Bevacizumab-containing Regimens Research Articles

Efficacy and safety of bevacizumab plus irinotecan in patients with recurrent malignant poor-prognosis glioma.

e12555 Background: There is currently no standard of care for recurrent glioblastoma multiforme (GBM), although the anti-VEGF monoclonal antibody bevacizumab (Bev) has shown efficacy in conjunction with irinotecan (Iri). We present a retrospective analysis of patients with recurrent malignant brain tumors treated with Bev-Iri at our clinic. Methods: 37 adult patients with recurrent malignant brain tumors were included. Patient characteristics: median age 46 years, GBM diagnosis n = 26, other brain tumor histology n = 11. Prior surgery n = 34, prior chemotherapy n = 37, prior radiotherapy n = 32. Patients received Bev 10 mg/kg i.v. and Iri 125 mg/m2 i.v. (340 mg/m2 in one patient receiving enzyme-inducing antiepileptic drugs) every 14 days. Treatment was stopped on progression, patient's wish or physician's decision. Response was assessed using MacDonald's criteria on post-contrast MRI with inclusion of FLAIR, T2 and perfusion-weighted MRI. Adverse events (AEs) were monitored throughout therapy. Results: Patients received a median of 7 cycles of Bev-Iri (range 3–15) and 8 patients received maintenance Bev until progression. 26 patients (70%) achieved a complete or partial response with Bev-Iri, and 4 (11%) had stable disease. Median time to progression was 5.8 months (range 1.4–not reached) and median overall survival was 11.1 months (range 2.7–not reached) without difference between GBM patients and the group with other types of malignant brain tumors. The bevacizumab/irinotecan combination was well tolerated, with few grade 3 AEs (8 lymphocytopenia, 2 leucocytopenia, 1 diarrhea); there were no AEs of grade > 3. The most common grade 1–2 AEs were leucocytopenia (n = 7), hypertension (n = 5) and lymphocytopenia (n = 4). Conclusions: Our data show that bevacizumab plus irinotecan is an effective combination for recurrent malignant brain tumors and correspond with Phase II data for this strategy. The median overall survival of over 11 months in our study represents a considerable improvement in prognosis for these patients and warrants a larger, more thorough prospective exploration of this combination. The potential for bevacizumab-containing maintenance regimens also exists. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche

SPIRITT: A multicenter, open-label, randomized, phase II clinical trial evaluating safety and efficacy of FOLFIRI with either panitumumab or bevacizumab as second-line treatment in patients with metastatic colorectal cancer (mCRC) with wild-type KRAS tumors.

TPS195 Background: The optimal treatment of patients with mCRC who have progressed on a bevacizumab-containing regimen remains unclear. Many patients receive second-line chemotherapy with bevacizum...

Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8-34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3-28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients.

Efficacy and Safety of Pazopanib in Patients With Metastatic Renal Cell Carcinoma

Inactivation of the von Hippel-Lindau gene in clear-cell renal cell carcinomas (RCC) leads to overexpression of hypoxia inducible factor, a transcription factor regulating vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) gene expression. Pazopanib, an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor, and c-KIT, was evaluated in patients with RCC. This phase II study was designed as a randomized discontinuation study but was revised to an open-label study on the recommendation of the data monitoring committee (based on week 12 response rate [RR] of 38% in the first 60 patients). The primary end point was changed from progressive disease rate at 16 weeks postrandomization to RR. Pazopanib 800 mg was administered orally once daily. Pazopanib 800 mg was administered orally once daily. The study enrolled 225 patients with metastatic RCC; 155 patients (69%) were treatment naïve, and 70 patients (31%) had received one prior cytokine- or bevacizumab-containing regimen. Overall RR was 35%; median duration of response was 68 weeks. Median progression-free survival (PFS) was 52 weeks. Eastern Cooperative Oncology Group performance status of 0 and time from diagnosis to treatment of more than 1 year were correlated with prolonged PFS. Pazopanib was generally well tolerated. The most common adverse events were diarrhea, fatigue, and hair depigmentation. The most common laboratory abnormalities were elevated AST and ALT. Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of pazopanib in advanced RCC.

