Ovarian cancer is the leading cause of death due to gynecologic cancer in Japan. In 2008, there were 9120 new ovarian cancer cases and 4990 deaths.1 At diagnosis, approximately half of the patients were diagnosed with stage III or IV with peritoneal dissemination.
Primary debulking surgery (PDS) followed by chemotherapy is considered the standard of care in patients with advanced ovarian cancer2; however, recently, it has been reported that neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) is an alternative for patients with unresectable tumors during PDS.3,4 A randomized controlled trial that compared PDS with NAC followed by IDS in patients with advanced epithelial ovarian cancer demonstrated similar progression-free and overall survival (OS) rates between the 2 groups.5 Moreover, the trial concluded that, similar to the objective during PDS, the objective during IDS was complete resection of all macroscopic diseases. However, most patients develop recurrent disease even after complete cytoreduction during IDS. In a recent article, the recurrence rate among patients with diffuse peritoneal carcinomatosis treated by IDS with no residual tumor after surgery was 76.3%.6 Although this recurrence rate is high, there are few reports reporting the recurrence patterns. This study aims to identify the recurrence patterns and risk factors among patients with ovarian, fallopian tube, and peritoneal cancers who have undergone complete cytoreduction during IDS.
PATIENTS AND METHODS
We retrospectively reviewed the data of patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers who were treated at the Department of Gynecology of the Cancer Institute Hospital in Tokyo, Japan, from January 1, 2005, to December 31, 2011. Clinical records were reviewed and summarized for age, origin of cancer, International Federation of Gynecology and Obstetrics stage, histological type, chemotherapy, surgical procedure, peritoneal cytology during IDS, pretreatment and pre-IDS serum CA125 levels, and recurrence patterns. Patients with stage IIIC cancers without disseminated lesions (those diagnosed with stage IIIC because of lymph node metastases) were excluded. Peritonectomy was not included as an upper abdominal/intestinal surgery. Before 2008, pelvic and paraaortic lymphadenectomy was routinely performed during IDS; however, since then, removal of only the bulky lymph nodes has been performed.
During this period, a total of 598 patients with ovarian, fallopian tube, and peritoneal cancers were treated in this hospital. Of these, 213 patients were diagnosed as having stage III or IV disease with disseminated lesions. The PDS was only used if safe, complete cytoreduction was possible without an extended upper abdominal or intestinal surgery. Thus, 43 patients underwent PDS after adjuvant chemotherapy, and 170 were treated with NAC. Of these 170 patients, 139 (81.8%) underwent IDS after NAC. The remaining 31 patients (18.2%) were treated by chemotherapy only because of disease progression, age, or complications or if patients refused surgery. Of the 139 patients who received IDS, 128 (92.1%) and 11 (7.9%) achieved optimal (residual tumor of <1 cm in diameter) and suboptimal cytoreduction, respectively. Of the 128 patients who underwent optimal cytoreduction, 105 (82.0%) had no macroscopic residual tumor (complete cytoreduction), whereas the remaining 23 (18.0%) had a residual tumor of smaller than 1 cm in diameter. In this study, we examined the records of 105 patients without macroscopic residual tumor after IDS.
Recurrence was confirmed by computed tomography, positron emission tomography, or magnetic resonance imaging. The site of recurrence was classified as either intraperitoneal, lymph node, or distant organ. Intraperitoneal recurrence was further classified into the following 3 groups: upper abdomen, middle abdomen, and pelvis. The upper abdomen was classified into the diaphragm, liver, spleen, and pancreas, whereas the middle abdomen was classified into below the upper abdomen and above the external pelvis.
Progression-free survival (PFS) was defined as the time from initiation of treatment to the first recurrence, and OS was defined as the time from initiation of treatment to death or the last follow-up. Time to recurrence was defined as that from the completion of treatment to the diagnosis of recurrence.
This study was approved by the Cancer Consortium Institutional Review Board at the Cancer Institute Hospital.
Survival curves were estimated by the Kaplan-Meier method, and differences were tested using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Comparison of intergroup proportions was performed using the χ2 test. Statistical analyses were performed using R software. P value was calculated using the likelihood ratio test, and Ps ≤ 0.05 were considered statistically significant.
