|NEURO ONCOLOGY: REVIEW ARTICLE
|Year : 2015 | Volume
| Issue : 4 | Page : 163-173
Recurrent Glioblastoma: Where we stand
Sanjoy Roy, Debarshi Lahiri, Tapas Maji, Jaydip Biswas
Department of Radiotherapy, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India
|Date of Web Publication||8-Feb-2016|
Department of Radiotherapy, Chittaranjan National Cancer Institute, Kolkata, West Bengal
Source of Support: Phase II and III rct/non rct study; PubMed; 2004-2011., Conflict of Interest: None
Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy.
Keywords: Chemotherapy, glioblastoma multiforme, glioma, targeted therapy, temozolomide
|How to cite this article:|
Roy S, Lahiri D, Maji T, Biswas J. Recurrent Glioblastoma: Where we stand. South Asian J Cancer 2015;4:163-73
| Introduction|| |
Glioblastoma multiforme (GBM) is one of the most aggressive primary brain tumors, with a grim prognosis despite maximal treatment. Advancements in the past decades have not significantly increased the overall survival of patients with this disease. The recurrence of GBM is inevitable, its management often unclear and case dependent. In this report, the authors summarize the current literature regarding the natural history, surveillance algorithms, and treatment options of recurrent GBM. In addition, they provide brief discussions regarding current novel efforts in basic and clinical research. They conclude that although recurrent GBM remains a fatal disease, the literature suggests that a subset of patients may benefit from maximal treatment efforts.
Glioblastoma multiforme is a World Health Organization Grade IV tumor that represents 15-20% of all primary intracranial tumors.  It is the most malignant astrocytic tumor, with histopathological features that include cellular polymorphism, brisk mitotic activity, microvascular proliferation, and necrosis. The current standard of care for patients with newly diagnosed glioblastoma was established in 2005, following the pivotal trial by the European Organization for the Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group, in which concurrent temozolomide (TMZ) (75 mg/m 2 /d for ≤7 weeks) and radiotherapy followed by 6 maintenance cycles of adjuvant chemotherapy (150-200 mg/m 2 on 5-d therapy every 28 d) improved progression-free survival (PFS) and OS. 
Despite advances in imaging techniques and multi-modal treatment options, the overall prognosis of patients with GBM remains grim. The median duration of patient survival is estimated to be between 12 and 18 months with maximal treatment, but those without any intervention die soon after diagnosis. , So far, very few cases of curative outcome or long-term survival have been reported. ,, In a large retrospective study, Scott et al.,  estimated that 2.2% of the cohort survived for >2 years. Overall, the 5-year survival rate is <10%, with a final mortality rate of close to 100%. ,
Glioblastoma has an unfavorable prognosis mainly due to its high propensity for tumor recurrence. It has been suggested that GBM recurrence is inevitable after a median survival time of 32-36 weeks. , The natural history of recurrent GBM, however, is largely undefined for the following reasons: (1) Lack of uniform definition and criteria for tumor recurrence; (2) institutional variability in treatment philosophy; and (3) the heterogeneous nature of the disease, including location of recurrence and distinct mechanisms believed to contribute to known subtypes of GBM.
The criteria used to define recurrent GBM remain ambiguous due to the varied presentation of new lesions. First, the infiltrative nature of GBM cells makes it difficult to eliminate microscopic disease despite macroscopic gross-total resection. Studies have shown that GBM recurrence most often occurs in the form of a local continuous growth within 2-3 cm from the border of the original lesion. ,, Choucair et al.,  reported that more than 90% of patients with glioma showed recurrence at the original tumor location and that multiple lesions developed in 5% after treatment. Second, although less common, GBM may also recur through the development of new parenchymal lesions that fail to exhibit continuous growth patterns, intraventricular spread, or dissemination.  Baumann et al.,  have shown that uncommon relapse patterns are more prevalent in midline tumors and tumors that infiltrate both hemispheres. Finally, in an attempt to preserve neurological function and maintain patient QOL, subtotal resections are sometimes performed when tumors infiltrate eloquent areas of the brain. Tumor recurrence is also defined by the appearance of residual tumor growth on imaging studies or the manifestation of new clinical symptoms. The term "tumor recurrence" is frequently used synonymously with "tumor progression" because of the spectrum from which new lesions can develop.
| Diagnosis of Progression|| |
Serial neuroimaging remains the primary monitoring tool for glioblastoma. Standard magnetic resonance imaging (MRI) contrast studies though beneficial for monitoring, may be misleading and confounding the recurrence even strictly adhered to Mcdonald criteria  in first couple of months it becomes difficult to differentiate recurrence from pseudoprogression using T2-weighted, T1-weighted gadolinium, fluid-attenuated inversion-recovery (FLAIR)  sequence of MRI. Pseudo progression is featured in 20-30% patient treated with concurrent radiation cum TMZ followed by adjuvant TMZ. , Radionecrosis also appears earlier in patients received chemoradiation than radiotherapy alone.  Both pseudoprogression and radionecrosis are likely related to increased tumor cell killing or enhanced host normal tissue reaction. Nonetheless, the recurrence of this type of tumor is purely local. , It is thus advocated to do reimaging in case of suspected pseudoprogression with no rapid change in treatment with no or minimal new symptoms. The first scan after radio chemotherapy should be considered as a new baseline for all further imaging assessment.
