Neoadjuvant Chemotherapy for Ovarian Cancer
Neoadjuvant Chemotherapy for Ovarian Cancer
Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in stage IIIC and IV patients. Interval debulking is defined as an operation performed after a short course of induction chemotherapy. Based on the randomized European Organization for Research and Treatment of Cancer–Gynecological Cancer Group (EORTC-GCG) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on Gynecologic Oncology Group (GOG) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery.
The importance of cytoreductive surgery in the treatment of advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage III and IV) was first suggested as early as 1934 by Meigs. But this procedure was long disputed until, in the 1970s, Aure et al and Griffiths et al showed that the amount of residual tumor following primary surgery was an important prognostic factor in advanced ovarian carcinoma. Unfortunately, no prospective randomized controlled trials have investigated the role of primary cytoreductive surgery in advanced ovarian carcinoma. Despite this lack of randomized controlled trials, primary cytoreductive surgery should be the standard of care in advanced ovarian cancer. In the 1980s, the European Organization for Research and Treatmentof Cancer-Gynecological Cancer Group (EORTC-GCG) launched a randomized study of the role of interval debulking surgery in women who did not or could not have a successful primary debulking operation (reduction of disease to < 1 cm). During the same time period, several institutions started using neoadjuvant chemotherapy in patients with advanced ovarian cancer (without a primary attempt at debulking) followed by an interval debulking surgery. We will try to define the current role of primary or neoadjuvant chemotherapy followed by interval debulking surgery in the primary management of advanced ovarian cancer. Definitions Agreement about the terminology for surgical procedures is essential for a clear understanding. The following standard definitions were recommended during the 1998 consensus meeting on advanced ovarian cancer: Primary cytoreductive surgery: an operation to remove as much of the tumor and its metastases as possible before subsequent therapy is initiated. Interval cytoreductive surgery: an operation performed in patients after a short course of induction chemotherapy- usually two or three cycles of chemotherapy-to remove as much primary and metastatic disease as possible, in order to facilitate response to subsequent chemotherapy and to improve survival. Secondary cytoreductive surgery: an operation performed in patients who have either persistent disease at the completion of a planned course of chemotherapy or who subsequently experienced clinical relapse. Surgery in Primary Management of Advanced Ovarian Cancer Primary Debulking Surgery
- Conclusion-Although evidence from retrospective studies suggests that neoadjuvant chemotherapy followed by interval debulking surgery is a valid alternative in a selected group of patients with stage III or IV ovarian carcinoma, this needs to beconfirmed in a prospective randomized trial. Therefore, the EORTCGCG, in cooperation with the National Cancer Institute of Canada, launched a prospective randomized trial to compare primary debulking surgery with neoadjuvant chemotherapy (Figure 3). To be eligible, patients must have biopsy- proven stage IIIC or IV epithelial ovarian cancer or peritoneal or fallopian tube carcinoma (with the biopsy taken at laparoscopy or laparotomy, or image-guided). The study is expected to close in the summer of 2006, with a target accrual of 704 patients.
