- Email: [email protected]
The surgical management of ovarian cancer
C ANCER TREATMENT REVIEWS 2001; 27: 111–118 doi: 10.1053/ctr v.2000.0196, available online at http://www.idealibr ar y.com on
ANTITUMOUR TREATMENT
The surgical management of ovarian cancer J. F. Stratton, J. A.Tidy and M. E. L. Paterson Department of Obstetrics and Gynaecology, Northern General Hospital, Sheffield, UK This article aims to cover current concepts and controversies in the surgical management of ovarian cancer. While there have been significant advances in the surgical management of vulval, cervical and even endometrial cancer there have been few developments in the surgical management of ovarian cancer. This situation is likely to continue until we get a clearer understanding of the natural history of this disease and better therapeutic options become available. © 2001 Harcourt Publishers Ltd Key words: Ovarian cancer; surgical management.
INTRODUCTION At the present time the surgical management of ovarian cancer is carried out by a number of specialists including general surgeons, general gynaecologists and gynaecological oncologists. Recent evidence suggests that who undertakes the surgery has an important influence on outcome with patients operated on by gynaecological oncologists having a 25% improvement in 3-year survival (1–3).
SURGICAL PROCEDURE AND STAGING The incision of choice used for the staging and treatment of ovarian cancer is an extended midline. This gives access to the whole abdomen and pelvis for a thorough laparotomy, which is the most important diagnostic objective. The staging of the woman with ovarian cancer is important because it will determine her prognosis and decide what treatment schedule she will receive (Table 1). In the majority of patients, the stage will be obvious from the advanced nature of the disease. In early stage disease, surgery on its own can be curative and therefore this group of women should be confidently identified (4). Correspondence to: Mr J.F. Stratton, Department of Obstetrics and Gynaecology, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK Fax: 0114 2715984; E-mail: john@fstratton. freeserve.co.uk 0305-7372/01/020111 + 08 $35.00/0
Standard treatment includes sending ascites or washings for cytological assessment followed by a total abdominal hysterectomy (TAH), bilateral salpingo-oophrectomy (BSO) and infracolic omentectomy (Tables 2 and 3). There may be a role for biopsies of peritoneal surfaces and selective pelvic and paraaortic lymphadenectomy. The appendix is often a site of metastases in advanced ovarian cancer and some authorities routinely advocate its removal (5–10). Perhaps the main benefit from appendicectomy in ovarian cancer surgery is the diagnosis of appendiceal adenocarcinomas that may present as a kruckenberg tumour of the ovary as this will influence adjuvant treatment (11–15). The co-existence of appendiceal and ovarian tumours in pseudomyxoma peritonei is as frequent as 90% and recent studies have concluded that the origin of pseudomyxoma peritonei is in the appendix (16, 17) and therefore its removal should be considered in such cases (18–20). In early ovarian cancer, the staging is often suboptimal because the malignancy was not suspected. The significance of the accuracy of staging in stage I disease can be seen in the improved survival seen TABLE 1 5-year survival according to stage (from Vanesmaa 1994) (21) Stage All I II III IV
5-year survival 35–42 70–100 55–63 10–27 3–15 © 2001 HARCOURT PUBLISHERS LTD
112
J. F. STRATTON ET AL. TABLE 2 Staging procedure for ovarian cancer Appropriate surgeon Appropriate incision — extended midline allowing access to upper abdomen Cytology: ascites or washings Laparotomy with clear documentation Biopsies from adhesions and suspicious areas Random biopsies of peritoneum TAH, BSO and infra-colic omentectomy D&C if unable to remove uterus Bilateral selective pelvic and para-aortic lymphadenectomy
TABLE 3 European guidelines of staging of ovarian cancer (produced by the EORTC Gynaecology Group) (81) Peritoneal washings Careful inspection and palpation of all peritoneal surfaces Biopsy of any lesion suspect of tumour metastases Total abdominal hysterectomy and bilateral salpingo-oophorectomy Infracolic omentectomy Biopsy of any adhesion adjacent to the primary tumour Blind biopsies (≥2) of bladder peritoneum and cul de sac Blind biopsies (≥3) of right and left paracolic gutter Blind biopsies (≥2) or smear of the right hemidiaphragm Blind biopsies (≥2) of the pelvic sidewall peritoneum at the side of the primary tumour Lymphnode sampling along the external and common iliac arteries and veins Lymphnode sampling along the aorta and vena cava including the area between the inferior mesenteric artery and the left renal vein
over the last three decades by Vanesmaa (1994) where there has been more accurate staging leading to less use of chemotherapy in true early stage disease (21). Less than 25% of women with presumed early disease had an adequate staging because they did not have a suitable incision (22, 23). However although re-staging laparotomies provide important prognostic information, they provide little benefit to those patients already requiring chemotherapy based on the original operative findings (24). In early disease, ascites is not malignant in 50% women. In women without ascites 20% will have positive washings. Multiple random biopsies will detect disease in 10% of cases (23). The macroscopic assessment of the omentum has poor sensitivity for the detection of metastases (25). If at operation for benign indications, the adnexal mass appears malignant, it is important to confirm this histologically. This can be done by frozen section. Alternatively the conservative operation can be completed, the histology reviewed and a decision can then be made on further management. The morbidity of a second laparotomy has been reported to be up to 33% in some studies (23).
CYTOREDUCTIVE SURGERY Maximum cytoreductive primary surgery is an accepted treatment for ovarian cancer since the work of Griffiths showing survival benefit in those women who had their tumour debulked to a residual disease
of less than 2 cm diameter (26). His findings were collaborated by Hacker (27), but have never been proven by a randomized controlled trial. The critical question is whether or not there are biological differences between tumours which allow some tumours to be optimally debulked and which have a better prognosis compared to those tumours which cannot be optimally debulked despite the best attempts of appropriately skilled and trained individuals. The ability to resect tumours depends on the ability of the surgeon as well as the biology of the tumour and the proportion of optimally debulked tumours varies markedly between centres (1,28). Theoretically, early debulking reduces the number of chemoresistant clones and removes bulky tumour that has a low fraction of growing cells and is therefore resistant to chemotherapy. Ovarian cancer tends to metastasize transcoelomically and therefore disease is often confined to the abdominal cavity. Furthermore tumour tends to spread along the surface of the peritoneum without invading the abdominal viscera thereby allowing the surgeon to find a plane of dissection for the removal of metastatic lesions. That being said, those patients with extensive carcinomatosis, high tumour grades, and extensive intestinal mesenteric involvement have a poor prognosis (29). Patients with stage IV disease may survive just as long without surgery (30), while the role of neoadjuvant chemotherapy remains to be elucidated. For women with advanced disease optimal cytoreduction to < 1 cm is the aim of primary surgery. This
THE SURGIC AL MANAGEMENT OF OVARIAN C ANCER
measurement refers to the diameter of the largest nodule remaining. No account is taken of the confluent plaques that are often seen in the paracolic gutters and on the subdiaphragmatic surfaces. The standard surgical approach involves a TAH, BSO and infracolic omentectomy. Delgado reported only 17.3% of women with stage III disease had complete removal of tumour while a further 10.7% had optimal de-bulking performed (31). Using radical surgery including bowel resection and peritoneal stripping, the number of patients that can be optimally debulked doubles but this does not appear to improve survival (32). Hoskins reported that the survival of women with small volume disease at presentation was better than those women with large volume disease, regardless of whether optimal cytoreduction was achieved (33). It would seem from this that optimal cytoreduction is a prognostic factor in that it reflects a subset of tumours that are less biologically aggressive.
INTERVAL DE-BULKING SURGERY Interval de-bulking surgery refers to surgery performed after two or three cycles of chemotherapy in patients who started chemotherapy without primary debulking or after it failed (34). Approximately 89% of these tumours can be optimally resected at this stage (35). Van der Burg in the EORTC collaborative study showed a marginal benefit of interval debulking surgery in patients who showed a response to chemotherapy but this benefit was minimal: 37% complete response vs 33% in those who did not undergo surgery (36). There was a 6-month median increase in the progression-free interval in the group who underwent surgery. Redman, in a study of 24 patients with gross residual disease after primary surgery and who subsequently were optimally debulked after 14 weeks of chemotherapy, found that the initial improved survival was short-term and that at 18 months there was a rapid deterioration in survival so that overall survival was similar to an historical control group of patients who had > 2 cm residual disease, but who had not undergone interval debulking surgery. A subsequent prospective multicentre randomized study of 79 patients by the same author again failed to show a significant advantage for women undergoing interval surgery (37,38). Gershenson et al. (1989) in a study of 50 patients with stage III and IV disease found that patients who underwent primary debulking had a longer median survival than patients who underwent interval debulking surgery (n = 11, 29.2 months vs 17.3 months, p = 0.04) (39). Wils et al. (1986) reported that patients who had responded to
113
chemotherapy and then had interval cytoreduction had a survival rate close to women who had primary surgical debulking followed by chemotherapy (40).
