Secondary Cytoreduction Plays Role in Recurrent Ovarian Cancer Management, But Selection Is Key

Michael Guy, MD

Secondary cytoreduction plays a role in the management of patients with recurrent ovarian cancer, but it is important to consider some of the historical models that have been created to identify those who are optimal candidates for the procedure, according to Michael Guy, MD, who added that the AGO score is a useful tool for predicting surgical outcomes.

“There is definitely a role for secondary cytoreductive surgery in patients with recurrent ovarian cancer. I believe that the patient selection algorithm is one of the most important variables that we must consider as surgeons, when bringing patients to the operating room,” said Guy. “As shown in the DESKTOP III trial, patients who achieve a complete resection (CR) do better than those who receive chemotherapy alone. Even so, we need to continue to investigate this area of cancer care, as well as the role of surgery in the space, because discordant results were shown in the GOG-0213 trial.”

Results from the final analysis of the DESKTOP III trial (NC01166737) presented during the 2020 ASCO Virtual Scientific Program showed that cytoreductive surgery in patients with a platinum-free interval of greater than 6 months and selected by the AGO score significantly prolonged both overall survival (OS) and progression-free survival (PFS).¹ The OS benefit was found to be highest in the cohort of patients with CR, underscoring the importance of thorough patient selection. In contrast, results from the GOG-0213 trial (NCT00565851) showed that secondary cytoreduction followed by chemotherapy did not result in longer OS compared with chemotherapy alone.²

“It’s of critical importance to take the cost of being wrong into consideration. Between both studies, no benefits were discovered in patients who still had residual disease after their cytoreductive surgeries, and there could potentially be a detriment to their OS,” Guy added. “At the end of the day, we're here to help our patients, not harm them.”

In an interview with OncLive^® during the Institutional Perspectives on Cancer webinar on Ovarian Cancer,Guy, an assistant professor of obstetrics and gynecology at the University of Cincinnati Cancer Center, as well as a gynecologic oncologist at Premier Health, discussed pivotal trials that have helped to define the role of secondary cytoreductive surgery in recurrent ovarian cancer.

OncLive^®: Could you discuss the role of secondary cytoreductive surgery in patients with recurrent ovarian cancer?

Guy: When discussing the role of secondary cytoreductive surgery in patients with recurrent ovarian cancer, [it’s important to] look at some of the historical models that have been created to identify the optimal patients for these [procedures]. Prospective data on how patients have done in the real-world setting with secondary cytoreductive operations [have also emerged in recent years].

The role for secondary cytoreductive surgery comes from the success that we have seen with primary cytoreductive surgery in patients with newly diagnosed disease. Historically, good data from several institutions, as well as meta analyses, have demonstrated the benefit of these operations. However, you always want to hold that up to the critical light of prospective trials. That’s what has been done with the DESKTOP trials and others such as the GOG-0213 trial. Some data were also published from the SOC 1 trial in China earlier this year. Most importantly, the DESKTOP III trial data finally matured and were presented at the 2020 ASCO Virtual Scientific Program.

Could you elaborate on how you select appropriate candidates for the procedure?

Candidates for a secondary cytoreductive surgery have been identified in retrospective data by being platinum sensitive and by having early stage disease at the time of their initial diagnosis. Their residual disease that was present at the time of primary cytoreduction was also a predictor of secondary cytoreduction. Notably, patients who had long disease-free intervals did better after these secondary surgeries.

Performance status always plays an important role in terms of how well a treatment is tolerated. Moreover, the presence of ascites and whether the disease was limited to just a few sites or multiple sites across the abdomen also played an important role in patient selection.

Could you expand on the DESKTOP series and how these trials led to the utilization of the AGO score to predict surgical outcomes?

DESKTOP is a series of trials, the first of which was published in 2006, called the DESKTOP OVAR trial. The goal was to establish selection criteria for patients who would achieve R0 resection at the time of secondary debulking. The score that the investigators generated from this effort was called an AGO score.

Investigators conducted a retrospective study looking through hospital records of 267 patients. Variables associated with complete resection included the patient's performance status of 0, having early stage I or II disease at the initial diagnosis, having no residual tumor after their primary surgeries, and the absence of ascites were all associated with complete resection (CR) at second operation. When you combine all of this together, CR was achieved in 79% of patients. This study set the stage for the DESKTOP II trial, which was published in 2011.

The goal of DESKTOP II was to prospectively evaluate the AGO score to predict complete cytoreduction in patients with platinum-sensitive ovarian cancer. Again, the AGO score included complete resection at primary surgery, having an ECOG performance status of 0, and the absence of ascites. A total of 516 patients were screened for this trial: 261 had positive scores, and 129 patients underwent secondary surgeries. Moreover, 76% of patients in the surgery cohort achieved CR. The complication rates were fairly high; 11% of patients required secondary operations, and a 0.8% mortality rate was reported. The conclusion was that the AGO score was a good instrument to predict surgical outcomes in platinum-sensitive recurrent ovarian cancer.

