Surgical Staging and Cytoreductive Surgery of Epithelial Ovarian Cancer

Transcription

1 1534 Surgical Staging and Cytoreductive Surgery of Epithelial Ovarian Cancer William 1. Hoskins, M.D. Background. Surgery remains the cornerstone of the treatment for epithelial ovarian cancer. In early ovarian cancer, the initial operation is a complete assessment of the spread of disease. In this staging operation, 33% of patients thought to have either Stage I or I1 tumors will be found to have advanced-stage disease. The correct diagnosis of advanced disease prevents improper treatment of patients originally thought to have early disease. For patients with advanced disease, the initial cytoreductive operation reduces tumor bulk and produces increased sensitivity to chemotherapy for the remaining tumor. The principles of cellular kinetics provide good theoretic evidence for the benefit of cytoreductive surgery. Methods. Current studies relating to primary and secondary surgical cytoreduction of epithelial ovarian cancer were reviewed. Results. Current indirect evidence indicates a significant survival benefit for patients with epithelial ovarian cancer who undergo successful surgical cytoreduction. Several recent studies also have shown the importance of the biology of the tumor, the extent of tumor spread, the location of the tumor, the cell type, the histologic grade, and the age of the patient. Although the literature contains fewer reports of secondary cytoreductive surgery than of primary cytoreductive surgery at the time of second-look, surgical reassessment appears to provide a survival benefit. Conclusions. The potential benefit of secondary cytoreduction will be increasingly important as new salvage therapies become available. Cancer 1993; 71: Key words: neoplasm, malignant, ovary, surgery, cytoreduction, staging, treatment. Presented at the National Conference on Gynecologic Cancers, Orlando, Florida, April 2-4, From the Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, and the Comell University Medical College, New York, New York. Address for reprints: William J. Hoskins, M.D., Chief, Gynecology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY Accepted for publication September 2, Therapy for all but the earliest stages of epithelial ovarian cancer requires a combination of surgery and chemotherapy. Irradiation also may play a role in disease management in some patients. However, surgery remains the cornerstone of therapy for ovarian cancer. The multiple roles of surgical treatment begin with the initial diagnosis and staging and often end with palliation of intestinal obstruction. To provide adequate comprehensive surgical treatment of patients with ovarian cancer, the surgeon must understand the natural history and patterns of spread of the disease and must make use of appropriate surgical treatment within the context of other treatment techniques. In other words, the surgeon must be aware of the indications for and the potential benefits of chemotherapy and irradiation and how these methods are related to surgical treatment. This article provides a discussion of the patterns of spread of ovarian cancer in regard to surgical staging, the techniques and rationale for surgical staging, and the principles of cytoreductive surgery. Although primary cytoreductive surgery is the major emphasis, a brief discussion of secondary cytoreduction is also included. Patterns of Spread of Epithelial Ovarian Cancer Ovarian carcinoma has three primary methods of spread: direct extension, exfoliation of clonogenic cells, and lymphatic spread. Although other types of spread (e.g., metastasis through the blood stream) have been reported, these occur rarely. Direct Extension When ovarian carcinoma penetrates the capsule of the ovary, it involves pelvic structures by direct contact. The most commonly involved structures are the fallopian tubes, uterus, and contralateral adnexa. The pelvic side wall peritoneum, the bladder or rectal serosa, and the cul-de-sac are involved by either direct contact or drop metastases. The posterior cul-de-sac and the