SECONDARY DE-BULKING SURGERY AND SECOND LOOK LAPAROTOMY Secondary debulking surgery is performed after chemotherapy in patients who have had optimal primary surgery but have persistent disease or who subsequently experience clinical relapse. In these situations debulking surgery is performed before initiating salvage second-line chemotherapy (41). This is distinct from a second look laparotomy which is performed at the completion of chemotherapy in patients who are clinically and radiographically free of disease (42). Approximately 60–80% of women will respond to chemotherapy following primary surgery (43). Second look operations have been used to assess this response. Approximately 40% of stage III patients will have a negative second look operation and of these 50% will relapse (44,45). No survival benefit has been demonstrated for those women who undergo second cytoreductive surgery to no residual disease but this group only accounts for 5% of all those women who underwent second look laparotomy. The outlook for women with progressive disease on firstline chemotherapy or within 1 year of treatment is poor with a median survival of 7 months (41,44). For those women that relapse after 3 or 4 years repeat laparotomy may have a role in confirming the diagnosis and excluding a second malignancy. The role of aggressive secondary debulking surgery in this group of patients is controversial. Morris (46) showed no survival advantage while Janicke (47) found a significant survival advantage. Vaccarello demonstrated a survival advantage in women (who had a negative second look laparotomy) with recurrent disease (mean interval of 20 months from second look surgery) who could be optimally debulked to residual disease of < 0.5 cm (48).
THE ROLE OF LYMPHADENECTOMY Lymphadenectomy can be classified into three groups namely biopsies of palpable nodes, radical lymphadenectomy and lymph node sampling. The main problem with biopsy of palpable nodes is that 55% of lymph nodes metastases are less than 2 mm (49,50). Radical lymphadenectomy results in higher complication rates and so far has not been convincingly shown to result in a survival benefit (51). The technique of selective lymph node sampling has been described by Burke (52). While some studies
114
have shown a benefit using this technique in endometrial cancer, its role in ovarian cancer remains to be evaluated, particularly in stage IA and IB disease who may not receive chemotherapy and who would be upstaged and therefore receive chemotherapy if positive nodes were found. Burghardt, in his analysis of nodal involvement in ovarian cancer, found the incidence of positive nodes was 24% in stage I, 50% in stage II, 74% in stage III and 73% in stage IV disease (53). Most patients with positive nodes have only one or two groups of nodes involved, or one to three positive individual nodes. Greater numbers of positive nodes were found in advanced disease. The size of the largest nodal metastases was not related to clinical stage or survival, but did correlate with the number of positive nodes. Based on this evidence it would seem that if lymph nodes are removed at surgery this is only likely to alter the staging and prognosis if a radical lymphadenectomy is undertaken, otherwise positive lymph nodes will be missed. Lymphadenectomy has been purported to confer a survival advantage (50,54,55). However, Onda did not show a survival difference between those with stage one and two tumours who had positive lymph nodes and those who had negative lymph nodes (56). On the other hand Kigawa showed a survival advantage for lymphadenectomy in patients with advanced stage ovarian cancer (57). This was not supported by Parazzini in his review of 456 women (58). In the absence of gross extrapelvic disease, a selective pelvic and paraaortic lymphadenectomy will result in upstaging 29% of stage I and II disease to stage III (22,25,59).
THE ROLE OF CONSERVATIVE SURGERY Less than 25% of cases of ovarian cancer will have disease confined to the pelvis. Patients with stage IA
J. F. STRATTON ET AL.
and IB lesions which are well to moderately differentiated may be cured by conservative surgery alone (22,60–62) (Table 4). Patients with stage IC and II lesions or poorly differentiated lesions will usually receive adjuvant chemotherapy. If the tumour is grade III, densely adherent, or stage IC, the chance of relapse and subsequent death from ovarian cancer is substantial (up to 20%), although the importance of tumour rupture if it is the only adverse characteristic is not clear (63–65). In selected patients who desire further childbearing and who have grade I tumours, unilateral salpingo-oophorectomy may not be associated with a high risk of recurrence (60). However, Sevelda (66) reported a poorer prognosis for patients treated by unilateral oophorectomy. In this study accurate staging was not uniform and the reported poorer prognosis in early stage cancers may have be due to understaging of cancers. Finn (67) did not find a benefit from lymphadenectomy in these early stage cancers. In this study of 373 patients only 30% had lymph nodes biopsied. No mention was made of performing a systematic lymphadenectomy. The role of laparoscopy in the surgical management of ovarian cancer is highly contentious and most authorities advocate strict selection criteria to ensure only benign ovarian tumours are operated on laparoscopically (Table 5). However laparoscopy may have a role in re-staging procedures which are most important for early ovarian cancer. The case of the referred patient with unsatisfactory staging because the diagnosis was not suspected at the initial surgery is not uncommon and may be managed laparoscopically rather than by repeat laparotomy, combining staging surgery and additional surgery such as hysterectomy and contralateral oophorectomy (68). Laparoscopy may also have a role in the diagnosis of ovarian cancer prior to initiating neoadjuvant chemotherapy. Most of the criticisms of laparoscopy in the management of ovarian cancer relate
TABLE 4 Guidelines for conservative surgery of epithelial ovarian cancer The patient must be of reproductive age and wishing to have further children The surgery must include a complete surgical staging.The contralateral ovary must be normal The FIGO stage should be 1a with a well to moderately differentiated serous histology Close follow-up The contralateral ovary is removed when childbearing is complete TABLE 5 Guidelines for selecting patients with adnexal masses suitable for laparoscopic surgery (from Crawford et al. 1995) (82) ACOG: On U.S. mass diameter < 10 cm, cystic with a distinct border and no solid elements. No ascites or matted bowel. Normal CA125 (< 35 i.u.) and no family history of ovarian cancer BGCS: On U.S. mass diameter <8 cm, cystic with no solid elements, no multiloculation, not bilateral. No increased blood flow on doppler. Caution if raised CA125. No family history of ovarian cancer. Adnexal mass should be completely removed without rupture. ACOG: American College of Obstetricians and Gynaecologists BGCS: British Gynaecological Cancer Society
THE SURGIC AL MANAGEMENT OF OVARIAN C ANCER
to improper staging, peritoneal spillage and abdominal wall contamination (69). Many simple ovarian cysts in pre-menopausal women can be managed expectantly unless they are greater than 6 cm in diameter or persistent. Aspiration of cysts is associated with a high recurrence rate of 66% and cytological assessment of the aspirate is a poor predictor of malignancy with a false negative rate of 2–42% (70). The incidence of malignancy in ovarian cysts assumed to be benign on the basis of ultrasound assessment and CA125 is 0.04–3.7% (71–74).
SALVAGE SURGERY The predominant symptom in advanced incurable ovarian cancer is that of bowel obstruction. The obstruction may be in large bowel, small bowel or both or even a functional obstruction due to infiltration and contraction of the mesentery. Operations to resect focal recurrences associated with bowel obstruction are of value unless obstruction is caused by diffuse carcinomatosis. Intermittent surgical debulking may be necessary in Pseudomyxoma peritonei to maintain quality of life (75). It is difficult to predict which women with bowel obstruction in advanced ovarian cancer are likely to benefit from surgical treatment of the obstruction. Clinically detectable ascites, low serum albumin and palpable intra-abdominal disease are poor prognostic features (76). Total parenteral nutrition (TPN) may correct a low serum albumin if it is felt that surgery is warranted. The operative morbidity is up to 64% and mortality 32%. A percutaneous gastrostomy tube may be useful in those women with vomiting due to inoperable obstruction (77). Medical management is often the most appropriate treatment for intestinal obstruction in women with advanced disease.
SURGERY IN NON-EPITHELIAL OVARIAN CANCERS Ovarian germ cell tumours occur principally in adolescent girls between the ages 16 and 20. Recurrence is unlikely after surgery for stage I grade I immature teratomas while 85% of grade III stage I tumours will recur without adjuvant treatment (78). The histologic grade of the tumour is based on three factors: degree of immaturity, presence of a neuroepithelial component and the quantity of the latter. Germ cell tumours are sensitive to chemotherapy and the majority present in stage I. For patients with more advanced disease the role of debulking remains controversial.
