Temozolomide Failure Research Articles

7856 In Pursuit of Solutions: Exploring Novel Therapeutic Strategies in the Treatment of a Rare, Aggressive Macroprolactinoma Post-Temozolomide: A Case Report

Abstract Disclosure: N. Konindala: None. H. Darapu: None. K. Ruddiman: None. Introduction: Prolactinomas comprise 40-60% of all pituitary tumors. Most prolactinomas respond well to dopamine agonist treatment. About 10% of these tumors are aggressive prolactinomas (APRL). Although rare, APRLs pose a significant challenge in clinical practice as treatment beyond dopamine agonists, surgery and radiotherapy is limited. A fourth-line therapy called temozolomide may be needed. After temozolomide failure, treatment options are minimal, as there are no evidence-based therapies available for such aggressive pituitary tumors. The efficacy of novel treatment agents remains to be explored. Notably, our case is one of the few where investigational agents, including Pembrolizumab and Pazopanib have been used. We present a case report that contributes to the evolving understanding of potential therapeutic options and highlights the ongoing challenges in refractory prolactinoma management. Case Presentation: A 77-year-old male was diagnosed with a macroprolactinoma in 2001 and was started on cabergoline with a good therapeutic response. In 2011, there was hormonal and imaging evidence of progression, and the patient underwent transsphenoidal hypophysectomy with gross resection followed by gamma knife radiation. The patient was found to have a recurrence of his tumor five years later and underwent repeat transsphenoidal resection. He continued to show evidence of recurrence and was recommended for chemoradiation and adjunct temozolomide (TMZ). After 12 cycles of TMZ, a repeat MRI was done, which showed radiographic recurrence. The patient had a third transsphenoidal surgery done in August 2022, followed by the initiation of a PARP-1 inhibitor, Olaparib. The development of adverse effects complicated this, and treatment was transitioned to capecitabine and TMZ in Jan 2023. The patient had persistent tumor burden symptoms, and a VEGF inhibitor Avastin was initiated. His symptoms initially improved, but unfortunately, his prolactin levels rose from 895 mg/dL to 1,547mg/dL, indicating evidence of disease progression. Immunotherapy with pembrolizumab was started on 6/2023, and he was given three doses before a follow-up MRI showed continued progression of the disease. He was recommended to start pazopanib, a kinase inhibitor. Discussion: Aggressive Prolactinomas present a rare and intricate management challenge, necessitating a multidisciplinary approach. Despite standard therapies, achieving remission can be elusive. While Pembrolizumab showed promise in reported cases, our patient remained refractory. Literature indicates favorable responses to Pazopanib in a small number of refractory cases. A reassessment in a few months will evaluate our patient's response to Pazopanib. This case emphasizes the need for further research to refine refractory prolactinoma management and develop response indicators for investigational agents. Presentation: 6/3/2024

Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide.

Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study.

After temozolomide failure, no evidence-based treatment is available for pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). To date, only 12 cases treated with immune-checkpoint inhibitors (ICIs) have been published, showing encouraging efficacy. Predictive factors of response are lacking. Here, we aimed to assess the real-life efficacy and predictors of response to ICIs in PCs and APTs. This study is a multicentric, retrospective, observational cohort study, including all PCs and APTs treated with ICIs in France up to March 2022. PD-L1 immunohistochemistry and CD8+ T cell infiltration were evaluated centrally. Six PCs (four corticotroph and two lactotroph) and nine APTs (five corticotroph and four lactotroph) were included. The real-life efficacy of ICIs was lower than previously published data. Three corticotroph tumors (33.3%) showed partial response, one (11.1%) stable disease, while five (55.6%) progressed. One lactotroph tumor (16.7%) showed partial response, one (16.7%) stable disease, while four (66.7%) progressed. PCs responded far better than APTs, with 4/6 PCs showing partial response compared to 0/9 APTs. Corticotroph tumors responded slightly better than lactotroph tumors. In the four responsive corticotroph tumors, PD-L1 staining was negative and CD8+ T cell infiltration attained a maximum of 1% in the tumor center. Confirmation of the presence or absence of metastases is necessary before starting ICIs. After temozolomide failure, ICIs appear as a good therapeutic option for PCs, especially for corticotroph carcinomas. Negative PD-L1 staining and very low CD8+ T cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. This is the first study to assess the real-life efficacy of ICIs in pituitary carcinomas (PCs) and aggressive pituitary tumors. We also assessed potential predictors of response and are the first to assess the predictive value of CD8+ cell infiltration. We identified the tumor type as a major predictor, ICIs proving far more effective in treating PCs. Our study provides evidence that ICIs are a good option after temozolomide failure for PCs (four of six responded), especially for corticotroph carcinomas (three of four responded). We also provide evidence that negative PD-L1 staining and very low CD8+ cell infiltration in the tumor center should not preclude ICI administration in corticotroph carcinomas. Moreover, our findings point toward the need to systematically perform extension workup before starting ICIs.

