Residual disease at second cytoreductive surgery identified patients with ovarian cancer associated with improved progression-free (PFS) and overall survival, suggesting potential as a surrogate for survival, according to a study reported here.
Patients who had pathologic complete response (pCR, no microscopic disease) had a median PFS of 16.1 months, decreasing to 13.5 months for patients with microscopic disease at second surgery, and 11.5 months for patients with gross residual disease. Median overall survival decreased from 51.5 months to 30.8 months as residual disease status increased from pCR to gross residual tumor.
The retrospective observation suggests that residual disease at second cytoreductive surgery might offer an alternative to overall survival for evaluating the efficacy of ovarian cancer therapy and help speed up the approval process for new therapies, Peter G. Rose, MD, of the Cleveland Clinic, reported at the Society of Gynecologic Oncology (SGO) meeting.
“If the pathologic response rates following neoadjuvant chemotherapy can be reliably determined and stratified by BRCA/BRCAoid status, neoadjuvant chemotherapy followed by early surgical reassessment may be a new platform for accelerated oncology therapeutic approval in ovarian cancer,” said Rose.
In another report at the SGO meeting, data from a randomized British study showed that three cycles of neoadjuvant chemotherapy led to pCR in about 4% of patients, as compared with 18% in the study reviewed by Rose. Additionally, 10% of patients had normalization of levels of the CA-125 cancer marker, but decline in CA-125 levels had no association with disease extent at laparotomy, said Sean Kehoe, MD, of the University of Birmingham.
In a discussion that followed the two presentations, Sanjeeve Bala, MD, of the FDA, suggested that patients who were suboptimally debulked in the U.S. study might have biologically different disease as compared with the subgroup that achieved pCR. Although the results suggested a correlation of pCR with PFS and overall survival, the analysis raised questions that need to be addressed in future trials, including questions that have implications for regulatory decisions: the precise nature of the association between pCR and long-term outcome, the optimal definition of pCR, and the magnitude of pCR improvement to predict benefit.
As for the British study, Bala said the randomized trial offered the “ideal platform for establish pCR as a valid surrogate endpoint,” but he questioned whether three cycles of neoadjuvant chemotherapy are adequate.
“Neoadjuvant chemotherapy trials should incorporate pCR evaluation in all enrolled women,” said Bala. “Establishing pCR as a surrogate endpoint correlated with overall survival would be a powerful step in accelerating clinical trials and potentially drug approval.”
Rose’s presentation had its genesis in an ovarian cancer endpoints workshop held last fall, cosponsored by the FDA, American Association for Cancer Research, American Society of Clinical Oncology, and SGO. One workshop objective was to explore novel treatment designs that might facilitate discovery and regulatory approval. In particular, investigators were encouraged to examine the Gynecologic Oncology Group 152 trial with respect to surgical findings at second cytoreductive surgery.
To emphasize the lengthy process that leads to therapeutic discovery and approval, Rose noted that the GOG 152 protocol received final approval from GOG and NCI during at a meeting that ended July 19, 2003, the same day his son was born. By the time the study results were published, his son was 11 years old.
Studies in multiple types of cancer have demonstrated positive relationships between pCR achieved with neoadjuvant therapy and subsequent survival. However, limited data exist with regard to pCR, residual disease, and second cytoreductive surgery in ovarian cancer. Moreover, the few available studies have employed different chemotherapy regimens and courses/cycles of therapy, said Rose.
In GOG 152, patients who had suboptimal primary debulking received paclitaxel-cisplatin chemotherapy and then were randomized to second cytoreductive surgery or no additional surgery, followed by additional chemotherapy, which was identical in both arms.
The new analysis focused on 216 patients randomized to second cytoreductive surgery in GOG 152. At second surgery, 70.8% of patients had gross residual disease, 3.7% had microscopic disease, and 18.5% had achieved pCR. The remaining 7% of patients did not have surgery for various reasons.
The results showed a significant association between extent of disease at second surgery (pCR to gross residual) and both PFS (P=0.002) and overall survival (P=0.018).
“Secondary cytoreductive surgery is not standard of care,” Rose noted. “Therefore, the findings of this study are only thought provoking.”
Moreover, recent data from members of the National Comprehensive Cancer Network suggest that about 40% to 50% of patients with stage III-IV ovarian cancer receive neoadjuvant chemotherapy, he added.
Kehoe reported findings from a subgroup analysis of the CHORUS trial, which compared primary surgery followed by six cycles of chemotherapy versus three cycles of neoadjuvant chemotherapy followed by surgery and three more cycles of chemotherapy. The analysis focused on 252 patients randomized to initial neoadjuvant chemotherapy, of whom 217 had cytoreductive surgery.
CT scans before and after neoadjuvant chemotherapy showed that 10 patients (4.25%) pCR, 204 had no change in disease burden, and 21 had progressive disease. Findings at surgery showed that seven patients (4%) had no evidence of disease, 24 (12%) had <1 cm residual disease, and 166 (84%) had gross residual disease.
Kehoe reported that neoadjuvant chemotherapy resulted in a complete response rate of 10% as defined by serum CA-125 levels, and 34% of the patients had at least a 50% reduction in CA-125. Bala, however, noted that the FDA does not recognize CA-125 as an endpoint.
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