Reversible posterior leucoencephalopathy syndrome associated with anticancer drugs

Reversible posterior leucoencephalopathy syndrome (RPLS) is an underappreciated clinical-radiologic syndrome characterized by reversible cortical dysfunction preferentially involving the occipital lobes in conjunction with imaging findings of reversible subcortical oedema. As RPLS is being increasingly identified within the oncology population in association with cytotoxic chemotherapy and targeted agents, a review of the published work in English was carried out. A MEDLINE search of the published work in English was conducted to identify cases of RPLS in patients more than 16 years of age who were treated with anticancer drugs for documented malignancy. Only cases with adequate documentation regarding demographic and treatment data, cerebral magnetic resonance imaging and outcome were selected. We identified 24 patients with RPLS associated with a variety of anticancer drugs, most commonly complicating polychemotherapy and/or bevacizumab-containing regimens. There was a female predominance: 18 females and 6 males (P= 0.023). Women were of premenopausal age and were younger than males: 49.3 +/- 16.4 years versus 60.7 +/- 6.4 years (P= 0.09). Most patients presented with acute headache (67%), seizures (63%), confusion (54%) or cortical blindness (46%) with mean systolic and diastolic blood pressure of 168 +/- 15 and 98 +/- 15 mm Hg, respectively. Findings on magnetic resonance imaging showed hyperintense lesions on T(2)-weighted images in all patients, which involved the occipital lobes in 75% of patients; all patients experienced clinical and radiologic resolution within days to weeks. No deaths were directly attributed to RPLS. Combination and single-agent chemotherapy as well as novel anticancer drugs are associated with RPLS. We found RPLS to be overrepresented in premenopausal woman; the prevalence in this subgroup may be related to an anticancer drug-oestrogen interaction inducing altered cerebral vasoreactivity and endothelial dysfunction.

Cisplatin-Based Chemotherapy Is Associated with An Unacceptably High Incidence of Thromboembolic Events: A Large Retrospective Analysis.

Abstract 456▪▪This icon denotes an abstract that is clinically relevant. Introduction:Cancer is a well established risk factor for the development of venous and arterial thromboembolic events (TEEs), including deep venous thrombosis, pulmonary embolus, cerebrovascular accident, and unstable angina/myocardial infarction. In addition to cancer itself, cytotoxic chemotherapy has been shown to potentiate the risk of TEEs. Among chemotherapeutic agents, cisplatin may be associated with a particularly high incidence of TEEs as suggested by few small series. The objective of this study was to determine the incidence of TEEs in patients treated with cisplatin based chemotherapy. Patients and Methods:We performed a large retrospective analysis of all patients treated at MSKCC for a variety of malignancies with cisplatin-based chemotherapy in 2008. Patients were included if they were at least 18 years of age, had received their first dose of their planned chemotherapy regimen between January 1, 2008 and December 31, 2008, and had at least 4 weeks of follow-up since the last dose of cisplatin. Patients were identified using the pharmacy information system. The diagnosis of TEE was based on documentation provided by angiography, magnetic resonance imaging, computed tomography, venous Doppler ultrasound, ventilation/perfusion scan, as well as clinical and laboratory documentation of myocardial infarction by EKG/troponin as per the patients' electronic medical record. A TEE was considered cisplatin-associated if it occurred between the time of the first dose of cisplatin administration and 4 weeks after the last dose. Results:Overall, 1,098 patients received at least one dose of cisplatin in 2008, of whom 936 met the inclusion criteria. The underlying cancer diagnoses included lung (21.7%), head and neck (10%), gastric (8.2%), pancreatic (8.1%), and melanoma (7.3%). The extent of disease at the time of cisplatin administration included metastatic disease (46.7%), locally advanced disease (43.6%) and early stage disease (7%). Among the 936 patients, 171 (18.3%) experienced a TEE during cisplatin administration or within 4 weeks of the last dose. TEEs occurred within 90 days of initiation of treatment in 146 out of 171 (85.4%) patients. The thrombotic events included a DVT in 86 patients (50.3%); PE in 45 patients (26.3%); a DVT and a PE in 22 patients (12.9%); an arterial TEE (CVA, MI, or distal arterial thrombosis) in 13 patients (7.6%); or DVT and an arterial TEE in 5 patients (2.9%). The incidence of TEEs varied according to the underlying primary cancer diagnosis with a TEE occurring in 38.2% of patients with pancreatic cancer, 31.2% with gastric cancer, 25% with gastroesophageal junction cancer, 20.7% with ovarian cancer, and 18.9% with germ cell cancer. The incidence of TEEs also varied according to extent of disease with TEEs most frequently seen in patients with metastatic disease (97 patients, 22.2%) compared to locally advanced (60 patients, 14.7%) or early stage disease (11 patients, 16.7%). Likewise, the incidence of TEE varied according to the type of cisplatin based chemotherapeutic combinations with TEE occurring in 27.3% for gemcitabine-containing regimens; in 26.4% for docetaxel-containing regimens; in 24.6% for bevacizumab-containing regimens; in 19.5% for irinotecan-containing regimens; and in 14.1% for vinblastine-containing regimen. Of note, a TEE occurred in 11 out of 16 patients receiving cisplatin plus docetaxel plus 5-FU/leucovorin plus bevacizumab. Conclusions:This large retrospective analysis confirms the unacceptable high incidence of TEEs in patients receiving cisplatin based chemotherapy, which is 18.3% across all underlying primary cancers. As one would expect, the incidence of TEE varied according to primary cancer, extent of disease, and chemotherapeutic regimens. It is likely that the incidences reported in this retrospective analysis represent an under-estimate of the real incidence of TEEs since some patients with TEE may have been missed because of lack of adequate documentation. It is important to highlight that the majority of events occurred within 90 days of the first dose of cisplatin. This study suggests that TEE prophylaxis may be advisable for patients receiving cisplatin-based chemotherapy. A prospective study is currently in progress. Disclosures:No relevant conflicts of interest to declare.