Laparoscopy to Select Patients for Neoadjuvant Chemotherapy
Nelson et al proposed computed tomographic (CT) criteria to predict operability in patients with suspected ovarian masses. Tumor localization on the spleen or tumors larger than 2 cm on the diaphragm, liver surface, mesentery, or gall bladder on CT were regarded as inoperable. However, 6 out of 18 patients (33%) judged to be inoperable based on these criteria were optimally debulked. Therefore, we do not believe that operability can be judged based on CT findings. Others proposed newer CT criteria, CA-125, or microarrays analyses to predict operability.[54-56] We concluded that CT with peritoneography was superior to standardCT but still less sensitive than laparoscopy to evaluate operability. The technique of an open laparoscopy decreases the risk of a "blind" insertion of a Veress needle or trocar. During open laparoscopy, a small incision in or underneath the umbilicus is made. Consecutively, the different layers of the abdominal wall are opened (ie, a mini-laparotomy), and a blunt trocar is introduced under direct vision. Between 1995 and 2002, we performed an open laparoscopy in 173 patients to establish the diagnosis of stage III or IV ovarian carcinoma and found that open laparoscopy was the best technique to evaluate the operability. This procedure also provides the opportunity to perform biopsies and to exclude other primary tumors metastatic to the pelvis (eg, intestinal tumors, pancreatic tumors, and so forth). The possible development of port site metastases might prevent some surgeons from performing laparoscopy. We explored this issue further and completely excised all port sites at the time of primary debulking surgery or interval debulking surgery in the last 71 cases. Twenty-two of these sites contained malignant cells. The total number of port site metastases (clinically detected or diagnosed at microscopic examination of the excised port site) in the whole series of 173 patients was 30 (17%). It should be noted that, in this series, all port site metastases disappeared during the neoadjuvant chemotherapy or were excised at the time of surgery. None of the patients developed a subsequent recurrence in the port sites during follow- up, and none of the patients had a port site metastasis at the time of death. Therefore, we believe that port site metastases in advanced ovarian cancer are frequent but not of prognostic significance.
- Conclusion-Open laparoscopy is an important tool in the evaluation of the operability of patients with ovarian cancer. To date, this technique has produced no proven detrimental effects on the prognosis of these patients.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Meigs JV: Tumors of the Pelvic Organs. New York, Macmillan, 1934.
2. Aure JC, Hoeg K, Kolstad P: Clinical and histologic studies of ovarian carcinoma. Longterm follow-up of 990 cases. Obstet Gynecol 37:1-9, 1971.
3. Griffiths CT, Fuller AF: Intensive surgical and chemotherapeutic management of advanced ovarian cancer. Surg Clin North Am 58:131-142, 1978.
4. Berek JS, Trope C, Vergote I: Surgery during chemotherapy and at relapse of ovarian cancer. Ann Oncol 10:3-7, 1999.
5. Berek JS, Bertelsen K, du Bois A, et al: Advanced epithelial ovarian cancer: 1998 consensus statements. Ann Oncol 10:87-92, 1999.
6. Skipper HE: Thoughts on cancer chemotherapy and combination modality therapy. JAMA 230:1033-1035, 1974.
7. Goldie JH, Coldman AJ: Mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979.
8. Smith JP, Day TG: Review of ovarian cancer at the University of Texas Systems Cancer Center, MD Anderson Hospital and Tumor Institute. Am J Obstet Gynecol 135:984-993, 1979.
9. Bertelsen K, Jakobsen A, Andersen JE, et al: A randomized study of cyclophosphamide and cisplatinum with or without doxorubicin in advanced ovarian carcinoma. Gynecol Oncol 28:161-169, 1987.
10. Marsoni S: Randomized comparison of cisplatin with cyclophosphamide cisplatin and with cyclophosphamide doxorubicin cisplatin in advanced ovarian cancer. Lancet 2:353-359, 1987.
11. Voest EE, Vanhouwelingen JC, Neijt JP: A meta-analysis of prognostic factors in advanced ovarian cancer with median survival and overall survival (measured with the log (relative risk)) as main objectives. Eur J Cancer Clin Oncol 25:711-720, 1989.
12. Hunter RW, Alexander NDE, Soutter WP: Metaanalysis of surgery in advanced ovarian carcinoma: Is maximum cytoreductive surgery an independent determinant of prognosis. Am J Obstet Gynecol 166:504-511, 1992.
13. 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 20:1248-1259, 2002.
14. Heintz AP, Hacker NF, Berek JS, et al: Cytoreductive surgery in ovarian-carcinoma: Feasibility and morbidity. Obstet Gynecol 67:783-788, 1986.
15. Potter ME, Partridge EE, Hatch KD, et al: Primary surgical therapy of ovarian cancer: How much and when. Gynecol Oncol 40:195- 200, 1991.
16. Redman JR, Petroni GR, Saigo PE, et al: Prognostic factors in advanced ovarian carcinoma. J Clin Oncol 4:515-523, 1986.
17. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al: Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma. J Clin Oncol 5:1157-1168, 1987.
