Results of Primary Cytoreductive Surgery in Advanced-stage Epithelial Ovarian Cancer: A Single-center Experience

Discussion

It has been more than eight decades since Meigs first described the principles of debulking surgery in ovarian cancer: “as much tumor as possible should be removed to enhance the effectiveness of postoperative radiation therapy” (10). Four decades later, in 1975, Griffiths et al. reported the first series of patients operated on according to these principles (11). Since then, numerous studies have been conducted on this subject in an attempt to establish the rules that should be applied in advanced ovarian cancer in order to improve outcome. Firstly, it was the dimension of the minimum residual disease which was modified: although historically, residual disease less than 2 cm was considered acceptable, in time, this dimension decreased to 1 cm and even 0.5 cm since better survival seemed to correlate inversely to residual tissue (5-8). Early studies from our Centre by Setlacec et al. (12) at the beginning of the 1980s tackled different aspects, some still under discussion, such as the extent of resection to the superior abdomen, surgical procedures required for proper staging of early ovarian cancer, extent of lymph node dissection, secondary cytoreductive surgery. A study from the same institution by Popescu et al. (13) on 59 patients concluded on the importance of the first intervention performed for ovarian cancer; patients with sub-optimal debulking lived for a shorter period than patients in whom appropriate R0 cytoreduction was obtained by complex procedures, including gynaecological, visceral, urological and even thoracic surgery. A recent study from our Institution emphasized the survival benefit of intra-peritoneal chemotherapy associated with R0 resection versus R0 resection alone (14). In 1992 and 1994, Hoskins et al. conducted two studies in which they included 349 patients with advanced epithelial ovarian cancer submitted to debulking surgery with residual disease less than 1 cm and 294 patients with residual disease greater than 1 cm. The overall survival incrementally improved as the maximum residual disease decreased from 2 cm to no macroscopic residual disease (5-year overall survival was 60% for patients with no macroscopic residual disease, 35% for cases with residual disease less than 2 cm, and only 20% for patients with residual disease larger than 2 cm (7,15).

Bristow et al. reported a meta-analysis conducted on 6,885 cases with advanced ovarian cancer (FIGO stages III-IV) submitted to cytoreductive surgery and concluded that each 10% increase in the proportion of cases undergoing maximal debulking surgery was associated with a 5.5% increase in the median survival time of the cohort (16).

Once the efficacy of complete debulking surgery was widely demonstrated, a similar aggressive surgical approach was also proposed for cases with upper abdominal disseminations. Chi et al. conducted a study on two different groups: the first consisted of 168 patients submitted to primary cytoreductive surgery during a period in which debulking surgery did not include extensive upper abdominal resections, while in the second group, 210 patients who also benefited from upper abdomen resections were included. The authors defined upper abdominal resections as partial phrenectomy, diaphragmatic peritonectomy, splenectomy, distal pancreatectomy, chole-cystectomy atypical hepatectomy or tumor resection from the porta hepatis. The 5-year progression-free survival rates for the second group versus the first were 31% versus 14%, respectively (p=0.01), while the five-year overall survival rates were 47% versus 35%, respectively (p=0.03). The same study concluded that the median overall survival for the second group was 54 months, which was significantly longer than that of 43 months for the first group (p=0.03) (17).

Another study conducted on this theme at the Memorial Sloan Kettering Hospital involved patients with stage IIIC ovarian cancer organized into two groups: the first group presented disease in the upper abdominal cephalad to the great omentum, while the second group had no signs of disease in the upper abdomen. Although complete resection was performed in both groups, patients with no upper abdominal burden had a progression-free survival of 33 months, while for those with upper abdominal tumoral disseminations it was 22 months (p=0.003) (18). We report on similar results, with a median overall survival of 40 months for cases submitted to upper abdominal resection compared to 50 months for cases with pelvic-confined disease, although all the patients had been submitted to R0 resection. We consider that this difference in terms of survival can be explained by a more aggressive biological behaviour or a longer period of evolution of the disease for cases with upper abdominal disease.

Association of diaphragmatic resection is another widely discussed topic when evaluating the possibility of achieving complete resection. Studies have shown that diaphragmatic surgery can be safely performed in patients with advanced ovarian cancer presenting diaphragmatic involvement and it can also provide a benefit in terms of survival (19, 20). In our case, diaphragmatic surgery as part of complete R0 cytoreduction was performed in 64 cases and consisted of diaphragmatic peritonectomy and partial phrenectomy; diaphragmatic surgery was associated with a median overall survival of 41 months, while in cases with no diaphragmatic involvement it was 50 months. The survival difference between the two groups was not statistically significant (p=0.446) and we consider that it was associated with there being more advanced disease.

Another frequently performed visceral resection during primary cytoreduction was bowel resection. In our study, more than 40% of the patients were submitted to bowel resection in order to achieve complete R0 resection. Large studies have already demonstrated that bowel resection is one of the most frequently performed procedures in order to remove bulky tumoral masses (21, 22) and estimated that this kind of surgery is required in almost 50% of optimal debulking operations. Multiple studies have demonstrated that bowel resection can significantly increase the percentage of complete cytoreduction and is associated with similar survival rates when compared to patients submitted to R0 resection, but who did not require intestinal surgery (21-23). Gillette-Cloven et al. demonstrated that association of bowel resection in order to obtain complete resection was associated with a median overall survival of 35 months compared to a median survival of 18 months for cases with no bowel resection but with residual disease (22). In their study of 48 cases diagnosed with FIGO stage III-IV epithelial cancer submitted to bowel resection as part of complete cytoreduction surgery, Estes et al. demonstrated that bowel resection can provide a benefit in survival outcomes by increasing the rate of R0 resection; bowel resection was performed with acceptable perioperative morbidity; anastomotic leak was encountered in 2% of cases, while postoperative mortality rate was 4% (23).