Bevacizumab for recurrent ependymoma

Ependymoma is a rare type of glioma, representing 5% of all CNS malignancies. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. At recurrence, ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed. In this Institutional Review Board-approved study, we retrospectively analyzed the records of 8 adult patients treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria), median time to progression (TTP), and median overall survival (OS; Kaplan-Meier method). There were 4 men and 4 women with a median age of 40 years (range, 20-65). Prior treatment included surgery (n = 8), RT (8), temozolomide (5), and carboplatin (4). Bevacizumab (5-15 mg/kg every 2-3 weeks) was administered alone (2) or concurrently with cytotoxic chemotherapy including irinotecan (3), carboplatin (2), or temozolomide (1). Six patients achieved a partial response (75%) and 1 remained stable for over 8 months. Median TTP was 6.4 months (95% confidence interval 1.4-7.4) and median OS was 9.4 months (95% confidence interval 7.0-not reached), with a median follow-up of 5.2 months among 5 surviving patients (63%). The radiographic response rate to bevacizumab-containing regimens is high. A prospective study is warranted.

The role of salvage reirradiation for malignant gliomas that progress on bevacizumab

Bevacizumab and irinotecan are effective against recurrent malignant gliomas. However, at subsequent progression, patients rarely respond to a second bevacizumab-containing chemotherapeutic regimen. Salvage re-irradiation with bevacizumab for recurrent but bevacizumab naive malignant gliomas showed encouraging results. We performed a retrospective review of the medical records of 23 patients treated with either fractionated stereotactic radiotherapy (FSRT) or stereotactic radiosurgery (SRS) after progression on an initial bevacizumab regimen. Patients were treated after re-irradiation with bevacizumab but combined with a different chemotherapy. We then compared them to another 23 patients who progressed on an initial bevacizumab + chemotherapy regimen. These patients did not receive re-irradiation but bevacizumab was continued combined with a different chemotherapy. Patients treated with FSRT/SRS/bevacizumab had a longer median progression-free period (2.6 vs. 1. 7 months, P = 0.009), longer median post FSRT/SRS treatment survival (7.2 vs. 3.3 months, P = 0.03) and higher radiographic response rate (22 vs. 0%, P = 0.049). FSRT or SRS followed by bevacizumab + chemotherapy may have a role for patients who progress on bevacizumab.

Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that has efficacy in recurrent malignant gliomas, particularly in combination with irinotecan. However, responses are rarely durable. Continuation of bevacizumab in combination with another chemotherapeutic agent may demonstrate some activity. In this article we present a retrospective review of 54 patients with recurrent malignant gliomas who progressed on a bevacizumab-containing regimen and were then treated with an alternate bevacizumab-containing regimen. All patients received intravenous bevacizumab (5-10 mg/kg) every 2 weeks alone or in combination with an additional chemotherapeutic agent, such as irinotecan. There was no limit on the number of prior therapies. Clinical characteristics and outcomes were reviewed. Tumor progression was determined by a combination of clinical status and radiographic changes. Patients were 33 men, 21 women (median age, 50 years; range, 23-72 years) with a median KPS score of 80 prior to the first bevacizumab-containing regimen and 70 prior to the second regimen; median prior chemotherapy regimens including the first bevacizumab-containing regimen was 3 (range, 2-5). Median progression-free survival (PFS) on the first bevacizumab-containing regimen was 124 days (95% confidence interval [CI], 87-154 days); 6-month (6M)-PFS was 33%. Median PFS on the second bevacizumab-containing regimen was 37.5 days (95% CI, 34-42 days); 6M-PFS was 2%. Ten patients on the first regimen and 12 patients on the second regimen suffered grade 3/4 toxicities. Those patients with malignant gliomas who progressed despite a bevacizumab-containing regimen rarely responded to the second bevacizumab-containing chemotherapeutic regimen. In such patients, alternate therapies should be considered.

Bevacizumab for salvage treatment of metastatic breast cancer: a systemic review and meta-analysis of randomized controlled trials

Although various new agents have been developed for the treatment of patients with metastatic breast cancer (MBC), overall survival rates have changed little in the last half century. We conducted meta-analysis to verify the clinical efficacy of bevacizumab for the salvage treatment of MBC. Event-based hazard ratios (HR) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Four studies, with a total of 2,860 patients, met the inclusion criteria for analysis. The pooled results of clinical efficacies were: HR for progression free survival 0.69 (95% CI, 0.58-0.81, z = 4.54, P <0.001); HR for overall survival 0.92 (95% CI, 0.82-1.03, z =1.44, P = 0.15); and HR for the clinical objective response rate 1.53 (95% CI, 1.37-1.71, z = 7.37, P < 0.001). In terms of overall survival, subgroup analysis demonstrated statistically significant improvement for the bevacizumab combination in the initial therapy subgroup (HR, 0.878; 95% CI, 0.771-0.999, z = 1.98, P = 0.048). Hypertension and proteinura were more common in the bevacizumab combination arm; however, these toxicities were managed with therapy. In conclusion, meta-analysis suggested benefits of a carefully managed bevacizumab-containing salvage regimen for patients with histologically or cytologically confirmed Her-2 negative MBC who have not received previous cytotoxic therapy. This treatment could improve both progression free survival and overall survival rates.

Bevacizumab Plus Platinum-Based Chemotherapy

black triangle Bevacizumab is a recombinant, humanized vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits tumor growth and tumor metastases. VEGF stimulates angiogenesis in tumors, is involved in early metastatic processes, and is overexpressed in non-small cell lung cancer (NSCLC). black triangle The addition of bevacizumab to standard chemotherapy significantly delayed disease progression in two large, randomized, phase III trials in chemotherapy-naive patients with advanced, nonsquamous NSCLC. In the open-label E4599 trial, median overall survival duration was significantly extended by 2 months and median progression-free survival was significantly increased by 1.7 months when intravenous bevacizumab 15 mg/kg once every 3 weeks was added to first-line carboplatin/paclitaxel therapy compared with carboplatin/paclitaxel alone. black triangle In the double-blind AVAiL trial, median progression-free survival was significantly increased (by 0.6 and 0.4 months) by the addition of intravenous bevacizumab 7.5 or 15 mg/kg once every 3 weeks to first-line cisplatin/gemcitabine therapy compared with placebo plus cisplatin/gemcitabine. However, median overall survival duration was not significantly improved (13.6 and 13.4 months vs 13.1 months). black triangle Response rates in the E4599 and AVAiL trials were 30-35% in patients receiving bevacizumab plus platinum-based chemotherapy compared with 15% and 20% without bevacizumab. black triangle The safety and tolerability profile of bevacizumab-containing treatment regimens in patients with advanced NSCLC was generally manageable in the E4599 and AVAiL trials, and in two large, ongoing, trials (the open-label SAiL and the observational ARIES studies).

