Cytoreductive Surgery Is the Best Way to Affect Survival Outcomes
Historically, cytoreductive or debulking surgery has been the cornerstone of treatment for advanced ovarian cancer. Initially proposed by Meigs in 1934, primary debulking surgery (PDS) has repeatedly been associated with improved overall survival (OS).[1-4] However, this approach is the subject of much debate. Some providers question the value of extensive debulking surgery as the first step in the treatment of advanced ovarian cancer, arguing instead for the use of neoadjuvant chemotherapy (NACT). The only two published prospective randomized studies comparing PDS and NACT are the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial and the CHORUS trial. These have served as the foundation for those advocating the NACT approach.
The EORTC 55971 study was conducted by the EORTC’s Gynecological Cancer Group and the National Cancer Institute of Canada Clinical Trials Group. From 1998 to 2006, EORTC 55971 enrolled more than 600 women with bulky stage III or IV advanced ovarian cancer. The investigators reported no significant difference in progression-free survival (PFS) or OS between the two treatment arms, concluding that NACT with interval debulking surgery (IDS) was not inferior to, and was possibly safer than, PDS.[5,7]
The CHORUS trial, which enrolled and randomized over 550 women with advanced ovarian cancer, supported these results, concluding that NACT/IDS yielded comparable survival and decreased surgical morbidity, compared with PDS.[6,8]
In 2016, the Society of Gynecologic Oncology and the American Society of Clinical Oncology published clinical practice guidelines for the use of NACT in the setting of newly diagnosed advanced ovarian cancer. Included was a recommendation that women with resectable disease who were fit for PDS could be offered either NACT or PDS. This recommendation was based, in large part, on the conclusions of the aforementioned randomized trials.
We argue that PDS is the best treatment option for women with resectable disease who are medically fit for surgery, and that NACT is not equivalent to PDS in this population.
Ovarian cancer surgery is different from other cancer surgeries in that the goal is to resect all macroscopic tumor implants, rather than leave a microscopic margin. In 1975, Griffiths reported an association between survival and maximum diameter of residual disease after PDS. Since then, numerous studies have demonstrated that maximal surgical efficacy, as demonstrated by the amount of residual disease, is the one and only significant modifiable prognostic factor (factors such as age, tumor grade, stage, etc, are not modifiable) for survival, other than the type of postoperative chemotherapy administered.[2,3,11-17] However, resectability was not part of the preoperative inclusion criteria in either the EORTC or the CHORUS trial. Thus, only 41% of patients were left with residual disease of less than 1 cm (ie, were optimally debulked). This means that the majority of patients in whom PDS was attempted had a suboptimal surgical outcome; even the most ardent supporters of PDS would admit that suboptimal surgery does not improve survival. Reported optimal cytoreduction rates in the literature range from 15% to greater than 85%.[4,18] Centers experienced in ovarian tumor cytoreductive surgery usually achieve optimal resection rates of 75% or greater. These findings raise two questions:
1) Were the primary debulking surgeries attempted in EORTC 55971 and the CHORUS trials equivalent to those one would find in high-volume, specialized, more experienced tertiary care centers?
2) Was the patient population skewed towards cases that were more difficult to resect?
In the EORTC trial, residual tumor was most frequently documented on the diaphragm, abdominal peritoneum, and pelvis. Ultimately, the decision to debulk depends on the training and expertise of the surgeon. Surgical paradigms have shifted since these trials began recruiting patients over a decade ago. Many gynecologic oncologists have moved toward more extensive and radical surgeries in an attempt to decrease residual disease at the time of PDS. Debulking surgeries now include more extensive upper abdominal procedures, such as diaphragm stripping and/or resection, splenectomy, distal pancreatectomy, partial liver resection, cholecystectomy, and resection of tumor from the porta hepatis. These extensive procedures require utilization of all the surgical resources at an institution. The patient deserves whatever treatment is necessary to safely achieve maximal cytoreduction. Safe resection of diaphragmatic and peritoneal disease may be beyond the capacity of a general gynecologic or gynecologic oncology surgeon; however, these procedures are well within the capabilities of a hepatobiliary surgeon or general surgical oncologist. Contemporary approaches that enhance the surgical armamentarium in advanced ovarian cancer have resulted in higher rates of complete gross resection and optimal resection (residual disease ≤ 1 cm), and, consequently, longer OS.[13,14,19,20] Multiple US and international studies have demonstrated the feasibility and safety of a more radical surgical approach in specialty centers, with morbidity, mortality, and the timing of chemotherapy not statistically different from what are seen with surgery limited to the pelvis.[21-25]
While randomized controlled trials (RCTs) are the gold standard for determining the best treatment option, they are not without limitations. Most notably, the results cannot be generalized to populations that are not represented in the study. RCTs usually represent a very distinct subset of a population. The EORTC and CHORUS trials are prime examples of this potential for selection bias.
