NEW YORK (Reuters Health) – Platinum-based chemotherapy followed by delayed surgery appears to be an effective and safe alternative to primary surgical debulking followed by chemotherapy in women newly diagnosed with advanced ovarian carcinoma, according to results from the CHORUS noninferiority trial.
“This issue, the timing of the chemotherapy before or after surgery, is the most critical issue facing women today with ovarian cancer. Therefore, the results are important,” Dr. Steven A. Narod, from Women’s College Research Institute’s Breast Cancer Research Unit, Toronto, Ontario, Canada, who was not involved in the study, told Reuters Health by email.
In earlier observational studies, the primary chemotherapy strategy seemed to increase optimal debulking rates and reduce surgery-related complications, but two meta-analyses of nonrandomized studies produced conflicting results on the effect of delaying surgery on survival.
Dr. Matthew Nankivell, from University College London, and colleagues investigated whether primary chemotherapy with delayed surgery could yield survival results similar to those with primary surgery but with reduced surgical morbidity.
They chose a noninferiority design, they note, “because we judged that a reduction in surgery related morbidity without detriment to survival would justify the use of this treatment strategy in clinical practice.”
Three-year survival, though lower than suspected in both groups, did not differ significantly between primary chemotherapy (34%) and primary surgery (32%). Median overall survival came to 24.1 months with primary chemotherapy and 22.6 months with primary surgery, a difference that was not significant and met the predefined noninferiority criterion.
Median progression-free survival also proved to be noninferior for primary chemotherapy (12.0 months) versus primary surgery (10.7 months), according to the May 20 online report in The Lancet.
Results were similarly noninferior in the per-protocol population of all women who began their allocated treatment (253 assigned to primary chemotherapy, 251 assigned to primary surgery), and the researchers found no good evidence in exploratory analyses that any subgroups benefited more or less from primary chemotherapy.
Significantly more patients in the primary surgery group (24%) than in the primary chemotherapy group (14%) had grade 3 or 4 adverse events, and significantly more women in the primary chemotherapy group (39%) than in the primary surgery group (17%) had debulking to no macroscopic disease despite identical median operation times for the two groups.
Significantly more postoperative deaths occurred within 28 days of surgery in the primary surgery group (14/255, 6%) than in the primary chemotherapy group (1/219, <1%, p=0.001).
“In summary,” the authors conclude, “CHORUS shows that for patients with advanced ovarian cancer and a poor performance status profile, primary chemotherapy followed by delayed surgery are associated with similar overall survival as patients given primary surgery. The associated reduction in treatment-associated morbidity and mortality, combined with a trend towards better quality of life suggests that primary chemotherapy is a valid option for treating these patients.”
“Unfortunately, the CHORUS trial has a similar weakness to the EORTC-NCIC trial-the low quality of surgical care,” writes Dr. Sokbom Kang, from the National Cancer Center, Goyang, South Korea, in an accompanying commentary. “Even after neoadjuvant chemotherapy, more than 40% of patients with advanced ovarian cancer had gross upper abdominal metastasis that needed radical upper abdominal surgeries to be completely removed.”
“Neoadjuvant chemotherapy is not, and should not be, the opposite of high-quality surgical care,” Dr. Kang writes.
Dr. Kang congratulated the research team for “showing that neoadjuvant chemotherapy lowers treatment-related morbidity without sacrificing treatment efficacy. However, efforts should now be directed towards identifying and resolving the remaining uncertainties.”
“I would always go with primary surgery if I think there is any possibility of reaching a state of no residual disease,” Dr. Narod said. “This is the best way to give a woman a chance of cure. At Princess Margaret Hospital, the goal for all patients is to achieve a status of no residual disease wherever possible and if so follow up with intraperitoneal chemotherapy. In this situation we have very good long-term survival for the majority of our patients treated this way but we are continuing to evaluate this.”
“Our long-term survival is far superior to the patients in the CHORUS study, which was less than 10%,” Dr. Narod said. “Perhaps it is the sickness of the patients or their age, but I suspect the difference is in the quality of the surgery.”
“For rare patients, sick women who are not candidates for surgery, neoadjuvant (therapy) is a good idea compared to no treatments,” Dr. Narod said. “But I would give the benefit of the doubt and go for surgery in questionable cases.”
“One thing for sure, if the two treatments are equivalent, many more will get neoadjuvant therapy because it is a lot simpler and makes surgery much easier and shorter, and there is a lot of convenience for the patients, doctor, and the hospital,” Dr. Narod said. “We must be confident we are not putting women’s lives at risk by doing so.”
“I, for one, am not confident that this is the case,” he concluded.
Dr. Nankivell did not respond to a request for comments.
Five coauthors are employed by the Medical Research Council, sponsor of the CHORUS trial.
— Will Boggs, MD0