A complete resolution of blood brain disturbance detected by contrast extravasation on MRI or computed tomography will no longer qualify as a response if there is increased T2-weighted or FLAIR abnormality and such responses are now termed as "pseudoresponses." The new Response Assessment in Neuro-Oncology (RANO) criteria integrates a qualitative measure for T2-weighted/FLAIR changes and appears to be an improvement over Mcdonald criteria to interpret the outcome. These criteria are likely to be more valuable in daily practice and clinical trial set up with further validation [Table 1].
| Role of Repeat Surgery and Radiotherapy|| |
A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80%. , Repeat surgery is not recommended for patients with the involvement of critical structures. Controversial practice sustains with implantation of biodegradable chemotherapy wafers containing carmustine.  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.
Reirradiation remains a palliative option for few patients. Patients with KPS more than 60%, tumor size up to 40 mm and progression more than 6 months of the time of surgery appear to be the best candidates.  The most common approach could be precision radiotherapy with a total median dose 30-36 Gy.  Median survival after various methods of re-irradiation was 26-30 weeks. In a recent review of more than 300 patients, palliative re-irradiation achieved PFS6 of 28-39% and 1-year survival of 18-48%, which compares favorably with systemic targeted therapy for recurrent GBM. ,,,
Hypofractionated stereotactic radiotherapy is able to deliver treatment over a short course of time, using daily fraction of 3.5 Gy with a median dose of 35 Gy investigators achieved a median survival time of 11 months comparable with other systemic agents in a retrospective study of 147 patients from 1994 to 2008.  An analysis of 20 patients with recurrent GBM was designed to test the safety and efficacy of hypofractionated radiotherapy in combination with bevacizumab treatment.  The PFS6 was 65% with GBM patients, and median OS was 12.5 months, this result suggests that this combination may be further evaluated in the treatment of both newly diagnosed and recurrent glioblastoma.
A recent retrospective review analyzed 26 consecutive patients who underwent gamma knife radiosurgery for small recurrent high-grade glioma after radical resection, external-beam radiation therapy, TMZ between 2004 and 2009. Median OS was 12.9 months,  which was comparable to prospective cohort of 114 patients published by Kong et al. 
The most likely reason why radiotherapy is unable to control long-term disease is the inability to detect the spread pattern of GBM.  An area of significant interest is the use of systemic radiosensitizers that may enhance the effect of local radiation as well as exert cytotoxic activity on distal cell population. 
| Monotherapy and Combination Chemotherapeutic Trials for Recurrent Disease|| |
The objective of the analysis was to identify clinical efficacy trials following systemic treatment with nitrosoureas, TMZ, bevacizumab, and/or combinations of these agents in patients with recurrent or progressive glioblastoma. This report is a systematic review that used PubMed and American Society of Clinical Oncology abstract reports from 2006 to 2013 as the primary sources of data.
| Nitrosoureas - Single and Combination Therapy|| |
Two phase II trials , and 1 retrospective series  evaluated a similar carmustine monotherapy regimen for recurrent/progressive disease in 104 patients, some of whom had received prior TMZ therapy. For 2 studies, PFS6 and median OS ranged 13.0-17.5% and 5.1-7.5 months, respectively; no complete remissions were observed. , Efficacy end points for the one study were unevaluable (data not presented separately for carmustine).  The predominant side effects following carmustine monotherapy were hematologic and long-lasting hepatic and pulmonary toxicity [Table 2].
A recent prospective phase III trial in 92 lomustine treated patients (70 at first relapse) reported a 19% PFS6 response rate, with a median OS of 7.1 months.  In a double-blind, randomized, multicenter phase III trial of 325 patients who received prior radiation and TMZ, the lomustine monotherapy arm (n ¼ 65) provided PFS6 and median OS of 24.5% and 9.8 months. ,
Fotemustine is another nitrosourea compound, studied mostly in Europe, notably in Italy and France.  Four prospective phase II trials, using slightly different induction/maintenance dosage regimens, evaluated fotemustine in TMZ-pretreated patients with recurrent or progressive glioblastoma. ,,, Two studies were exclusively in patients experiencing their first relapse. , Overall, PFS6 and median OS ranged 20.9-61% and 6.0-11.1 months, respectively. Grades 3 and 4 hematologic toxicities were commonly reported following fotemustine therapy; however, lower rates were observed. 
Significant hematologic-toxicity concerns and the availability of more effective agents have made the use of nitrosoureas overall less desirable. New schedules at lower doses may prove beneficial. The nitrosoureas seem comparable in terms of efficacy at clinically tolerated doses, whereas nonhematologic toxicity, notably lung fibrosis, may be more common with carmustine than with lomustine or nimustine.
| Temozolomide Monotherapy Rechallenge|| |
Six studies of TMZ-pretreated patients evaluated TMZ rechallenge. ,,,,, A variety of metronomic schedules were employed, including 40-100 mg/m 2 daily doses given for 21-365 consecutive days, as well as alternating 1-week-on/1-week-off regimens. Overall, PFS6 and median OS ranged 23-58.3% and 5.1-13 months, respectively. One retrospective analysis compiled data on 5 different TMZ dosing regimens among 47 patients (re) challenged while receiving adjuvant TMZ or after a TMZ-free interval.  [Table 3] PFS6 is 26.3-28.6% for patients progressing on TMZ versus after TMZ; corresponding median OS is 6.6 and 5.3 months, respectively.