2 Staging and Cytoreductive Surgery in Ovarian CancerlHoskins 1535 uterovesicle fold often are involved because of the effect of gravity on an upright woman. If the ovarian mass becomes large before it penetrates the capsule, other abdominal organs may be involved by direct extension. With large masses, the omentum, small intestine, and cecum frequently are involved by direct extension. Occasionally, a redundant loop of the transverse colon is involved directly. Exfoliation of Clonogenic Cells After the carcinoma penetrates the ovarian capsule, clonogenic cells can escape into the peritoneal cavity. Respiratory movements result in a clockwise flow of peritoneal fluid that transports the malignant cells along the right abdominal gutter toward the right diaphragm. The normal movements of daily activity and the normal peristalsis of the intestines result in distribution of malignant cells throughout the abdomen. Although serum is an inhospitable environment for tumor cells, limiting the frequency of metastases by the blood stream, the peritoneal fluid appears to allow a prolonged life span for malignant cells and to provide an opportunity for the cancer to implant and grow. Commonly, the omentum is involved by exfoliated ovarian cancer cells. Autopsy studies have shown that essentially all patients who die of ovarian cancer have omental involvement. Microscopic metastases were reported in 22% of grossly negative omenta. The exfoliated cells that reach the right diaphragm are picked up by the lymphatic vessels in the diaphragm and transported to the pleural surfaces. Diaphragmatic implants commonly occur early in the course of spread of ovarian cancer. Peritoneoscopic evaluation of the diaphragm has led to upstaging of patients otherwise thought to have Stage I or I1 disea~e.~,~ Lymphatic Spread of Ovarian Cancer The most frequently involved lymph nodes in ovarian cancer are the iliac nodes. From these nodes, the disease spreads to the common iliac and paraaortic lymph nodes. Less frequently, aortic lymph nodes are involved directly by the lymphatic route, which follows the ovarian vessels. Involvement of the inguinal lymph nodes occurs either by retrograde flow from the iliac nodal chain or by direct spread via the lymphatic vessels in the round ligament. Using lymphadenectomies in 123 patients with ovarian cancer, positive pelvic metastases were found in 61.8% of patients and aortic metastases in 41.4%.5 Others report lymph node metastases in 57% of patients6 Although the authors of the first article cited5 did not detect any aortic metastases without the presence of pelvic metastases, the second group6 found aortic metastases in 19% of patients who did not have pelvic nodal metastases. Table 1. International Federation of Gynecology and Obstetrics Staging for Carcinoma of the Ovary Staging of ovarian carcinoma is based on findings at clinical examination and by surgical exploration. The histologic findings are to be considered in the staging, as are the cytologic findings as far as effusions are concerned. It is desirable that a biopsy be taken from suspicious areas outside of the pelvis. Stage 1 Growth limited to the ovaries. Stage 1A Growth limited to one ovary; no ascites present containing malignant cells. No tumor on the external surface; capsule intact. Stage IB Growth limited to both ovaries; no ascites present containing malignant cells. No tumor on the external surfaces; capsules intact. Stage IC* Tumor classified as either Stage 1A or IB but with tumor on the surface of one or both ovaries; or with ruptured capsule(s); or with ascites containing malignant ceiis present or with positive peritoneal washings. Stage 11 Growth involving one or both ovaries, with pelvic extension. Stage IIA Extension and/or metastases to the uterus and/or tubes. Stage IIB Extension to other pelvic tissues. Stage IIC* Tumor either Stage IIA or IIB but with tumor on the surface of one or both ovaries; or with capsule(s) ruptured; or with ascites containing malignant cells present or with positive peritoneal washings. Stage Ill Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals Stage 111. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum. Stage llia Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal Stage liib Stage lllc Stage 1V surfaces. Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces none exceeding 2 cm in diameter; nodes are negative. Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes. Growth involving one or both ovaries, with distant metastases. If pleural effusion is present, there must be positive cytologic findings to allot a case to Stage IV. Parenchymal liver metastasis equals Stage IV. * Notes about the staging: To evaluate the impact on prognosis of the different criteria for allotting cases to Stage 1C or IIC, it would be of value to know whether the rupture of the capsule was spontaneous or caused by the surgeon and if the source of malignant cells detected was Deritoneal washings or ascites. Reproduced with permission from the International Federation of Gynecology and Obstetrics. Annual report on the results of treatment in gynecological cancer. lrif I Gw~ccol Ohsrer 1989: 28:

3 1536 CANCER Supplement February 25, 2993, Volume 71. No. 4 Staging of Ovarian Cancer The staging classification of ovarian cancer, as revised by the International Federation of Gynecology and Obstetrics in 1985, is a surgical staging This staging system is shown in Table 1. The 1985 revisions eliminated Stages IAii and IBii and grouped these findings (surface tumor or rupture of the capsule) with positive peritoneal cytologic findings in Stage IC. Also, whereas the presence of ascites in the pre-1985 staging resulted in a classification of Stage IC, malignant cells currently must be documented for classification of Stage IC. A similar change was made in Stage IIC, in which the documentation of malignant cells in either the peritoneal washings or ascites is currently required. The most significant changes in the staging system occurred in Stage 111. In the pre-1985 staging classification, any extrapelvic abdominal disease (except parenchymal liver metastases) was classified as Stage 111, and any extraabdominal disease was categorized as Stage IV. In the 1985 classification, Stage I11 was divided into Stage IIIA (microscopic abdominal disease and negative lymph nodes), Stage IIIB (abdominal disease of 2 cm or less and negative lymph nodes), and Stage IIIC (abdominal disease of greater than 2 cm or positive retroperitoneal lymph nodes). Positive inguinal lymph nodes result in categorization of a tumor as Stage IIIC rather than Stage IV as in the pre-1985 classification. The 1985 classifications were based on findings when the abdomen was explored, not after cytoreductive surgery. In advanced ovarian cancer, patients usually have obvious intraabdominal metastases, and surgical staging is seldom difficult. When surgical exploration reveals bulky upper abdominal disease, the surgical intent becomes primary cytoreduction rather than appropriate staging. At the Memorial Sloan-Kettering Cancer Center, we do not do lymph node biopsies routinely on patients with obvious Stage IIIB or IIIC disease at exploration. However, we will do lymphadenectomy as part of the surgical cytoreductive operation if this procedure is likely to be effective in reducing the disease volume. The diagnosis of Stage IV disease is often made on the basis of the preoperative diagnostic evaluation and, less frequently, during surgical exploration. The most common manifestation of Stage IV epithelial ovarian cancer is a malignant pleural effusion. The second most common manifestation is parenchymal liver metastases that are usually diagnosed by computed tomographic scan and confirmed by intraoperative liver biopsy. Although advanced disease is usually obvious during exploration, disease that apparently is confined to either the ovary or the pelvis requires meticulous surgi- Table 2. Surgical Procedure for the Staging of Patients With Apparent Early Ovarian Cancer Total abdominal hysterectomy and bilateral salpingo-oophorectomy (Unilateral salpingo-oophorectomy may be appropriate for selected patients who desire to defer definitive surgery to complete child bearing.) Pelvic peritoneal biopsies Lateral pelvic sidewalls (minimum of one per side) Cul-de-sac Uterovesicle fold Rectal and bladder serosa Abdominal biopsies Infracolic omentum Both abdominal gutters Both diaphragms Any adhesions Lymph nodes Right and left paraaortic Right and left pelvic Peritoneal washings Pelvis Both abdominal gutters Both subdiaphragmatic areas cal staging. Table 2 outlines the process of surgical staging for early ovarian cancer. As shown, the technique of surgical staging is based on a knowledge of the spread patterns of the disease process. Biopsy specimens are taken from the lateral abdominal gutters and the peritoneal surfaces of the diaphragms. The infracolic omentum is removed, and any intraabdominal adhesions are sampled. A biopsy of intraabdominal adhesions is important because microscopic tumor implants tend to cause adhesion formation. In the pelvis, biopsy specimens are taken from the pelvic sidewall peritoneum, the cul-de-sac, and the uterovesicle fold. In all of these, every