Phase II study of bevacizumab in combination with cetuximab plus irinotecan in irinotecan-refractory colorectal cancer (CRC) patients who have progressed on a bevacizumab-containing regimen (The BOND 2.5 Study)

4087 Background: We previously showed that adding bevacizumab (bev) to cetuximab (cetux) plus irinotecan (IRI) in bev-naïve, IRI-refractory CRC patients is feasible, and yielded a favorable response rate and time to tumor progression (TTP) compared with historical controls (Saltz: JCO, 2007). Since most CRC patients now receive a bev-containing regimen prior to cetux, we evaluated the addition of bev to cetux plus IRI (CBI) in patients with metastatic CRC who had previously progressed on chemo + bev. Methods: All patients were naïve to cetux. The importance of KRAS mutation was not appreciated when the trial was designed and this has not yet been evaluated. Patients received IRI at the same dose and schedule as last received prior to study, Cetux 400 mg/m2 loading dose, then weekly at 250 mg/m2, plus Bev 5 mg/kg given every two weeks or 7.5 mg/kg given every three weeks. Results: 33 received treatment. Median age was 58 (range 29–85). Median number of prior regimens was 2 (range 1–2). Median performance status was ECOG 1 (range 0–1). Patients received a median of 2 cycles (range 1–15). Grade 3/4 Toxicities: Acneiform Rash 18%, hypomagnesemia 6%, hypophosphatemia 6%, Neutropenia 15%, Diarrhea 6%. One patient developed neutropenic fever and one patient had a hypersensitivity reaction to cetux. At a median follow up of 32 months (range 21–32 months) in 33 evaluable patients, we observed 3 (9%) partial responses and 11 (33%) patients with stable disease for &gt; 4 months. Median TTP was 3.9 months (95% CI: 1.3 - 6.8). Median survival was 10.6 months (95% CI: 6.6 - 13.8). Conclusions: The toxicity profile was similar to what would have been expected from the individual agents alone. Recognizing the limitations of cross-study comparisons, the response rates and TTP seen with CBI in patients who have previously progressed on bev do not appear to be as encouraging as the 37% response rate and 7.3 months TTP seen in the BOND 2 trial of bev-naïve CRC patients. Ongoing randomized trials, including SWOG 0600, will be needed to definitively determine the contribution of continued use of bev after progression on a bev-containing regimen. Supported by Genentech. [Table: see text]

Perioperative chemotherapy with bevacizumab (BV) for liver metastases (LM) in colorectal cancer (CRC): McGill University pilot study

e15027 Background: Colorectal liver metastases treated with perioperative chemotherapy were previously shown to increase progression free survival. Given the survival benefit of bevacizumab in metastatic CRC, the aim of this study was to assess the efficacy and safety of bevacizumab based chemotherapy in the perioperative setting. Methods: In this single arm prospective pilot study, patients with resectable LM eligible to receive perioperative BV and chemotherapy were included. Kaplan Meier survival analysis was used to calculate overall survival and progression free survival. Results: A total of 60 patients were recruited, 41 male, with an average age of 55. Forty-three patients had synchronous LM. All but seven patients received pre and post-operative BV-based chemotherapy (34/60 oxaliplatin based, 22/60 CPT-11 based and 4/60 CPT-11 and oxaliplatin based). All patients underwent hepatectomy 6–8 weeks post last dose of BV. Overall response rate was 80% (48/60), 4pt with stable diseaase; 10% had a complete pathological response and 27% had no evidence of disease post hepatectomy with a median follow up of 33 months.8 patients progressed prior to surgery. Overall survival (OS) rates at 12, 24, 36 and 48 months were: 100%, 86%, 74% and 66% respectively and 5 year median survival of 55%. Progression free survival (PFS) was 14 months. Subgroup analysis of the data according to the chemotherapy pts received showed that PFS in the CPT-11 and the oxaliplatin arm were 13 and 15 months respectively. Most of the adverse events recorded were associated with the post-operative period and included wound healing (8pts), infections (2pts) and thromboemblic (6pts) disease. No sudden deaths or bowel perforations were reported. Conclusions: Bevacizumab-containing chemotherapy regimens in the peri-operative setting is effective in patients with colorectal liver metastases. Our 80% response rate and 10% complete pathological response is one of the highest reported and warrants further investigation in phase III trials. [Table: see text]