18. Hacker NF, Berek JS, Lagasse LD, et al: Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 61:413-420, 1983.
19. Heintz AP, Van Oosterom AT, Baptist J, et al: The treatment of advanced ovarian carcinoma (I): Clinical variables associated with prognosis. Gynecol Oncol 30:347-358, 1988.
20. Hoskins WJ, Bundy BN, Thigpen JT, et al: The influence of cytoreductive surgery on recurrence-free interval and survival in smallvolume stage III epithelial ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 47:159-166, 1992.
21. Vergote I, De Wever I, Tjalma W, et al: Neoadjuvant chemotherapy or primary debulking surgery in advanced ovarian carcinoma: A retrospective analysis of 285 patients. Gynecol Oncol 71:431-436, 1998.
22. Eisenkop SM, Spirtos NM: What are the current surgical objectives, strategies, and technical capabilities of gynecologic oncologists treating advanced epithelial ovarian cancer? Gynecol Oncol 82:489-497, 2001.
23. Burghardt E, Girardi F, Lahousen M, et al: Patterns of pelvic and paraaortic lymph-node involvement in ovarian cancer. Gynecol Oncol 40:103-106, 1991.
24. Friedlander ML, Hedley DW, Swanson C, et al: Prediction of long-term survival by flow cytometric analysis of cellular DNA content in patients with advanced ovarian cancer. J Clin Oncol 6:282-229, 1988.
25. Berchuck A, Iversen ES, Lancaster JM, et al: Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays. Am J Obstet Gynecol 190:910-922, 2004.
26. Kehoe S, Powell J, Wilson S, et al: The influence of the operating surgeons specialization on patient survival in ovarian carcinoma. Br J Cancer 70:1014-1017, 1994.
27. Farias-Eisner R, Teng F, Oliveira M, et al: The influence of tumor grade, distribution, and extent of carcinomatosis in minimal residual stage III epithelial ovarian cancer after optimal primary cytoreductive surgery. Gynecol Oncol 55:108-110, 1994.
28. Eisenkop SM, Nalick RH, Wang HJ, et al: Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: Impact on survival. Gynecol Oncol 51:224-229, 1993.
29. van Dam PA, Tjalma W, Weyler J, et al: Ultraradical debulking of epithelial ovarian cancer with the ultrasonic surgical aspirator: A prospective randomized trial. Am J Obstet Gynecol 174:943-950, 1996.
30. Wright JD, Herzog TJ, Powell MA: Morbidity of cytoreductive surgery in the elderly. Am J Obstet Gynecol 190:1398-1400, 2004.
31. Naik R, Nordin A, Cross PA, et al: Optimal cytoreductive surgery is an independent prognostic indicator in stage IV epithelial ovarian cancer with hepatic metastases. Gynecol Oncol 78:171-175, 2000.
32. Akahira J-I, Yoshikawa H, Shimizu Y, et al: Prognostic factors of stage IV epithelial ovarian cancer: A multicenter retrospective study. Gynecol Oncol 81:398-403, 2001.
33. Zang RY, Zhang ZY, Cai SM, et al: Cytoreductive surgery for stage IV epithelial ovarian cancer. J Exp Clin Cancer Res 18:449- 454, 1999.
34. 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 332:629-634, 1995.
35. Rose PG, Nerenstone S, Brady MF, et al: Gynecologic Oncology Group: Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 351:2489-2497, 2004.
36. Lawton FG, Redman CW, Luesley DM, et al: Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced, unresected epithelial ovarian cancer. Obstet Gynecol 73:61-65, 1989.
37. Jacob JH, Gershenson DM, Morris M, et al: Neoadjuvant chemotherapy and interval debulking for advanced epithelial ovarian cancer. Gynecol Oncol 42(2):146-150, 1991.
38. Lim JT, Green JA: Neoadjuvant carboplatin and ifosfamide chemotherapy for inoperable FIGO stage III and IV ovarian carcinoma. Clin Oncol (Royal College of Radiologists (Great Britain)) 5:198-202, 1993.