Immunotherapy in aggressive pituitary tumors and carcinomas: a systematic review.

Once temozolomide has failed, there is no recommended treatment option for pituitary carcinomas and aggressive pituitary tumors. Immune-checkpoint inhibitors (ICIs) represent the most recent therapeutic avenue, having raised hope with the publication of the first successful case in 2018. Here, we present an overview of immunotherapy in pituitary carcinomas and aggressive pituitary tumors, starting with the rationale for using ICIs and the implications of tumor-infiltrating lymphocytes in anterior pituitary tumors, followed by a systematic review of all published cases, analyzing both treatment response and potential predictors of response and finishing with research and clinical perspectives. Seven corticotroph and four lactotroph tumors have been so far treated with ICIs. Corticotroph tumors showed radiological partial response in 57% of cases, followed by stable disease in 29% of cases, which was accompanied by biochemical partial or complete response in 83% of cases. Half of lactotroph tumors showed radiological complete or partial response, accompanied by biochemical complete response in 33% of the cases. In the case of a dissociate response, continuation of immunotherapy combined with local treatment represents a good option. At this time, a high tumor mutational burden appears to be the most promising predictive marker of response. MMR deficiency does not guarantee a response. Negative PD-L1 staining should not preclude ICIs administration. Therefore, ICIs are a promising option after temozolomide failure. This review highlights key clinical aspects that can already be implemented into practice and also discusses tumor biology concepts and perspectives expected to improve immunotherapy outcomes.

DDRE-31. MITOCHONDRIAL TRAFFICKING AS A TARGET FOR GBM THERAPY

Abstract Glioblastoma (WHO Grade IV glioma) is the most aggressive brain cancer. The current standard of care treatment includes surgery, radiation, and chemotherapy. Tumor recurrence is almost inevitable as less than 50% of patients survive more than two years. The low survival rate poses a dire need to develop an effective therapy for GBM patients. GBM cells are resistant to treatment, as they activate their DNA damage response mechanisms to overcome the effects of radiation and temozolomide (TMZ) treatments. Recurrent tumors can arise from slow cycling and self-renewing stem/tumor-initiating cells resistant to radiation and TMZ. No second-line therapy was proven to prolong survival after TMZ failure. Magmas (Mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a subunit of the TIM23 complex regulating precursor protein trafficking into the mitochondrial matrix. Magmas is encoded by pam16, known to be upregulated in human pituitary adenomas, prostate cancer and GBM. Previous studies have demonstrated that Magmas negatively regulates the stimulatory activity of Pam18, which in turn stimulates the ATPase activity of mitochondrial heat shock protein 70 (mtHsp70). No small molecules targeting Magmas are in clinical use. We developed a novel small molecule inhibitor (BT9) that has been specifically designed to inhibit Magmas binding to Pam18. BT9 induces apoptosis through cleavage of caspase-3, reduced mitochondrial respiration and glycolysis. Our recent findings also demonstrate that BT9 treatment reduced protein trafficking of Lon protease into the mitochondrial matrix. Pretreatment of glioma cells with BT9 sensitizes cells to radiation treatment and enhances the TMZ activity. BT9 can cross the blood-brain-barrier and improve survival in intracranial glioma PDX models. BT9 has potential therapeutic value by directly dysregulating mitochondrial function in GBM, enhancing radiation and chemotherapy response, and improving survival in a relevant animal model.

