Response to the letter of Fagotti et al. regarding the manuscript: "Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery".

We thank Fagotti et al. for their interest in our paper describing the patterns and sites of residual disease (RD) in patients with advanced ovarian cancer who have undergone primary debulking surgery (PDS) (Heitz et al., 2016) in an expert referral center. The colleagues compare their own data with ours even though the patients populations are quite different with all incoming patients being analyzed in our series as opposed to only pre-selected patient cohorts reported in the Rome series. Nevertheless, we appreciate and acknowledge that their continuous surgical training led to an improvement of their complete resection rates and overall surgical quality over the last years.

Fagotti et al. focus their discussion mainly around selection criteria for ideal treatment strategies in patients with advanced ovarian cancer. This was however not the main purpose of our analysis. Our aim was to identify and describe the patterns and sites of residual disease in patients operated in centers where not the skill of the surgical team is the limit but rather the anatomical and tumor-biological factors. We described the outcome of all incoming patients providing all associated information unbiased and without any preselection. Moreover, the interpretation that we reported 30.3% of patients being not suitable for PDS is inaccurate. Fagotti et al. added together all patients who did not have primary surgery and those who underwent PDS with large residual disease. They missed the statement that half of the 161 patients who did not undergo PDS was due to the reason of having already started neoadjuvant therapy in centers elsewhere. Obviously, we were not involved in the initial decision making process whether or not these patients could have been candidates for PDS. As stated, the rate of patients deemed not suitable for PDS in the cohort of patients that have started treatment in our center was only 10.9%. In fact, PDS was retrospectively not the best choice in 8.5% of the patients due to RD > 1 cm – a pretty low rate compared with other series. Nevertheless, this was sufficient motivation for us to further define selection criteria for PDS without withholding a high chance for (curative) complete resection (ongoing protocol AGO-OVAR 19). Laparoscopy as selection aid had been shown to be beneficial in Rome when complete resection rates were much lower and comparable to ours at the beginning of our learning curve (Harter et al., 2011). However, even with laparoscopy complete resection rates were still lower than in our center without pre-selection – and the same accounted for the cited SCORPION trial in which 13.7% of patients were excluded before randomization due to suspected inoperable disease but still 9.0% and 9.6% in the PDS and interval debulking groups, respectively, were left with RD > 1 cm (Fagotti et al., 2016).

Our comments on the risk of abdominal wall metastases (AWM) were obviously misunderstood. Our group reported a slightly higher surgical impact of AWM (Heitz et al., 2010) but we did not postulate any negative impact on survival (Ataseven et al., 2016a). In contrast, we even advocated modifying the FIGO classification, as we showed that prognosis of patients with stage IVB due to AWM is superior compared to all other FIGO IV locations (Ataseven et al., 2016b).

Finally, we disagree with Fagotti et al. regarding the statement about upfront chemotherapy and interval debulking (NACT-IDS), that “.. The future is designing small clinical trials for groups of patients, inserted into a clear clinical scenario, showing specific markers of the disease”. As reported in our actual (Heitz et al., 2016) and previous (Vergote et al., 2010) papers, we doubt that the design of the EORTC- (Vergote et al., 2010) and the CHORUS-trials (Kehoe et al., 2015) could reliably test the hypothesis, that upfront chemotherapy followed by interval debulking is non-inferior or even superior to PDS. We rather interpret these trials as proof that NACT-IDS is non-inferior to primary surgery in a setting of low surgical effort and limited success. Therefore, the AGO-Trial on Radical Upfront Surgery in Advanced Ovarian Cancer (TRUST; NCT#02828618) was designed to compare maximum effort PDS performed in centers with proven high surgical quality with equally maximal effort NACT-IDS, more rigorously as the first randomized phase III trials. A large cohort of patients is needed to prove the hypothesis of an overall survival benefit of patients undergoing PDS compared to patients undergoing NACT-IDS. We believe that surgical questions should be addressed only by experienced surgeons, therefore, the TRUST trial only includes centers with externally proven surgical skills and audited by experienced surgeons.

Not a single chemotherapy trial would ever have been accepted if the dose intensity or protocol completion rate achieved had been at such low ranges similar to the low complete resection rates described in the NACT-IDS trials.

In any case, the fate of a patient should not depend on through which door she enters – Rome or Essen or elsewhere. Rather robust quality improvement criteria and strategies should be implemented in all centers performing this kind of treatments. Fagotti et al. have their merits by assessing the value of laparoscopy in this setting, our focus lies rather on other areas but nevertheless each of us has a small piece to contribute to the bigger picture.

Conflicts of interest

Dr. Heitz reports personal fees from Roche, another from AstraZeneca, outside the submitted work; Dr. Harter reports another from Astra Zeneca, another from Roche, outside the submitted work; Dr. Ataseven reports personal fees from Roche, personal fees from Astra Zeneca, personal fees from Celgene, outside the submitted work; Dr. du Bois reports no conflicts of interest.