115
Dysgerminomas are radiosensitive and chemosensitive, most are confined to the ovary, 10% are bilateral, although retroperitoneal nodal spread is more common than in germ cell tumours. Fifteen to twenty five percent will recur after unilateral salpingo-oophorectomy for stage IA disease, and most of these will occur in the first 2 years. Ninety per cent of granulosa cell tumours are stage I at presentation and conservative surgery (unilateral salpingo-oophorectomy, D&C and accurate staging) is indicated in those women wishing to preserve their fertility. Removal of the uterus and contralateral ovary are recommended following completion of childbearing. Women with more advanced stage tumours should have a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Approximately 18% of granulosa cell tumours recur. Recurrence is associated with a high mortality rate. Of those tumours that recur, 20% will recur more than 10 years following initial treatment (79). Tumour recurrence is most often localized in the pelvis (one third recur in the reproductive tract) or abdomen. The extent of the initial surgical procedure affects recurrence rates. Six per cent of women undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy develop recurrence compared to 25% of women undergoing less extensive surgical procedures. Fifty five per cent of granulosa cell tumours are associated with endometrial hyperplasia while a concomitant uterine carcinoma is present in 13%. Sertoli-stromal cell tumours can be treated by unilateral salpingo-oophorectomy as the majority are stage I lesions. However prognosis is adversely affected by rupture and stage II lesions have a poor prognosis (80).
CONCLUSION Surgery remains the cornerstone for the diagnosis and staging of ovarian cancer. While conservative surgery may have a role in a small number of selected women with early stage disease, ultraradical surgery involving bowel resection is only indicated in a few cases where the disease can be completely eradicated by surgery or there is evidence of impending bowel obstruction. Secondary de-bulking surgery has a role in recurrent disease which occurs one or more years following successful primary treatment. Interval debulking surgery has a limited role in women who have had an unsuccessful initial attempt at debulking surgery, while neoadjuvant chemotherapy is currently under review. Salvage surgery is confined to women with a surgically correctable bowel obstruction. Most non-epithelial
116
ovarian cancers occur in young women and can be managed with conservative surgery in the majority of cases.
J. F. STRATTON ET AL.
18.
19.
REFERENCES 1. Eisenkop SM, Spirtos NM, Montag TW, Nalick RH, Wang HJ. The impact of subspecialty training on the management of advanced ovarian cancer. Gynecol Oncol 1992; 47: 203–209. 2. Nguyen HN, Averette HE, Hoskins W, Penalver M, Sevin BU, Steren A. National survey of ovarian carcinoma. Part V. The impact of physician’s specialty on patients’ survival. Cancer 1993; 72: 3663–3670. 3. Junor EJ, Hole DR, McMurty L et al. Specialist gynaecologists and survival outcomes in ovarian cancer. A Scottish National Study of 1866 patients. Br J Obstet Gynaecol 1999; 106: 1130–1136. 4. Trimbos JB, Schueler JA, Burg M et al. Watch and wait after careful surgical treatment and staging in well-differentiated early ovarian cancer. Cancer (Philadelphia) 1999; 67: 597–602. 5. Ayhan A, Tuncer ZS, Tuncer R, Yuce K. Is routine appendectomy beneficial in the management of ovarian cancer? Eur J Obstet Gynecol Reprod Biol 1994; 57: 29–31. 6. Bese T, Kosebay D, Kaleli S, Oz AU, Demirkiran F, Gezer A. Appendectomy in the surgical staging of ovarian carcinoma. Int J Gynaecol Obstet 1996; 53: 249–252. 7. Corfitsen MT, Pedersen IR, Lebech AM, Kaae HH. Appendectomy and carcinoma ovarii. Cytoreduction, palliation, or simple tradition? Acta Obstet Gynecol Scand 1991; 70: 601–604. 8. Fawzi HW, Robertshaw JK, Bolger BS, Monaghan JM. Role of appendicectomy in the surgical management of ovarian cancer. Eur J Gynaecol Oncol 1997; 18: 34–35. 9. Fontanelli R, Paladini D, Raspagliesi F, di Re E. The role of appendectomy in surgical procedures for ovarian cancer. Gynecol Oncol 1992; 46: 42–44. 10. Rose PG, Reale FR, Fisher A, Hunter RE. Appendectomy in primary and secondary staging operations for ovarian malignancy. Obstet Gynecol 1991; 77: 116–118. 11. Cortina R, McCormick J, Kolm P, Perry RR. Management and prognosis of adenocarcinoma of the appendix. Dis Colon Rectum 1995; 38: 848–852. 12. Hirschfield LS, Kahn LB, Winkler B, Bochner RZ, Gibstein AA. Adenocarcinoid of the appendix presenting as bilateral Krukenberg’s tumor of the ovaries. Immunohistochemical and ultrastructural studies and literature review. Arch Pathol Lab Med 1985; 109: 930–933. 13. Ikeda E, Tsutsumi Y, Yoshida H, Yanagi K. Goblet cell carcinoid of the vermiform appendix with ovarian metastasis mimicking mucinous cystadenocarcinoma. Acta Pathol Jpn 1991; 41: 455–460. 14. Merino MJ, Edmonds P, LiVolsi V. Appendiceal carcinoma metastatic to the ovaries and mimicking primary ovarian tumors. Int J Gynecol Pathol 1985; 4: 110–120. 15. Thomas R, Barnhill D, Worsham F, Hoskins W. Krukenberg tumor of the ovary from an occult appendiceal primary: case report and literature review. Obstet Gynecol 1985; 65: 95S–98S. 16. Young RH, Gilks SB, Scully RE. Mucinous tumours of the appendix associated with mucinous tumours of the ovary and pseudomyxoma peritonei: a clinicopathological analysis of 22 cases. Am J Surg Pathol 1991; 15: 415–429. 17. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei: a clinicopathologic study of 19 cases with emphasis on site of
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34. 35.
36.
origin and nature of associated ovarian tumours. Am J Surg Pathol 1994; 18: 591–603. Long RT, Spratt JSJ, Dowling E. Pseudomyxoma peritonei. New concepts in management with a report of seventeen patients. Am J Surg 1969; 117: 162–169. Nogales FF, Caballero T, Fernandez PL, Linares J, Ruiz-Avila I. Pseudomyxoma peritonei et ovarii associated with sequential ovarian and appendicular tumors and acromegaly. Gynecol Oncol 1991; 40: 78–80. Wertheim I, Fleischhacker D, McLachlin CM, Rice LW, Berkowitz RS, Goff BA. Pseudomyxoma peritonei: a review of 23 cases. Obstet Gynecol 1994; 84: 17–21. Vanesmaa P. Epithelial ovarian cancer: Impact of surgery and chemotherapy on survival during 1977–1990. Obstet Gynecol 1994; 79: 8–11. Young RC, Walton LA, Ellenberg SS et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 1990; 322: 1021–1027. Soper J, Johnson P, Johnson V, Berchuck A, Clarke-Pearson DL. Comprehensive restaging laparotomy in women with apparent early ovarian carcinoma. Obstet Gynecol 1992; 80: 949–953. Stier EA, Barakat RR, Curtin JP, Brown CL, Jones WB, Hoskins WJ. Laparotomy to complete staging of presumed early ovarian cancer. Obstet Gynecol 1996; 87: 737–740. Buschbaum HJ, Brady MF, Delgado G, Miller AB, Hoskins WJ, Manetta A. Surgical staging of carcinoma of the ovaries. Surg Gynecol Obstet 1989; 83: 707–712. Griffiths CT, Parker LM, Fuller AF. Role of cytoreductive surgeral treatment in the management of advanced ovarian cancer. Cancer Treatment Rep 1979; 63: 235–240. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983; 61: 413–420. Hunter RW, Alexander NDE, Soutter WP. Meta-analysis of surgery in advanced ovarian carcinoma, is maximum cytoreductive surgery an independent determinant on prognosis? Am J Obstet Gynecol 1992; 166: 511. Farias-Eisner PE, 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 1994; 55: 108–110. Schwartz MD, Chambers JT, Makuch R. Neoadjuvant chemotherapy for advanced ovarian cancer. Gynecol Oncol 1994; 53: 33–37. Delgado G, Oram D, Petrilli ES. Stage III epithelial ovarian cancer: the role of maximal surgical reduction. Gynecol Oncol 1984; 18: 293–298. Potter ME, Partridge EE, Hatch KD, Soong S-J, Austin JM, Shingleton HM. Primary surgical therapy of ovarian cancer: How much and when. Gynecol Oncol 1991; 40: 195–200. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992; 47: 159–166. Berek JS. Interval debulking of ovarian cancer — an interim measure. New Engl J Med 1995; 332: 675–677. Lawton FG, Redman CWE, Luesley DM et al. Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced unresected epithelial ovarian cancer. Obstet Gynecol 1989; 73: 61–65. Van der Burg, MEL, Van Lent M, Buyse M, Kobierska A. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced ovarian cancer. New Engl J Med 1995; 332: 629–634.