39. Shimizu Y, Hasumi K: Treatment of stage III and IV ovarian cancer: Is neoadjuvant chemotherapy effective? Nippon Sanka Fujinka Gakkai Zasshi 45:1007-1014, 1993.
40. Onnis A, Marchetti M, Padovan P, et al: Neoadjuvant chemotherapy in advanced ovarian cancer. Eur J Gynaecol Oncol 17:393-396, 1996.
41. Surwit E, Childers J, Atlas I, et al: Neoadjuvant chemotherapy for advanced ovarian cancer. Int J Gynecol Cancer 6:356-361, 1996.
42. Schwartz PE, Rutherford TJ, Chambers JT, et al: Neoadjuvant chemotherapy for advanced ovarian cancer: Long-term survival. Gynecol Oncol 72:93-99, 1999.
43. Ansquer Y, Leblanc E, Clough K, et al: Neoadjuvant chemotherapy for unresectable ovarian carcinoma: A French multicenter study. Cancer 91:2329-2334, 2001.
44. Kuhn W, Rutke S, Spathe K, et al: Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics stage IIIC ovarian carcinoma. Cancer 92:2585-2591, 2001.
45. Recchia F, De Filippis S, Rosselli M, et al: Primary chemotherapy in stage IV ovarian cancer. A prospective phase II study. Eur J Gynaecol Oncol 22:287-291, 2001.
46. Kayikcioglu F, Kose MF, Boran N, et al: Neoadjuvant chemotherapy or primary surgery in advanced epithelial ovarian carcinoma. Int J Gynecol Cancer 11:466-470, 2001.
47. Ushijima K, Ota S, Komai K, et al: Clinical assessment of neoadjuvant chemotherapy and interval cytoreductive surgery for unresectable advanced ovarian cancer. Int Surg 87:185-190, 2002.
48. Fanfani F, Ferrandina G, Corrado G, et al: Impact of interval debulking surgery on clinical outcome in primary unresectable FIGO stage IIIC ovarian cancer patients. Oncology 65:316- 322, 2003.
49. Shibata K, Kikkawa F, Mika M, et al: Neoadjuvant chemotherapy for FIGO stage III or IV ovarian cancer: Survival benefit and prognostic factors. Int J Gynecol Cancer 13:587-592, 2003.
50. Morice P, Dubernard G, Rey A, et al: Results of interval debulking surgery compared with primary debulking surgery in advanced stage ovarian cancer. Am Coll Surg 197:955-963, 2003.
51. Mazzeo F, Berliere M, Kerger J, et al: Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in patients with primarily unresectable, advanced-stage ovarian cancer. Gynecol Oncol 90:163-169, 2003.
52. Vrscaj MU, Rakar S: Neoadjuvant chemotherapy for advanced epithelial ovarian carcinoma: A retrospective case-control study. Eur J Gynecol Oncol 23:405-410, 2002.
53. Nelson BE, Rosenfield AT, Schwartz PE: Preoperative abdominopelvic computed tomographic prediction of optimal cytoreduction in epithelial ovarian carcinoma. J Clin Oncol 11:166-172, 1993.
54. Bristow RE, Duska LR, Lambrou NC, et al: A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography. Cancer 89:1532- 1540, 2000.
55. Tate S, Hirai Y, Takeshima N, et al: CA125 regression during neoadjuvant chemotherapy as an independent prognostic factor for survival in patients with advanced ovarian serous adenocarcinoma. Gynecol Oncol 96:143- 149, 2005.
56. Berchuck A, Iversen ES, Lancaster JM, et al: Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays. Am J Obstet Gynecol 190:910-925, 2004.
57. Gryspeerdt S, Clabout L, Van Hoe L, et al: Intraperitoneal contrast material combined with CT for detection of peritoneal metastases of ovarian cancer. Eur J Gynecol Oncology 19:434-437, 1998.
58. Vergote I, Marquette S, Amant F, et al: Port site metastases after open laparoscopy: A study in 173 patients with advanced ovarian carcinoma. Int J Gynecol Cancer 15:776-779, 2005.