Prediction Models for Complete Resection in Secondary Cytoreductive Surgery of Patients With Recurrent Ovarian Cancer

The most advanced epithelial ovarian cancer develops recurrent disease despite maximal surgical cytoreduction and adjuvant platinum-based chemotherapy. Treatment with secondary cytoreductive surgery (SCS) combined with chemotherapy or with chemotherapy alone for patients with platinum-sensitive recurrent ovarian cancer (ROC) is currently under heated discussion. Encouragingly, the results of the AGO DESKTOP III Study and the SOC1/SGOG-OV2 trial, which have been published recently, showed a striking advantage in terms of overall survival (OS) and progression-free survival (PFS) of ROC patients undergoing SCS compared to chemotherapy alone; moreover, a benefit of SCS exclusively for patients with complete gross resection (CGR) was particularly highlighted. CGR is considered the ultimate goal of SCS, on condition that the balance between maximal survival gain and minimal operative morbidity is maintained. Several models have been proposed to predict the rate of CGR, such as the MSK criteria, the AGO score, and the Tian model, over the last 15 years. This summary is mainly about the several previously published prediction models for CGR in SCS of ROC patients and discusses the effectiveness and limitations of these prediction models.

Improving the prediction of surgical outcome at secondary cytoreduction in patients with ovarian cancer: Results from retrospective part of HELP-ER study NOGGO TR2/ENGOT OV47-TR.

5558 Background: Complete resection at secondary cytoreductive surgery is associated with prolonged progression free and overall survival for patients with relapsed ovarian cancer. Secondary cytoreductive surgery has no impact on survival rates, if macroscopically tumor clearance cannot be achieved. Therefore, in order to avoid unnecessary perioperative morbidity and mortality, selection of patients who will undergo secondary tumor debulking is crucial. This study aims to improve upon the contemporary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) score by including additional clinical variables like circulating HE4 and CA125 levels to predict surgical outcome at secondary cytoreduction. Methods: A total of 90 patients underwent secondary cytoreductive surgery and were retrospectively assigned a positive AGO score. Of those patients, 62 (68.9%) achieved optimal surgical outcome at secondary debulking with 28 (31.1%) patients retaining residual tumor mass ( > 0mm). Utilizing clinical variables including circulating HE4 and CA125 levels, we implemented a machine learning workflow to predict suboptimal surgical outcome in patients despite a positive AGO score. Results: We elucidated significantly lower levels of circulating HE4 (p = 0.0038) in patients with optimal surgical outcome compared to patients that retain macroscopic residual tumor at secondary cytoreductive surgery. Moreover, machine learning algorithms trained on clinical variables (e.g. serum HE4 level, serum CA125 level, age, Risk of Ovarian Malignancy Algorithmus (ROMA) score and occurrence of peritoneal carcinomatosis) achieved a mean area under the curve (AUC) of 78.4% based on 100 consecutive executions with randomized training and test sets. Conclusions: The application of machine learning allows to further improve the prediction of patients with high likelihood of achieving optimal surgical outcome at secondary cytoreduction. In turn, it might identify patients that would benefit from amplified treatment efforts. However, machine learning relies on large amounts of data to account for biological and clinical variation and produce predictions of sufficient/adequate quality. Given this limitation, we would validate this data within the prospective multicentric cohort of patients collected within NOGGO/ENGOT HELP_ER Trial.

Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: Final analysis of AGO DESKTOP III/ENGOT-ov20.