THE SURGIC AL MANAGEMENT OF OVARIAN C ANCER 37. Redman CW, Blackledge G, Lawton FG, Varma R, Luesley DM, Chan KK. Early second surgery in ovarian cancer— improving the potential for cure or another unnecessary operation? Eur J Surg Oncol 1990; 16: 426–429. 38. Redman CW, Warwick J, Luesley DM, Varma R, Lawton FG, Blackledge GR. Intervention debulking surgery in advanced epithelial ovarian cancer. Br J Obstet Gynaecol 1994; 101: 142–146. 39. Gershenson DM, Wharton JT, Copeland L. Treatment of advanced epithelial ovarian cancer with cisplatin and cisplatin and cyclophosphamide. Gynecol Oncol 1989; 32: 336–341. 40. Wils J, Blijham G, Naus A et al. Primary or delayed debulking surgery and chemotherapy of cisplatin, doxorubicin and cyclophosphamide in stage III–IV epithelial ovarian carcinoma. J Clin Oncol 1986; 4: 1068. 41. Berek JS, Hacker NF, Lagasse LD, Nieberg RK, Elashoff RM. Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol 1983; 61: 189. 42. Berek JS, Hacker NF, Lagasse LD, Poth T, Resnick B, Nieberg, RK. Second look laparotomy in stage III epithelial ovarian cancer: clinical variables associated with disease status. Obstet Gynecol 1984; 64: 207–212. 43. Clarke-Pearson DL, Kohler MF, Hurteau JA, Elbendary A. Surgery for advanced ovarian cancer. Clin Obstet Gynecol 1994; 37: 439–460. 44. Potter ME, Hatch KD, Soong S-J, Partridge EE, Austin JM, Shingleton HM. Second look laparotomy and salvage therapy: A research modality only? Gynecol Oncol 1992; 44: 3–9. 45. Podratz KC, Kinney WK. Second-look operation in ovarian cancer. Cancer (Philadelphia) 1993; 71: 1551–1558. 46. Morris M, Gershenson DM, Wharten T, Copeland L, Edwards CL, Stringer A. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol 1989; 34: 334–338. 47. Janicke F, Holscher M, Kuhn W et al. Radical surgery procedure improves survival time in patients with recurrent ovarian cancer. Cancer (Philadelphia) 1992; 70: 2129–2136. 48. Vaccarello L, Rubin SC, Vlamis V et al. Cytoreductive surgery in ovarian carcinoma patients with a documented previously complete surgical response. Gynecol Oncol 1995; 57: 61–65. 49. Petru E, Lahousen M, Tamussino K et al. Lymphadenectomy in stage 1 ovarian cancer. Am J Obstet Gynecol 1994; 170: 656–662. 50. Wu PC, Qu JY, Lang JH et al. Lymph node metastases of ovarian cancer. A preliminary survey of 74 cases of lymphadenectomy. Am J Obstet Gynecol 1986; 155: 1103. 51. Benedetti-Panici P, Pickel H, Lahousen M, Stettner H. Randomised study comparing systematic pelvic (PE) and aotic (A) lymphadenectomy in early ovarian carcinoma or at second look surgery versus no lymphadenectomy: feasibility and complications. Am J Obstet Gynecol 1986; 60: 129. 52. Burke TW. Selective pelvic and para-aortic lymphadenectomy. Operat Techniq Gynecol Surg 1996; 1: 17–21. 53. Burghardt E, Girardi F, Lahousen M et al. Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 1991; 40: 103–106. 54. Burghardt E, Pickel O, Lahousen M, Stettner H. Pelvic lymphadenectomy in operative treatment of ovarian cancer. Am J Obstet Gynecol 1996; 155: 315. 55. DiRe F, Fontanelli F, Raspagliesi F, di Re E. Pelvic and paraaortic lymphadenectomy in cancer of the ovary. In: Burghardt E, Monaghan JM (eds.) Clinics in Obstetrics and Gynaecology London: Balliere Tindall, 1989. 56. Onda T, Yoshikawa H, Yasugi T et al. Patients with ovarian carcinoma upstaged to stage III after systematic lymphadenctomy have similar survival to stage I/II patients and superior survival to other stage III patients. Cancer 1998; 83: 1555–1560.
117 57. Kigawa J, Minagawa Y, Ishihara H, Kanamori Y, Itamochi H, Terakawa N. Evaluation of cytoreductive surgery with lymphadenectomy including para-aortic nodes for advanced ovarian cancer. Eur J Surg Oncol 1993; 19: 273–278. 58. Parazzini F, Valsecchi G, Bolis G et al. Pelvic and paraortic lymph nodal status in advanced ovarian cancer and survival. Gynecol Oncol 1999; 74: 7–11. 59. Helewa ME, Krepart GV, Lotocki R. Staging laparatomy in early ovarian cancinoma. Am J Obstet Gynecol 1986; 169: 226–232. 60. Zanetta G, Chiari S, Rota S et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 1997; 104: 1030–1035. 61. Young RC. Initial therapy for early ovarian carcinoma. Cancer 1987; 60: 2042–2049. 62. Young RC. The treatment of early stage ovarian cancer. Semin Oncol 1995; 22: 76–79. 63. Ahmed FY, Wiltshaw E, A’Hern RP et al. Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 1996; 14: 2968–2975. 64. Monga M, Carmichael JA, Shelley WE et al. Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecol Oncol 1991; 43: 195–197. 65. Dembo AJ, Davy M, Stenwig AE. Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 1990; 75: 263–273. 66. Sevelda P, Vavra N, Schemper M, Salzer H. Prognostic factors for survival in stage I epithelial ovarian carcinoma. Cancer (Philadelphia) 1990; 65: 2349–2352. 67. Finn CB, Luesley D, Buxton EJ et al. Is stage I epithelial ovarian cancer overtreated both surgically and systemically? Results of a five year cancer registry review. Br J Obstet Gynaecol 1992; 99: 54–58. 68. Querlue D, LeBlanc E. Laparoscopic infrarenal node dissection for restaging of carcinomas of the ovary or fallopian tube. Cancer (Philadelphia) 1994; 73: 1467–1471. 69. Hsiu JG, Given F, Kemp GM. Tumor implantation after diagnostic laparoscopic biopsy of serous ovarian tumors of low malignant potential. Obstet Gynecol 1986; 68: 905–935. 70. Nicklin JL, Van Eijkeren M, Athanasatos P, Wain GV, Hacker NF. A comparison of ovarian cyst aspirate cytology and histology. The case against aspiration of cystic pelvic masses. Aust N Z J O 1994; 34: 546–549. 71. Peterson H, Hulka J, Phillips J. American Association of Gynecologic Laparoscopists 1998 membership survey on operative laparoscopy. J Reprod Med 1990; 35: 587–589. 72. Hulka JF, Parker WH, Surrey MW, Phillips JM. Management of ovarian masses: AAGL 1990 survey. J Reprod Med 1992; 37: 559–602. 73. Nezhat C, Winter W, Nezhat F. Laparoscopic removal of dermoid cysts. Obstet Gynecol 1989; 73: 278–280. 74. Canis M, Mage G, Pouly JL, Wattiez A, Manhes H, Bruhat MA. Laparoscopic diagnosis of adnexal cystic masses: a 12 year experience with long term follow-up. Obstet Gynecol 1994; 83: 707–712. 75. Carter J, Carson LF, Moradi MM et al. Pseudomixoma peritonei, a review. Int J Gynaecol Cancer 1991; 1: 243–247. 76. Clarke-Pearson DL, DeLong ER, Chin NO, Rice R, Creasman WT. Intestinal obstruction in patients with ovarian cancer: Variables associated with surgical complications and survival. Arch Surg 1988; 123: 42–45. 77. Marks WH, Perkal MF, Schwartz PE. Percutaneous endoscopic gastrotomy for decompression in metastatic gynecologic malignancies. Surg Gynecol Obstet 1993; 177: 573–576. 78. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary. Cancer (Philadelphia) 1976; 37(2359): 2372.
118 79. Evans AJ, Gaffey TA, Malkasian GD, Annegers JF. Clinicopathological review of 118 granulosa cell tumour and 82 theca cell tumours. Obstet Gynecol 1980; 55: 231–238. 80. Prendiville J, Murphy D, Rennison J, Buckley H, Crowther D. Carcinosarcoma of the ovary treated over a ten year period at the Christie Hospital. Int J Gynecol Cancer 1994; 4: 200–205.
J. F. STRATTON ET AL. 81. Trimbos JB, Bolis G. Guidelines for surgical staging of ovarian cancer. Obstet Gynecol Surv 1994; 49: 814–816. 82. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 1989; 96: 889–892.