|Table 3: TMZ monotherapy trials in recurrent or progressive glioblastoma|
Click here to view
Of importance in recurrent GBM treatment consideration is the expression of the O6-methylguanine-DNA methyltransferase (MGMT) promoter, which confers resistance to TMZ. , The large multi-center phase II Canadian (RESCUE) study use a continuous dose intense TMZ regimen of 50 mg/m 2 /day  in patients who had previous exposure to TMZ. This dosing represented dose intensification from 750 to 1000 mg/m 2 /28 days cycle with conventional dosing to 1400 mg/m 2 /28 days cycle. The overall PFS6 for patients with GBM was 23.9%, and median survival was 9.3 months. The most significant benefit was shown in patients who had completed a previous course of concomitant TMZ/radiotherapy with adjuvant TMZ followed by a draft free period of at least 2 months (PFS6 35.7%). The patients who progressed while still on extended adjuvant TMZ therapy beyond 6 cycles did significantly worse (PFS6 7.4%), but who progressed before completing 6 cycles of adjuvant TMZ had better response (PFS6 27.3%). The investigators hypothesized that a continuous regimen might lead to a depletion of MGMT and restoration of TMZ (Temozolomide) sensitivity as had been previously reported.  In addition, the median time from the end of radiotherapy in this early group was 5.2 months, thus minimizing the influence of pseudoprogression on these results.
Three randomized clinical trials were conducted using single-agent TMZ. ,, In one study, a standard TMZ regimen was more efficacious than procarbazine (PFS6 ¼ 21% vs. 8%), with a median survival time 1.5 months longer.  The latter study was conducted in TMZ-naive patients and led to the approval of TMZ in Europe for recurrent glioblastoma, although it is still not approved in the United States. The BR12 study did not provide separate data for glioblastoma patients but indicated that TMZ dose-intense regimens do not provide a survival or PFS benefit compared with standard doses in the treatment of TMZ-naive patients. The DIRECTOR trial evaluated 2 dose-intense regimens of TMZ (120 mg/m 2 /d 1-week on/1-week off vs. 80 mg/m 2 /d 3 weeks on/1-week off) in patients experiencing a first relapse after at least 2 cycles of TMZ.  Specifically, patients were enrolled based on the first progression of glioblastoma documented by MRI no earlier than 180 days after the first surgery and no earlier than 90 days after completion of radiotherapy.
| Bevacizumab Monotherapy Trials|| |
Bevacizumab is a human recombinant monoclonal antibody to vascular endothelial growth factor (VEGF), was approved in 2009 by the Food and Drug Administration in the United States for the treatment of recurrent glioblastoma based on response rate; , but not in the European Union. The rejection in Europe was based on the absence of a randomized trial with a bevacizumab-free control arm. In a phase II trial of 35 patients with GBM, Vredenburgh et al.  found PFS6 with Bivacizumab + Irinotecan was 46%, and OS6 was 77%. In another phaseII trial, evaluating the role of Bivacizumab alone or in combination with Irinotecan, the PFS6 was 42.6% and 50.3%, respectively.  Secondary end points showed OS of 9.2 months with single agent Bivacizumab and 8.7 months for those treated with combination with Irinotecan. The study did show a trend for decreasing steroid dose in patients on therapy.
A recent meta-analysis comprising fifteen studies published between 2005 and 2009,  on recurrent GBM showed median OS, PFS6 and OS6 were 9.3 months, 45%, and 76% respectively. The analysis found no difference in Bivacizumab dose response benefit between 5, 10 and 15 mg/kg. A retrospective study of 161 patients with recurrent GBM treated with Bivacizumab found an incidence of 1.9% and 1.9% for ischemic stroke and intracranial bleeding respectively.  Prolonged anti angiogenic therapy may produce ischemic stroke whereas intratumoral bleed may be caused from tumor progression. Despite its efficacy in recurrent GBM, patients inevitably relapse and patients progressing on one Bivacizumab containing regime respond poorly on alternative Bivacizumab containing regime. 
Meanwhile, data from 2 large randomized trials, AVAglio and Radiation Therapy Oncology Group 0825, adding Bevacizumab to TMZ chemoirradiation, are likely to shape the future standards of care both at diagnosis and at recurrence.
| Other Anti-angiogenic Agents|| |
The VEGF receptor (VEGFR) inhibitor cediranib was explored in patients with recurrent glioblastoma in a very sophisticated fashion using advanced neuroimaging and biomarker studies. , PFS6 of 31 patients with recurrent glioblastoma treated with cediranib monotherapy at a starting dose of 45 mg/d was 25.8%. Response rates were 56.7% for three-dimensional measurements and 27% for two-dimensional measurements. Toxicities were moderate.
Aflibercept (VEGF trap) that inhibits both VEGF and placental growth factor, was administered to 42 patients with recurrent glioblastoma at first relapse.  Efficacy of VEGF trap as a single agent for recurrent disease was minimal, with PFS6 of 7.7%, although 2 patients had durable response (alive at 150 weeks). XL184, an inhibitor of MET, VEGFR2, and RET, was given p.o. (125 mg/d or 175 mg/d) to 124 patients with recurrent glioblastoma.  Overall, interim PFS6 for the 125-mg and 175-mg groups were 25% and 21%, respectively.  Cilengitide, an inhibitor of avb3 and avb5 integrin receptors, showed modest single-agent activity that is, PFS6 of 15% and median OS of 9.9 months, following a 2000-mg twice-daily continuous regimen among 40 patients with recurrent glioblastoma. 