Proteomic profiling to identify therapeutics targets in glioblastoma (GBM).

2555 Background: Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. Treatment at diagnosis is largely confined to surgery, radiation and temozolomide (TMZ) with median progression-free survival (PFS) of 7 months and median overall survival (mOS) of 15 months. GBM tumors recur in most cases and in patients with recurrent GBM, the mOS is 6.2 months. The lack of effective therapies underscores the importance of exploring other agents. We propose that quantitating therapy-associated protein biomarkers can improve treatment personalization for GBM. Methods: 97 FFPE GBM tissues were microdissected and solubilized for mass spectrometry-based proteomic analysis of therapy-associated protein biomarkers in our CLIA certified lab. We quantified protein levels of MGMT, hENT1, RRM1, TOPO1 and EGFR/TUBB3 (antibody target and payload resistance markers, respectively, for anti-EGFR ADCs) simultaneously. The multiplexed assay also quantified additional 24 clinically relevant proteins. Results: 43/57 patients were predicted to respond to TMZ based on undetectable levels of MGMT, confirming wide utility of this agent. 42/97(43%) patients were predicted to have gemcitabine sensitivity based on high expression of the response marker (hENT1 > 100 amol/ug) and low expression of the resistance marker (RRM1 < 700 amol/ug). 11/97(11%) patients expressed TOPO1 > 1350 amol/ug (75th percentile of all indications tested by author’s laboratory), suggesting likely response to irinotecan and topotecan. EGFR expression ranged from < 100 amol/ug to > 25000 amol/ug, including overexpression (> 1500 amol/ug) in 22%(21/97) of cases. While expression of EGFR(81/97, 84%) suggested likely response to anti-EGFR ADC, concurrent expression of TUBB3(78/81) may indicate resistance to several known payloads, such as taxanes and MMAE. Conjugation with another payload that targets sensitivity marker TOPO1 (68% expression) is a likely option. Proteomic analysis also revealed detectable levels of multiple RTKs (FGFR(4), AXL(20), IGF1R(10), MET overexpression(1), and HER2 overexpression(2)), indicating potential response to RTK inhibitors. Exploratory investigation in tumor vs TME using proteomics and metabolomics is ongoing. Conclusions: In this population of GBM patients, proteomic analysis identified protein targets of multiple approved and investigational therapies. Gemcitabine, which crosses the blood-brain barrier, may be considered as a salvage option after TMZ failure. Proteomic quantitation of EGFR and TUBB3 may improve patient selection for EGFR-targeting ADCs.

Aggressive prolactinomas: how to manage?

Aggressive prolactinomas are defined as radiologically invasive tumors which cannot be cured by surgery, and that have an unusually rapid rate of tumor growth despite dopamine agonist treatment and surgery. In some cases, metastasis occurs, defining prolactin carcinoma which is the second most frequent pituitary carcinoma. A literature search was performed to review the available data on the treatment of aggressive pituitary prolactinomas or carcinomas. When optimal standard therapies (high dose cabergoline, surgery and radiotherapy) failed, temozolomide, an alkylating drug, is currently the best option, allowing to control tumor growth in about 50% of treated prolactinomas and improving overall survival of these patients. However, long-term complete response occurs in a limited subgroup of tumors. Alternative drugs could be discussed in a subset of aggressive prolactinomas either before temozolomide (pasireotide, peptide receptor radionuclide therapy…) or after temozolomide failure. Despite the significant improvement obtained with the use of temozolomide, a need for alternative drugs persists since a majority of these tumors are resistant or will recur during the follow-up. Patients suffering from such a rare condition should have access to clinical trials available for other types of rare cancers, such as tyrosine kinase inhibitors or immunotherapy.