Hidden Biases in an Observational Study of Bevacizumab Beyond Progression

TO THE EDITOR: Grothey et al 1 recently reported a prospective observational study that monitored oncologists’ use of bevacizumab after patients experienced disease progression while receiving a prior bevacizumab-containing regimen. The conclusion formed on the basis of this study was that there was a suggested survival benefit from continuing bevacizumab after failure of a first-line bevacizumabcontaining regimen, with a hazard ratio (HR) of 0.46 on multivariate analysis. Generally, observational studies can provide important data on toxicities and practice patterns, but these types of studies have significant limitations when they are used to answer comparative questions of efficacy. Grothey et al 1 clearly acknowledge the potential bias with this study design and attempt to adjust for several factors. Unfortunately, it is impossible to quantify the extent to which this bias formed or altered the outcome of the trial. Several important sources of bias cannot be controlled for in the absence of randomization to treatment in this study, as will undoubtedly be delineated in this space by other readers of this journal. As a result, factors that are correlated with survival also affect the oncologist’s decision to continue bevacizumab. Several poor prognosis factors that may decrease an oncologist’s enthusiasm to continue bevacizumab include poor performance status at progression, higher vascular comorbidities, rapid tumor growth while receiving the prior bevacizumab-containing regimen, or peritoneal disease. Each of these factors would generally have predicted shorter survival in patients in whom bevacizumab was discontinued. However, in lieu of enumerating the number and reasoning for such biases in greater detail, we conducted similar analyses that may help to highlight the extent to which the conclusions in this observational trial may have been formed by these unseen biases. Since the US Food and Drug Administration’s approval of bevacizumab in 2004, most previously untreated metastatic colorectal patients at our institution have been treated with a bevacizumab-containing regimen. We chose to retrospectively examine these sequential patients to determine if patients treated again with bevacizumab as part of a later-line regimen had improved outcomes than those who did not receive a later-line bevacizumab-containing regimen. Indeed, we were able to demonstrate a similar HR of 0.62 (P .01) in favor of patients receiving bevacizumab after failing a prior bevacizumab-containing regimen.

Bevacizumab Beyond Progression: Does This Make Sense?

Bevacizumab Beyond Progression: Does This Make Sense?

Bevacizumab -- News from the Fast Lane?