ANTITUMOUR TREATMENT
The surgical management of ovarian cancer J. F. Stratton, J. A.Tidy and M. E. L. Paterson Department of Obstetrics and Gynaecology, Northern General Hospital, Sheffield, UK This article aims to cover current concepts and controversies in the surgical management of ovarian cancer. While there have been significant advances in the surgical management of vulval, cervical and even endometrial cancer there have been few developments in the surgical management of ovarian cancer. This situation is likely to continue until we get a clearer understanding of the natural history of this disease and better therapeutic options become available. © 2001 Harcourt Publishers Ltd Key words: Ovarian cancer; surgical management.
INTRODUCTION At the present time the surgical management of ovarian cancer is carried out by a number of specialists including general surgeons, general gynaecologists and gynaecological oncologists. Recent evidence suggests that who undertakes the surgery has an important influence on outcome with patients operated on by gynaecological oncologists having a 25% improvement in 3-year survival (1–3).
SURGICAL PROCEDURE AND STAGING The incision of choice used for the staging and treatment of ovarian cancer is an extended midline. This gives access to the whole abdomen and pelvis for a thorough laparotomy, which is the most important diagnostic objective. The staging of the woman with ovarian cancer is important because it will determine her prognosis and decide what treatment schedule she will receive (Table 1). In the majority of patients, the stage will be obvious from the advanced nature of the disease. In early stage disease, surgery on its own can be curative and therefore this group of women should be confidently identified (4). Correspondence to: Mr J.F. Stratton, Department of Obstetrics and Gynaecology, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK Fax: 0114 2715984; E-mail: john@fstratton. freeserve.co.uk 0305-7372/01/020111 + 08 $35.00/0
Standard treatment includes sending ascites or washings for cytological assessment followed by a total abdominal hysterectomy (TAH), bilateral salpingo-oophrectomy (BSO) and infracolic omentectomy (Tables 2 and 3). There may be a role for biopsies of peritoneal surfaces and selective pelvic and paraaortic lymphadenectomy. The appendix is often a site of metastases in advanced ovarian cancer and some authorities routinely advocate its removal (5–10). Perhaps the main benefit from appendicectomy in ovarian cancer surgery is the diagnosis of appendiceal adenocarcinomas that may present as a kruckenberg tumour of the ovary as this will influence adjuvant treatment (11–15). The co-existence of appendiceal and ovarian tumours in pseudomyxoma peritonei is as frequent as 90% and recent studies have concluded that the origin of pseudomyxoma peritonei is in the appendix (16, 17) and therefore its removal should be considered in such cases (18–20). In early ovarian cancer, the staging is often suboptimal because the malignancy was not suspected. The significance of the accuracy of staging in stage I disease can be seen in the improved survival seen TABLE 1 5-year survival according to stage (from Vanesmaa 1994) (21) Stage All I II III IV
5-year survival 35–42 70–100 55–63 10–27 3–15 © 2001 HARCOURT PUBLISHERS LTD
112
J. F. STRATTON ET AL. TABLE 2 Staging procedure for ovarian cancer Appropriate surgeon Appropriate incision — extended midline allowing access to upper abdomen Cytology: ascites or washings Laparotomy with clear documentation Biopsies from adhesions and suspicious areas Random biopsies of peritoneum TAH, BSO and infra-colic omentectomy D&C if unable to remove uterus Bilateral selective pelvic and para-aortic lymphadenectomy
TABLE 3 European guidelines of staging of ovarian cancer (produced by the EORTC Gynaecology Group) (81) Peritoneal washings Careful inspection and palpation of all peritoneal surfaces Biopsy of any lesion suspect of tumour metastases Total abdominal hysterectomy and bilateral salpingo-oophorectomy Infracolic omentectomy Biopsy of any adhesion adjacent to the primary tumour Blind biopsies (≥2) of bladder peritoneum and cul de sac Blind biopsies (≥3) of right and left paracolic gutter Blind biopsies (≥2) or smear of the right hemidiaphragm Blind biopsies (≥2) of the pelvic sidewall peritoneum at the side of the primary tumour Lymphnode sampling along the external and common iliac arteries and veins Lymphnode sampling along the aorta and vena cava including the area between the inferior mesenteric artery and the left renal vein
over the last three decades by Vanesmaa (1994) where there has been more accurate staging leading to less use of chemotherapy in true early stage disease (21). Less than 25% of women with presumed early disease had an adequate staging because they did not have a suitable incision (22, 23). However although re-staging laparotomies provide important prognostic information, they provide little benefit to those patients already requiring chemotherapy based on the original operative findings (24). In early disease, ascites is not malignant in 50% women. In women without ascites 20% will have positive washings. Multiple random biopsies will detect disease in 10% of cases (23). The macroscopic assessment of the omentum has poor sensitivity for the detection of metastases (25). If at operation for benign indications, the adnexal mass appears malignant, it is important to confirm this histologically. This can be done by frozen section. Alternatively the conservative operation can be completed, the histology reviewed and a decision can then be made on further management. The morbidity of a second laparotomy has been reported to be up to 33% in some studies (23).
CYTOREDUCTIVE SURGERY Maximum cytoreductive primary surgery is an accepted treatment for ovarian cancer since the work of Griffiths showing survival benefit in those women who had their tumour debulked to a residual disease
of less than 2 cm diameter (26). His findings were collaborated by Hacker (27), but have never been proven by a randomized controlled trial. The critical question is whether or not there are biological differences between tumours which allow some tumours to be optimally debulked and which have a better prognosis compared to those tumours which cannot be optimally debulked despite the best attempts of appropriately skilled and trained individuals. The ability to resect tumours depends on the ability of the surgeon as well as the biology of the tumour and the proportion of optimally debulked tumours varies markedly between centres (1,28). Theoretically, early debulking reduces the number of chemoresistant clones and removes bulky tumour that has a low fraction of growing cells and is therefore resistant to chemotherapy. Ovarian cancer tends to metastasize transcoelomically and therefore disease is often confined to the abdominal cavity. Furthermore tumour tends to spread along the surface of the peritoneum without invading the abdominal viscera thereby allowing the surgeon to find a plane of dissection for the removal of metastatic lesions. That being said, those patients with extensive carcinomatosis, high tumour grades, and extensive intestinal mesenteric involvement have a poor prognosis (29). Patients with stage IV disease may survive just as long without surgery (30), while the role of neoadjuvant chemotherapy remains to be elucidated. For women with advanced disease optimal cytoreduction to < 1 cm is the aim of primary surgery. This
THE SURGIC AL MANAGEMENT OF OVARIAN C ANCER
measurement refers to the diameter of the largest nodule remaining. No account is taken of the confluent plaques that are often seen in the paracolic gutters and on the subdiaphragmatic surfaces. The standard surgical approach involves a TAH, BSO and infracolic omentectomy. Delgado reported only 17.3% of women with stage III disease had complete removal of tumour while a further 10.7% had optimal de-bulking performed (31). Using radical surgery including bowel resection and peritoneal stripping, the number of patients that can be optimally debulked doubles but this does not appear to improve survival (32). Hoskins reported that the survival of women with small volume disease at presentation was better than those women with large volume disease, regardless of whether optimal cytoreduction was achieved (33). It would seem from this that optimal cytoreduction is a prognostic factor in that it reflects a subset of tumours that are less biologically aggressive.
INTERVAL DE-BULKING SURGERY Interval de-bulking surgery refers to surgery performed after two or three cycles of chemotherapy in patients who started chemotherapy without primary debulking or after it failed (34). Approximately 89% of these tumours can be optimally resected at this stage (35). Van der Burg in the EORTC collaborative study showed a marginal benefit of interval debulking surgery in patients who showed a response to chemotherapy but this benefit was minimal: 37% complete response vs 33% in those who did not undergo surgery (36). There was a 6-month median increase in the progression-free interval in the group who underwent surgery. Redman, in a study of 24 patients with gross residual disease after primary surgery and who subsequently were optimally debulked after 14 weeks of chemotherapy, found that the initial improved survival was short-term and that at 18 months there was a rapid deterioration in survival so that overall survival was similar to an historical control group of patients who had > 2 cm residual disease, but who had not undergone interval debulking surgery. A subsequent prospective multicentre randomized study of 79 patients by the same author again failed to show a significant advantage for women undergoing interval surgery (37,38). Gershenson et al. (1989) in a study of 50 patients with stage III and IV disease found that patients who underwent primary debulking had a longer median survival than patients who underwent interval debulking surgery (n = 11, 29.2 months vs 17.3 months, p = 0.04) (39). Wils et al. (1986) reported that patients who had responded to
113
chemotherapy and then had interval cytoreduction had a survival rate close to women who had primary surgical debulking followed by chemotherapy (40).