Angiogenesis is also regulated by integrin-mediated signaling. Integrins, cell-surface adhesion molecules that are often overexpressed in gliomas, mediate cell adhesion, migration and invasion into the surrounding tissue. Agents that target integrins, such as EMD121974 (cilengitide), found to be active when combined with TMZ and RT in newly diagnosed GBM patients,  were evaluated as a single agent in a Phase IIa trial in patients with recurrent GBM; the toxicity profile was manageable, no cases of grade 4 toxicity occurred and the PFS-6 was 15%. 
| Temozolomide - Containing Combination|| |
During last decade, a number of studies have investigated the efficacy and safety of TMZ in combination with VEGF, Nitrosoureas, interferon, as well as plenty of other conventional chemotherapeutic agents for recurrent GBM. Desjardins et al.  evaluated the combination of protracted TMZ (50 mg/m 2 /d) and Bevacizumab (10 mg/kg intravenous [i.v.] every 2 weeks) in 32 TMZ pretreated patients who predominantly were experiencing a first or second recurrence (94%). A radiographic response was observed in 9/32 patients. PFS6 was 18.8% with a median OS of 8.7 months. MGMT status did not appear to be related to the outcome.
A protracted daily TMZ and sorafenib regimen had very limited activity, despite a good safety profile, in 32 patients with recurrent disease.  PFS6 was very low (9.4%). The poor results may be attributed to heavy pretreatment, higher failure rate to previous Bevacizumab therapy, lack of selection of patients with sorafenib target expression, and the relatively high use of CYP3Ainducing antiepileptic drugs that may have compromised sorafenib activity.
The combination of TMZ and afatinib (40 mg/d), an irreversible blocker of the epidermal growth factor receptor (EGFR), was investigated in a phase II study.  PFS6 was 10% for the combination compared with 3% for afatinib alone (P ¼.008) and 23% for TMZ alone (P ¼.59).
A retrospective study of 28 patients found that the combination of continuous low-dose TMZ (10 mg/m 2 b.i.d.) and celecoxib (200 mg/d) had some activity in treating recurrent glioblastoma without significant toxicity.  The majority of patients (86%) were being treated for their first recurrence. PFS6 was 43%. MGMT promoter methylation did not predict a favorable outcome.
Gaviani et al.  evaluated the combination of TMZ and fotemustine in 10 patients with recurrent disease following chemoradiation. The study was terminated early (planned enrollment of 105) because of severe hematologic toxicities.
Overall, the TMZ combination studies available to date do not suggest that one particular chemotherapy combination regimen is more effective than administration of TMZ alone.
| Bevacizumab-Containing Combination|| |
In theory, the combination of Irinotecan and Bevacizumab might improve efficacy owing to a synergy of antiangiogenic and cytostatic properties. Six studies in 357 evaluable patients, including 1 retrospective analysis, evaluated Bevacizumab in combination with irinotecan. ,,,,, Overall PFS6 was 30.0-50.3% with median OS of 6.1-9.7 months. Overall, no additional benefit of Irinotecan over Bevacizumab alone became apparent. The addition of cetuximab was relatively well tolerated, except for skin toxicity; however, overall efficacy did not appear to be enhanced with the addition of Cetuximab to the Bevacizumab + Irinotecan combination regimen.
Reardon et al.  evaluated the efficacy of Bevacizumab and Eoposide among 27 patients with primarily first recurrences. Complete and partial response was observed in 1 and 6 patients, respectively. PFS6 of 44.4% and median OS of 10.2 months were reported. Notably, high VEGF expression was associated with a better PFS.
Sathornsumetee et al.  evaluated bevacizumab in combination with erlotinib, an EGFR tyrosine kinase inhibitor. PFS6 and median OS were 29.2% and 10.3 months, respectively. Survival end points of patients treated more than 3 months postradiotherapy were similar to those of the overall population. In summary, this combination did not appear to provide improved survival benefits compared with historical bevacizumab-containing regimens.
| Targeted Therapies|| |
Recent advances in the understanding of molecular and cytogenetic pathways that influence tumor growth, invasion, angiogenesis, and apoptosis have led to the direct targeting of the aberrant pathways found in cancer. Treatments against specific molecular targets, in particular, the EGFR, have been investigated in brain tumor patients. EGFR amplification and overexpression, present in approximately 50% of GBM patients, are associated with a poor prognosis. In recent years, small-molecule inhibitors targeting tyrosine kinases, such as erlotinib and gefitinib have been widely evaluated in neuro-oncology.
In Phase II gefitinib trial on a series of 53 patients with recurrent GBM, no objective responses were found.  The PFS-6 (13%) was the same as in historical controls, with other agents considered inactive. In this trial, EGFR protein expression and gene status, and EGFRvIII protein expression were not significantly correlated with PFS-6 and survival, and gefitinib as a single agent was considered inactive in this setting. Haas-Kogan et al. observed that the response to erlotinib treatment was greater in GBM patients with high EGFR expression and low phospho-Akt levels than in those with low EGFR expression and high phospho-Akt levels. The authors found no correlation between EGFRvIII expression and response.  In their study on 49 GBM patients treated with erlotinib or gefitinib, Mellinghoff et al. found that EGFRvIII and PTEN protein co-expression was correlated with the response to treatment.  More recently, a large and well-conducted randomized Phase II study of the EORTC 26034 trial compared first-line erlotinib with either TMZ or BCNU as standard treatments  and found that results were disappointing when the EGFR inhibitor was given as a single agent for recurrent disease: PFS-6 was 12% in the erlotinib arm and 24% in the control arm. Furthermore, a Phase II trial of erlotinib in combination with carboplatin showed that the activity of this regimen was modest, with the PFS-6 being 14%. In addition, no correlation was observed between EGFR, Akt or PTEN expression, and PFS or OS.  Other targeted therapies have been investigated in the neuro-oncological setting [Table 2]. In addition, a small exploratory study on  F-fluorothymidine PET in malignant glioma patients treated with Bevacizumab and Irinotecan showed that metabolic response was predictive of OS while MRI radiological response showed only a trend, and that metabolic responders did not clearly correlate with PFS, confirming that classical neuroradiological imaging should not provide conclusive information about the activity of this regimen. 
