Secondary Cytoreductive Surgery Requires Careful Selection in Recurrent Ovarian Cancer

Three clinical trials produced mixed results regarding the survival benefit achieved with secondary cytoreductive surgery in patients with recurrent ovarian cancer, according to Amer Karam, MD. However, one thing is clear: this approach is only beneficial for patients who can achieve a complete resection. As such, pairing existing scoring systems with a diagnostic laparoscopy may be key to informing optimal patient section for this procedure.

The phase 3 GOG-0213 (NCT00565851), DESKTOP III (NCT01166737), and SOC-1 (NCT01611766) trials all explored the use of secondary cytoreductive surgery in highly selected patients with recurrent ovarian cancer.¹

In the GOG-0213 trial, 485 patients were randomized to secondary cytoreductive surgery followed by chemotherapy (n = 240) vs chemotherapy alone (n = 245). Notably, patients underwent secondary randomization to platinum-based chemotherapy with or without concurrent bevacizumab (Avastin); those who were randomized to bevacizumab continued to receive the agent as maintenance treatment. Results showed that patients who underwent surgery experienced a worse median overall survival (OS) than those who did not, at 50.6 months and 64.7 months, respectively (HR 1.29; 95% CI, 0.97-1.72, P = .08). Additionally, the median progression-free survival (PFS) in the surgery cohort was 18.9 months vs 16.2 months in the non-surgery cohort (HR 0.82; 95% CI, 0.66-1.01).

However, the DESKTOP III and SOC-1 trial both produced survival benefits for patients who underwent surgery. In the DESKTOP III trial, patients who underwent secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) experienced a median OS of 53.7 months vs 46 months in the non-surgery group who received chemotherapy alone (n = 201; HR 0.75; 95% CI, 0.58-0.96, P = .02). Furthermore, the median PFS in these groups was 18.4 months and 14.0 months, respectively (HR, 0.66; 95% CI, 0.54-0.82, P < .001).

Data from the SOC-1 trial showed that those who received secondary cytoreductive surgery followed by chemotherapy (n = 182) experienced a median OS of 58.1 months vs 53.9 months in the non-surgery arm who received chemotherapy alone (n = 175; HR, 0.82; 95% CI, 0.57-1.19). Those in the surgery arm also had a median PFS of 17.4 months vs 11.9 months in the non-surgery arm (HR 0.58; 95% CI, 0.45-0.74, P < .001).

“One of the main messages of these 3 trials put together is if there is any advantage to secondary cytoreductive surgery, it is for patients [in whom] you can achieve complete cytoreduction. It seems [when] residual disease is left, patients do not end up doing well,” Karam explained. “It appears that findings from GOG-0213, but also from SOC-1 and DESKTOP III, all show that patients with residual disease do worse than maybe even those who are not undergoing surgery. As such, we must be very careful who we choose [for this procedure].”

In an interview with OncLive^® during the 2022 SGO Winter Meeting, Karam, gynecologic oncologist, medical oncologist, obstetrician, and gynecologist (OB-GYN), clinical professor, Obstetrics & Gynecology, Gynecologic Oncology, Stanford Health Care, discussed the results from these 3 clinical trials, the key differences between these efforts, and the role of secondary cytoreductive surgery in ovarian cancer.

OncLive^®: Could you provide an overview of how secondary cytoreductive surgery fits into the treatment paradigm ovarian cancer?

Karam: For most patients with advanced stage ovarian cancer, recurrences are unfortunately part of the natural history of the disease. At least for advanced stage disease, the initial debulking procedure is very important in terms of how much residual disease there was and in terms of dictating how well patients do over time.

Gynecologic oncologists have, for many years, been wondering [about] a secondary debulking surgery. When patients reoccur, would another procedure to debulk the cancer be helpful? Over the years, [practitioners] have refined who they offer the surgery to, and we found that it is mainly for patients with limited disease and those with disease that is generally viewed as sensitive to up-front platinum-based chemotherapy.

Ultimately, this led to several clinical trials to [further explore that question. All the retrospective data seem to indicate a possible advantage for interval or secondary cytoreductive surgery. This also led to several groups putting together randomized clinical trials to examine this question, almost in parallel.

You co-authored a paper exploring 3 clinical trials that focused on secondary cytoreductive surgery in recurrent ovarian cancer: GOG-0213, DESKTOP III, and SOC-1. Could you elaborate on these trials and how they differed from one another?

All 3 of were multi-institutional and 2 of them were international trials. They randomized patients with recurrent ovarian cancer that was platinum sensitive to undergo secondary cytoreductive surgery followed by chemotherapy, or to omit surgery altogether and just [receive] salvage chemotherapy.

