Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial
Coleman RL et al., Lancet Oncol. 2017 Jun;18(6):779-791.
PubMed ID: 28438473
Treatment for recurrent ovarian cancer remains a challenge due to acquired drug resistance. Studies have shown that despite treatment failure, some tumors continue to be platinum sensitive and achieve some clinical benefit with retreatment with platinum-based regimens. Anti-angiogenesis therapy with bevacizumab has demonstrated antitumor activity and improvement in PFS in platinum-sensitive recurrent ovarian cancer (J Clin Oncol 2012; 30: 2039–45).
Researchers investigated the efficacy of bevacizumab with chemotherapy followed by becavicumab maintenance (bevacizumab objective) and the role of secondary cytoreduction prior to chemotherapy (surgical objective) in platinum-sensitive recurrent ovarian cancer in the GOG0213 trial. Results for women in remission for at least 6 mos. after primary therapy are summarized below.
- Patients: histologically/cytologically confirmed recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer, surgically eligible (randomized to surgical cytoreduction) or not eligible (randomized to chemotherapy) with clinical response to at least 3 cycles of primary platinum-based chemotherapy (clinically negative, normal CA-125 level) and disease-free for at least 6 mos. from last platinum treatment, GOG performance status 0-2 * previous maintenance biologic therapy (e.g. bevacizumab) and hormonal therapy were allowed if recurrence was documented at least 6 mos. from primary chemotherapy completion * diffuse carcinomatosis, extra-abdominopelvic disease and ascites were excluded
- Study design: phase III, open-label RCT
- Bevacizumab objective:
- Experimental:Paclitaxel 175mg/m2 + carboplatin AUC 5 + bevacizumab 15mg/kg q3wks. X 6 cycles followed by bevacizumab 15mg/kg maintenance q3wks.
- Control: Paclitaxel + carboplatin q3wks. x 6 cycles
- Bevacizumab and surgical objective
- Experimental: B + PC followed by B maintenance +/- secondary cytoreductive surgery
- Control: PC +/- secondary cytoreductive surgery * 2 additional cycles were allowed for documented partial or complete response
- Primary: OS
- Secondary: PFS, incidence of paclitaxel/carboplatin sensitivity, patient-reported outcomes, QOL, safety
- 674 patients randomized to B + PC (n=337) vs. PC (n=337)
- Baseline patient characteristics: median age 60 yrs., 80% white race, 75.5% stage III, 81% serous histology, 74% high grade, 84% not randomized to cytoreductive surgery, 69% previous treatment-free interval ≥12 mos., 74% previous platinum-free interval ≥12 mos., 83% measurable disease, 100% previous systemic chemotherapy, 82% intraperitoneal chemotherapy, 3% hormonal therapy, 100% anti-VEGF/bevacizumab, 7% maintenance taxane, 95% maintenance bevacizumab
- 16% in each arm randomized to surgery vs. no surgery
TABLE 1: EFFICACY OUTCOMES
- Platinum-free interval >12 mos.: 73% vs. 75%.
- Most common grade ≥ 3 adverse event with B + PC: hypertension (12% vs. 1%), fatigue (8% vs. 2%), proteinuria (8% vs. 0)
- Serious adverse event in >5% in both groups: febrile neutropenia (5% vs. 2%)
TABLE 2: ADVERSE EVENTS AND TREATMENT SUMMARY
- Most common grade ≥ 3 toxicities: abdominal pain (12% vs. 0), nausea (9% vs. 3%), small bowel obstruction (6% vs. 3%), hypertension (6% vs. 0), proteinuria (6% vs. 0), dyspnea (6% vs. 0)
- One patient developed grade 4 intracranial hemorrhage after 6 cycles of PC and 8 cycles of B
- Subsequent therapy: 82% vs. 86% (bevacizumab 8% vs. 17%)
- FACT-O-TOI scores declined during therapy but returned to baseline after 6 mos. No difference was observed in FACT-O-TOI scores in both arms.s
- The addition of bevacizumab to platinum-based chemotherapy provided 3.9 mos. PFS advantage compared to chemotherapy alone in recurrent, platinum-sensitive ovarian cancer. Bevacizumab reduced the risk of disease progression and death by 38%. OS curves began to separate at around 24 mos.;18% risk reduction for death was found after adjusting for treatment-free interval. Triple therapy improved OS by 4.9 mos. compared to paclitaxel/carboplatin.
- Tumor responses significantly improved with bevacizumab + paclitaxel/carboplatin. CR rates doubled compared to chemotherapy alone.
- Significantly higher rates of adverse events were reported with triple therapy, resulting in treatment discontinuation in 25%. A quarter of patients in each arm developed hypersensitivity reactions. Common VEGF-related adverse events like hypertension and proteinuria occurred in 6% (each) and are consistent with the known safety profile of bevacizumab. Nine patients died of treatment-related causes in the bevacizumab arm.
- Study authors acknowledged an error in calculating treatment-free interval that was adjusted for using post-hoc sensitivity analysis and revealed results consistent with primary analysis. Treatment-free interval was calculated from the last cycle of primary platinum therapy. The factorial study design was based on the assumption on the absence of an interaction between surgery and chemotherapy, which may not necessarily be true. The study population in this trial was selective, consisting of a favorable prognostic group and thereby limiting its external validity. Furthermore, around 80% in each arm received subsequent therapy.
- In summary, GOG0213 trial revealed that bevacizumab with paclitaxel/carboplatin provided significant clinical benefit with respect to OS and PFS as well as objective tumor response in recurrent, platinum-sensitive ovarian cancer. The toxicity profile of triple therapy did not appear to significantly compromise QOL. However, it's use is potentially limit to younger patients with good performance status and few comorbidities and with platinum/treatment-free interval >12 mos.