The introduction of bevacizumab (Avastin), an antibody to the vascular endothelial growth factor (VEGF), into the repertoire of the medical management of malignant gliomas has influenced the area of glioma treatment quite markedly. First, after decades of aiming at stopping tumor growth and being quite satisfied with documenting “stable disease,” we are suddenly observing objective response rates at a never-seen frequency exceeding 50%.1 Admittedly, we have not been convinced by any report that the high response rate translates into a gain in survival. The progression-free survival rate at 6 months— our current gold standard of assessing novel treatments for recurrent glioblastoma—may be in the range of 40%, but similar figures are also achieved with dose-intense regimens of temozolomide. Second, we may need to reconsider the MacDonald response criteria, which overall have served us well in assessing the efficacy of novel treatments, but which are heavily based on contrast enhancement. Yet in the era of antiangiogenic agents like bevacizumab, which may soon be joined by cilengitide or enzastaurin, altered patterns of recurrence resulting from a change from vessel/VEGF-dependent growth to vessel/VEGF-independent tumor growth2 may necessitate the development of new response criteria. Third, and perhaps heralding new patterns of toxicity common to the new class of antiangiogenic agents for glioma treatment, the fear of intratumoral hemorrhages may not have been justified, but craniotomy site dehiscence is increasingly noted as a relevant complication in a minority of glioma patients treated with bevacizumab.3 Fourth, the impressive effects of the combination of bevacizumab and irinotecan were unexpected and initially suggested strong synergistic potential for two agents that appeared to have limited activity when administered alone. Yet the results from the first randomized trial of bevacizumab alone versus bevacizumab plus irinotecan presented by Cloughesy and colleagues at the 2008 American Society for Clinical Oncology meeting in Chicago appear to confirm the suspicion that irinotecan is contributing little to the overall effect of this novel regimen. Along these lines, switching patients who progress under bevacizumab and irinotecan to another bevacizumab-containing regimen seems to offer little hope for response.2 In the current issue of Neuro-Oncology, Ingeborg Fischer and colleagues report on their investigation into histological features of malignant gliomas after treatment with bevacizumab.4 Five paired tissues obtained prior to and after exposure to bevacizumab were available and compared with four paired tissues from patients never exposed to bevacizumab. Decreased vessel density correlated with radiographic responses to bevacizumab, whereas the levels of VEGF-A and various other histological and immunochemistry parameters did not. While the case numbers of this study are low, such tissues are difficult to assemble, and approaches as outlined here are very important. They are likely to result in the identification of biomarkers associated with response, or the lack thereof, to experimental brain tumor treatments and will help to design a scientific basis and possibly new endpoints for upcoming clinical trials, notably in the emerging field of novel antiangiogenic agents.

Role of a second chemotherapy in recurrent malignant glioma patients who progress on a bevacizumab-containing regimen

2008 Background: Bevacizumab is a humanized VEGF monoclonal antibody with promising activity in recurrent glioblastomas, alone and in combination with irinotecan. Patients who progress on this regimen are frequently maintained on bevacizumab and the concurrent chemotherapeutic agent is changed. The benefit of this therapeutic strategy is unknown. Methods: We retrospectively reviewed the clinical features and radiologic studies of 44 patients with recurrent malignant glioma who progressed on a bevacizumab-containing regimen and were then treated with an alternate bevacizumab-containing regimen. All patients received bevacizumab 10 mg/kg IV every 2 weeks. As the initial bevacizumab-containing regimen, 37 patients received irinotecan, 4 bevacizumab alone, 1 temozolomide and 2 carboplatin. As a second bevacizumab-containing regimen, 32 patients received carboplatin, 6 irinotecan, 2 BCNU, 1 CCNU, 1 etoposide, 1 erlotinib/rapamycin and 1 erlotinib. There was no limit on the number of prior therapies. Clinical characteristics and outcomes were reviewed. Tumor progression was determined by a combination of clinical status and radiographic changes. Results: Patient characteristics were 28 male, 16 female; median age 49 years (range 22–72); median KPS prior to receiving both regimens 70 (range 60–100 with first regimen and 40–100 with second regimen); median prior chemotherapy regimens including the first bevacizumab-containing regimen was 3 (range 2–5). Median PFS on first bevacizumab-containing regimen was 123.5 days. 6 month PFS was 33%. Median PFS on the second bevacizumab-containing regimen was 40 days (range 14 to 359 days). 6 month PFS was 2%. The number of grade 3/4 adverse events was similar between the two groups (7 with the first regimen and 8 with the second regimen). Conclusions: Patients with malignant gliomas who progress following treatment with a bevacizumab-containing chemotherapeutic regimen generally respond poorly to a second chemotherapy combined with bevacizumab. Other therapeutic options should be considered for these patients. No significant financial relationships to disclose.

A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable?