Abstract CT064: Intranasal brain delivery using NEO100 for recurrent glioblastoma

Abstract NO CHANGES TO ORIGINAL ABSTRACT NEO100 is a GMP quality, purified perillyl alcohol (POH) which has been undergoing clinical trials under IND approval (144,595) entitled "Open label, Phase I/IIa dose escalation study of safety and efficacy of NEO100 in recurrent grade IV glioma." It was granted orphan drug and fast track status by the FDA. Inclusion criteria include temozolomide failure, bevacizumab naïve, tumor less than 3x3 cm, and Karnofsky score greater than or equal to 60. Patients were enrolled from University of Southern California (USC), Cleveland Clinic, and University of Washington. Total number of patients to be enrolled for Phase I is 12 with four dose escalating cohorts of 3 patients per cohort. The remaining 31 patients would be enrolled after maximal tolerated dosage (MTD) for Phase IIa. The delivery is intranasal via a nasal nebulizer using the concept of nasal brain delivery via the olfactory and trigeminal nerves for delivery to the brain and tumor. To date, 8 patients have been enrolled. Cohort 1 received 96 mg/dose qid, Cohort 2 received 144 mg/dose qid, cohort 3 received 192 mg/dose qid, and cohort 4 will receive 288mg/dose qid. No toxicities were detected. Inhalation was very well tolerated. The duration of the trial is for 6 months. To date, 3 patients have not shown evidence of progression for greater than 6 months (one patient 1 year (cohort 2), one patient 7 months (cohort 3), one patient 6 months) (cohort 3). This is the first FDA approved trial for intranasal delivery to malignant gliomas. Although preliminary, we are encouraged by the progression free survival of 3/8 patients in this dose escalation trial. Citation Format: Thomas C. Chen, Naveed Wagle, David Peereboom, Lynne Taylor. Intranasal brain delivery using NEO100 for recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT064.

Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas: a systematic review.

Pituitary tumors represent 10-15% of all intracranial tumors; of these, prolactinomas account for 40-50% of cases. Prolactinomas usually respond well to dopamine agonists (DA) as first-line therapy. However, treatment resistance remains a concern. Temozolomide (TMZ) is an oral alkylating agent that has shown promise in treating aggressive pituitary adenomas and carcinomas that are resistant to other therapies. To date, no control trials have been undertaken and only single case reports of pituitary tumors treated with TMZ have been published. A systematic literature search was conducted for studies reporting the use of TMZ for the treatment of prolactinomas that were resistant to standard therapy. In total, 42 reported cases were identified and included in our analysis: 23 cases of prolactin-secreting adenomas and 19 of prolactin-secreting carcinomas. Prior to TMZ administration, patients had exhibited tumor progression and had previously undergone various treatments including surgery, radiotherapy, and drug therapy. Tumor shrinkage was reported in 76% of patients. Reduced prolactin levels were observed in 75% of patients, while normalization of prolactin was reported in 8%. TMZ failure occurred in 20.6% of cases. Most patients exhibited no serious adverse effects. In conclusion, TMZ has potential for the treatment of highly aggressive and resistant prolactin-secreting adenomas and carcinomas, as demonstrated by tumor shrinkage or complete response and normalization of hormone hypersecretion, and exhibits good tolerability and few side effects.

Abstract 41: DCA bind to EGFR/EGFRvIII/PDK1 and affect the proliferation and growth in TMZ resistant glioblastoma model

Abstract Glioblastomas are characterized by amplification of epidermal growth factor receptor (EGFR). Approximately half of the GBM tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). This phenotype represents a tumor specific target correlating with a high growth potential. Despite advances in treatment, whether surgery, chemotherapeutics or molecular targeted therapies, very few have shown promise. Temozolomide (TMZ), as standard of care alkylation therapy, demonstrates improved survival when administered with concomitant radiotherapy. Unfortunately, acquired TMZ chemo-resistance is observed in more than 90% of recurrent GBMs. To understand the mechanisms in the context of TMZ resistance, we generated an in vitro TMZ resistant model by continuous exposure of U373 cells constitutively expressing EGFRvIII (U373vIII) to 150uM TMZ for 6 months (U373vIIIR). Dicholoroacetate (DCA) is a known metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1). Its application to cancer has recently been revived in the realm of metabolic oncology, where reversal of the Warburg effect has resulted in decreased tumor growth. Treatment of U373, U373vIII, and U373vIIIR GBM cell lines with DCA was found to induce cytotoxicity and reduced cell survival across all cell lines. Further, micro array studies conducted on U373vIII or U373vIIIR and their subsequent treatment with DCA revealed that PDK1 is the sole target in TMZ resistant tumors expressing EGFRvIII. Additionally, we demonstrated that 1mM DCA induced mitochondrial membrane potential change as evidenced in JC-1 staining and electron microscopic studies confirming mitochondrial apoptosis. Consistent with our previous findings that EGFR interacts with PDK1, our computational analysis revealed that DCA aligns itself to the binding sites of both EGFR and EGFRvIII with strong binding affinity apart from its binding to PDK1. Clinically, expression of EGFRvIII correlated with PDK1 when compared to EGFR in GBM surgical specimens. Collectively, our studies demonstrate that principles of metabolic oncology and DCA are active in GBM treatment despite resistance providing new insight into the development of alternative treatment in TMZ failure. Citation Format: Kiran Kumar Velpula, Kamlesh Sahu, Jack Tuszynski, Maheedhara R. Guda, Swapna Asuthkar, Sarah E. Martin, Justin D. Lathia, Andrew J. Tsung. DCA bind to EGFR/EGFRvIII/PDK1 and affect the proliferation and growth in TMZ resistant glioblastoma model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 41.