SECONDARY DE-BULKING SURGERY AND SECOND LOOK LAPAROTOMY Secondary debulking surgery is performed after chemotherapy in patients who have had optimal primary surgery but have persistent disease or who subsequently experience clinical relapse. In these situations debulking surgery is performed before initiating salvage second-line chemotherapy (41). This is distinct from a second look laparotomy which is performed at the completion of chemotherapy in patients who are clinically and radiographically free of disease (42). Approximately 60–80% of women will respond to chemotherapy following primary surgery (43). Second look operations have been used to assess this response. Approximately 40% of stage III patients will have a negative second look operation and of these 50% will relapse (44,45). No survival benefit has been demonstrated for those women who undergo second cytoreductive surgery to no residual disease but this group only accounts for 5% of all those women who underwent second look laparotomy. The outlook for women with progressive disease on firstline chemotherapy or within 1 year of treatment is poor with a median survival of 7 months (41,44). For those women that relapse after 3 or 4 years repeat laparotomy may have a role in confirming the diagnosis and excluding a second malignancy. The role of aggressive secondary debulking surgery in this group of patients is controversial. Morris (46) showed no survival advantage while Janicke (47) found a significant survival advantage. Vaccarello demonstrated a survival advantage in women (who had a negative second look laparotomy) with recurrent disease (mean interval of 20 months from second look surgery) who could be optimally debulked to residual disease of < 0.5 cm (48).
THE ROLE OF LYMPHADENECTOMY Lymphadenectomy can be classified into three groups namely biopsies of palpable nodes, radical lymphadenectomy and lymph node sampling. The main problem with biopsy of palpable nodes is that 55% of lymph nodes metastases are less than 2 mm (49,50). Radical lymphadenectomy results in higher complication rates and so far has not been convincingly shown to result in a survival benefit (51). The technique of selective lymph node sampling has been described by Burke (52). While some studies
114
have shown a benefit using this technique in endometrial cancer, its role in ovarian cancer remains to be evaluated, particularly in stage IA and IB disease who may not receive chemotherapy and who would be upstaged and therefore receive chemotherapy if positive nodes were found. Burghardt, in his analysis of nodal involvement in ovarian cancer, found the incidence of positive nodes was 24% in stage I, 50% in stage II, 74% in stage III and 73% in stage IV disease (53). Most patients with positive nodes have only one or two groups of nodes involved, or one to three positive individual nodes. Greater numbers of positive nodes were found in advanced disease. The size of the largest nodal metastases was not related to clinical stage or survival, but did correlate with the number of positive nodes. Based on this evidence it would seem that if lymph nodes are removed at surgery this is only likely to alter the staging and prognosis if a radical lymphadenectomy is undertaken, otherwise positive lymph nodes will be missed. Lymphadenectomy has been purported to confer a survival advantage (50,54,55). However, Onda did not show a survival difference between those with stage one and two tumours who had positive lymph nodes and those who had negative lymph nodes (56). On the other hand Kigawa showed a survival advantage for lymphadenectomy in patients with advanced stage ovarian cancer (57). This was not supported by Parazzini in his review of 456 women (58). In the absence of gross extrapelvic disease, a selective pelvic and paraaortic lymphadenectomy will result in upstaging 29% of stage I and II disease to stage III (22,25,59).
THE ROLE OF CONSERVATIVE SURGERY Less than 25% of cases of ovarian cancer will have disease confined to the pelvis. Patients with stage IA
J. F. STRATTON ET AL.
and IB lesions which are well to moderately differentiated may be cured by conservative surgery alone (22,60–62) (Table 4). Patients with stage IC and II lesions or poorly differentiated lesions will usually receive adjuvant chemotherapy. If the tumour is grade III, densely adherent, or stage IC, the chance of relapse and subsequent death from ovarian cancer is substantial (up to 20%), although the importance of tumour rupture if it is the only adverse characteristic is not clear (63–65). In selected patients who desire further childbearing and who have grade I tumours, unilateral salpingo-oophorectomy may not be associated with a high risk of recurrence (60). However, Sevelda (66) reported a poorer prognosis for patients treated by unilateral oophorectomy. In this study accurate staging was not uniform and the reported poorer prognosis in early stage cancers may have be due to understaging of cancers. Finn (67) did not find a benefit from lymphadenectomy in these early stage cancers. In this study of 373 patients only 30% had lymph nodes biopsied. No mention was made of performing a systematic lymphadenectomy. The role of laparoscopy in the surgical management of ovarian cancer is highly contentious and most authorities advocate strict selection criteria to ensure only benign ovarian tumours are operated on laparoscopically (Table 5). However laparoscopy may have a role in re-staging procedures which are most important for early ovarian cancer. The case of the referred patient with unsatisfactory staging because the diagnosis was not suspected at the initial surgery is not uncommon and may be managed laparoscopically rather than by repeat laparotomy, combining staging surgery and additional surgery such as hysterectomy and contralateral oophorectomy (68). Laparoscopy may also have a role in the diagnosis of ovarian cancer prior to initiating neoadjuvant chemotherapy. Most of the criticisms of laparoscopy in the management of ovarian cancer relate
TABLE 4 Guidelines for conservative surgery of epithelial ovarian cancer The patient must be of reproductive age and wishing to have further children The surgery must include a complete surgical staging.The contralateral ovary must be normal The FIGO stage should be 1a with a well to moderately differentiated serous histology Close follow-up The contralateral ovary is removed when childbearing is complete TABLE 5 Guidelines for selecting patients with adnexal masses suitable for laparoscopic surgery (from Crawford et al. 1995) (82) ACOG: On U.S. mass diameter < 10 cm, cystic with a distinct border and no solid elements. No ascites or matted bowel. Normal CA125 (< 35 i.u.) and no family history of ovarian cancer BGCS: On U.S. mass diameter <8 cm, cystic with no solid elements, no multiloculation, not bilateral. No increased blood flow on doppler. Caution if raised CA125. No family history of ovarian cancer. Adnexal mass should be completely removed without rupture. ACOG: American College of Obstetricians and Gynaecologists BGCS: British Gynaecological Cancer Society
THE SURGIC AL MANAGEMENT OF OVARIAN C ANCER
to improper staging, peritoneal spillage and abdominal wall contamination (69). Many simple ovarian cysts in pre-menopausal women can be managed expectantly unless they are greater than 6 cm in diameter or persistent. Aspiration of cysts is associated with a high recurrence rate of 66% and cytological assessment of the aspirate is a poor predictor of malignancy with a false negative rate of 2–42% (70). The incidence of malignancy in ovarian cysts assumed to be benign on the basis of ultrasound assessment and CA125 is 0.04–3.7% (71–74).
SALVAGE SURGERY The predominant symptom in advanced incurable ovarian cancer is that of bowel obstruction. The obstruction may be in large bowel, small bowel or both or even a functional obstruction due to infiltration and contraction of the mesentery. Operations to resect focal recurrences associated with bowel obstruction are of value unless obstruction is caused by diffuse carcinomatosis. Intermittent surgical debulking may be necessary in Pseudomyxoma peritonei to maintain quality of life (75). It is difficult to predict which women with bowel obstruction in advanced ovarian cancer are likely to benefit from surgical treatment of the obstruction. Clinically detectable ascites, low serum albumin and palpable intra-abdominal disease are poor prognostic features (76). Total parenteral nutrition (TPN) may correct a low serum albumin if it is felt that surgery is warranted. The operative morbidity is up to 64% and mortality 32%. A percutaneous gastrostomy tube may be useful in those women with vomiting due to inoperable obstruction (77). Medical management is often the most appropriate treatment for intestinal obstruction in women with advanced disease.
SURGERY IN NON-EPITHELIAL OVARIAN CANCERS Ovarian germ cell tumours occur principally in adolescent girls between the ages 16 and 20. Recurrence is unlikely after surgery for stage I grade I immature teratomas while 85% of grade III stage I tumours will recur without adjuvant treatment (78). The histologic grade of the tumour is based on three factors: degree of immaturity, presence of a neuroepithelial component and the quantity of the latter. Germ cell tumours are sensitive to chemotherapy and the majority present in stage I. For patients with more advanced disease the role of debulking remains controversial.