The PFS and OS for the NACT arms of the EORTC and CHORUS trials are consistent with those described in other NACT studies; however, the median survival times of 23 to 30 months in the PDS arms are dismally low.[7,8,26] Other RCTs in this population of primary surgery recipients report median survival times of 45 to 66 months.[9,27,28] Moreover, a retrospective review of an identical sample population of patients treated during the same time period at Memorial Sloan Kettering Cancer Center (MSKCC) demonstrated a median survival of 50 months for all patients treated with PDS, and a more recent publication from MSKCC reported a median survival of 72 months for all patients who had undergone PDS, regardless of residual disease status (including both those who had optimal cytoreduction and those who had suboptimal reduction). The large survival differences between EORTC 55971 and CHORUS and the MSKCC series lead us to infer that there may have been a selection bias in the EORTC and CHORUS trials. There were likely some unique characteristics in those patients whom the providers chose to recruit and/or those willing to be randomized. For example, the women in the CHORUS trial were older, had a higher proportion of poorly differentiated tumors, and had a poorer performance status than patients in other comparable studies. Moreover, both trials had surprisingly low recruitment rates. The shorter-than-expected median operative time of 165 minutes in the PDS arm also is an indication of the surgical commitment, expertise, and comprehensiveness of the operative teams. Despite the inclusion of some very-high-volume centers, each large institution recruited only 1 to 2 patients per year on average. Who were these patients, and how were the remaining nonrecruited patients managed? We cannot extrapolate data from this population of patients, who may have already had a poorer prognosis compared with the average patient with advanced ovarian cancer.
At the time of diagnosis and initiation of treatment, a patient presents with tumor composed of both chemosensitive and chemoresistant cells. Surgical debulking removes the vast majority of tumor cells of both types and decreases the quantity of cells that can spontaneously mutate into drug-resistant phenotypes. NACT is essentially a form of “chemical tumor debulking.” However, if chemotherapy is a patient’s first treatment, more tumor cells are present, and they have a longer time in which to build increased chemoresistance. Also, interrupting the chemotherapy by introducing IDS in the middle of the 6 to 8 cycles of chemotherapy may give the tumor cells still present additional time in which to build chemoresistance. This poses a significant risk because almost all patients whose disease recurs eventually develop chemoresistance, and 1 in 4 present with platinum-resistant disease at the time of their first recurrence. The risk of developing chemoresistance is higher in patients treated with NACT even if complete gross resection is achieved at the time of their surgery.[34,35] Additionally, patients who have been treated with NACT are less likely to respond to a platinum combination at the time of recurrence.[35,36]
The rates of NACT utilization in stage IIIC and IV disease have been increasing over the past decade.[30,37] This is not necessarily a bad thing, since PDS is not appropriate for every patient diagnosed with advanced ovarian cancer. However, it is imperative that this increase in the use of NACT occur in the appropriate patient population. The goal is to personalize medical care such that each patient receives the best treatment for her specific tumor burden-one that will provide her with the longest OS and the highest quality of life possible. Data suggest that patients over age 75 with poor performance and nutritional status, who would require extensive surgery to attain optimal cytoreduction, may be best served by a neoadjuvant approach. Patients who cannot be optimally debulked are also best treated with NACT. Recently, Makar et al published an analysis of five phase III trials, three Cochrane reviews, and four meta-analyses. The authors proposed stratifying patients with advanced ovarian cancer into five categories based on patterns of tumor spread, response to chemotherapy, and prognosis, in order to better determine which patients to select for PDS and which for NACT. They concluded that NACT is preferable only in cases in which the main tumor bulk is restricted to the upper abdomen, and is associated with massive ascites or the presence of miliary spread and/or massive mesenteric metastases, which would require multiple intestinal resections at the time of PDS. They also noted that NACT is preferable in stage IV ovarian cancer with multiple intrahepatic and/or lung metastases, or with massive ascites with miliary spread. In 2014, Suidan et al published an algorithm identifying three clinical and six radiologic findings associated with an increased risk of suboptimal outcome at time of PDS. Once validated, this algorithm may prove to be a beneficial tool for patient selection. Laparoscopy for patients with questionable resectability may also be useful in patient selection. It affords the surgeon the opportunity to assess the peritoneal cavity and collect tissue without subjecting the patient to the morbidity of a laparotomy that will not improve survival.