effort should be made to obtain a 2-3-cm strip of peritoneum as a representative sample for pathologic analysis. At our institution, we have found that the biopsies can be done easily with minimal bleeding by using a long clamp to tent the peritoneum and electrocautery to excise the specimen. Nodal sampling of the pelvic and paraaortic lymph nodes should be done in all patients with apparently early ovarian cancer. In 5 of 26 patients with Stage I epithelial ovarian cancer, metastases to paraaortic lymph nodes were found, resulting in upstaging to Stage IIIC.9 Three of these five patients would have been staged as Stage IA without the finding of nodal metastases. A 10.3% incidence rate of aortic lymph node metastasis was detected in patients with Stage I or I1 epithelial ovarian cancer." Similar results were reported by other group~."*'~

4 Staging and Cytoreductive Surgery in Ovarian CancerlHoskins 1537 Table 3. Results of Complete Surgical Staging and Patients Thought to Have Stage I or I1 Epithelial Ovarian Cancer Site of biopsy No. of biopsies No. positive % positive Omentum Diaphragm Cul-de-sac Other abdomen Other pelvic Pelvic nodes Aortic nodes Modified from Young et al." When patients who have not had complete surgical staging are restaged properly, approximately 33% will be found to have more advanced stage disease. Of the patients who are upstaged, approximately 67% will have Stage 111 disease. Table 3 is a modification of data from a previous report" that shows the frequency and location of biopsy specimens resulting in the upstaging of disease in patients thought to have Stage I or I1 epithelial ovarian carcinoma. A thorough evaluation of the pelvis and abdomen is necessary for proper staging in patients thought to have early ovarian cancer. Surgical Therapy Surgical therapy for epithelial ovarian cancer usually refers to primary cytoreductive surgery. The usefulness of secondary cytoreduction in patients with persistent or recurrent disease is not as well established as that of primary cytoreduction, and the literature contains less evidence of its effectiveness. Other aspects of the surgical therapy of ovarian cancer include vascular and intraperitoneal access and surgery for palliation. The latter topics will not be covered in this article. Primary Cytoreductive Surgery Primary cytoreductive surgery refers to the removal of as much tumor as possible at the time of initial surgery for ovarian cancer. Historically, several gynecologic surgeons recommended removal of as much tumor as possible in the early 1990s.I3 In 1968, a retrospective review of patients with epithelial ovarian cancer who had been treated with irradiation was pub1i~hed.l~ Patients who had undergone partial removal of tumor did better than those who underwent only laparotomy and biopsy. At approximately the same time, others reported similar res~1ts.i~ In the latter study, a 4-year sur- vival rate of 72% for nonpalpable Stage I1 disease was found versus a 4-year survival rate of 33% for palpable disease of the same stage. For Stage 111 disease, a 25% 4-year survival rate for nonpalpable disease was contrasted with a 9% 4-year survival rate for palpable disease. In 1975, a series was published of patients managed by single alkylating agent chemotherapy after primary cytoreduction.'6 The patients were divided into categories by the amount of the residual disease they had before chemotherapy. For patients with no gross residual disease, the median survival was 39 months. Those with gross residual disease of less than 0.5 cm had a median survival of 29 months. Patients with residual disease of cm had a median survival of 18 months, and those with more than 1.5 cm of residual disease had a median survival of only 11 months. Since this report, several investigators have found differences in survival related to the amount of residual disease left before the onset of chern~therapy.'