INTRODUCTION — The majority of ovarian cancer patients experience recurrence of disease [1]. The pattern varies from isolated nodal disease to isolated peritoneal disease to peritoneal carcinomatosis. Extra-abdominal sites of recurrence are uncommon. Most patients with recurrent ovarian cancer are treated with chemotherapy alone. Surgical treatment is reserved for a select group of patients.
Surgery for recurrent ovarian cancer is reviewed here. Monitoring patients for recurrence and medical treatment of recurrence are discussed separately.
SCOPE AND GOALS OF SURGERY — Surgery for recurrent ovarian cancer may involve secondary (rarely tertiary or quaternary) cytoreductive surgery, partial liver resection, splenectomy, or surgery for bowel obstruction. The goal of additional cytoreductive surgery is to prolong survival by resecting all visible disease (complete gross [R0] resection). The goal of surgery for bowel obstruction is palliative: to improve quality of life.
CANDIDATES — In our practice, we apply the Memorial Sloan Kettering Cancer Center (MSKCC) criteria to determine if patients should be offered secondary cytoreductive surgery for recurrent ovarian cancer (table 1).
In general, candidates for secondary cytoreduction are patients with limited sites of recurrence and platinum-sensitive disease, which is defined as a recurrence beyond six months after completion of adjuvant platinum-based chemotherapy. Patients with an early recurrence (platinum-resistant disease) often have a decreased response to additional chemotherapy; thus, they are not ideal candidates for secondary cytoreduction. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease" and "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease".)
Several studies have supported the ability to achieve complete secondary cytoreduction as a key prognostic factor for survival [2-12]. However, preoperatively predicting whether complete secondary cytoreduction will be possible remains a challenge.
PREDICTING SUCCESSFUL DISEASE RESECTION — Risk models are often applied in determining which patients are candidates for secondary surgical cytoreduction. Other factors, such as imaging findings as well as laparoscopy, are also utilized to determine whether sites of recurrence are limited and potentially resectable.
●Findings at the time of surgery usually correlate with imaging findings. If there is clinical concern for recurrent disease (patient-reported symptoms or elevation in serum cancer antigen 125 [CA 125]), imaging studies, such as chest/abdominal/pelvic computed tomography (CT) or magnetic resonance imaging, should be obtained to evaluate for presence and sites of recurrent disease. Positron emission tomography/CT scans can be very helpful prior to surgery to rule out disease that may be unresectable, such as mediastinal nodes.
●Diagnostic laparoscopy may be useful for distinguishing patients who can be optimally debulked at secondary surgery, but data are limited [13,14]. This follows the paradigm applied in primary disease to assess feasibility of successful disease resection. In our experience, laparoscopy is not routinely utilized in secondary cytoreductive surgery.
●Prognostic models have been developed to predict the likelihood of complete secondary cytoreductive surgery in patients with recurrent ovarian cancer.
•One study developed an international model (iMODEL) based on individual data from 1075 patients with recurrent ovarian cancer from seven international centers [15]. Complete secondary cytoreduction was achieved in 53 percent of patients with a low score and 20 percent of patients with a high score for the following variables: International Federation of Gynecology and Obstetrics (FIGO) stage at initial diagnosis (I/II versus III/IV), residual disease after primary cytoreduction (absent versus present), progression-free interval (≥16 versus <16 months), performance status, serum CA 125 at recurrence (≤105 versus >105 U/mL), and ascites at recurrence (absent versus present). In external validation, the sensitivity and specificity were 83.3 and 57.6 percent, respectively.
•The DESKTOP OVAR trial (Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian Cancer) evaluated an Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score for predicting complete gross resection (R0) at secondary cytoreductive surgery. A positive AGO score was characterized by Eastern Cooperative Oncology Group (ECOG) performance status of 0, ascites <500 mL, and complete resection at initial surgery [16].
The DESKTOP II trial applied the AGO score to prospectively evaluate patients with recurrent disease (after a platinum-free interval of >6 months) for secondary cytoreductive surgery [17]. Complete gross resection (R0) was achieved in 76 percent of patients with a positive AGO score.
•Parallel with the AGO DESKTOP trials, a study comparing Memorial Sloan Kettering Cancer Center (MSKCC) criteria (disease-free interval, single versus multiple sites of recurrence versus carcinomatosis) to predict complete gross resection with the AGO model reported the complete gross resection (R0) rate was 86 percent for both [18]. However, MSKCC criteria rendered a higher proportion of patients eligible for secondary cytoreductive surgery (98 versus 46 percent).
PROCEDURE — The goal of surgery in recurrent ovarian, fallopian tube, or peritoneal cancer is complete gross resection.
Secondary cytoreductive surgery — The approach to secondary cytoreductive surgery depends on the distribution of disease on preoperative imaging. The potential for adhesions and distortion of abdominal and pelvic anatomy due to prior surgery also needs to be considered in making this decision. An open approach is always reasonable, but if disease appears to be limited to a solitary site, a laparoscopic or robotic approach may be feasible, depending on the surgeon's expertise. Rarely, recurrence is limited to a single lymph node, termed isolated lymph node relapse. Prolonged post-relapse survival and overall survival appear to be more likely in these cases than with extranodal relapse [19].
Hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of surgical cytoreduction is an investigational modality for treating patients with recurrent ovarian cancer and its clinical benefit is unclear. In a randomized phase II trial including 98 patients with recurrent ovarian cancer, patients receiving carboplatin HIPEC followed by five cycles of carboplatin-based chemotherapy versus no HIPEC and six cycles of carboplatin-based chemotherapy had similar median overall survival (52.5 and 59.7 months, respectively) [20]. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'Heated intraperitoneal chemotherapy'.)
Tertiary cytoreductive surgery — After secondary cytoreductive surgery, few data are available on the role of additional cytoreductive surgery for recurrent ovarian cancer [21-24]. The survival benefit appears to be limited to patients in whom the procedure results in no residual disease. In the largest series, a retrospective multicenter study of 406 patients, median overall survival in patients with no versus some gross residual disease after tertiary cytoreduction was 49 and 12 months, respectively [23]. Survival benefit also appears more favorable in those with high grade serous ovarian cancer. In a subsequent retrospective review including 114 patients with recurrent epithelial ovarian cancer undergoing tertiary cytoreduction, patients with high-grade serous ovarian cancer and a single site of recurrence who were ≥2 years from secondary cytoreduction had the longest survival (median 79.5 months) [24].
Independent factors predictive of complete cytoreduction in these patients include limited extent of disease (in particular, a single site of disease), lack of carcinomatosis, and no extrapelvic tumor involvement [22,25].
Beyond the tertiary setting, data are even more limited [25,26]. In the largest series, which included 49 patients, mean overall survival for patients without versus any residual tumor after quaternary cytoreduction was 43.0 and 13.4 months, respectively [26]. Multifocal tumor dissemination was predictive of incomplete tumor resection, higher operative morbidity, and lower survival in multivariate analysis, whereas postoperative systemic chemotherapy improved overall survival.
Partial liver resection — In three retrospective reports from single institutions, a total of 68 patients underwent hepatic resection for recurrent ovarian cancer along with resection of other gross disease [27-29]. Median survival was approximately 26, 38, and 62 months in the three series. Factors associated with longer survival after hepatic resection included negative margin status of the hepatic resection, optimal cytoreduction of nonhepatic disease, pelvic versus abdominal disease, and longer time from initial diagnosis and surgery.
Splenectomy — Similar to liver resection, the data on splenectomy in surgery for recurrent ovarian cancer are extremely limited. In one report of six patients with isolated parenchymal splenic metastasis at a median of 57 months after initial surgery and platinum-based chemotherapy for stage III disease, all were alive and free of disease at median follow-up of 25.5 months (range 6 to 65 months) after splenectomy [30].
In another report, 24 patients underwent splenectomy as part of secondary cytoreduction; 15 had multiple splenic lesions (8 with disease at other sites), and 9 had a solitary splenic lesion [31]. At a median follow-up of 30 months, median progression-free and overall survival from the time of secondary surgery were 34 and 56 months, respectively.
Relief of bowel obstruction — Bowel obstruction in patients with recurrent ovarian cancer is generally related to external compression from carcinomatosis. Less commonly, mesenteric tumor may angulate the bowel and provoke an extramural bowel occlusion. Additionally, pericancer inflammation can lead to adhesions, which can cause obstruction. In some cases, decreased bowel motility results in pseudo-obstruction.
Surgery for relief of bowel obstruction is controversial because its benefit appears to be only palliative, it is associated with high rates of morbidity and mortality, and nonoperative alternatives exist (see "Palliative care of bowel obstruction in cancer patients"). In small, single-institution observational studies that have addressed the issue of surgery for bowel obstruction in recurrent ovarian cancer, two-thirds of patients had successful symptom control, but major surgical morbidity occurred in over 20 percent, and perioperative mortality occurred in 4 to 18 percent [32-36]. Median survival after surgery ranged from approximately 3 to 12 months.