The GOG-0213 trial had 2 objectives. One was to look at secondary cytoreductive surgery, [and the second was] to look at the value of adding bevacizumab [Avastin] to chemotherapy, followed by bevacizumab maintenance therapy, to the platinum-combination chemotherapy backbone. Patients were randomized to the surgical arm or the chemotherapy arm, [which] made it a more complicated clinical trial.

The key difference between the trials [was the eligibility] criteria for patients to qualify for secondary cytoreductive surgery. The AGO group [DESKTOP III] had developed AGO scoring, which relied on the patient's functional status, the completeness of initial cytoreduction surgery, and the absence of ascites. Patients who had a positive AGO score, meaning they fulfilled all these criteria and were at least 6 months from the last platinum-based chemotherapy, could qualify for secondary cytoreductive surgery.

The Chinese GOG group [SOC-1] had more complicated inclusion criteria. They used a prognostic model called the iMODEL, which was very similar to the AGO scoring group, in that it incorporated the absence of ascites, but also CA-125 and the length of time from when the platinum-based chemotherapy ended. Patients had to meet these criteria, and they also had to have a PET/CT scan, which had to be viewed favorably for them to be included in the trial.

With the GOG-0213 trial, the only requirements to be included in the surgical arm were for the surgeon, or the treating oncologist, to feel that patients were actually a good candidate. There wasn't anything specific, although most patients who were included in the surgical arm of the trial had oligometastatic disease.

What was learned from these trials?

All 3 trials had some similar results and some key different results. The first trial to come out was the GOG-0213 trial. The results of that trial came out in 2 phases. The first phase was the chemotherapy arm, and that showed that the addition of bevacizumab significantly improved outcomes for patients with platinum-sensitive recurrent ovarian cancer. The surgical arm took a little bit more time to [yield results], but that showed there was no OS advantage for secondary cytoreductive surgery.

On the other hand, the 2 other trials, DESKTOP III and SOC-1, showed that there was a survival advantage for patients undergoing secondary cytoreductive surgery for ovarian cancer. The DESKTOP III trial showed there was both an improvement in PFS, but also a significant improvement in OS for patients who received secondary cytoreductive surgery. The SOC-1 trial showed that there was a definite PFS advantage. Although their data were not mature enough to comment on OS, the preliminary findings did not show a significant difference between the groups.

One of the main [takeaways] of those 2 trials that showed OS advantage was that the survival advantage was limited to those patients who had complete excision of their disease. In the DESKTOP III trial and the SOC-1 trial, the survival advantage was limited to those patients where all the cancer was resected. The data seemed to indicate that patients who had suboptimal disease or any residual cancer at the end of their secondary cytoreductive surgery, did not have an improvement in OS, and they even suffered a detriment.

Another difference between the trials was the number of patients undergoing complete resection. In the GOG-0213 trial, a little bit more than two-thirds of patients had complete resection, [leaving] about one-third of patients with incomplete resection. That number was higher in the [DESKTOP III] and [SOC-1] trials, where a little bit more than three-quarters of patients had complete cytoreduction.

One of the key differences between the trials that could explain the difference in results is the addition of maintenance therapy or a third agent to the chemotherapy. The addition of bevacizumab, which most patients in the GOG-0213 trial [were administered], may have made a difference. It may have equalized the results between the 2 groups, whereas in SOC-1 and in DESKTOP III, a minority of patients had either bevacizumab and/or maintenance therapy following their platinum-based chemotherapy.

We have moved from the era of just chemotherapy in the salvage setting to chemotherapy plus maintenance therapy for patients with recurrent ovarian cancer. Now that we have PARP inhibitors, VEGF inhibitors like bevacizumab, more in use in the recurrent setting, that may change the outcomes of patients undergoing secondary cytoreductive surgery and it may diminish the usefulness of the technique.

What can be done to help inform who should receive secondary cytoreductive surgery?

People will argue about whether there is a survival advantage to secondary cytoreductive surgery. We need to flesh this out a little bit more. I am personally someone who has done secondary cytoreductive surgery in the past and will still offer it to patients. However, [we must] be very precise or very prescriptive in terms of who you would select for secondary cytoreductive surgery, and you want to choose patients as best as you can to ensure you have complete resection—anything short of that could potentially harm the patients.

One thing I do bring up that I have offered to patients is diagnostic laparoscopy. If we decide together to go for surgery, I offer these patients a diagnostic laparoscopy to decide whether they can get a complete resection. The hope is that by doing diagnostic laparoscopy, in addition to the scoring systems, the diagnostic laparoscopy could help potentially weed out those patients who would have ended up with suboptimal resections.

Reference

1. Harrison R, Zighelboim I, Clover NG, et al. Secondary cytoreductive surgery for recurrent ovarian cancer: an SGO clinical practice statement. Gynecol Oncol. 2021;163(3):448-452. doi:10.1016/j.ygyno.2021.10.008