0.02), but not Karnofsky Performance Scale (KPS) score at the time of diagnosis or recurrence, predicted a higher chance of selection for reoperation after initial tumor recurrence. Twenty-eight percent of the patients had improved KPS scores after undergoing reoperation, 49% were stable, and 23% had declines in KPS scores of 10 to 30 points. There was no operative mortality. After reoperation, 85% of the patients received chemotherapy, 11% received brachytherapy or underwent stereotactic radiosurgery, and 17% underwent third resections. The median survival period after reoperation was 36 weeks. Higher preoperative KPS scores predicted longer survival periods after reoperation (P = 0.03). Age and interval since diagnosis were not significant prognostic factors. The median high-quality survival period (KPS score, > or =70) was 18 weeks. The median survival period after first tumor progression was 23 weeks for 130 patients treated using the same protocols who did not undergo reoperations. Patients who did undergo reoperations experienced clinically and statistically significantly longer survival periods. However, this was determined to be partially because of selection bias.
Survival after resection of recurrent GM remains poor despite advances in imaging, operative technique, and adjuvant therapies. High-quality survival after resection of recurrence to treat GM seems to have increased significantly since an earlier report from our institution 17)
Brem et al. conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas 18).
The results of a second operation for tumor removal in 24 adult patients with supratentorial glioblastoma multiforme or anaplastic astrocytoma were analyzed. The median survival time after reoperation was 14 weeks. Five of the 24 patients lived 6 months or longer after reoperation. Only three of these patients maintained a Karnofsky rating (KR) of at least 60 for 6 months or longer after reoperation. Preoperative neurological status (KR) is the most significant determinant of survival after reoperation (p = 0.02). When the KR is at least 60, median survival after reoperation is 22 weeks. When the KR prior to reoperation is less than 60, median survival is 9 weeks. Only one of 13 patients with a KR of less than 60 prior to reoperation survived longer than 6 months after the second operation. The interval between first and second operation is significantly related to survival (p = 0.03), but when adjustment is made for the KR the interoperative interval is no longer significantly related to survival after the second operation (p = 0.39). Age, sex, and location of tumor were not significantly related to duration of survival. This study suggests that reoperation is most likely to produce the best result when the KR is at least 60 and the interval between operations is longer than 6 months. Using these criteria, one-third of the patients could be expected to survive with a KR of at least 60 for 6 months. The study indicates that reoperation should not be carried out when the KR is less than 60 19).