Surgical palliation of symptoms may be warranted, particularly in the setting of limited peritoneal disease causing a bowel obstruction, but patients should be appropriately counseled regarding the success rates and durability of palliation, as well as the significant morbidity associated with surgery.
OUTCOME OF CYTOREDUCTION
Overall survival — Observational studies have found that cytoreduction to no macroscopic disease is associated with longer overall survival (OS) compared with any visible residual disease, but these studies are likely limited by selection bias [2,37-40]. In a 2013 systematic review of nine studies (seven retrospective) including 1194 patients with recurrent ovarian cancer, complete cytoreduction to no visible disease was associated with a greater than threefold increase in OS compared with leaving any gross residual disease (hazard ratio [HR] 3.59, 95% CI 2.45-5.24) [38]. Most patients received adjuvant chemotherapy as well.
Whether secondary (or tertiary) cytoreduction is more effective than chemotherapy is less clear. In a population-based study using Surveillance, Epidemiology, and End Results (SEER) Medicare data from 1635 patients with recurrent ovarian cancer, the median OS of patients treated with surgery plus chemotherapy, chemotherapy alone, and hospice care was 5.4, 4.1, and 2.2 years, respectively [39]. In a subsequent meta-analysis of 36 studies including over 2800 patients with platinum-sensitive recurrent ovarian cancer, secondary surgical cytoreduction with maximal tumor resection resulted in an increase in OS by up to 9 percent (median) [41].
Three phase III trials investigating the role of cytoreductive surgery in patients with recurrent ovarian cancer have reported results:
●In Germany, the DESKTOP III trial randomized 407 patients with recurrent platinum-sensitive ovarian cancer who had a first relapse after a platinum-free interval of at least six months and a positive Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score (which predicts likelihood of a complete surgical resection for recurrent disease and described above (see 'Predicting successful disease resection' above)) to undergo secondary cytoreductive surgery plus chemotherapy or chemotherapy alone [42]. OS was higher in patients undergoing surgical resection plus chemotherapy versus chemotherapy alone (median 54 versus 46 months; HR 0.75, 95% CI 0.59-0.96) during the 70-month (median) follow-up period. Complete surgical resection was achieved in 76 percent of patients assigned to the surgery group and predicted a better survival outcome than patients in whom complete resection could not be performed (62 versus 28 months, respectively).
●Similarly, in China, the Shanghai Gynecologic Oncology Groups' SOC-1 trial randomized 357 patients with platinum-sensitive relapsed epithelial ovarian cancer who had a platinum-free interval of at least six months and potentially resectable disease (as predicted by international model (iMODEL) score (see 'Predicting successful disease resection' above) and positron emission tomography-computed tomography [PET-CT] imaging) to secondary cytoreduction followed by chemotherapy or chemotherapy alone; 92 percent of patients received their planned therapy [43]. Median progression-free survival was higher for patients who underwent surgery and chemotherapy (17.4 months) versus patients who underwent chemotherapy alone (11.9 months; HR 0.58, 95% CI 0.45-0.74) during the 36-month (median) follow-up period. At the interim analysis, median OS for patients undergoing surgery and chemotherapy versus chemotherapy alone was 58 and 54 months, respectively (HR 0.82, 95% CI 0.57-1.19); long-term survival data were immature at the interim analysis.
●In the United States, the Gynecologic Oncology Group (GOG) 213 trial randomly assigned 485 patients with recurrent platinum-sensitive ovarian or primary peritoneal cancer who had a complete response to front-line chemotherapy, a treatment-free interval longer than six months, and investigator-determined resectable disease to secondary surgical cytoreduction followed by platinum-based chemotherapy or platinum-based chemotherapy alone (carboplatin and paclitaxel with or without bevacizumab or carboplatin and gemcitabine with or without bevacizumab) [44]. Complete gross resection (R0) was achieved in two-thirds of patients who underwent surgery, comparable with the rate in the DESKTOP III study. Most patients had a platinum-free interval >12 months, and the median platinum-free interval was 20.4 months.
At 48 months median follow-up, the HR for death was similar for both groups (surgery versus no surgery HR 1.29, 95% CI 0.97-1.72), which corresponded to a median overall survival after surgery versus chemotherapy of 50.6 and 64.7 months, respectively. The HR for disease progression or death was also similar (surgery versus no surgery HR 0.82, 95% CI 0.66-1.01), with median progression-free survival after surgery versus chemotherapy of 18.9 and 16.2 months, respectively.
In addition, 9 percent of patients in the surgical group experienced surgical morbidity, and one patient died from postoperative complications. Although patient-reported quality of life decreased postoperatively, it did not differ significantly between the groups after recovery.
The discordant results from DESKTOP III and SOC-1 compared with GOG 213 need to be evaluated further, and final data on OS in SOC-1 are essential since only interim analysis data have been reported. The favorable effect on progression-free survival is a poor surrogate since secondary cytoreduction removes the disease that would be monitored. One major difference among the trials is the substantial difference in use of bevacizumab (84 percent in GOG 213, approximately 23 percent in DESKTOP III, and <10 percent in SOC-1). Another difference is the patient selection criteria, which were stricter in DESKTOP III and SOC-1 than in GOG 213. The positive AGO score used in DESKTOP III required a complete gross resection (R0) at primary surgery; SOC-1 predicted the feasibility of complete resection with computerized scoring and imaging. Despite these differences, all three trials demonstrated survival benefit with secondary surgical cytoreduction when complete gross resection was achieved.
While awaiting final results of SOC-1 to further inform our approach, we continue to reserve secondary cytoreduction for patients with ovarian cancer that recurred at least six months after platinum-based chemotherapy and that has a limited number of involved sites, as described in the table (table 1).
Quality of life — Quality of life is not discussed in the vast majority of the studies evaluating the role of surgical cytoreduction for recurrent ovarian cancer. In the DESKTOP III trial (see 'Overall survival' above), results of quality-of-life analyses did not show any between-group differences in the surgery versus chemotherapy alone groups [42]. A retrospective study including 54 patients undergoing surgical cytoreduction followed by chemotherapy or chemotherapy alone also showed similar quality-of-life scores on questionnaires at three and six months after treatment, with the exception of pain and constipation, which were worse at three months in the surgery group [45].
FOLLOW-UP — After surgical cytoreduction for recurrent ovarian cancer, post-treatment surveillance is similar to that after primary cytoreductive surgery. These patients must be monitored for possible tertiary or quaternary recurrence. (See "Approach to survivors of epithelial ovarian, fallopian tube, or peritoneal carcinoma", section on 'Post-treatment surveillance'.)
Systemic chemotherapy should be administered adjuvantly. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian, fallopian tube, and peritoneal cancer".)
SUMMARY AND RECOMMENDATIONS
●Scope – The majority of ovarian cancer patients experience recurrence of disease. Most patients with recurrent ovarian cancer are treated with chemotherapy alone. Surgical treatment is reserved for a select group of patients. (See 'Introduction' above and 'Overall survival' above.)
●Goals – The goal of additional cytoreductive surgery is to prolong survival by resecting all visible disease (complete gross [R0] resection). The goal of surgery for bowel obstruction is palliative: to improve quality of life. (See 'Scope and goals of surgery' above and 'Procedure' above.)
●Patient selection – Patient selection is critical in the decision to proceed with secondary debulking. In general, candidates for secondary cytoreduction are patients with limited sites of recurrence and disease-free interval greater than 6 to 12 months (table 1). For such patients, we suggest secondary surgical cytoreduction plus chemotherapy rather than chemotherapy alone (Grade 2C). Risk models, imaging findings, and possibly laparoscopy are utilized to identify these patients. (See 'Candidates' above and 'Predicting successful disease resection' above.)
●Overall survival – In observational studies of patients with recurrent ovarian cancer, complete secondary cytoreduction plus platinum-based chemotherapy was associated with longer overall survival than chemotherapy alone, but these studies are limited by selection bias. Data from randomized trials are limited and conflicting. (See 'Overall survival' above.)
●Quality of life – While quality of life is not discussed in the vast majority of studies evaluating the role of surgical cytoreduction for recurrent ovarian cancer, it appears that quality of life is similar for those undergoing surgery or chemotherapy alone; pain and constipation may be worse in patients undergoing surgery. (See 'Quality of life' above.)
●Post-treatment surveillance – After surgical cytoreduction for recurrent ovarian cancer, post-treatment surveillance is similar to that after primary cytoreductive surgery. These patients must be monitored for possible tertiary or quaternary recurrence. (See 'Follow-up' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges William J Mann, Jr, MD; Eva Chalas, MD, FACOG, FACS; and Fidel A Valea, MD, who contributed to previous versions of this topic review.
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