115
Dysgerminomas are radiosensitive and chemosensitive, most are confined to the ovary, 10% are bilateral, although retroperitoneal nodal spread is more common than in germ cell tumours. Fifteen to twenty five percent will recur after unilateral salpingo-oophorectomy for stage IA disease, and most of these will occur in the first 2 years. Ninety per cent of granulosa cell tumours are stage I at presentation and conservative surgery (unilateral salpingo-oophorectomy, D&C and accurate staging) is indicated in those women wishing to preserve their fertility. Removal of the uterus and contralateral ovary are recommended following completion of childbearing. Women with more advanced stage tumours should have a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Approximately 18% of granulosa cell tumours recur. Recurrence is associated with a high mortality rate. Of those tumours that recur, 20% will recur more than 10 years following initial treatment (79). Tumour recurrence is most often localized in the pelvis (one third recur in the reproductive tract) or abdomen. The extent of the initial surgical procedure affects recurrence rates. Six per cent of women undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy develop recurrence compared to 25% of women undergoing less extensive surgical procedures. Fifty five per cent of granulosa cell tumours are associated with endometrial hyperplasia while a concomitant uterine carcinoma is present in 13%. Sertoli-stromal cell tumours can be treated by unilateral salpingo-oophorectomy as the majority are stage I lesions. However prognosis is adversely affected by rupture and stage II lesions have a poor prognosis (80).
CONCLUSION Surgery remains the cornerstone for the diagnosis and staging of ovarian cancer. While conservative surgery may have a role in a small number of selected women with early stage disease, ultraradical surgery involving bowel resection is only indicated in a few cases where the disease can be completely eradicated by surgery or there is evidence of impending bowel obstruction. Secondary de-bulking surgery has a role in recurrent disease which occurs one or more years following successful primary treatment. Interval debulking surgery has a limited role in women who have had an unsuccessful initial attempt at debulking surgery, while neoadjuvant chemotherapy is currently under review. Salvage surgery is confined to women with a surgically correctable bowel obstruction. Most non-epithelial
116
ovarian cancers occur in young women and can be managed with conservative surgery in the majority of cases.
J. F. STRATTON ET AL.
18.
19.
REFERENCES 1. Eisenkop SM, Spirtos NM, Montag TW, Nalick RH, Wang HJ. The impact of subspecialty training on the management of advanced ovarian cancer. Gynecol Oncol 1992; 47: 203–209. 2. Nguyen HN, Averette HE, Hoskins W, Penalver M, Sevin BU, Steren A. National survey of ovarian carcinoma. Part V. The impact of physician’s specialty on patients’ survival. Cancer 1993; 72: 3663–3670. 3. Junor EJ, Hole DR, McMurty L et al. Specialist gynaecologists and survival outcomes in ovarian cancer. A Scottish National Study of 1866 patients. Br J Obstet Gynaecol 1999; 106: 1130–1136. 4. Trimbos JB, Schueler JA, Burg M et al. Watch and wait after careful surgical treatment and staging in well-differentiated early ovarian cancer. Cancer (Philadelphia) 1999; 67: 597–602. 5. Ayhan A, Tuncer ZS, Tuncer R, Yuce K. Is routine appendectomy beneficial in the management of ovarian cancer? Eur J Obstet Gynecol Reprod Biol 1994; 57: 29–31. 6. Bese T, Kosebay D, Kaleli S, Oz AU, Demirkiran F, Gezer A. Appendectomy in the surgical staging of ovarian carcinoma. Int J Gynaecol Obstet 1996; 53: 249–252. 7. Corfitsen MT, Pedersen IR, Lebech AM, Kaae HH. Appendectomy and carcinoma ovarii. Cytoreduction, palliation, or simple tradition? Acta Obstet Gynecol Scand 1991; 70: 601–604. 8. Fawzi HW, Robertshaw JK, Bolger BS, Monaghan JM. Role of appendicectomy in the surgical management of ovarian cancer. Eur J Gynaecol Oncol 1997; 18: 34–35. 9. Fontanelli R, Paladini D, Raspagliesi F, di Re E. The role of appendectomy in surgical procedures for ovarian cancer. Gynecol Oncol 1992; 46: 42–44. 10. Rose PG, Reale FR, Fisher A, Hunter RE. Appendectomy in primary and secondary staging operations for ovarian malignancy. Obstet Gynecol 1991; 77: 116–118. 11. Cortina R, McCormick J, Kolm P, Perry RR. Management and prognosis of adenocarcinoma of the appendix. Dis Colon Rectum 1995; 38: 848–852. 12. Hirschfield LS, Kahn LB, Winkler B, Bochner RZ, Gibstein AA. Adenocarcinoid of the appendix presenting as bilateral Krukenberg’s tumor of the ovaries. Immunohistochemical and ultrastructural studies and literature review. Arch Pathol Lab Med 1985; 109: 930–933. 13. Ikeda E, Tsutsumi Y, Yoshida H, Yanagi K. Goblet cell carcinoid of the vermiform appendix with ovarian metastasis mimicking mucinous cystadenocarcinoma. Acta Pathol Jpn 1991; 41: 455–460. 14. Merino MJ, Edmonds P, LiVolsi V. Appendiceal carcinoma metastatic to the ovaries and mimicking primary ovarian tumors. Int J Gynecol Pathol 1985; 4: 110–120. 15. Thomas R, Barnhill D, Worsham F, Hoskins W. Krukenberg tumor of the ovary from an occult appendiceal primary: case report and literature review. Obstet Gynecol 1985; 65: 95S–98S. 16. Young RH, Gilks SB, Scully RE. Mucinous tumours of the appendix associated with mucinous tumours of the ovary and pseudomyxoma peritonei: a clinicopathological analysis of 22 cases. Am J Surg Pathol 1991; 15: 415–429. 17. Prayson RA, Hart WR, Petras RE. Pseudomyxoma peritonei: a clinicopathologic study of 19 cases with emphasis on site of
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34. 35.
36.
origin and nature of associated ovarian tumours. Am J Surg Pathol 1994; 18: 591–603. Long RT, Spratt JSJ, Dowling E. Pseudomyxoma peritonei. New concepts in management with a report of seventeen patients. Am J Surg 1969; 117: 162–169. Nogales FF, Caballero T, Fernandez PL, Linares J, Ruiz-Avila I. Pseudomyxoma peritonei et ovarii associated with sequential ovarian and appendicular tumors and acromegaly. Gynecol Oncol 1991; 40: 78–80. Wertheim I, Fleischhacker D, McLachlin CM, Rice LW, Berkowitz RS, Goff BA. Pseudomyxoma peritonei: a review of 23 cases. Obstet Gynecol 1994; 84: 17–21. Vanesmaa P. Epithelial ovarian cancer: Impact of surgery and chemotherapy on survival during 1977–1990. Obstet Gynecol 1994; 79: 8–11. Young RC, Walton LA, Ellenberg SS et al. Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 1990; 322: 1021–1027. Soper J, Johnson P, Johnson V, Berchuck A, Clarke-Pearson DL. Comprehensive restaging laparotomy in women with apparent early ovarian carcinoma. Obstet Gynecol 1992; 80: 949–953. Stier EA, Barakat RR, Curtin JP, Brown CL, Jones WB, Hoskins WJ. Laparotomy to complete staging of presumed early ovarian cancer. Obstet Gynecol 1996; 87: 737–740. Buschbaum HJ, Brady MF, Delgado G, Miller AB, Hoskins WJ, Manetta A. Surgical staging of carcinoma of the ovaries. Surg Gynecol Obstet 1989; 83: 707–712. Griffiths CT, Parker LM, Fuller AF. Role of cytoreductive surgeral treatment in the management of advanced ovarian cancer. Cancer Treatment Rep 1979; 63: 235–240. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983; 61: 413–420. Hunter RW, Alexander NDE, Soutter WP. Meta-analysis of surgery in advanced ovarian carcinoma, is maximum cytoreductive surgery an independent determinant on prognosis? Am J Obstet Gynecol 1992; 166: 511. Farias-Eisner PE, 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 1994; 55: 108–110. Schwartz MD, Chambers JT, Makuch R. Neoadjuvant chemotherapy for advanced ovarian cancer. Gynecol Oncol 1994; 53: 33–37. Delgado G, Oram D, Petrilli ES. Stage III epithelial ovarian cancer: the role of maximal surgical reduction. Gynecol Oncol 1984; 18: 293–298. Potter ME, Partridge EE, Hatch KD, Soong S-J, Austin JM, Shingleton HM. Primary surgical therapy of ovarian cancer: How much and when. Gynecol Oncol 1991; 40: 195–200. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992; 47: 159–166. Berek JS. Interval debulking of ovarian cancer — an interim measure. New Engl J Med 1995; 332: 675–677. Lawton FG, Redman CWE, Luesley DM et al. Neoadjuvant (cytoreductive) chemotherapy combined with intervention debulking surgery in advanced unresected epithelial ovarian cancer. Obstet Gynecol 1989; 73: 61–65. Van der Burg, MEL, Van Lent M, Buyse M, Kobierska A. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced ovarian cancer. New Engl J Med 1995; 332: 629–634.