6000 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59-0.97, p=0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54-0.82, p<0.001), median time to start of first subsequent therapy (TFST) was 17.9 vs. 13.7 mos in favor of the surgery arm (HR 0.65, 95%CI 0.52-0.81, p<0.001). An analysis according to treatment showed an OS benefit exceeding 12 mos for pts with complete resection (CR) compared to pts without surgery (median 60.7 vs. 46.2 mos); pts with surgery and incomplete resection even did worse (median 28.8 mos). 60 d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparotomies were performed in 3.7% of operated pts. Further grade 3/4 adverse events did not differ significantly between arms. Conclusions: This is the first surgical study demonstrating a meaningful survival benefit in OC: Surgery in pts with first relapse and TFIp of 6+ mos and selected by a positive AGO-Score resulted in a significant increase of OS, PFS and TFST with acceptable morbidity and, therefore, should be offered to suitable pts. The benefit was exclusively seen in pts with CR indicating the importance of both the optimal selection of pts (eg. by AGO score) and of centres with expertise and a high chance of achieving a CR. Clinical trial information: NCT01166737.

Ovarialkarzinomrezidiv: Sollte operiert werden oder reicht die medikamentöse Therapie?

<b>Background:</b> The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. <b>Methods:</b> Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. <b>Results:</b> 407pts were randomized 2010–2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59–0.97, p = 0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54–0.82, p &#x3c; 0.001), median time to start of first subsequent therapy (TFST) was 17.9 vs. 13.7 mos in favor of the surgery arm (HR 0.65, 95%CI 0.52–0.81, p &#x3c; 0.001). An analysis according to treatment showed an OS benefit exceeding 12 mos for pts with complete resection (CR) compared to pts without surgery (median 60.7 vs. 46.2 mos); pts with surgery and incomplete resection even did worse (median 28.8 mos). 60 d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparotomies were performed in 3.7% of operated pts. Further grade 3/4 adverse events did not differ significantly between arms. <b>Conclusions:</b> This is the first surgical study demonstrating a meaningful survival benefit in OC: Surgery in pts with first relapse and TFIp of 6+ mos and selected by a positive AGO-Score resulted in a significant increase of OS, PFS and TFST with acceptable morbidity and, therefore, should be offered to suitable pts. The benefit was exclusively seen in pts with CR indicating the importance of both the optimal selection of pts (eg. by AGO score) and of centres with expertise and a high chance of achieving a CR. Clinical trial information: NCT01166737.

Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20.

5501 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (OC) has not been defined by level-1 evidence. Methods: Pts with OC and 1st relapse after 6+ mos platin-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were randomized to 2nd-line chemotherapy alone vs cytoreductive surgery followed by chemo. Chemo regimens were selected according to the institutional standard. We report here results of the predetermined interim analysis. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% and 76% pts in both arms. 8.9% of 203 pts were operated despite of randomization to the no-surgery arm, whereas 6.9% of 204 pts in the surgery arm did not undergo operation. Complete resection was achieved in 67% of pts; 87% and 88% received a platinum-containing 2nd-line therapy. Median PFS was 14 mos without and 19.6 mos with surgery (HR: 0.66, 95%CI 0.52-0.83, p<0.001). Median time to start of first subsequent therapy (TFST) was 21 vs 13.9 mos in favor of the surgery arm (HR 0.61, 95%CI 0.48-0.77, p=p<0.001). PFS-2 between 1st and 2nd relapse equaled or even exceeded PFS-1 before 1strelapse in 26% after surgery and only 16% without-surgery. Analysis of the primary endpoint OS is kept blinded due to immaturity and will be evaluated after extended follow-up (the observed pooled unblinded 2-YSR was 83% instead of the initially in the protocol assumed 55-66%). 60d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparatomies were performed in 7 pts (3.5%) in the surgery arm.With the exception of myelosuppression which occurred more frequently in the no-surgery arm no further significant differences were observed with respect to grade 3+ acute adverse events. Conclusions: Surgery in pts with 1st relapse of OC after a TFIp of 6+ mos and selected by a positive AGO-Score resulted in a clinically meaningful increase of PFS and TFST with acceptable treatment burden. Until final OS data will definitively define the role of secondary cytoreductive surgery it should at least be considered as valuable option in pts with a positive AGO-Score. Clinical trial information: NCT01166737.