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Is There a Future Role for Secondary Cytoreductive Surgery in the Treatment of Recurrent Ovarian Cancer?


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In a recent issue of The New England Journal of Medicine, Coleman et al released the results from the GOG-0213 trial, a multicenter, randomized prospective trial that compared secondary cytoreduction followed by chemotherapy with chemotherapy alone in women with platinum-sensitive recurrent ovarian cancer.1 Ovarian cancer is a devastating diagnosis, with more than 22,000 new cases diagnosed each year and more than 14,000 deaths annually. Even if the cancer is initially controlled, more than 80% of patients eventually have recurrence.

Jocelyn Ray, MD, PhD

Jocelyn Ray, MD, PhD

Christina S. Chu, MD

Christina S. Chu, MD

Not surprisingly, promising treatments for recurrent ovarian cancer are under active investigation. A number of studies have supported the application of secondary cytoreduction for resectable recurrent disease, and the National Comprehensive Cancer Network Guidelines Clinical Practice Guidelines in Oncology: Ovarian Cancer lists surgery as an option for patients who have relapsed more than 6 months after complete response to prior chemotherapy.

Closer Look at GOG-0213

In the current trial, reviewed in this issue of The ASCO Post, 485 patients with recurrent ovarian cancer who were historically considered candidates for secondary cytoreduction (one prior therapy, platinum-free interval of more than 6 months, small volume of recurrent disease, investigator-determined resectable disease) were randomly assigned to receive secondary cytoreduction followed by chemotherapy vs chemotherapy alone. Overall, 67% of the patients in the surgery arm achieved complete gross resection. All patients received platinum-based chemotherapy of the treating physician’s choice (carboplatin/paclitaxel or carboplatin/gemcitabine); 84% of the patients also received bevacizumab with chemotherapy and as maintenance, and this was equally distributed between the two groups.

At a median of 48.1 months of follow-up, the median overall survival was statistically similar at 50.6 months for those undergoing surgery plus chemotherapy compared with 64.7 months for those undergoing chemotherapy alone (P = .08). The median progression-free survival was also similar. However, among those patients not receiving bevacizumab, surgical patients demonstrated significantly poorer survival than did those receiving chemotherapy alone (hazard ratio = 2.26, 95% confidence interval = 1.3–3.88). Although no significant difference was noted in overall survival between those undergoing complete surgical resection vs chemotherapy alone, there was a significant advantage to surgery in terms of progression-free survival. As expected, patients undergoing complete cytoreduction had improved overall and progression free survival compared with those who had residual disease.

Dr. Ray is a gynecologic oncology fellow at Fox Chase/Temple University Hospital, Philadelphia. Dr. Chu is Professor, Department of Surgical Oncology, and Director, Gynecologic Oncology Fellowship Program, Fox Chase/Temple University Hospital, Philadelphia.

Who May Benefit From Secondary Surgery?

A number of prior studies have focused at identifying candidates who will benefit from secondary cytoreductive surgery. Patients with a prolonged platinum-free interval (> 6 months) and those with an isolated or limited volume of disease (< 0.5 cm) at recurrence have the greatest benefit from secondary surgery compared with those with a shorter progression-free interval or abundant disease.2-4 In a pooled analysis of 1,100 patients in 2011,4 Zang et al showed a median survival of 57.6 months after complete secondary cytoreductive surgery, compared with 27.0 months in those with residual disease of 0.1 to 1 cm and 15.6 months in those with residual disease of more than 1 cm, respectively (P < .0001). Even after selecting for a group of patients with favorable characteristics, GOG-0213 found no improvement in survival with the addition of surgery to chemotherapy.

But do these findings realistically apply to our patient populations? The GOG-0213 trial was a well-designed, open-label phase III multicenter international randomized clinical trial with more than 50% of the patients enrolled in the United States. The randomization also accounted for prior length of progression-free interval and type of second-line chemotherapy. The authors did acknowledge that the median overall survival was nearly three times longer than expected, based on previous studies. They suggested that the improved overall survival is a reflection of advances in clinical care and more effective treatment options in current use.