THE SURGIC AL MANAGEMENT OF OVARIAN C ANCER 37. Redman CW, Blackledge G, Lawton FG, Varma R, Luesley DM, Chan KK. Early second surgery in ovarian cancer— improving the potential for cure or another unnecessary operation? Eur J Surg Oncol 1990; 16: 426–429. 38. Redman CW, Warwick J, Luesley DM, Varma R, Lawton FG, Blackledge GR. Intervention debulking surgery in advanced epithelial ovarian cancer. Br J Obstet Gynaecol 1994; 101: 142–146. 39. Gershenson DM, Wharton JT, Copeland L. Treatment of advanced epithelial ovarian cancer with cisplatin and cisplatin and cyclophosphamide. Gynecol Oncol 1989; 32: 336–341. 40. Wils J, Blijham G, Naus A et al. Primary or delayed debulking surgery and chemotherapy of cisplatin, doxorubicin and cyclophosphamide in stage III–IV epithelial ovarian carcinoma. J Clin Oncol 1986; 4: 1068. 41. Berek JS, Hacker NF, Lagasse LD, Nieberg RK, Elashoff RM. Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol 1983; 61: 189. 42. Berek JS, Hacker NF, Lagasse LD, Poth T, Resnick B, Nieberg, RK. Second look laparotomy in stage III epithelial ovarian cancer: clinical variables associated with disease status. Obstet Gynecol 1984; 64: 207–212. 43. Clarke-Pearson DL, Kohler MF, Hurteau JA, Elbendary A. Surgery for advanced ovarian cancer. Clin Obstet Gynecol 1994; 37: 439–460. 44. Potter ME, Hatch KD, Soong S-J, Partridge EE, Austin JM, Shingleton HM. Second look laparotomy and salvage therapy: A research modality only? Gynecol Oncol 1992; 44: 3–9. 45. Podratz KC, Kinney WK. Second-look operation in ovarian cancer. Cancer (Philadelphia) 1993; 71: 1551–1558. 46. Morris M, Gershenson DM, Wharten T, Copeland L, Edwards CL, Stringer A. Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol 1989; 34: 334–338. 47. Janicke F, Holscher M, Kuhn W et al. Radical surgery procedure improves survival time in patients with recurrent ovarian cancer. Cancer (Philadelphia) 1992; 70: 2129–2136. 48. Vaccarello L, Rubin SC, Vlamis V et al. Cytoreductive surgery in ovarian carcinoma patients with a documented previously complete surgical response. Gynecol Oncol 1995; 57: 61–65. 49. Petru E, Lahousen M, Tamussino K et al. Lymphadenectomy in stage 1 ovarian cancer. Am J Obstet Gynecol 1994; 170: 656–662. 50. Wu PC, Qu JY, Lang JH et al. Lymph node metastases of ovarian cancer. A preliminary survey of 74 cases of lymphadenectomy. Am J Obstet Gynecol 1986; 155: 1103. 51. Benedetti-Panici P, Pickel H, Lahousen M, Stettner H. Randomised study comparing systematic pelvic (PE) and aotic (A) lymphadenectomy in early ovarian carcinoma or at second look surgery versus no lymphadenectomy: feasibility and complications. Am J Obstet Gynecol 1986; 60: 129. 52. Burke TW. Selective pelvic and para-aortic lymphadenectomy. Operat Techniq Gynecol Surg 1996; 1: 17–21. 53. Burghardt E, Girardi F, Lahousen M et al. Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 1991; 40: 103–106. 54. Burghardt E, Pickel O, Lahousen M, Stettner H. Pelvic lymphadenectomy in operative treatment of ovarian cancer. Am J Obstet Gynecol 1996; 155: 315. 55. DiRe F, Fontanelli F, Raspagliesi F, di Re E. Pelvic and paraaortic lymphadenectomy in cancer of the ovary. In: Burghardt E, Monaghan JM (eds.) Clinics in Obstetrics and Gynaecology London: Balliere Tindall, 1989. 56. Onda T, Yoshikawa H, Yasugi T et al. Patients with ovarian carcinoma upstaged to stage III after systematic lymphadenctomy have similar survival to stage I/II patients and superior survival to other stage III patients. Cancer 1998; 83: 1555–1560.
117 57. Kigawa J, Minagawa Y, Ishihara H, Kanamori Y, Itamochi H, Terakawa N. Evaluation of cytoreductive surgery with lymphadenectomy including para-aortic nodes for advanced ovarian cancer. Eur J Surg Oncol 1993; 19: 273–278. 58. Parazzini F, Valsecchi G, Bolis G et al. Pelvic and paraortic lymph nodal status in advanced ovarian cancer and survival. Gynecol Oncol 1999; 74: 7–11. 59. Helewa ME, Krepart GV, Lotocki R. Staging laparatomy in early ovarian cancinoma. Am J Obstet Gynecol 1986; 169: 226–232. 60. Zanetta G, Chiari S, Rota S et al. Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 1997; 104: 1030–1035. 61. Young RC. Initial therapy for early ovarian carcinoma. Cancer 1987; 60: 2042–2049. 62. Young RC. The treatment of early stage ovarian cancer. Semin Oncol 1995; 22: 76–79. 63. Ahmed FY, Wiltshaw E, A’Hern RP et al. Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 1996; 14: 2968–2975. 64. Monga M, Carmichael JA, Shelley WE et al. Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecol Oncol 1991; 43: 195–197. 65. Dembo AJ, Davy M, Stenwig AE. Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 1990; 75: 263–273. 66. Sevelda P, Vavra N, Schemper M, Salzer H. Prognostic factors for survival in stage I epithelial ovarian carcinoma. Cancer (Philadelphia) 1990; 65: 2349–2352. 67. Finn CB, Luesley D, Buxton EJ et al. Is stage I epithelial ovarian cancer overtreated both surgically and systemically? Results of a five year cancer registry review. Br J Obstet Gynaecol 1992; 99: 54–58. 68. Querlue D, LeBlanc E. Laparoscopic infrarenal node dissection for restaging of carcinomas of the ovary or fallopian tube. Cancer (Philadelphia) 1994; 73: 1467–1471. 69. Hsiu JG, Given F, Kemp GM. Tumor implantation after diagnostic laparoscopic biopsy of serous ovarian tumors of low malignant potential. Obstet Gynecol 1986; 68: 905–935. 70. Nicklin JL, Van Eijkeren M, Athanasatos P, Wain GV, Hacker NF. A comparison of ovarian cyst aspirate cytology and histology. The case against aspiration of cystic pelvic masses. Aust N Z J O 1994; 34: 546–549. 71. Peterson H, Hulka J, Phillips J. American Association of Gynecologic Laparoscopists 1998 membership survey on operative laparoscopy. J Reprod Med 1990; 35: 587–589. 72. Hulka JF, Parker WH, Surrey MW, Phillips JM. Management of ovarian masses: AAGL 1990 survey. J Reprod Med 1992; 37: 559–602. 73. Nezhat C, Winter W, Nezhat F. Laparoscopic removal of dermoid cysts. Obstet Gynecol 1989; 73: 278–280. 74. Canis M, Mage G, Pouly JL, Wattiez A, Manhes H, Bruhat MA. Laparoscopic diagnosis of adnexal cystic masses: a 12 year experience with long term follow-up. Obstet Gynecol 1994; 83: 707–712. 75. Carter J, Carson LF, Moradi MM et al. Pseudomixoma peritonei, a review. Int J Gynaecol Cancer 1991; 1: 243–247. 76. Clarke-Pearson DL, DeLong ER, Chin NO, Rice R, Creasman WT. Intestinal obstruction in patients with ovarian cancer: Variables associated with surgical complications and survival. Arch Surg 1988; 123: 42–45. 77. Marks WH, Perkal MF, Schwartz PE. Percutaneous endoscopic gastrotomy for decompression in metastatic gynecologic malignancies. Surg Gynecol Obstet 1993; 177: 573–576. 78. Norris HJ, Zirkin HJ, Benson WL. Immature (malignant) teratoma of the ovary. Cancer (Philadelphia) 1976; 37(2359): 2372.
118 79. Evans AJ, Gaffey TA, Malkasian GD, Annegers JF. Clinicopathological review of 118 granulosa cell tumour and 82 theca cell tumours. Obstet Gynecol 1980; 55: 231–238. 80. Prendiville J, Murphy D, Rennison J, Buckley H, Crowther D. Carcinosarcoma of the ovary treated over a ten year period at the Christie Hospital. Int J Gynecol Cancer 1994; 4: 200–205.
J. F. STRATTON ET AL. 81. Trimbos JB, Bolis G. Guidelines for surgical staging of ovarian cancer. Obstet Gynecol Surv 1994; 49: 814–816. 82. Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol 1989; 96: 889–892.