A significant percentage of GBMs have PTEN gene suppression alterations, resulting in the increased activation of the downstream PI3K/Akt/mTOR pathway, which regulates cell survival and proliferation; the deregulation of this pathway is thought to play a role in tumor pathogenesis. Thus, another target for new compounds is mTOR, a serine/threonine kinase that acts as a central component of the PI3K/Akt signaling pathway that mediates cell growth and proliferation. Efforts to downregulate this pathway have been pursued through inhibitors of mTOR, such as rapamycin (sirolimus), RAD-001 (everolimus) and CCI-779 (temsirolimus). Two recently completed trials on temsirolimus in patients with recurrent GBM report a PFS-6 of 2.5 and 7.8%, respectively [Table 4].
|Table 4: Results of phase II trials of small molecule-targeted therapies|
Click here to view
Finally, imatinib mesylate, a small-molecule inhibitor of KIT, Bcr/Abl and PDGF receptor (PDGFR), has been evaluated in recurrent gliomas in a multicenter EORTC Phase II trial. In patients with recurrent GBM, PFS-6 was 16%, and overall PFS was not correlated with PDGFR-a single nucleotide polymorphisms. 
Another promising treatment modality lies in immunotherapy. Early-stage immunotherapeutic treatments can be divided into two major categories: Targeted toxin therapy and anticancer vaccinations.  These two mechanisms use separate aspects of human immune response to targeted toxins or T cells, which are directed toward tumoral remnants. Authors of one study examined the effects of lymphokine-activated killer-cell implantation on recurrent GBMs. Of 40 patients in whom recurrent GBM was diagnosed, a median survival of 9 months and a 1-year survival rate of 34% were achieved.  Techniques involving gene therapy are producing comparable results. In a small study in which the authors examined the effects of an intratumoral injection of retroviral vector-producing cells combined with i.v. ganciclovir, they noted a 1-year patient survival rate of 25% with tumor response in 50% of the cases.  The future role of immunotherapy and gene therapies will become clearer as more Phase I and II clinical trials are completed. However, current experimental applications may provide a case-specific increase in survival time.
| Standard of Care Recommendations for Recurrent Glioblastoma|| |
Appropriate management outside of clinical trials requires individualization based on patient age, performance status, histology, extent of initial resection, type of and response to initial therapy, time since diagnosis, and whether the recurrence is local or diffuse. Repeat surgery, reirradiation, and second-line mono or combination therapy are all directed primarily at reducing tumor burden and extension. All therapies aim to improve neurologic symptoms, such as headaches or seizures; reduce the need for certain medications or lower total daily doses, e.g., corticosteroids or antiepileptic drugs; and prevent thromboembolic complications.
Currently, limited evidence exists from randomized studies to explain the variable nature of the recurrent GBM and differences among institutional first-line treatment. Among patients determined to be favorable surgical candidates (those with high KPS scores, noneloquent location, and no medical contraindications), the addition of BCNU wafers appears to provide additional benefits. Regarding the administration of chemotherapy, either as the primary or an adjunctive therapy, the potential benefits appear to be independent of the number of agents used. Currently, TMZ is rapidly becoming the standard chemotherapy agent due to its ease of administration, minimal side-effect profile, and established improvement in survival rates.
Repeated resection should be considered in patients with high preoperative KPS scores or in those whose symptoms are secondary to mass effect from superficial noneloquent regions. The benefits of stereotactic radiosurgery and chemotherapy are similar and should be chosen based on their corresponding side-effect profiles. In general, improved outcomes are witnessed with combined radiotherapy and chemotherapy compared with each treatment alone.
Current trends indicate that the treatment of recurrent GBM will remain multimodal in nature. Further understanding of underlying tumor biology is essential in developing more effective strategies. Research in gene therapy, antiangiogenic antagonists, and immunotherapies holds great promise. With continual improvements in treatments and imaging techniques, it is the hope of clinicians, researchers, and patients that GBM may become a controllable disease with a favorable prognosis.
| Conclusions|| |
A plethora of monotherapy and combination chemotherapy strategies have been evaluated in patients with recurrent glioblastoma. Despite some minor improvements in PFS, no obvious increase in survival has been associated with any particular regimen. Future clinical trials that adopt the revised Macdonald criteria (RANO) may provide new clues as to which agent or combination is most beneficial. Despite definitive data, the standard of care guidance for managing patients with recurrent glioblastoma is evolving. However, the development of novel therapeutic options for patients with recurrent GBM remains a priority. The results to date for anti-angiogenic treatments appear promising but definitive results are needed. Other agents currently in clinical development for recurrent GBM include new molecular targeted therapies; whenever possible, patients should be given the opportunity to participate in experimental trials.
| Acknowledgment|| |
All the staff of Radiotherapy department, CNCI.
| References|| |
Apuzzo ML. Malignant Cerebral Glioma (Neurosurgical Topics, 2). Park Ridge, IL: American Association of Neurological Surgeons; 1990.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
Davis FG, Freels S, Grutsch J, Barlas S, Brem S. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: An analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991. J Neurosurg 1998;88:1-10.
McLendon RE, Halperin EC. Is the long-term survival of patients with intracranial glioblastoma multiforme overstated? Cancer 2003;98:1745-8.