Patient Characteristics and Treatment
A total of 105 patients underwent NAC followed by IDS and achieved complete cytoreduction. Patients and treatment characteristics are summarized in Table 1. Six patients (5.7%) had disease classified as stage IIIB, 67 (63.8%) had stage IIIC, and 32 (30.5%) had stage IV. The median number of NAC cycles was 4. All patients underwent total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Upper abdominal and/or intestinal surgery was performed in 42 patients (40.0%), including rectosigmoid resections in 28, partial hepatectomies in 6, splenectomies in 6, small intestinal resections in 4, diaphragmatic resections in 3, ileocecal resections in 3, transverse colostomies in 2, and cholecystectomy in 1. In total, 103 patients (98.1%) underwent adjuvant chemotherapy after IDS; the median number of chemotherapy cycles was 8.
Outcome and Risk Factors for Recurrence
At the time of analysis, the median follow-up period was 42.1 months. Recurrence was documented in 70 patients (66.7%), whereas no evidence of disease was documented in 35 patients (33.3%). Group characteristics are summarized in Table 1.
The median OS and PFS were 78.4 (range, 7.0–95.4) months and 24.1 (range, 4.9–94.8) months, and the 2-year OS and PFS rates were 92.2% and 51.0%, respectively. The median time for recurrence was 8.9 (range, 1.0–47.2) months.
Univariate and multivariate analyses were performed to identify the risk factors associated with cancer recurrence (Table 2). In the univariate analysis, positive peritoneal cytology and elevated pre-IDS serum CA125 levels were significantly associated with recurrence. Furthermore, in the multivariate analysis, positive peritoneal cytology and elevated pre-IDS serum CA125 levels were independent risk factors. Peritoneal cytology was identified as the strongest risk factor for recurrence (P = 0.0003, Fig. 1).
As first recurrence patterns, 42 patients (60.0%) had peritoneal dissemination, 37 (52.9%) had lymph node metastases, and 16 (22.9%) had organ metastases. Of the 37 patients with lymph node metastases, recurrence at pelvic and/or paraaortic lymph nodes was observed in 23; and recurrence at distant lymph nodes, in 14. Among the 42 patients who had peritoneal dissemination, 27 (64.3%) had a recurrence focus in the pelvis; 21 (50.0%), in the middle abdomen; and 19 (45.2%), in the upper abdomen.
The median PFS and OS in the group with peritoneal dissemination recurrence were 19.3 and 46.8 months, respectively; in the group without peritoneal dissemination, the PFS and OS were 17.4 and 45.8 months, respectively. Survival rates in both groups were not significantly different. Furthermore, the median survival periods from recurrence in both groups were 20.9 and 25.8 months, respectively. There were no significant intergroup differences with and without peritoneal dissemination recurrence concerning the prognosis after recurrence.
In patients with positive peritoneal cytology during IDS, it was significantly more likely that peritoneal dissemination was the site of recurrence. Lymph node metastases as the site of recurrence were observed in 52.9%. There was no apparent trend between lymph node metastases and lymphadenectomy at the time of IDS. Organ metastases as the site of recurrence were observed in 22.9%, and recurrence in the same organ as that of pretreatment metastasis was observed in only 1 patient (6.3%).
Recent data of the European Organization for Research and Treatment of Cancer 55971 phase-3 randomized trial showed that outcomes of NAC followed by IDS were not inferior to those of PDS followed by chemotherapy for patients with advanced epithelial ovarian cancer, and complete resection of all macroscopic diseases remains the objective whenever cytoreductive surgery is performed.5 In this study, we showed a high rate of complete cytoreduction and a median OS and PFS of 78.4 and 24.1 months, respectively, thus providing additional support for the use of IDS.
However, the recurrence rate remains high even after complete cytoreduction during IDS.6 There are some reports of the prognostic factors in patients who underwent NAC followed by IDS.7–9 However, to the best of our knowledge, prognostic factors particularly among patients without macroscopic residual tumor (complete cytoreduction) have not yet been reported. Vergote et al5 reported that absence of residual tumor after surgery, stage IIIC tumor size before treatment, nonserous histology, and age were prognostic factors for patients with stage IIIC or IV ovarian cancer who underwent NAC followed by IDS. Rocconi et al10 reported that stage, debulking status, and normalization of serum CA125 levels were associated with OS. Other researchers have demonstrated that radical surgery as part of PDS is a good prognostic factor,11 whereas Stoeckle et al7 reported that no bowel surgery during IDS was associated with longer OS. In our series, stage, histological type, and resection of extra organs among patients without macroscopic residual tumor after IDS were not significant risk factors for recurrence. The tumor size before treatment was not examined, and systematic aortic and pelvic lymphadenectomy was not associated with recurrence in this study. In previous reports, systematic lymphadenectomy during IDS as well as PDS was not shown to improve OS in patients with advanced ovarian cancer.12–14
In this study, we reported that positive peritoneal cytology at IDS and elevated pre-IDS serum CA125 levels are independent risk factors for recurrence after complete debulking during IDS in patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers with peritoneal dissemination. In particular, positive peritoneal cytology was a strong risk factor for recurrence in this group. Peritoneal cytology status during IDS as a risk factor for recurrence has not been reported. In many institutions, routine peritoneal cytology is not a part of IDS in the treatment of advanced ovarian, fallopian tube, and peritoneal cancers, because it would not change the FIGO staging in most of these cases. However, we consider that peritoneal cytology should be done during IDS to identify patients with a high risk of recurrence. Previous studies have attempted to use preoperative CA125 levels to predict optimal surgical results in patients with advanced ovarian cancer. Rodriguez et al15 reported that, after treatment with taxane- and platinum-based chemotherapy, patients with advanced-stage ovarian cancer and a preoperative CA125 level of 100 U/mL or lower were most likely to be cytoreduced to no residual disease during IDS. In contrast, Furukawa et al16 reported that, in the setting of IDS after platinum-based NAC for advanced ovarian cancer, a pre-IDS CA125 level of less than 20 U/mL is an independent predictor of complete cytoreduction during IDS. In our study, there were 78 patients (74.3%) whose pre-IDS CA125 level was less than 20 U/mL. Moreover, a pre-IDS CA125 level of less than 15 U/mL was one of the independent risk factors for recurrence after complete cytoreduction during IDS.
Petrillo et al6 reported that carcinomatosis as a recurrent disease was observed in 57.3% of patients treated with NAC followed by IDS with no residual tumor after surgery. Amate et al17 reported that peritoneum is the main site of recurrence (75%) in patients with advanced disease treated by PDS and IDS. In this study, 60.0% of the patients had recurrence in the form of peritoneal dissemination after complete cytoreduction during IDS; these findings are similar to the findings reported by Petrillo et al and Amate et al. In addition, in this study, there was no difference in this recurrence pattern compared with the group that had a residual tumor smaller than 1 cm in diameter during IDS (χ2 test). There was also no difference in the area of abdominal recurrence focus (pelvis, middle abdomen, or upper abdomen) between the group that had no residual tumor and the group that had a residual tumor smaller than 1 cm in diameter during IDS (χ2 test).
Hynninen et al18 reported that microscopically carcinomatous areas may have a benign visual appearance after NAC (the false-negative rate was 14%) more often than that during primary surgery, and thus, NAC may lead to incomplete resection of the tumor in potentially resectable areas. This may explain why peritoneal dissemination is the most common recurrence site even after complete cytoreduction during IDS. Microscopic cancer cells remaining in the peritoneum may not be resected because of being judged as macroscopically healthy.
We acknowledge that the single-institution study and retrospective nature of our study represent limitations. However, our study is the first to examine the risk factors associated with recurrence in patients with ovarian, fallopian tube, and peritoneal cancers who underwent complete cytoreduction during IDS. The results of our study need to be confirmed in larger studies.
In conclusion, we documented positive peritoneal cytology during IDS and elevated pre-IDS serum CA125 levels as risk factors associated with recurrence after complete cytoreduction during IDS in patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers with peritoneal dissemination. In particular, positive peritoneal cytology at IDS is a strong predictive factor for poor outcomes in these patients. Thus, it will be important to closely monitor this group after the completion of initial therapy. Furthermore, additional treatment, such as bevacizumab, which has been proven to improve PFS significantly after PDS in the primary treatment of advanced ovarian, fallopian tube, and peritoneal cancers,19 may be beneficial to improve the prognosis in these patients. Furthermore, more large-scale, randomized trials are needed in the future to establish the most effective treatment to improve clinical outcomes in this group.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Ovarian cancer; Fallopian tube cancer; Peritoneal cancer; Complete cytoreduction; Interval debulking surgery; Neoadjuvant chemotherapy; Recurrence