In addition, as previously noted, this trial had narrow selection criteria, including only those patients with the most favorable prognostic indicators: small volume, easily resectable, chemotherapy-sensitive disease, with a median 20-month progression-free survival interval. The findings therefore may not be as applicable to patients with shorter progression-free survival intervals or a larger disease burden at presentation, who make up a large portion of the patients with recurrent ovarian cancer. Although patients may be willing to accept higher risks of complications in exchange for improvement in overall survival,5 the current study demonstrates no improvement in survival for patients undergoing surgery compared with chemotherapy alone.

Of note, this trial did allow for the use of bevacizumab therapy in either group, a reflection of the evolution in current practice. Bevacizumab has a proven benefit in this select patient population with respect to both progression-free and overall survival6 and may account for the longer-than-anticipated duration of overall survival. Any benefits of cytoreductive surgery may be minimized in the current era, where biologic therapies (bevacizumab, poly [ADP-ribose] polymerase inhibitors, checkpoint inhibitors) are being incorporated into front-line, maintenance, and recurrent treatment regimens.

Ongoing Phase III Trials

The lack of benefit for the addition of surgery to chemotherapy in this patient population leaves open the question of whether there is a different patient population that would benefit from surgery. Three other phase III trials are being conducted to compare surgery with chemotherapy vs chemotherapy alone, with slight differences in patient selection or selected adjuvant therapy.

DESKTOP III uses a similar trial design as GOG-0213 but includes only patients who had complete gross resection at the time of primary surgery, which has been shown to be another indicator of successful secondary cytoreduction.7 In contrast to GOG-0213, with 84% bevacizumab use, only approximately 20% of patients in DESKTOP III were treated with bevacizumab (ClinicalTrials.gov number NCT01166737).

The SOC 1 trial (NCT01611766) being conducted in China will assess progression-free and overall survival as primary endpoints. In addition, its secondary outcome is to validate the iMODEL risk model of patient selection criteria in platinum-sensitive recurrent ovarian cancer. A third trial, SOCceR (Netherlands Trial Register number NL3137), is also underway.

Although there continues to be clear interest in investigating the utility of secondary cytoreduction in patients with recurrent ovarian cancer, evaluation of the data from all the upcoming prospective randomized trials will help determine which patients, if any, will benefit from secondary cytoreduction. It is possible that with the development of newer effective pharmaceutical options, secondary cytoreductive surgery may no longer have a major role in the treatment of recurrent ovarian cancer. 

DISCLOSURE: Drs. Ray and Chu reported no conflicts of interest.

REFERENCES

1. Coleman RL, Spirtos NM, Enserro D, et al: Secondary surgical cytoreduction for recurrent ovarian cancer. N Engl J Med 381:1929-1939, 2019.

2. Al Rawahi T, Lopes AD, Bristow RE, et al: Surgical cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev 2:CD008765, 2013.

3. Chi DS, McCaughty K, Diaz JP, et al: Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer 106:1933-1939, 2006.

4. Zang RY, Harter P, Chi DS, et al: Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. Br J Cancer 105:890-896, 2011.

5. Havrilesky LJ, Yang JC, Lee PS, et al: Patient preferences for attributes of primary surgical debulking versus neoadjuvant chemotherapy for treatment of newly diagnosed ovarian cancer. Cancer 125:4399-4406, 2019.

6. Coleman RL, Brady MF, Herzog TJ, et al: Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213). Lancet Oncol 18:779-791, 2017.

7. Harter P, Sehouli J, Reuss A, et al: Prospective validation study of a predictive score for operability of recurrent ovarian cancer: The Multicenter Intergroup Study DESKTOP II. Int J Gynecol Cancer 21:289-295, 2011.

 


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