Salvati M, Cervoni L, Artico M, Caruso R, Gagliardi FM. Long-term survival in patients with supratentorial glioblastoma. J Neurooncol 1998;36:61-4.
Scott JN, Rewcastle NB, Brasher PM, Fulton D, Hagen NA, MacKinnon JA, et al.
Long-term glioblastoma multiforme survivors: A population-based study. Can J Neurol Sci 1998;25:197-201.
Yoshida T, Kawano N, Oka H, Fujii K, Nakazato Y. Clinical cure of glioblastoma - Two case reports. Neurol Med Chir (Tokyo) 2000;40:224-9.
Deen DF, Chiarodo A, Grimm EA, Fike JR, Israel MA, Kun LE , et al
. Brain Tumor Working Group Report on the 9 th
International Conference on Brain Tumor Research and Therapy. Organ System Program, National Cancer Institute. J Neurooncol 1993;16:243-72.
Kleihues P, Sobin LH. World Health Organization classification of tumors. Cancer 2000;88:2887.
Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial malignant gliomas. Neurosurgery 1987;21:607-14.
Choucair AK, Levin VA, Gutin PH, Davis RL, Silver P, Edwards MS, et al.
Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 1986;65:654-8.
Gaspar LE, Fisher BJ, Macdonald DR, LeBer DV, Halperin EC, Schold SC Jr, et al.
Supratentorial malignant glioma: Patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys 1992;24:55-7.
Halperin EC, Burger PC, Bullard DE. The fallacy of the localized supratentorial malignant glioma. Int J Radiat Oncol Biol Phys 1988;15:505-9.
Lee SW, Fraass BA, Marsh LH, Herbort K, Gebarski SS, Martel MK, et al.
Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: A quantitative dosimetric study. Int J Radiat Oncol Biol Phys 1999;43:79-88.
Loeffler JS, Alexander E 3 rd
, Hochberg FH, Wen PY, Morris JH, Schoene WC, et al.
Clinical patterns of failure following stereotactic interstitial irradiation for malignant gliomas. Int J Radiat Oncol Biol Phys 1990;19:1455-62.
Baumann F, Bjeljac M, Kollias SS, Baumert BG, Brandner S, Rousson V, et al.
Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. J Neurooncol 2004;67:191-200.
Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80.
Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9:453-61.
Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al.
MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 2008;26:2192-7.
Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA, et al.
Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 2008;113:405-10.
Oh J, Sahgal A, Sanghera P, Tsao MN, Davey P, Lam K, et al.
Glioblastoma: Patterns of recurrence and efficacy of salvage treatments. Can J Neurol Sci 2011;38:621-5.
Wick W, Stupp R, Beule AC, Bromberg J, Wick A, Ernemann U, et al.
A novel tool to analyze MRI recurrence patterns in glioblastoma. Neuro Oncol 2008;10:1019-24.
Barbagallo GM, Jenkinson MD, Brodbelt AR. 'Recurrent' glioblastoma multiforme, when should we reoperate? Br J Neurosurg 2008;22:452-5.
Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, et al.
Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 2010;28:3838-43.
Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al.
Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 1995;345:1008-12.
Nieder C, Grosu AL, Molls M. A comparison of treatment results for recurrent malignant gliomas. Cancer Treat Rev 2000;26:397-409.
Dhermain F, de Crevoisier R, Parker F, Cioloca C, Kaliski A, Beaudre A, et al.
Role of radiotherapy in recurrent gliomas. Bull Cancer 2004;91:883-9.
Combs SE, Debus J, Schulz-Ertner D. Radiotherapeutic alternatives for previously irradiated recurrent gliomas. BMC Cancer 2007;7:167.
Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, et al.
Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 2010;28:1168-74.
Combs SE, Gutwein S, Thilmann Ch, Huber P, Debus J, Schulz-Ertner D. Stereotactically guided fractionated re-irradiation in recurrent glioblastoma multiforme. J Neurooncol 2005;74:167-71.
Nieder C, Astner ST, Mehta MP, Grosu AL, Molls M. Improvement, clinical course, and quality of life after palliative radiotherapy for recurrent glioblastoma. Am J Clin Oncol 2008;31:300-5.
Combs SE, Widmer V, Thilmann C, Hof H, Debus J, Schulz-Ertner D. Stereotactic radiosurgery (SRS): Treatment option for recurrent glioblastoma multiforme (GBM). Cancer 2005;104:2168-73.
Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, et al.
Hypofractionated stereotactic radiation therapy: An effective therapy for recurrent high-grade gliomas. J Clin Oncol 2010;28:3048-53.
Gutin PH, Iwamoto FM, Beal K, Mohile NA, Karimi S, Hou BL, et al.
Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009;75:156-63.
Elliott RE, Parker EC, Rush SC, Kalhorn SP, Moshel YA, Narayana A, et al.
Efficacy of gamma knife radiosurgery for small-volume recurrent malignant gliomas after initial radical resection. World Neurosurg 2011;76:128-40.
Kong DS, Lee JI, Park K, Kim JH, Lim DH, Nam DH. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 2008;112:2046-51.
Romanelli P, Conti A, Pontoriero A, Ricciardi GK, Tomasello F, De Renzis C, et al.
Role of stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of recurrent glioblastoma multiforme. Neurosurg Focus 2009;27:E8.
Chang JE, Khuntia D, Robins HI, Mehta MP. Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol 2007;5:894-902, 907.
van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, et al.
Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 2009;27:1268-74.
Brandes AA, Tosoni A, Amistà P, Nicolardi L, Grosso D, Berti F, et al.
How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology 2004;63:1281-4.
