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Secondary surgery does not prolong survival in recurrent ovarian cancer
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Secondary surgical cytoreduction followed by chemotherapy did not extend OS compared with chemotherapy alone among women with platinum-sensitive, recurrent epithelial ovarian cancer, according to results of the randomized phase 3 GOG-0213 study published in The New England Journal of Medicine.
“It has been an unproven expectation that secondary cytoreduction surgery for certain patients is beneficial, which was predominantly a direct extension from our observations in the front-line setting,” Robert L. Coleman, MD, physician in the department of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, said during an interview with HemOnc Today. “Our thought was that surgery may play a role in the setting of recurrent disease because patients who are newly diagnosed are also essentially platinum-sensitive, and it is dogma that patients experience benefit from surgery.”
The open-label, multicenter, international GOG-0213 trial evaluated whether surgical cytoreduction would increase OS among women with platinum-sensitive, recurrent ovarian cancer who had received one previous therapy, had a platinum-free interval of 6 months or more, and had investigator-determined resectable disease.
Researchers randomly assigned 485 women to either secondary surgical cytoreduction before chemotherapy (n = 240) or chemotherapy alone (n = 245). Fifteen women in the surgery group declined surgery.
Eleven percent of patients (n = 55) had been treated previously with bevacizumab (Avastin, Genentech). The median platinum-free interval was 20.4 months (interquartile range [IQR], 13.2-34) for the surgery group vs. 18.8 months (IQR, 12.5-28.4) for the no-surgery group.
Median time to initiation of chemotherapy was 40 days (IQR, 28-51) in the surgery group vs. 7 days (IQR, 4-11) in the no-surgery group. Most patients (69%) received paclitaxel-platinum chemotherapy, and 84% received concomitant and maintenance bevacizumab.
OS served as the primary endpoint. Investigator-assessed PFS served as a secondary endpoint.
Median follow-up was 48.1 months.
Sixty-seven percent of women in the surgery group achieved complete gross resection. When the researchers compared the complete gross resection population (n = 150) with women in the no-surgery group, they found that complete gross resection did not increase OS (HR = 1.03; 95% CI, 0.74-1.46).
Median OS was 50.6 months in the surgery group vs. 64.7 months in the no-surgery group (adjusted HR [aHR] = 1.29; 95% CI, 0.97-1.72).
Median PFS was 18.9 months for the surgery group vs. 16.2 months for the no-surgery group (aHR for disease progression or death = 0.82; 95% CI, 0.66-1.01). Researchers observed 3-year PFS rates of 29% (95% CI, 22-35) in the surgery group and 20% (95% CI, 15-26) in the no-surgery group.
Adjustment for platinum-free interval and chemotherapy choice did not alter the effect, according to the researchers.
One patient death occurred due to postoperative complications. Surgical morbidity at 30 days was 9%. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery.
“We found that when surgery was introduced, it did not add to the primary endpoint of OS. This was surprising, because that had been the prevailing opinion,” Coleman said. “Additionally, post-progression survivorship of the entire patient cohort, whether they underwent surgery or not, was much longer than what we anticipated. When we looked at the intermediate endpoint of PFS, we observed a slight trend toward improvement, but it was quickly consumed by the long duration of postoperative follow-up.”
This raises the question of whether there may be subgroups of patients for whom surgery may work, Coleman said.
“For example, we do not have data on BRCA mutations, and it may be that patients who have BRCA mutations could achieve better outcomes,” he said. “This is hypothesis-generating and I would never say never as to whether or not there may be a benefit in a subgroup, even in different patient populations.” – by Jennifer Southall
For more information:
Robert L. Coleman, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1155 Herman Pressler Drive, CPB 6.3590, Houston, TX 77030; email: rcoleman@mdanderson.org.
Disclosures: The study was funded in part by Roche/Genentech. Coleman reports financial support from the Ann Rife Cox Chair in Gynecology and Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund. Please see the study for all other authors’ relevant financial disclosures.
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Christina S. Chu, MD
Coleman and colleagues evaluated the utility of secondary debulking surgery among women with platinum-sensitive recurrent ovarian, primary peritoneal and fallopian tube cancers. The study included women who had been previously treated for ovarian cancer with one course of chemotherapy and who did not progress for at least 6 months after completion of their chemotherapy, whose physicians felt that their disease recurrence was amenable to surgical removal. These women were randomly assigned to either surgery to remove the tumor followed by chemotherapy, or chemotherapy only. After a median 4 years of follow-up, the women who underwent surgery did not live longer than the women who underwent chemotherapy only. Although surgical patients reported their quality of life was worse right after surgery, there was no difference after recovery.
Clinical trials of surgical interventions are very difficult to perform. There may be bias in which patients are even offered the study — for example, by including only patients with good prognosis who can tolerate surgery. In this study, some bias was notable at the beginning — more than half of the women considered for this trial only had one or two spots of tumor recurrence. This may have made it more difficult for the investigators to identify an effect of surgery if most women already were predisposed to have a good prognosis.
It also should be noted that the OS of women on this trial was between 50 and 64 months, which is almost three times as long as the investigators had expected when they planned the trial. Both women undergoing surgery plus chemotherapy or chemotherapy alone fared much better than expected, perhaps because of advances in chemotherapies for these women after the study treatment was complete (perhaps in third- or fourth-line treatment, for example). Because women respond to better chemotherapy after initial recurrence, the effect of surgery to debulk the tumor may be difficult to observe the longer that patients survive after surgery.
Although this study did not show an improvement in survival for surgery in these particular women, there are at least three other large phase 3 trials underway comparing surgery plus chemotherapy with chemotherapy alone. Each of these trials is slightly different in their patient eligibility criteria and which chemotherapies are allowed. The results of these trials are expected to help define the possible benefits of surgery in the setting of recurrent ovarian and ovarian-like cancers.
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