A roomful of gynecologic oncologists walked away disappointed after results of a long-awaited ovarian cancer trial failed to show an advantage for any of three chemotherapy regimens.
The regimens — involving combinations of intraperitoneal (IP) and intravenous (IV) chemotherapy plus bevacizumab (Avastin) — led to a median progression-free survival (PFS) of 27 to 29 months in patients with optimally debulked stage II-III disease. An analysis limited to patients with optimal stage III disease yielded median PFS values of 31 to 34 months.
The results were a far cry from the 60-month median PFS in optimally debulked patients achieved with a higher dose of IP cisplatin in the Gynecologic Oncology Group (GOG) 172 trial reported more than a decade ago, and the three regimens’ median PFS values remained similar to the 24-month median for all patients in GOG 172.
Moreover, toxicity remained a problem, although not nearly as severe as what was observed in GOG 172, reported Joan L. Walker, MD, of Oklahoma University’s Stephenson Cancer Center in Oklahoma City, here at the Society of Gynecologic Oncology meeting.
Asked whether it might be time to move on from IP, Walker demurred.
“I honestly believe there is an uncertainty as to what is benefiting the patients in GOG 172. One of those options is that it allows the patient to have a more intense post-recurrence treatment. Carboplatin burns bone marrow and cisplatin doesn’t do as bad a job of that. It’s possible that patients actually survive longer after IP cisplatin because they have more tolerance to future chemotherapy,” she said.
“There also is a possibility of there being an immune response to intraperitoneal chemotherapy, and if there is an immune response the patient might not die as fast. I think the [60-month median] survival in GOG 172 was incredibly provocative, and I don’t know what this [current] study will show in terms of survival,” she added.
Invited discussant Gini Fleming, MD, of the University of Chicago, had a less-sanguine take on the trial’s implications.
“In the current situation, with regard to what is being prioritized in trials, to go back and develop a new IP regimen to test, just isn’t going to happen,” Fleming said. “In my mind, we don’t have the evidence to continue doing what we’re doing, unless we see some very positive data from the ongoing trials.”
Michael Bookman, MD, of Arizona Oncology in Scottsdale, might have captured much of the audience’s sentiment with a preface to his comments.
“I still have a drink ticket left from last night. Does anyone know how I can use it? Because I think I’m going to need [a drink].”
In a more serious vein, Bookman added, “Taking a look at where we are today, with better supportive care, perhaps better intravenous therapy, I think we really do have to debate what’s the path forward.
“We have a lot of interesting targeted agents, immunologic strategies, synthetic lethality, and other things we could be working on,” he noted. “If we have to study IV and IP chemotherapy and really flesh all of that out, it’s going to slow us down, we’re going to knock out financial resources to do those trials. It’s an important question on behalf of our patients, and on behalf of the research investigators, to understand how we should move forward.”
Walker reported findings from the GOG 252, the latest attempt to capture the unprecedented survival benefit observed in GOG 172 while sparing patients the toxicity associated with high-dose cisplatin: Only 42% of patients randomized to IP cisplatin 100 mg/m2 plus IV paclitaxel completed six cycles of therapy.
Results of the GOG 218 evaluation of bevacizumab further complicated efforts to replicate GOG 172 efficacy with less toxicity. GOG 218 showed a significant improvement in PFS with the angiogenesis inhibitor among patients with advanced ovarian cancer.
GOG 252 involved women with stage II-III epithelial carcinoma of the ovary, fallopian tube, or peritoneal cavity. All patients underwent optimal surgical debulking to 1 cm or less residual disease by surgeon report. Patients were then randomized to one of three chemotherapy regimens:
- Dose-dense IV paclitaxel, IV carboplatin, and bevacizumab (reference arm)
- Dose-dense IV paclitaxel, IP carboplatin, and bevacizumab
- Standard IV paclitaxel followed by reduced-dose IP paclitaxel, IP cisplatin, and bevacizumab
The primary endpoint was PFS. Data analysis comprised 1,560 patients,who had a median age of 58. Patients with stage III disease accounted for 84% of the study population, and 72% of patients had grade 3 serous ovarian cancer. Walker said 57% of the patients had no visible residual disease by surgeon report; however, she expressed doubt that the complete-resection rate would hold up when results of CT assessments become available.
In both of the carboplatin-containing arms, 90% of patients completed at least six cycles of platinum therapy compared with 84% of patients randomized to the cisplatin-containing regimen. In all three arms 87% to 88% of patients completed at least six cycles of taxane administration.
The results showed a median PFS of 26.8 months for patients with optimal stage II-III disease in the reference arm, 28.7 months among patients who received IP carboplatin, and 27.8 months for patients who received IP cisplatin. Follow-up for overall survival will continue, Walker said.
Toxicity and PROs
Two-thirds or more patients in each arm developed grade 3 neutropenia. Grade 3 thrombocytopenia occurred two to three times more often in the carboplatin groups as compared with the 6.1% rate in the cisplatin arm. Grade 3 hypertension occurred in 12% to 14% of patients in the carboplatin arms and 20.5% of patients randomized to the cisplatin-containing regimen, prompting Walker to suggest that IP cisplatin probably should not be used in combination with bevacizumab. Grade 3 nausea and vomiting occurred in 11.2% of the cisplatin group, two to three times higher than in the other two arms.
Grade 2-plus sensory neuropathy occurred in 21% to 24% of patients in the three arms.
In a second study, researchers analyzed patient-reported outcomes (PROs) — quality of life, neuropathy, nausea, fatigue, and abdominal discomfort — showed consistently lower scores among patients in the cisplatin arm, said Lari Wenzel, PhD, of the University of California Irvine Chao Comprehensive Cancer Center. PRO scores did not differ appreciably between the two carboplatin arms, with the exception of slower improvement in abdominal discomfort in patients treated with IP carboplatin.
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