Reithmeier T, Graf E, Piroth T, Trippel M, Pinsker MO, Nikkhah G. BCNU for recurrent glioblastoma multiforme: Efficacy, toxicity and prognostic factors. BMC Cancer 2010;10:30.
Ahluwalia MS. 2010 Society for Neuro-Oncology Annual Meeting: A report of selected studies. Expert Rev Anticancer Ther 2011;11:161-3.
Batchelor T, Mulholland P, Neyns B, et al
. The efficacy of cediranib as monotherapy and in combination with lomustine compared to lomustine alone in patients with recurrent glioblastoma: A phase III randomized trial. Neuro Oncol 2010;12 Suppl 4:75. [Abstract/slide set].
Balañá C, Villá S, Teixidor P. Evolution of care for patients with relapsed glioblastoma. Expert Rev Anticancer Ther 2011;11:1719-29.
Addeo R, Caraglia M, De Santi MS, Montella L, Abbruzzese A, Parlato C, et al.
A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma. J Neurooncol 2011;102:417-24.
Brandes AA, Tosoni A, Franceschi E, Blatt V, Santoro A, Faedi M, et al.
Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: A phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Cancer Chemother Pharmacol 2009;64:769-75.
Scoccianti S, Detti B, Sardaro A, Iannalfi A, Meattini I, Leonulli BG, et al.
Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: A single institution experience. Anticancer Drugs 2008;19:613-20.
Fabrini MG, Silvano G, Lolli I, Perrone F, Marsella A, Scotti V, et al.
A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma. J Neurooncol 2009;92:79-86.
Franceschi E, Omuro AM, Lassman AB, Demopoulos A, Nolan C, Abrey LE. Salvage temozolomide for prior temozolomide responders. Cancer 2005;104:2473-6.
Kong DS, Lee JI, Kim WS, Son MJ, Lim do H, Kim ST, et al.
A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma. Oncol Rep 2006;16:1117-21.
Berrocal A, Perez Segura P, Gil M, Balaña C, Garcia Lopez J, Yaya R, et al.
Extended-schedule dose-dense temozolomide in refractory gliomas. J Neurooncol 2010;96:417-22.
Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, et al.
Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 2010;28:2051-7.
Kong DS, Lee JI, Kim JH, Kim ST, Kim WS, Suh YL, et al.
Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol 2010;12:289-96.
Hammond A, Norden AD, Lesser GJ, et al
. Phase II study of dose-intense temozolomide in recurrent glioblastoma. J Clin Oncol 2011;29:2038.
Wick A, Pascher C, Wick W, Jauch T, Weller M, Bogdahn U, et al.
Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol 2009;256:734-41.
Pegg AE. Methylation of the O6 position of guanine in DNA is the most likely initiating event in carcinogenesis by methylating agents. Cancer Invest 1984;2:223-31.
Gerson SL. Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 2002;20:2388-99.
Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A, et al.
Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 2003;88:1004-11.
Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al.
A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83:588-93.
Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, et al.
Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 2010;28:4601-8.
M. Weller, G. Tabatabai, G. Reifenberger, U. Herrlinger, J. Pichler, O. Schnell, et al
. Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma. J Clin Oncol 2010;28 ASCO Annual Meeting Abstracts. Vol 28, No 15_suppl (May 20 Supplement), 2010: TPS154
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al.
Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al.
Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5.
Vredenburgh JJ, Desjardins A, Herndon JE 2 nd
, Marcello J, Reardon DA, Quinn JA, et al.
Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:4722-9.
Annick Desjardins, David A. Reardon, James E. Herndon II, Leighann Bailey, Katherine B. Peters, Henry S. Friedman, et al
. Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 2012;118:1302-12.
Wong ET, Gautam S, Malchow C, Lun M, Pan E, Brem S. Bevacizumab for recurrent glioblastoma multiforme: A meta-analysis. J Natl Compr Canc Netw 2011;9:403-7.
Fraum TJ, Kreisl TN, Sul J, Fine HA, Iwamoto FM. Ischemic stroke and intracranial hemorrhage in glioma patients on antiangiogenic therapy. J Neurooncol 2011;105:281-9.
Quant EC, Norden AD, Drappatz J, Muzikansky A, Doherty L, Lafrankie D, et al.
Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol 2009;11:550-5.
Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, et al.
AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95.
Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, et al.
Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 2010;28:2817-23.
de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, et al.
Phase II study of aflibercept in recurrent malignant glioma: A North American Brain Tumor Consortium study. J Clin Oncol 2011;29:2689-95.
Wen PY, Prados M, Schiff D. Phase II study of XL184 (BMS 907351), an inhibitor of MET, VEGFR2, and RET, in patients (pts) with progressive glioblastoma (GB). J Clin Oncol 2010;28 Suppl 15s:. [Abstract 2006].
Wen PY. American Society of Clinical Oncology 2010: Report of selected studies from the CNS tumors section. Expert Rev Anticancer Ther 2010;10:1367-9.
Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, et al.
Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008;26:5610-7.
R. Stupp, R. Goldbrunner, B. Neyns, U. Schlegel, P. Clement, G. G. Grabenbauer , et al
. Phase I/IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM). J Clin Oncol 2007;25 Supp18s: [Abstract 2000].
Desjardins A, Reardon DA, Coan A, Marcello J, Herndon JE 2 nd
, Bailey L, et al.
Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 2012;118:1302-12.
Reardon DA, Vredenburgh JJ, Desjardins A, Peters K, Gururangan S, Sampson JH, et al.
Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: Results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J Neurooncol 2011;101:57-66.