ATCT-03RETROSPECTIVE REVIEW OF GLIOBLASTOMA PATIENTS TREATED WITH BEVACIZUMAB-CONTAINING AND NON-BEVACIZUMAB-CONTAINING REGIMENS IN A SINGLE INSTITUTION

OBJECTIVE: Bevacizumab has been reported not to improve survival in patients with glioblastoma in addition to radiotherapy-temozolomide. The Japanese Ministry of Health, Labour and Welfare has approved BEV for newly-diagnosed and recurrent malignant glioma on June 14, 2013. Therefore, we analyze retrospectively clinical outcomes of glioblastoma patients treated with bevacizumab-containing and non-bevacizumab-containing regimens in our institution. SUBJECTS AND METHODS: Between 2006 and 2013, 94 patients with newly-diagnosed glioblastoma were treated with radiotherapy with concomitant and adjuvant temozolomide. To patients with tumor progression, we applied ICE (ifosfamide, carboplatin, and etoposide), CPT-11, etoposide, bevacizumab and bevacizumab-containing regimen with temozolomide, ICE, and CPT-11. RESULTS: 43 patients have been treated with bevacizumab-containing regimens (bevacizumab group) and 51 patients with non-bevacizumab-containing regimens (non-bevacizumab group). Median survival times in bevacizumab group and non-bevacizumab group were 21.7 and 17.2 months, respectively (p = 0.45). Recurrences were identified in 41 patients of bevacizumab group and 38 patients of non-bevacizumab group. In analysis of patients with recurrent glioblastoma, median survival time in bevacizumab group (21.7 months) was significantly longer than in non-bevacizumab group (14.2 months) (p = 0.031). CONCLUSION: Bevacizumab-containing regimens showed significant survival benefit in the patients with recurrence of glioblastoma and temozolomide failure, compared with non-bevacizumab-containing regimens.

Albumin-Linked Doxorubicin (Aldoxorubicin) as Treatment for Relapsed Glioblastoma: A Case Report

Glioblastoma multiforme (GBM) the most common primary brain malignancy in adults, has an approximately 25% 2-year overall survival despite improvements in both first and second-line therapies [1]. However, options still remain limited in those patients progressing after failure of temozolomide. IDH mutation and MGMT methylation status do predict whether patients will respond favorable to alkylator based therapies and clinical trials are ongoing to develop therapies specific to these GBM subtypes. In many cases, chemotherapy resistance is thought to be related to the inability of agents to cross the blood brain barrier into the tumor, limiting efficacy of otherwise effective agents.

Aggressive Silent GH Pituitary Tumor Resistant to Multiple Treatments, Including Temozolomide

Temozolomide (TMZ) has been proposed as a therapeutic option in aggressive pituitary tumors. Among the published cases, GH expressing tumors were rare. We describe a patient with initially benign silent GH adenoma that transformed into an aggressive GH secreting tumor resistant to usual therapy. MGMT expression was high and the MGMT promoter was unmethylated. Before this aggressive course, patient received three cycles of TMZ; no response was observed. Four cases of GH aggressive tumor treated by TMZ have been reported. Response to TMZ was observed in one of these four patients. Predictive factors of failure of TMZ remain unclear.