~-~~ The theoretic rationale for primary cytoreductive surgery in epithelial ovarian carcinoma is based on tumor growth kinetics. The growth of human cancer appears to have an exponential growth rate (a straight line when plotted on a logarithmic scale against time on a linear scale). The actual growth, however, is marked by an increase in the doubling time as the cancer becomes larger. This relationship has been shown mathematically by the Gompertz equation, and it is often called the Gompertzian phenomenon." The surgical removal of large tumor masses causes the remaining tumor nodules to have a high proportion of cells in an active growth phase, in which they are most sensitive to chemotherapy. In addition, the removal of large tumor masses removes the portion of the tumor with a poor blood supply that might not receive an adequate dose of the chemotherapeutic agent, Finally, the theory of firstorder kinetics suggests that the removal of large amounts of tumor results in an exponential reduction of tumor cells, leaving fewer cells that require eradication. This mechanism probably is important only in patients in whom it is possible to remove all gross disease. The technique of primary cytoreductive surgery requires a surgeon who is experienced and skillful and has an understanding of the growth patterns of this disease and alternative methods of therapy. The surgeon also must understand the patient's wishes in regard to future child bearing. Few operations call for as much surgical skill and judgment as the primary operation for ovarian cancer. For patients with early-stage disease, the major procedure is the operative staging of the cancer. The

5 1538 CANCER Supplement February 25, 2993, Volume 71, No. 4 choice of therapy often depends on the findings of the staging evaluation. Also, in early disease, the capacity for child bearing may be preserved in some patients. Those whose tumors have a low malignant potential or are Grade 1 and confined to one ovary may retain their reproductive capacity after a full staging operation. Patients with Grade 2 tumors also may fall into this category, but the degree of risk for these patients is not clear. Some investigators have allowed patients with Grade 3 tumors to retain their opposite ovary and uterus if they undergo postoperative chemotherapy. This practice has a precedent in the treatment of germ cell tumors, but it is still investigational for epithelial tumors. The patient must understand the risk of this conservative therapy. In advanced disease, primary cytoreduction is often a technical challenge for the surgeon. The disease may fill the pelvis and involve multiple intraabdominal structures. The surgical approach should be through the retroperitoneum. By entering the retroperitoneum, the surgeon can obtain control of the blood supply (the infundibulopelvic ligament and uterine artery) and identify and protect the ureter and pelvic vasculature. After the blood supply has been controlled and the ureter and pelvic vessels are protected, the disease and pelvic viscera can be swept to the midline. The cancer usually can be separated from the bladder and rectum, although resection of these organs is occasionally necessary. If a portion of the rectum must be resected, the integrity of the colon usually can be reestablished by a transanal stapled anastomosis. On occasion, a retrograde hysterectomy must be done by anterior entrance into the vagina and dissection of the ureters out of the parametrium; this allows transsection of the cardinal and uterosacral ligaments. After this maneuver, the entire mass can be lifted out of the pelvis. Inversion of the cul-de-sac facilitates removal of the tumor from both the cul-de-sac and the rectal surface. This technique was described first by Hudson.22 Removal of the omentum is usually not difficult, particularly when only the infracolic omentum is involved by the disease. In this instance, the omentum can be separated below the colon. When the supracolic omentum is involved, the entire omentum must be separated from the colon, and the omentum is removed along the greater curvature of the stomach. Tumor on the diaphragm may be resected when the lesions are discrete, but confluent tumor usually cannot be resected on the diaphragm. The surgeon must use judgment in deciding when to resect the intestine to achieve cytoreduction. A good rule is that resection that allows significant cytoreduction is indicated, but resection in a patient with unresectable disease elsewhere is rarely Table 4. Effect of the Amount of Residual Tumor After Primary Cytoreduction on Survival of Patients With Advanced Ovarian Cancer Treated With Chemotherapy Survival (mo) Reference in orieinal article Ovtimal* SubovtimaP Hacker'" (1983) 18 6 V~gl'~' (1983) Delgado"' (1984) Pohl"' (1984) Conte"' (1985) Posada"' (1985) Sutton"' (1986) Louie"5 (1986) Redman"' (1986) Neijt1I7 (1987) Hainsworth"' (1988) Piver"' (1988) Mean Original author's definition. Reproduced with permission from Ozols RF, Rubin SC, Dembo A, Robboy S. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC editors. Principles and practice of gynecologic oncology. Philadelphia: JB Lippincott Co., helpful. An obvious indication for resection is an obstructed intestine. The evidence for the benefit of primary cytoreductive surgery is indirect. No prospective randomized trials have addressed this question. Many investigators have argued that the indirect evidence in favor of cytoreductive surgery is so strong that it would be unethical to randomize patients to a treatment arm that did not include surgical cytoreduction. Table 4 is a review of the current literature, using this author's definition of optimal cytoreduction, that shows the significant difference in survival for patients who have undergone successful surgical cytoreduction. As shown, patients who were rendered "optimal" had a median survival of 39 months compared with a survival of only 17 months in patients with "suboptimal" residual disease. Recently, a series was reported of 163 patients in whom there was an attempt to evaluate the role of cytoreductive surgery.23 All patients had Stage I11 or IV epithelial ovarian cancer. Although a direct correlation was found between the amount of residual disease and survival, patients who required extensive operations (peritoneal stripping or bowel resection) did not have as good a median survival as those who underwent cytoreduction by less extensive operations. In a Gynecologic Oncology Group study, similar results were found.24 This study compared a group of patients found at initial surgery to have disease of 1 cm or less with a group of patients with more extensive disease who underwent surgical cytoreduction to 1 cm or less. The survival rate

6 Staging and Cytoreductive Surgery in Ovarian CancerlHoskilrs 1539 was better in the patients found at exploration to have optimal disease. These investigators concluded that, although cytoreductive surgery was beneficial, other factors also were important. Successful surgical cytoreduction alone could not correct for other biologic factors. Secondary Cytoreductive Surgery Although primary cytoreductive surgery generally is accepted as having a significant benefit for patients with ovarian cancer, less literature is available to indicate the benefit of secondary cytoreductive surgery. Approximately 50% of patients who undergo second-look surgical reassessment are found to have disease, and in 80% of these patients, the disease is macroscopic. The success of secondary cytoreduction ranges from 24-84% in the literat~re. ~ A 55% 4-year survival rate was found for patients with microscopic disease after second-look laparotomy with a 4-year survival rate of only 19% for patients with macroscopic disease.26 No difference was seen in the survival rates of patients who had microscopic disease and those who underwent cytoreduction to microscopic disease. Patients whose tumors were reduced to less than 5 mm had a 21% 4-year survival rate, and those whose lesions could not be resected to less than 5 mm had a 4-year survival rate of only 14%. Similar results were found when patients underwent cytoreduction to microscopic disease at second-look laparotomy (5-year survival rate, 51 These authors did not detect any survival difference in patients with microscopic disease versus those who underwent secondary cytoreduction to microscopic disease. A survival benefit was also reported for secondary cytoreduction at the time of second-look laparotomy in patients whose tumors were reduced to less than 2 cm of disease. Conclusion The role of surgery in the management of epithelial ovarian cancer is extremely important. The initial operation provides both surgical staging and primary cytoreduction. Increasing evidence supports a survival benefit for secondary cytoreduction. In all these aspects of the surgical management of ovarian cancer, the role of surgery in relation to other therapeutic methods must be considered. The initial staging operation may determine the potential need for chemotherapy, and maximal cytoreduction improves the response to chemotherapy by reducing tumor volume and causing increased sensitivity of the tumor cells to chemotherapy. As better salvage regimens become available, they will be most effective in patients with minimal residual disease. Secondary cytoreduction will assume increasing importance in the management of patients with persistent or recurrent disease. When intraperitoneal therapy is used, only those patients who have undergone cytoreduction to small-volume disease will benefit. Ovarian cancer responds to a multimodal treatment approach. Surgery will remain a vital part of this approach. References 1. Young RC, Fuks 2, Hoskins WJ. Cancer of the ovary. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: JB Lippincott, 1989: Steinberg JJ, Demopoulos RI, Bigelow B. The evaluation of the omentum in ovarian cancer. Gynecol Oncol 1986; 24: Bagley CM, Young RC, Schein PS, Chabner BA, DeVita T. Ovarian carcinoma metastatic to the diaphragm: frequently undiagnosed at laparotomy. Am / Obstet Gynecol 1973; 116: Rosenoff SH, DeVita VT, Hubbard S, Young RC. Peritoneoscopy in the staging and follow-up of ovarian carcinoma. Semin Oncol 1975; 2: Burghardt E, Pickel H, Lahousen M, Stettner H. Pelvic lymphadenectomy in operative treatment of ovarian cancer. Am / Obstef Gyriecol 1986; 155: Wu PC, Qu JY, Lang JH, Huang RL, Tang MY, Lian LJ. Lymph node metastasis of ovarian cancer: a preliminary survey of 74 cases of lymphadenectomy. Am / Obsfef Gyrrecol 1986; 155: International Federation of Gynecology and Obstetrics Cancer Committee. Staging announcement. Gyriecol Oncol 1986; 25: International Federation of Gynecology and Obstetrics. Annual report on the results of treatment in gynecologic cancer. Irif / Gyriecol Obstet 1985; 28: Knapp RC, Friedman EA. Aortic lymph node metastases in early ovarian cancer. Arn ] Obstet Gynecol 1974; 119: Piver MS, Barlow JJ, Lele SB. Incidence of subclinical metastases in stage I and I1 ovarian carcinoma. Obstet Gynecol 1978; 52: Young RC, Decker DG, Wharton JT, Piver MS, Sindelar WF, Edwards BK, et al. Staging laparotomy in early ovarian cancer. ] A M 1983; 250~ Buchsbaum HJ, Brady MF, Delgado G, Miller A, Hoskins WJ, Manetta A, et al. Surgical staging of carcinoma of the ovaries. Surg Gyriecol Obstet 1989; 169: Griffiths CT. Surgery at the time of diagnosis in ovarian cancer. In: Blackledge G, Chan KK, editors. Management of ovarian cancer. London: Butterworths, 1986: Munnell EW. The changing prognosis and treatment in cancer of the ovary: a report of 235 patients with primary ovarian cancer Am / Obstef Gyrlecol 1968; 100: Elclos L, Quinlan EJ. Malignant tumors of the ovary managed with postoperative megavoltage irradiation. Radiology 1969; Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian cancer. Moriogr Nut/ Cancer lnsl 1975; 42: Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashnff RM. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gyriecol 1983; 61:

7 1540 CANCER Supplement February 25, 2993, Volume 71, No Delgado G, Oram DH, Petrelli ES. Stage Ill ovarian cancer: the role of maximal surgical cytoreduction. Gynecol Oncol 1984; 18: Redman JR, Petroni GR, Saigo PE, Geller NL, Hakes TB. Prognostic factors in advanced ovarian cancer. CIin Oncol 1986; Neijt JP, ten Bokkel-Huinink W, van der Burg ME, van Oosterom AT, Vriesendorp R, Kooyman CD, et al. Randomized trial comparing two chemotherapy regimens (Hexa-CAF vs CHAP- 5) in advanced ovarian carcinoma. Lancet 1984; 2: Tannock IF. Principles of cell proliferation: cell kinetics. In: De- Vita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. 3rd ed. Philadelphia: JB Lippincott, 1989: Hudson CN. Surgical treatment of ovarian cancer. Gynecol Oncol 1973; 1: Potter ME, Partridge EE, Hatch KD, Soong SJ, Austin JM, Shingleton HM. Primary surgical therapy of ovarian cancer: how much and when? Gynecol Oncol 1991; 40: Hoskins WJ, Bundy BN, Thigpen IT, Omura GA. The influence of initial surgery on recurrence-free interval and survival in small-volume stage 111 epithelial ovarian cancer: a Gynecologic Oncology Group study [abstract]. Gynecol Oncol. In press. 25. Ozols RF, Rubin SC, Dembo AJ, Robboy S. Epithelial ovarian cancer. In: Hoskins WJ, Perez CA, Young RC. Principles and practice of gynecologic oncology. Philadelphia: JB Lippincott, Podratz KC, Schray MF, Wieand HS, Edmonson JH, Jefferies JA, Long HJ, et al. Evaluation of treatment and survival after positive second-look laparotomy. Gynecol Oncol 1988; 31: Hoskins WJ, Rubin SC, Dulaney E, Chapman D, Almadrones L, Saigo P, et al. Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 1989; 34: Lippman SM, Alberts DS, Slymen DJ, Weiner S, Aristizabal SA, Luditch A, et al. Second-look laparotomy in epithelial ovarian carcinoma: prognostic factors associated with survival duration. Cancer 1988; 61: