Serial analysis of imaging parameters in patients with newly diagnosed glioblastoma multiforme

The objective of this study was to test the predictive value of serial MRI data in relation to clinical outcome for patients with glioblastoma multiforme (GBM). Sixty-four patients with newly diagnosed GBM underwent conventional MRI and diffusion-weighted and perfusion-weighted imaging postsurgery and prior to radiation/chemotherapy (pre-RT), immediately after RT (post-RT), and every 1-2 months thereafter until tumor progression, up to a maximum of 1 year. Tumor volumes and perfusion and diffusion parameters were calculated and subject to time-independent and time-dependent Cox proportional hazards models that were adjusted for age and MR scanner field strength. Larger volumes of the T2 hyperintensity lesion (T2ALL) and nonenhancing lesion (NEL) at pre-RT, as well as increased anatomic volumes at post-RT, were associated with worse overall survival (OS). Higher normalized cerebral blood volumes (nCBVs), normalized peak height (nPH) and normalized recirculation factors (nRF) at pre-RT, and nCBV at post-RT, in the T2ALL and NEL, were associated with shorter progression-free survival (PFS). From pre- to post-RT, there was a reduction in nCBV and nPH and an increase in apparent diffusion coefficient (ADC). Patients with lower nRF values at pre-RT, or a larger increase in nRF from pre-RT to post-RT, had significantly longer PFS. Time-dependent analysis showed that patterns of changes in ADC and anatomic volumes were associated with OS, while changes in nCBV, nPH, and the contrast-enhancing volume were associated with PFS. Our studies suggest that quantitative MRI variables derived from anatomic and physiological MRI provide useful information for predicting outcome in patients with GBM.     

Survival with dacarbazine and fotemustine in newly diagnosed glioblastoma multiforme

A total of 55 patients with histologically proven glioblastoma multiforme (total gross resection: n=24, subtotal resection: n=20, stereotactic biopsy: n=11) were treated with the combination of dacarbazine (D) (200 mg m(-2)) and fotemustine (F) (100 mg m(-2)) and concomitant radiotherapy (2 Gy day(-1), 5 days per week using limited fields up to 60 Gy) to assess efficacy and toxicity of this regimen. Survival (median survival, 12-, 18- and 24-month survival rates) and time to progression (median time to progression (TTP), 6-month progression-free survival) were analysed by Kaplan-Meier's method. A total of 268 (range 1-8, median: 5) cycles were administered. Median survival is 14.5+ (range: 0.5-40+) months, and the 12-, 18- and 24-month survival rates are 58, 29 and 23%, respectively. Median TTP from the start of D/F therapy is 9.5+ (range: 0.5-33+) months. The 6-month progression-free survival is 54%. Partial remissions were observed in 3.6%. Main toxicity was thrombocytopenia. Five patients were excluded from further D/F application, four patients because of prolonged thrombocytopenia NCI-CTC grades 3 and 4 and one patient because of whole body erythrodermia. One patient died because of septic fever during thrombocytopenia and leukopenia NCI-CTC grade 4 after the first cycle. No other toxicities of NCI-CTC grade 3 or 4 occurred. The treatment is feasible in a complete outpatient setting and the results of the D/F regimen justify further investigations with these compounds.     

Survival following CyberKnife radiosurgery and hypofractionated radiotherapy for newly diagnosed glioblastoma multiforme

Current therapeutic goals for treatment of Glioblastoma Multiforme (GBM) involve gross total resection followed by multifractionated focal external beam radiation therapy (EBRT). Patients treated with optimal therapy have a median survival of approximately 12-15 months. In the present study, we sought to determine whether a hypofractionated dosing schedule using CyberKnife is at least as effective as multifractionated focal EBRT. A retrospective analysis was conducted on 20 histopathologically confirmed GBM patients treated with CyberKnife at Okayama Kyokuto Hospital in Japan after gross total resection (n=11), subtotal resection (n=8), or biopsy (n=1). Eight patients also received adjuvant ACNU and Vincrisitine chemotherapy according to local protocol; however, no patient received any other form of radiation besides post surgical/biopsy CyberKnife treatment. The treated tumor volumes ranged from 9.62 cm(3)-185.81 cm(3) (mean: 86.08 cm(3)). The marginal dose (D90) ranged from 19.99 Gy-41.47 Gy (mean: 34.58 Gy) with a maximum mean dose of 43.99 Gy (range: 23.33 Gy-56.89 Gy). The prescribed isodose line ranged from 50.38%-85.68% with a mean of 79.25%. Treatment was delivered in 1-8 fractions (mean: 5.65). Patients were followed from 2-36 months (mean: 16.45 months). Overall median survival was 16 months with 55% of patients alive at 12 months and 34% of patients alive at 24 months. Median survival of patients in Recursive Partitioning Analysis (RPA) classes III or IV was 32 months versus 12 months for those in RPA class V. Median survival for patients who received gross total resection was 36 months versus 8 months for those who underwent subtotal resection or biopsy. The results of this study using CyberKnife stereotactic radiosurgery (SRS) and hypofractionated radiotherapy compared favorably to historic data using focal EBRT in newly diagnosed post surgical GBM patients. A larger prospective analysis that compares CyberKnife SRS and hypofractionated radiotherapy to focal EBRT is warranted.     

The timing of cranial radiation in elderly patients with newly diagnosed glioblastoma multiforme

There are few and conflicting studies on the optimal timing of initial cranial radiation in the treatment of glioblastoma multiforme (GBM) but none of them have addressed this issue in the elderly population. We used the linked Surveillance, Epidemiology, and End Results (SEER) Medicare database to investigate whether the time interval from surgery to initiation of radiation is a significant prognostic factor for survival in subjects aged ≥65 years with newly diagnosed GBM. Cox modeling was used to assess the effect of waiting time on overall survival. We identified a total of 1,375 patients, 296 with biopsies and 1,079 with resections. The median time to the initiation of radiotherapy was 15 days post operation (interquartile range 12–21). In the univariate Cox analysis of those who had debulking surgeries, a waiting time of >22 days showed a significant inverse relationship with survival (hazard ratio [HR] = 0.82, 95% CI 0.70–0.97, p = 0.02), but after adjustment for confounders, it was not a statistically significant factor in the final Cox model (HR = 0.99, 95% CI 0.97–1.01, p = 0.14). Therefore, waiting time was not a significant prognostic factor for subjects with biopsies in both the univariate and multivariate analyses. Although effort should be made to initiate radiotherapy as soon as possible after surgical resection/biopsy, a brief delay similar to that experienced by our cohort does not have a significant impact on survival.     

Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme

Approximately 40–50% of glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active against refractory GBM. Patients with non-small cell lung cancer and ≥grade 2 erlotinib-induced rash have improved survival. This phase 2 study assessed the efficacy and safety of concurrent radiation therapy (RT) and temozolomide with pharmacodynamic dose escalation of erlotinib in patients with newly diagnosed GBM. Patients received RT 60 Gy in 30 fractions with concurrent temozolomide 75 mg/m²/day × 42 days, followed in four weeks by temozolomide 150–200 mg/m²/day × 5, every 28 days for 12 cycles. Patients received erlotinib, 50 mg/day and increased by 50 mg/day every 2 weeks until the occurrence of grade 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease progression. Twenty-seven patients were treated in this study. Twenty-two (81%) patients came off study for progressive disease (18 [67%]) or adverse events (4 [15%]). Eighteen patients (67%) have died. Median progression-free survival was 2.8 months, and the median overall survival was 8.6 months. Five patients remain on study with a median follow-up of 16 months. Grade 3/4 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and febrile neutropenia. There were four deaths on study, three definitely treatment-related; therefore, the trial was terminated after accrual of 27 of 30 planned patients. Erlotinib co administered with RT and temozolomide was not efficacious and had an unacceptable toxicity.     

Assessment of perfusion MRI-derived parameters in evaluating and predicting response to antiangiogenic therapy in patients with newly diagnosed glioblastoma

The paradigm for treating patients with glioblastoma multiforme (GBM) is shifting from a purely cytotoxic approach to one that incorporates antiangiogenic agents. These are thought to normalize the tumor vasculature and have shown improved disease management in patients with recurrent disease. How this vascular remodeling evolves during the full course of therapy for patients with newly diagnosed GBM and how it relates to radiographic response and outcome remain unclear. In this study, we examined 35 patients who were newly diagnosed with GBM using dynamic susceptibility contrast (DSC) MRI in order to identify early predictors of radiographic response to antiangiogenic therapy and to evaluate changes in perfusion parameters that may be predictive of progression. After surgical resection, patients received enzastaurin and temozolomide, both concurrent with and adjuvant to radiotherapy. Perfusion parameters, peak height (PH) and percent recovery, were calculated from the dynamic curves to assess vascular density and leakage. Six-month radiographic responders showed a significant improvement in percent recovery between baseline and 2 months into therapy, whereas 6-month radiographic nonresponders showed significantly increased PH between baseline and 1 month. At 2 months into therapy, percent recovery was predictive of progression-free survival. Four months prior to progression, there was a significant increase in the standard deviation of percent recovery within the tumor region. DSC perfusion imaging provides valuable information about vascular remodeling during antiangiogenic therapy, which may aid clinicians in identifying patients who will respond at the pretherapy scan and as an early indicator of response to antiangiogenic therapy.     

Potential new gene therapy option with sitimagene ceradenovec for newly diagnosed patients with glioblastoma multiforme

Glioblastoma multiforme (GBM) is associated with a poor prognosis with a 5-year survival rate of less than 5%, making GBM one of the most aggressive neoplastic malignancies. However significant strides have been made over the past few years with respect to understanding the pathophysiology as well as treatment modalities. The use of local therapies, particularly gene therapy, has been evaluated, but have yet to make a major clinical impact on treatment of GBM. In a study published by Westphal and colleagues in The Lancet Oncology, the use of sitimagene ceradenovec, a first generation replication-deficient adenovirus containing a prodrug converting enzyme, herpes-simplex virus thymidine kinase, followed by intravenous ganciclovir administration and standard therapy was evaluated compared with standard therapy alone. Patients who received sitimagene ceradenovec had improved time to death or re-intervention, but did not show improvement in overall survival. Patients receiving sitimagene ceradenovec experienced more adverse effects related to treatment, including seizures and hyponatremia. While further studies need to be conducted to determine clinical significance, gene therapy appears to be a viable approach for patients who may be resistant to chemotherapy.     

Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of carmustine (BCNU) in combination with temozolomide as first-line chemotherapy before and after radiotherapy (RT) in patients with inoperable, newly diagnosed glioblastoma multiforme (GBM). PATIENTS AND METHODS: Forty patients were treated with BCNU (150 mg/m2) on day 1 and temozolomide (110 mg/m2/day) on days 1 through 5 of each 42-day cycle for up to four cycles prior to conventional RT (2 Gy fractions to a total of 60 Gy). After RT, BCNU + temozolomide was administered for four additional cycles or until progression. The primary end point was response rate; secondary end points included progression-free survival (PFS); overall survival (OS) and safety. RESULTS: Sixty per cent of patients completed four cycles of neo-adjuvant BCNU + temozolomide. Objective response rate (intention-to-treat) was 42.5% (95% confidence interval 27% to 58%), including two (5%) complete and 15 (37.5%) partial responses. In the eligible population (n=37) the objective response rate was 46%. Nine (24%) patients had stable disease and 14 (35%) had progressive disease. Median PFS and OS were 7.4 and 12.7 months, respectively. Age was the only significant prognostic factor and tumor location (lobar versus multifocal versus corpus callosum) showed a trend. Grade 3-4 toxicities included thrombocytopenia (n=11) and neutropenia (n=7) for both pre- and post-RT chemotherapy. Four patients required platelet transfusions. No patient discontinued treatment because of toxicity. CONCLUSIONS: The combination of BCNU plus temozolomide as neo-adjuvant therapy in inoperable GBM exhibited promising activity with a good safety profile and warrants further evaluation.     

Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study

Despite resection, radiochemotherapy, and maintenance temozolomide chemotherapy (TMZm), the prognosis of patients with glioblastoma multiforme (GBM) remains poor. We integrated immunotherapy in the primary standard treatment for eight pilot adult patients (median age 50 years) with GBM, to assess clinical and immunological feasibility and toxicity in preparation of a phase I/II protocol HGG-2006. After maximum, safe resection, leukapheresis was performed before radiochemotherapy, and four weekly vaccinations with autologous GBM lysate-loaded monocyte-derived dendritic cells were given after radiochemotherapy. Boost vaccines with lysates were given during TMZm. During the course of vaccination, immunophenotyping showed a relative increase in CD8+CD25+ cells in six of the seven patients, complying with the prerequisites for implementation of immunotherapy in addition to postoperative radiochemotherapy. In five patients, a more than twofold increase in tumor antigen-reacting IFN-γ-producing T cells on Elispot was seen at the fourth vaccination compared with before vaccination. In three of these five patients this more than twofold increase persisted after three cycles of TMZm. Quality of life during vaccination remained excellent. Progression-free survival at six months was 75%. Median overall survival for all patients was 24 months (range: 13–44 months). The only serious adverse event was an ischemic stroke eight months postoperatively. We conclude that tumor vaccination, fully integrated within the standard primary postoperative treatment for patients with newly diagnosed GBM, is feasible and well tolerated. The survival data were used to power a currently running phase I/II trial.     

Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma

Reliable data on large cohorts of patients with glioblastoma are needed because such studies differ importantly from trials that have a strong bias toward the recruitment of younger patients with a higher performance status. We analyzed the outcome of 676 patients with histologically confirmed newly diagnosed glioblastoma who were treated consecutively at a single institution over a 7-year period (1997-2003) with follow-up to April 30, 2006. Survival probabilities were 57% at 1 year, 16% at 2 years, and 7% at 3 years. Progression-free survival was 15% at 1 year. Prolongation of survival was significantly associated with surgery in patients with a good performance status, whatever the patient's age, with an adjusted hazard ratio of 0.55 (p < 0.001) or a 45% relative decrease in the risk of death. Radiotherapy and chemotherapy improved survival, with adjusted hazard ratios of 0.61 (p = 0.001) and 0.89 (p = 0.04), respectively, regardless of age, performance status, or residual tumor volume. Recurrence occurred in 99% of patients throughout the follow-up. Reoperation was performed in one-fourth of these patients but was not effective, whether performed within 9 months (hazard ratio, 0.86; p = 0.256) or after 9 months (hazard ratio, 0.98; p = 0.860) of initial surgery, whereas second-line chemotherapy with procarbazine, lomustine, and vincristine (PCV) or with temozolomide improved survival (hazard ratio, 0.77; p = 0.008). Surgery followed by radiotherapy and chemotherapy should be considered in all patients with glioblastoma, and these treatments should not be withheld because of increasing age alone. The benefit of second surgery at recurrence is uncertain, and new trials are needed to assess its effectiveness. Chemotherapy with PCV or temozolomide seems to be a reasonable option at tumor recurrence.     

Early post-treatment pseudo-progression amongst glioblastoma multiforme patients treated with radiotherapy and temozolomide: a retrospective analysis

Introduction: To evaluate the incidence and impact of early post‐chemoradiation (cRT) ‘pseudoprogression’ (PsPD) amongst glioblastoma multiforme (GBM) patients treated with the current standard of care – 60 Gy conformal radiotherapy with concurrent low‐dose temozolomide, followed by six cycles of high‐dose temozolomide (the ‘Stupp protocol’). Methods: Clinical notes and radiology reports for GBM patients treated as per the Stupp protocol were reviewed. PsPD was defined as apparent radiological progression on the first post‐cRT scan, with further imaging within 3 months being stable or improving, while true early progression (ePD) was confirmed by continued progression in the subsequent 3 months following the first post‐cRT scan. Results: Of the 68 patients evaluated, 14 (21%) and 27 (40%) experienced PsPD and ePD, respectively; 3/14 (21%) patients experiencing PsPD and 14/27(52%), ePD were symptomatic for progression on first post‐cRT follow‐up (P = 0.096 for difference). Median survival for patients with ePD, PsPD and neither were 10.4, 27.4 and 13.0 months, respectively (P = 0.003 for ePD vs. PsPD, P = 0.19 for neither vs. PsPD groups). Conclusion: These data confirm a significant incidence of PsPD in post‐cRT GBM patients, associated with improved median survival compared with those with neither ePD nor PsPD (not statistically significant). It appears likely that PsPD actually represents tumour response, conflicting with the traditional notion that increase in lesion size on contrast‐enhanced imaging represents disease progression. Early post‐cRT imaging should thus be interpreted with caution. Accompanying clinical symptoms are more commonly associated with ePD, but do not reliably distinguish PsPD from ePD.     

Volumetric and MGMT parameters in glioblastoma patients: Survival analysis

Background  

In this study several tumor-related volumes were assessed by means of a computer-based application and a survival analysis was conducted to evaluate the prognostic significance of pre- and postoperative volumetric data in patients harboring glioblastomas. In addition, MGMT (O⁶-methylguanine methyltransferase) related parameters were compared with those of volumetry in order to observe possible relevance of this molecule in tumor development.     

Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme

PURPOSE: The chemotherapeutic agent temozolomide (TMZ) and the antiangiogenic agent thalidomide have both demonstrated antitumor activity in patients with recurrent malignant glioma. The objectives of this study were to determine if the combined strategy of these oral agents with radiation therapy (RT) is associated with an improved median survival of patients with newly diagnosed glioblastoma multiforme and to evaluate toxicity. METHODS AND MATERIALS: Sixty-seven patients were enrolled in this trial. Radiotherapy parameters were a total dose of 60 Gy delivered in 2 Gy fractions over 6 weeks. Temozolomide was administered starting the first day of RT at 150 mg/m(2) daily for 5 days every 4 weeks for the first cycle and escalated to a maximum dose of 200 mg/m(2). Thalidomide was started on Day 7 of RT at 200 mg and escalated by 100-200 mg every 1-2 weeks depending on patient tolerance, to a maximum of 1,200 mg daily. RESULTS: Sixty-one patients have progressed, with a median time to progression of 22 weeks. Fifty-six patients have died, and the median survival was 73 weeks. CONCLUSIONS: This strategy of combination TMZ, thalid and RT was relatively well tolerated with favorable survival outcome for patients with GM when compared to patients not treated with adjuvant chemotherapy and similar to those who have received nitrosourea adjuvant chemotherapy. It is unclear the added advantage thalid has in combination with TMZ for this patient population.     

Response assessment during chemoradiation using a hypercellular/hyperperfused imaging phenotype predicts survival in patients with newly diagnosed glioblastoma

BackgroundAdversely prognostic hypercellular and hyperperfused regions of glioblastoma (GBM) predict progression-free survival, and are a novel target for dose-intensified chemoradiation (chemoRT) recently implemented in a phase II clinical trial. As a secondary aim, we hypothesized that dose-intensified chemoRT would induce greater mid-treatment response of hypercellular/hyperperfused tumor regions vs standard chemoradiation, and that early response would improve overall survival (OS).MethodsForty-nine patients with newly diagnosed GBM underwent prospective, multiparametric high b value diffusion-weighted MRI (DW-MRI) and perfusion dynamic contrast-enhanced MRI (DCE-MRI) pre-RT and 3-4 weeks into RT. The hypercellular tumor volume (TV_HCV, mean contralateral normal brain + 2SD) and hyperperfused tumor volume (TV_CBV, contralateral normal frontal gray matter + 1SD) were generated using automated thresholding. Twenty-six patients were enrolled on a dose-escalation trial targeting TV_HCV/TV_CBV with 75 Gy in 30 fractions, and 23 non-trial patients comprised the control group. OS was estimated using the Kaplan-Meier method and compared using the log-rank test. The effect of TV_HCV/TV_CBV and Gd-enhanced tumor volume on OS was assessed using multivariable Cox proportional-hazard regression.ResultsMost patients had gross total (47%) or subtotal resection (37%), 25% were MGMT-methylated. Patients treated on the dose-escalation trial had significantly greater reduction in TV_HCV/TV_CBV (41% reduction, IQR 17%-75%) vs non-trial patients (6% reduction, IQR 6%-22%, P = .002). An increase in TV_HCV/TV_CBV during chemoRT was associated with worse OS (adjusted hazard ratio [aHR] 1.2, 95%CI 1.0-1.4, P = .02), while pre-treatment tumor volumes (P > .5) and changes in Gd-enhanced volume (P = .9) were not.ConclusionsMultiparametric MRI permits identification of therapeutic resistance during chemoRT and supports adaptive strategies in future trials.     

The efficacy and safety of extended adjuvant temozolomide following concurrent radio-chemotherapy among Egyptian patients with newly diagnosed glioblastoma multiforme

Although concurrent radio-chemotherapy and adjuvant temozolomide (TMZ) treatment for 6 cycles has been established as a standard of care for newly diagnosed glioblastoma multiforme (GBM) patients, the recommended duration of adjuvant TMZ remains a matter of debate. Hereby, we aimed to report for the first time our experience from Upper Egypt through comparing survival and toxicity profile between two treatment modalities of adjuvant TMZ (> six cycles versus six cycles) and delineating factors of prognostic significance in Egyptian patients with newly diagnosed GBM treated by radiation therapy with concomitant and adjuvant TMZ. Between June 2016 and February 2018, the medical records of 121 patients were eligible to be retrospectively reviewed to extract the study relevant data. All patients received concurrent radio-chemotherapy, followed by TMZ for 6 cycles in 29 patients (Group 1) and for >6 cycles in 26 patients (Group 2). Patients in Group 1 had a median PFS of 15 months (95% CI: 10.215-19.785), while those in Group 2 had a median PFS of 18 months (95% CI: 16.611-19.389). After a median follow up duration of 20 months (range: 12-41), the median OS was 18 months (95% CI: 13.420-22.580) in Group 1 and 22 months (95% CI: 18.777-25.223) in Group 2. There was no statistically significant correlation between the number of chemotherapy cycles and PFS (P=0.513) or OS (P=0.867). The extent of surgical resection was the only independent prognostic factor for both PFS (P=0.015) and OS (P=0.028) by multivariate analysis. Three grade ≥3 hematologic toxicity were encountered in 3 patients. One in the six-cycle group (neutropenia), and two in the extended cycles group (one had neutropenia and the other one developed thrombocytopenia). No statistically significant difference in the toxicity profile between both groups. The results of our study suggest that extended TMZ therapy is safe and tolerable, however it did not significantly improve PFS or OS as compared to the standard six-cycle course. Larger randomized studies are required to shed more light on this issue.     

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65–1.16; HR for PFS = 0.84; 95% CI = 0.64–1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68–1.38; HR for PFS = 1.02; 95% CI = 0.74–1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42–1.10; HR for PFS = 0.57; 95% CI = 0.36–0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51–1.56; HR for PFS = 1.05; 95% CI = 0.64–1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.