PDS followed by platinum-based chemotherapy affords patients with advanced ovarian cancer the best chance at the longest survival. If a patient is fit for surgery and has potentially resectable disease, she should be offered PDS. NACT does have its benefits, but should be reserved for women who are deemed inappropriate for surgical management or who have preoperative or laparoscopic findings indicative of unresectable disease.
Because primary cytoreductive surgeries can be complex, preoperative preparation is crucial. This sometimes requires consultation with general surgeons, surgical oncologists, or hepatobiliary surgeons, as well as the readiness of these colleagues to assist, in the event that disease encountered at PDS is difficult or impossible for the gynecologic oncologist to remove. This type of preparation may be difficult at medical centers with less experience in these types of surgeries and may influence the provider’s choice of NACT over PDS. Whenever possible, patients with advanced ovarian cancer should be treated by experienced gynecologic oncologists at specialized institutions that offer the infrastructural support necessary to accommodate these complex cases. As it stands, the issue of PDS vs NACT for advanced ovarian cancer has yet to be appropriately resolved. The international Trial on Radical Upfront Surgery in Advanced Ovarian Cancer (TRUST) is currently recruiting patients to centers with proven, robust surgical programs with physicians who are willing to randomize all eligible participants. Hopefully, results from this study will contribute to our understanding of this issue. Until then, we must rely on sound clinical judgment to appropriately select patients for primary surgery or primary chemotherapy.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Meigs JV, Greenough RB. Tumors of the female pelvic organs. Am J Med Sci. 1935;189:430.
2. Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol. 1998;69:103-8.
3. Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol. 1995;16:349-56.
4. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248-59.
5. Vergote I, TropÃ© CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363:943-53.
6. Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 2015;386:249-57.
7. Vergote I, Trope C, Amant F, et al. EORTC-GCG/NCIC-CTG randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIC-IV ovarian, fallopian tube and peritoneal cancer (OVCA). Presented at the 12th Biennial Meeting of the International Gynecologic Cancer Society; Oct 25–28, 2008; Bangkok. Abstr 1767.
8. Kehoe S, Hook J, Nankivell M, et al. Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: results from the MRC CHORUS trial. J Clin Oncol. 2013;31(suppl):abstr 5500.
9. Wright AA, Bohlke K, Armstrong DK, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34:3460-73.
10. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr. 1975;42:101-4.
11. Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol. 1994;170:974-80.
12. van der Burg ME, van Lent M, Buyse M, et al. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer: Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med. 1995;332:629-34.
13. Aletti GD, Dowdy SC, Gostout BS, et al. Aggressive surgical effort and improved survival in advanced-stage ovarian cancer. Obstet Gynecol. 2006;107:77-85.
14. Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol. 2009;114:26-31.
15. du Bois A, Reuss A, Pujade-Lauraine E, et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials. Cancer. 2009;115:1234-44.
16. Winter WE, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:3621-7.
17. Eisenkop SM, Spirtos NM, Friedman RL, et al. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003;90:390-6.
18. Dauplat J, Le BouÃ«dec G, Pomel C, Scherer C. Cytoreductive surgery for advanced stages of ovarian cancer. Semin Surg Oncol. 2000;19:42-8.
19. Zivanovic O, Eisenhauer EL, Zhou Q, et al. The impact of bulky upper abdominal disease cephalad to the greater omentum on surgical outcome for stage IIIC epithelial ovarian, fallopian tube, and primary peritoneal cancer. Gynecol Oncol. 2008;108:287-92.
20. Ren Y, Jiang R, Yin S, et al. Radical surgery versus standard surgery for primary cytoreduction of bulky stage IIIC and IV ovarian cancer: an observational study. BMC Cancer. 2015;15:583.
21. Angioli R, Plotti F, Aloisi A, et al. Does extensive upper abdomen surgery during primary cytoreduction impact on long-term quality of life? Int J Gynecol Cancer. 2013;23:442-7.
22. Barlin JN, Long KC, Tanner EJ, et al. Optimal (≤ 1 cm) but visible residual disease: is extensive debulking warranted? Gynecol Oncol. 2013;130:284-8.
23. Chi DS, Zivanovic O, Levinson KL, et al. The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas. Gynecol Oncol. 2010;119:38-42.
24. Fanfani F, Fagotti A, Gallotta V, et al. Upper abdominal surgery in advanced and recurrent ovarian cancer: role of diaphragmatic surgery. Gynecol Oncol. 2010;116:497-501.
25. Kehoe SM, Eisenhauer EL, Chi DS. Upper abdominal surgical procedures: liver mobilization and diaphragm peritonectomy/resection, splenectomy, and distal pancreatectomy. Gynecol Oncol. 2008;111:S51-S55.
26. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol. 2006;103:1070-6.
27. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-45.
28. Aghajanian C, Goff B, Nycum LR, et al. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer. Gynecol Oncol. 2015;139:10-6.
29. Chi DS, Musa F, Dao F, et al. An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT). Gynecol Oncol. 2012;124:10-4.
30. Mueller JJ, Zhou QC, Iasonos A, et al. Neoadjuvant chemotherapy and primary debulking surgery utilization for advanced-stage ovarian cancer at a comprehensive cancer center. Gynecol Oncol. 2016;140:436-42.
31. Fotopoulou C, Sehouli J, Aletti G, et al. Value of neoadjuvant chemotherapy for newly diagnosed advanced ovarian cancer: a European perspective. J Clin Oncol. 2017;35:587-90.
32. Goldie JH, Coldman AJ. The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res. 1984;44:3643-53.
33. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302-8.
34. Petrillo M, Ferrandina G, Fagotti A, et al. Timing and pattern of recurrence in ovarian cancer patients with high tumor dissemination treated with primary debulking surgery versus neoadjuvant chemotherapy. Ann Surg Oncol. 2013;20:3955-60.
35. Rauh-Hain JA, Nitschmann CC, Worley MJ, et al. Platinum resistance after neoadjuvant chemotherapy compared to primary surgery in patients with advanced epithelial ovarian carcinoma. Gynecol Oncol. 2013;129:63-8.
36. da Costa AA, Valadares CV, Baiocchi G, et al. Neoadjuvant chemotherapy followed by interval debulking surgery and the risk of platinum resistance in epithelial ovarian cancer. Ann Surg Oncol. 2015;22(suppl 3):S971-S978.
37. Melamed A, Hinchcliff EM, Clemmer JT, et al. Trends in the use of neoadjuvant chemotherapy for advanced ovarian cancer in the United States. Gynecol Oncol. 2016;143:236-40.
38. Makar AP, TropÃ© CG, Tummers P, et al. Advanced ovarian cancer: primary or interval debulking? Five categories of patients in view of the results of randomized trials and tumor biology: primary debulking surgery and interval debulking surgery for advanced ovarian cancer. Oncologist. 2016;21:745-54.
39. Suidan RS, Ramirez PT, Sarasohn DM, et al. A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer. Gynecol Oncol. 2014;134:455-61.