D. D. Eisenstat, L. B. Nabors, W. P. Mason, J. R. Perry, W. R. Shapiro, P. Kavan, et al
. A phase II study of daily afatinib (BIBW 2992) with or without temozolomide (21/28 days) in the treatment of patients with recurrent glioblastoma. J Clin Oncol 2011;29 Suppl 15:. [Abstract 2010].
Stockhammer F, Misch M, Koch A, Czabanka M, Plotkin M, Blechschmidt C, et al.
Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma. J Neurooncol 2010;100:407-15.
Gaviani P, Salmaggi A, Silvani A. Combined chemotherapy with temozolomide and fotemustine in recurrent glioblastoma patients. J Neurooncol 2011;104:617-8.
Narayana A, Kelly P, Golfinos J, Parker E, Johnson G, Knopp E, et al.
Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: Impact on local control and patient survival. J Neurosurg 2009;110:173-80.
Nghiemphu PL, Liu W, Lee Y, Than T, Graham C, Lai A, et al.
Bevacizumab and chemotherapy for recurrent glioblastoma: A single-institution experience. Neurology 2009;72:1217-22.
Vredenburgh JJ, Desjardins A, Herndon JE 2 nd
, Dowell JM, Reardon DA, Quinn JA, et al.
Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253-9.
M. R. Gilbert, M. Wang, K. Aldape, A. Lassman, A. G. Sorensen, T. Mikkelson, et al
. RTOG 0625: A phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM). J Clin Oncol 2009;27 Suppl 15:2011. [Abstract].
Reardon DA, Desjardins A, Vredenburgh JJ, Gururangan S, Sampson JH, Sathornsumetee S, et al.
Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: A phase II study. Br J Cancer 2009;101:1986-94.
Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, et al.
Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 2010;12:1300-10.
Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, et al.
Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22:133-42.
Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, et al.
Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005;97:880-7.
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, et al.
Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012-24.
de Groot JF, Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S, et al.
Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma. J Neurooncol 2008;90:89-97.
Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, et al.
Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: A pilot study. J Clin Oncol 2007;25:4714-21.
Raymond E, Brandes AA, Dittrich C, Fumoleau P, Coudert B, Clement PM, et al.
Phase II study of imatinib in patients with recurrent gliomas of various histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. J Clin Oncol 2008;26:4659-65.
Jaeckle KA, Hess KR, Yung WK, Greenberg H, Fine H, Schiff D, et al.
Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: A North American Brain Tumor Consortium study. J Clin Oncol 2003;21:2305-11.
Moscatello DK, Ramirez G, Wong AJ. A naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors. Cancer Res 1997;57:1419-24.
Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, et al.
Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17:2572-8.
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy
| ||Lei Yin,Heng Li,Wenjian Liu,Zhenglin Yao,Zhenzhen Cheng,Huabei Zhang,Hui Zou |
| ||European Journal of Medicinal Chemistry. 2017; |
|[Pubmed] | [DOI]|
||Identification of Driver Genes and Key Pathways of Glioblastoma Shows JNJ-7706621 as a Novel Antiglioblastoma Drug
| ||Sheng Zhong,Bo Wu,Xuechao Dong,Yujuan Han,Shanshan Jiang,Ying Zhang,Yang Bai,Sean X. Luo,Yong Chen,Huimao Zhang,Gang Zhao |
| ||World Neurosurgery. 2017; |
|[Pubmed] | [DOI]|
||Recurrent glioblastoma: a single-institution experience with reirradiation and temozolomide
| ||Tejinder Kataria,Deepak Gupta,Ratika Gupta,Shikha Goyal,Shyam Singh Bisht,Trinanjan Basu,Ashu Abhishek,Kushal Narang,Susovan Banerjee |
| ||Journal of Radiation Oncology. 2017; |
|[Pubmed] | [DOI]|
||Niclosamide induces protein ubiquitination and inhibits multiple pro-survival signaling pathways in the human glioblastoma U-87 MG cell line
| ||Benxu Cheng,Liza Doreen Morales,Yonghong Zhang,Shizue Mito,Andrew Tsin,Salvatore V Pizzo |
| ||PLOS ONE. 2017; 12(9): e0184324 |
|[Pubmed] | [DOI]|
||Randomized Trial for Short-Term Radiation Therapy With Temozolomide in Elderly Patients With Glioblastoma
| ||David J. McCarthy,Ricardo J. Komotar,Robert M. Starke,E. Sander Connolly |
| ||Neurosurgery. 2017; 81(3): N21 |
|[Pubmed] | [DOI]|
||Validation of an established prognostic score after re-irradiation of recurrent glioma
| ||Kerstin A. Kessel,Josefine Hesse,Christoph Straube,Claus Zimmer,Friederike Schmidt-Graf,Jürgen Schlegel,Bernhard Meyer,Stephanie E. Combs |
| ||Acta Oncologica. 2017; : 1 |
|[Pubmed] | [DOI]|
||Injectable nanomedicine hydrogel for local chemotherapy of glioblastoma after surgical resection
| ||C. Bastiancich,J. Bianco,K. Vanvarenberg,B. Ucakar,N. Joudiou,B. Gallez,G. Bastiat,F. Lagarce,V. Préat,F. Danhier |
| ||Journal of Controlled Release. 2017; |
|[Pubmed] | [DOI]|
||Harnessing nanomedicine for therapeutic intervention in glioblastoma
| ||Anna Gutkin,Zvi R. Cohen,Dan Peer |
| ||Expert Opinion on Drug Delivery. 2016; : 1 |
|[Pubmed] | [DOI]|