Updated results from the DESKTOP III trial were recently presented. Could you expand on what this trial revealed about the role of cytoreductive surgery in patients with a positive AGO score?

The interim analysis of this trial was published in 2017. The goal of this study was to evaluate the role of cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer with a positive AGO score. A total of 407 patients were included but it’s important to note that some patients had crossover. A little over 8.9% of patients in the no-surgery arm underwent surgeries and 6.9% of patients in the surgery arm did not undergo their operations.

Regardless, those who underwent surgery had a 72.5% CR rate. The PFS was significantly improved in the surgery arm, at 19.6 months, versus 14.0 months [in the no-surgery arm]. The time to first subsequent treatment was also prolonged in the surgery arm, at 21 months versus 13.9 months, respectively. The reoperation rates in this cohort were lower, at 3.5%, as compared with what was observed in DESKTOP II. The OS data were immature at the time of this presentation.

By the time of the 2020 ASCO Virtual Scientific Program, the OS data and the remainder of the analysis was complete. Seventy-five percent of patients achieved a CR with a positive AGO score. The PFS was 18.4 months, favoring the surgery arm versus 14 months with chemotherapy alone. The time to first subsequent treatment was also improved with surgery, at 17.9 months, versus 13.7 months [with chemotherapy alone]. Also, the OS also favored the surgery arm, at 53.7 months versus 46.0 months, respectively.

The subanalysis included all patients who underwent surgery but those who had an R0 resection at the time of their operation had a 61.9-month benefit in terms of survival compared with those who received chemotherapy alone; this was great improvement. It’s also important to note that the patients who had suboptimal surgeries, where gross residual disease was left behind, actually experienced a worse OS, at 28.8 months. The reoperation rate was 3.7%.

The results reported from the GOG-0213 trial conflict with those observed in the DESKTOP trials. Could you expand on this research?

In the United States, at the same time that the DESTKOP trials were being formulated, the GOG-0213 trial was underway. One portion of this study was evaluating the impact of secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer.

A total of 485 patients that were determined to have resectable disease by an investigator were included in this trial and the primary end point was OS. The total follow-up period was 48.1 months and 67% of patients who underwent surgery had complete gross resection. Notably, 84% of patients in this trial received bevacizumab (Avastin) at the investigator’s discretion and their PFS was 18.9 months in the surgery arm versus 16.2 months in the chemotherapy-alone arm and this was not significantly different. The OS was 50.6 months on the surgery arm versus 64.7 months; again, no significant difference or improvement with the surgical intervention was shown.

Morbidity rates were about 9% with mortality rates at about 0.4%. Also, no differences with regard to quality of life were observed; [these data were] collected in patients after they had completed their surgical recovery at 6 weeks.

How do you interpret the discordant results?

When we look at the outcomes between DESKTOP III and GOG-0213, there's some discordant results and we now wonder why this is so. One of the considerations is that the use of bevacizumab in addition to chemotherapy was different between both studies. There was a high utilization rate [of the agent] in GOG-0213, at 84%, versus only 20% in the DESKTOP III trial. As such, that might be a confounding variable.

Additionally, the selection criteria varied between these 2 trials. GOG-0213 had a looser evaluation process where the investigators had to determine whether the disease was resectable. The AGO score was also slightly more restricted in terms of patient inclusion. The patients who were included in the AGO positive score had to achieve CR at the initial operation with their primary debulking, while in the GOG-0213 trial, patients only had to have CR after initial therapy. As such, patients may have had residual disease left behind at the time of their initial operations, but again, just had a complete response after finishing their final chemotherapies.

Moreover, somatic or germline mutations and how they impact chemotherapy sensitivity in the general population should also be considered. It’s understood that patients who carry a BRCA1 or BRCA2 germline mutation are going to have better long-term response rates after their chemotherapy. If there's homologous recombination deficiency present in the tumor, the patients who carry those mutations may also be more chemotherapy sensitive in the long run. These were not accounted for in either the DESKTOP III or GOG-0213 trials.

References

1. Du Bois A, Sehouli J, Vergote I, et al. Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: final analysis of AGO DESKTOP III/ENGOT-ov20. J Clin Oncol. 2020;38(suppl 15):6000. doi:10.1200/JCO.2020.38.15_suppl.6000
2. Coleman RL, Spirtos NM, Enserro D, et al. Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med. 2019;381(20):1929-1939. doi:10.1056/NEJMoa1902626