- Data collection is currently ongoing for the cytoreducive surgery component; results are forthcoming..
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Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma
Perry JR et al., N Engl J Med. 2017 Mar 16;376(11):1027-1037.
PubMed ID: 28296618
Glioblastoma is a disease with relatively poor prognosis. Studies of therapy in the elderly are limited, due to patient selection in clinical trials and higher risk for toxicity. However, a phase III trial that randomized patients 60 yrs. and older with glioblastoma to temozolamide, hypofractionated RT or standard RT with or without temozolamide revealed significantly longer OS with temozolamide (8.3 mos. vs. 6 mos., HR 0.71; p=0.01) compared to standard RT but not with hypofractionated RT (Lancet Oncol 2012; 13: 916-26). In the >70 yr. old cohort, temozolamide and hypofractionated RT were significantly better than standard RT in terms of survival (T vs. RT HR 0.35; p<0.0001) and Hypo vs. RT HR 0.59; p=0.02). Patients with MGMT promoter methylation who received temozolamide also fared better (OS 9.7 mos. vs. 6.8 mos., HR 0.56; p=0.02).
Perry and colleagues conducted a study to determine the efficacy of temozolamide with RT vs. RT alone in elderly patients with glioblastoma.
- Patients: newly diagnosed, histologically confirmed glioblastoma, 65 yrs. or older, not suitable for temozolamide with conventional RT (60 Gy x 30 fractions over 6 wks.), ECOG 0-2
- Study design: phase III, open-label RCT
- Experimental: Temozolamide 150-200 mg/m2 x 5 days out of a 28-day cycle (up to 12 cycles)
- Control: Temozolamide 75 mg/m2 for 21 days till last day of RT RT 40.05 Gy x 15 daily fractions over 3 wks.
- Primary: OS
- Secondary: PFS, QOL, safety
- 562 patients randomized to TMZ vs. RT + TMZ (n=281 each arm)
- Baseline patient characteristics: median age 73 yrs., 41% 71-75 yrs. old, 61% male, median MMSE score 27, 53.6% ECOG 1, 75.3% on glucocorticoids, 46.6% methylated MGMT status, 68.3% underwent partial or complete surgical resection
- 503 samples were centrally assessed: 95.4% glioblastoma, 3% high grade glioma
- 4/481 specimens positive for IDH-1 R132H
- 40% received subsequent therapy after disease progression (similar in both arms)
- Grade 3-4 adverse events: lymphopenia (27.2% [RT + TMZ] vs. 10.3% [RT]), thrombocytopenia (11.1% vs. 0.4%), neutropenia (8.3% vs. 0.8%)
- 2 patients in the RT + TMZ arm developed low-grade opportunistic infection
- Serious adverse events leading to death: 38 vs. 35 patients; 2 events in each group were deemed treatment-related, the rest were due to disease progression
TABLE 1: EFFICACY OUTCOMES
- Patients who had partial or complete resection or those with high MMSE scores had longer survival.
- Patients 71 yrs. and older had greater survival benefit with RT and temozolamide compared to the younger cohort. In the 71-75 yrs. cohort, OS was 9.3 mos. vs. 7.6 mos., with RT (HR 0.63) while in patients ≥76 yrs. old, OS was 10 mos. vs. 7.1 mos. (HR 0.53).
- Partial or complete resection, high MMSE scores and older age were correlated with better PFS with RT + temozolamide.
- MGMT status
- 462 tissue samples evaluated; successful MGMT results obtained from 354 samples (n=181 RT + TMZ, n=173 RT alone)
- MGMT status was a predictor for survival in RT with temozolamide arm vs. RT alone.
- Nausea and constipation were worse during chemo-RT vs. RT alone.
- Shorter time to deterioration was observed in RT + temozolamide arm compared to RT alone in terms of nausea, vomiting and constipation.
- At a median follow-up of 17 mos., temozolamide with RT significantly prolonged OS by 1.7 mos. compared to RT alone in newly diagnosed glioblastoma patients ≥65 yrs. old. This treatment was associated with 33% reduction in the risk of death. The greatest magnitude of benefit was observed in patients with methylated MGMT status where combination therapy extended survival up to 13.5 mos. and reduced the risk of death by 46%. A similar trend was noted for PFS in favour of combination therapy.
- Adverse events were more frequently reported in the combination arm, most commonly hematologic toxicity. However, this did not seem to adversely affect QOL. Although time to deterioration was shorter with combination therapy due to nausea, vomiting and constipation, overall, this did not significantly impact QOL.
- Survival advantage with temozolamide in the elderly, especially with methylated MGMT status in this study is consistent with previous findings. In the phase III NOA-08 trial, patients 65 yrs. and older with anaplastic astrocytoma or glioblastoma were randomized to temozolamide or RT (Lancet Oncol 2012; 13:707-15). EFS and OS were similar in both arms. Patients with MGMT methylated tumor status had significantly better OS and EFS with temozolamide (11.9 mos. vs. 8.2 mos., HR 0.62; p=0.014 and 8.4 mos. vs. 4.6 mos., respecively).
Updates in Other Topics in Cancer
- In summary, temozolamide with short course RT demonstrated significant improvement in survival compared with RT alone in elderly patients with glioblastoma. Combination treatment was associated with a tolerable safety profile without significant decline in QOL. Although survival advantage was marginal in the ITT population, the greatest magnitude of benefit was reported in tumors with methylated MGMT status and patients 71 yrs. and older.