Retrospective Analysis of Bevacizumab in Combination With Ifosfamide, Carboplatin, and Etoposide in Patients With Second Recurrence of Glioblastoma

Bevacizumab has been reported to be effective for recurrent glioblastoma. In our hospital, ifosfamide, carboplatin, etoposide (ICE) is the second-line chemotherapy for first recurrence of glioblastoma after temozolomide failure. In the present analysis, we retrospectively investigated the feasibility and effectiveness of bevacizumab combined with ICE in patients with glioblastoma at second relapse during ICE treatment. Between 2010 and 2012, tumor progressions were diagnosed in consecutive 8 patients who were treated with ICE for the first recurrence of glioblastoma. These patients were administered 3 cycles of 10 mg/kg bevacizumab every two weeks in combination with ICE treatment. The objective response rate of bevacizumab combination was 75% in Neuro-Oncology Working Group (RANO criteria), including complete response and partial response. Median progression free survival (PFS) and median overall survival (OS) after second relapse were 3.7 months (95% confidence interval [CI], 2.5–18.5 months) and 6.0 months (95% CI, 3.2–19.7 months), respectively. The 6-month PFS rates were 25% (95% CI, 0–55.0%). The median OS after initial diagnosis was 23.3 months (95% CI, 16.2–55.8 months). The grade 2 or 3 hematologic adverse events were identified in 7 of 8 patients, most of which might be due to ICE chemotherapy. The results of our retrospective analysis suggest that combination treatment with bevacizumab and ICE may be safe and beneficial in patients with recurrent glioblastoma.

Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: A phase II study

O(6)-alkylguanine-DNA alkyltransferase (AGAT), involved in temozolomide-induced DNA damage repair, plays a key role in the efficacy of temozolomide. AGAT activity may be reduced by protracted temozolomide doses. On the basis of the preclinical findings, we treated patients with a histologically-proven diagnosis of glioblastoma (GBM) following adjuvant temozolomide failure with a low protracted dose of temozolomide (130 mg/m(2)/day, days 1-7 and 15-21, every 4 weeks). The primary endpoint of the study was 6-month progression-free survival (PFS-6 m). The secondary endpoints were overall survival (OS) from the start of temozolomide alternative schedule and toxicity. Enrolment was ceased at 27 patients due to the lack of effectiveness of this regimen. Results indicate that our schedule is well-tolerated, but ineffective in patients with GBM and further strategies are required to improve the outcome of these patients.

A retrospective pooled analysis of response patterns and risk factors in recurrent malignant glioma patients receiving a nitrosourea-based chemotherapy

BackgroundAt recurrence the use of nitrosoureas is widely-used as a therapeutic option for glioblastoma (GBM) patients. The efficacy of fotemustine (FTM) has been demonstrated in phase II clinical trials; however, these papers report a wide range of progression-free-survival (PFS-6 m) rates, ranging from 21% to 52%. We investigated whether FTM could have a different response pattern in respect to time to adjuvant temozolomide failure, or whether specific independent risk factors could be responsible for the wide range of response rates observed.MethodsRecurrent GBM patients have been treated with fotemustine 75-100 mg/sqm at day 1, 8, 15 and after 4/5 weeks of rest with 100 mg/sqm every 21 days. Patients were stratified in 4 groups according to time to temozolomide failure: before starting (B0), during the first 6 months (B1), after more than 6 months of therapy (B2), and after a treatment-free interval (B3). Primary endpoint was PFS-6 m. A multivariable analysis was performed to identify whether gender, time after radiotherapy, second surgery and number of TMZ cycles could be independent predictors of the clinical benefit to FTM treatment.Results163 recurrent GBM patients were included in the analysis. PFS-6 m rates for the B0, B1, B2 and B3 groups were 25%, 28%, 31.1% and 43.8%, respectively. The probability of disease control was higher in patients with a longer time after radiotherapy (p = 0.0161) and in those who had undergone a second surgery (p = 0.0306).ConclusionsFTM is confirmed as a valuable therapeutic option for patients with recurrent GBM and was active in all study patient groups. Time after the completion of radiotherapy and second surgery are independent treatment-related risk factors that were predictive of clinical benefit.

8743 POSTER Efficacy of Fotemustine in Recurrent Malignant Glioma According to Time to Adjuvant Temozolomide Failure – a Pooled Analysis

8743 POSTER Efficacy of Fotemustine in Recurrent Malignant Glioma According to Time to Adjuvant Temozolomide Failure – a Pooled Analysis

Ifosfamide, Carboplatin and Etoposide in Recurrent Malignant Glioma

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

Efficacy of nitrosourea-based chemotherapy in recurrent malignant glioma according to time to adjuvant temozolomide failure: A pooled analysis.

2060 Background: Concomitant and adjuvant temozolomide (TMZ) is the standard of care of the first-line treatment in glioblastoma (GBM) patients. At recurrence patients have few therapeutic options and the use of nitrosoureas, alternative schedule of TMZ and new target therapy have been widely studied. Recently Perry and colleagues (JCO 2010;28:2051-2057) have demonstrated that time to adjuvant temozolomide failure seems to be predictable to dose-intense TMZ treatment. The aim of our pooled analysis was to assess the efficacy of nitrosourea in recurrent GBM patients according to time to adjuvant TMZ progression. Methods: Patients with GBM who failed the standard Stupp regimen have been treated with a nitrosoureas based regimen of fotemustine (FTM) 75-100mg/sqm at day 1, 8, 15 (induction phase) and after 4/5 weeks of rest 100 mg/sqm every 21 days. The primary endpoint of the study was 6-months progression free survival (PFS-6m), Overall survival at 1 year (OS1y), response rate (RR) and toxicity were secondary endpoints. Patients were stratified in 3 groups according to time to TMZ failure: GBM patients failing during the first 6 months of adjuvant TMZ (B1), those who failed after more than 6 months of therapy (B2) and GBM patients who recurred after a treatment-free interval (B3). Results: Six Italian centers participated in this study. At that time preliminary results are available: 119 patients with recurrent GBM have been evaluated. Results have been summarized in the table. Conclusions: Nitrosourea is a valuable therapeutic option for patients with recurrent GBM, not depending on time to adjuvant temozolomide failure and also patients recurred after 6 cycles of adjuvant TMZ (B2) seem to get a benefit from FTM treatment. A prospective randomized trial is warranted to define if TMZ and FTM have a different pattern of response in recurrent GBM. B1 (%) B2 (%) B3 (%) PSF-6m OS1y RR PSF-6m OS1y RR PSF-6m OS1y RR FTM 24.5 24.5 12.2 31.3 31.3 18.8 34.2 28.9 7.9 TMZ* 27.3 27.3 3 7.4 14.8 0 35.7 28.6 11.1

An algorithm for chemotherapy treatment of recurrent glioma patients after temozolomide failure in the general oncology setting

The standard therapy for newly diagnosed malignant gliomas comprises surgery, radiotherapy, and commonly temozolomide chemotherapy. For recurrent or progressive disease after temozolomide failure, there is no consensus and only limited options for chemotherapy. We reviewed the English literature for phase II trials of therapies for recurrent malignant glioma conducted between January 2000 and September 2010. The search was supplemented by a review of articles published prior to 2000 on chemotherapy regimens that had shown activity on recurrent gliomas. To guide practice in the general oncology setting, an algorithm was constructed according to the activity of the reported chemotherapies at the time of writing. Some molecular studies performed on tumor tissue may help guide the selection of chemotherapy. Methylated MGMT in tumor tissue correlates with increased sensitivity to alkylating agents such as fotemustine or other nitrosoureas. Depending on MGMT status and bone marrow reserve, treatment with fotemustine, bevacizumab, bevacizumab with irinotecan, or cis-retinoic acid (cRA), might be of value. Unfortunately, progress in the development of new and more effective chemotherapy agents has been very limited and leaves the clinician treating high-grade glioma patients at relapse with few good options. The suggested algorithm is our objective evaluation of the currently existing knowledge. Hopefully, the ongoing phase II and III trials will provide us the needed chemotherapy agents in the years to come.