The role of bevacizumab, a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor, in the treatment of pancreatic cancer remains unclear. The objectives of this study were to determine safety and efficacy in chemotherapy-naive patients with metastatic pancreatic cancer receiving bevacizumab in combination with fixed-dose rate (FDR) gemcitabine and low-dose cisplatin. Eligible patients received gemcitabine 1,000 mg/m2 at FDR infusion (10 mg/m(2) per minute), cisplatin 20 mg/m(2), and bevacizumab 10 mg/kg, on days 1 and 15 of a 28-day cycle. Patients were monitored by computed tomography scans every two cycles and monthly serum CA19-9 measurements. Of 52 patients eligible for analysis, ten (19.2%) had an unconfirmed response and 30 (57.7%) had stable disease. Of 35 patients with elevated baseline CA19-9 levels, 20 (57.1%) had > or = 50% biomarker decline during treatment. Median time to tumor progression was 6.6 months and median survival was 8.2 months (estimated 1-year survival, 36%). Grade 3/4 toxicities possibly related to bevacizumab included thromboembolic events (15.1%), hypertension (13.2%), gastrointestinal bleeding (9.4%), cardiac events (7.5%), and bowel perforation (5.7%). Plasma vascular endothelial growth factor and basic fibroblast growth factor levels and circulating tumor cell concentration did not correlate with overall survival, either at baseline or after 2 months of therapy. This bevacizumab-containing study regimen is modestly effective in patients with metastatic pancreatic cancer, although occasional serious complications may occur. Given the negative results of CALGB 80303, future efforts should be focused on identifying those specific patients who are most likely to benefit from bevacizumab-based therapy.

Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin‐based chemotherapy for colorectal liver metastases

The current study evaluated the effect of bevacizumab added to fluoropyrimidine-plus-oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology. A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated. Bevacizumab-containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX-only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had <25% residual viable tumor cells (45% vs 23%; P = .02). However, the addition of bevacizumab to 5FU/OX did not appear to increase the incidence of complete pathologic response (11.3% vs 11.6%; P = .59). The incidence and severity of sinusoidal dilation was lower in patients treated with bevacizumab than in those treated with 5FU/OX only (any grade: 27.4% vs 53.5%; moderate or severe: 8.1% vs 27.9%; both P < .01). In patients treated with 5FU/OX chemotherapy, bevacizumab improves the pathologic response, as demonstrated by a reduction of the degree of tumor viability, and reduces the incidence and severity of hepatic injury. This retrospective study provides additional evidence supporting the use of bevacizumab in combination with 5FU/OX for CLM.

Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT)

5031 Background: Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that blocks tumor growth &amp; inhibits angiogenesis. This Phase II RDT determined effects of pazopanib on tumor growth in patients with adv/met RCC after 12 wks of treatment. Methods: Cytokine naïve and refractory (failed 1 prior cytokine or bevacizumab-containing regimen) patients with adv/met RCC, ECOG 1–2, were enrolled. Pazopanib 800 mg po qd was administered. Response (RECIST) assessed at wk 12: SD patients randomized to continue pazopanib or placebo (blinded); PR/CR patients continued pazopanib. Interim analysis (first 60 patients) endpoints: % randomized (SD) and % CR/PR at wk 12. Futility boundary was based on a randomization rate of &lt;40%. Safety was analyzed in enrolled patients (n=161) at the time of interim analysis. Results: In the first 60 patients, response at wk 12 by independent review: PR in 24 (40%); SD in 25 (42%); PD in 5 (8%); unknown response in 2 (3%); and withdrawal prior to wk 12 (reasons other than PD/AE) in 4 (7%). 27 (45%) patients were randomized based on investigator review at wk 12. Total disease control rate was 82% (PR + SD). 67% of patients were treatment naïve, 33% had failed one prior treatment regimen (23% cytokine, 8% bevacizumab, 2% both). Most common AEs/lab abnormalities in all patients (n=161; 71% M, 29% F; mean 60.3 yrs; 81% Caucasian) were ALT/AST elevations, diarrhea, fatigue, nausea, hair depigmentation, &amp; hypertension. Gr 3/4 AEs occurred in 26% of patients; most common were hypertension (8%) &amp; ALT elevation (8%). One patient had Gr 5 AE due to large intestinal perforation. AEs led to discontinuation in 5% of patients. Conclusions: Interim analysis of this Ph II study demonstrated that pazopanib treatment resulted in a PR rate at wk 12 of 40% among patients with adv/met RCC and an acceptable toxicity profile. Based on these results, the Independent Data Monitoring Committee recommended discontinuation of randomization to placebo. Patients without PD were offered continued treatment with pazopanib beyond wk 12. At the time of publication, efficacy and safety data will be available for all 225 patients. [Table: see text]