The staging and treatment of epithelial ovarian cancer

The transparency for the cover illustration, which depicts grades I to 4 anapiasia (according to Broder's classification) in advanced stages of serous cystadenocarcinoma of the ovary, was supplied by the authors. The stain used was heinatoxylineosin and the magnification was X 400.

The age-adjusted death rate for ovarian cancer has remained unchanged for the last 20 years in spite of attempts at earlier diagnosis and the use of surgery, radiotherapy or chemotherapy. The incidence, however, has doubled over the past 40 years; ovarian cancer will therefore present an increasingly serious problem in years to come. Approximately 60% to 70% of all persons with ovarian cancer present initially with advanced stages of the disease (stage III and IV of the International Federation of Gynecology and Obstetrics [FIGO] classification2). This distressing situation is a consequence of the fact that ovarian cancer usually remains asymptomatic until the tumour becomes large enough to interfere with the function of other pelvic or abdominal organs. In the 30% to 40% of patients who present with localized disease (FIGO stages I and II) an ovarian mass is usually discovered on routine pelvic examination or during an operation for another problem. Most patients with localized disease appear to be rendered diseasefree by surgical resection or pelvic radiotherapy or both, yet in at least one third the tumour recurs.3 Recent studies utilizing lymphangiography and peritoneoscopy (discussed later) have shown that many of these apparently localized tumours have metastasized to other areas of the abdomen by the time of their discovery. This biologic information about the behaviour and patterns of spread of ovarian cancer, plus a more detailed study of the newer chemotherapeutic agents, used both singly and in combination, may permit better and more appropriate forms of treatment of ovarian cancer.

st&ge I, grade 1 ovarian cancer (0 to 25% of cells undifferentiated) the 5-year survival was 90% for persons with intracystic lesions, 68% for those with extracystic excrescences, and 56% for those with cysts that ruptured during the operation.4 Stage Ic formerly consisted of cases with ascites; now either ascites or positive cytologic findings in peritoneal washings is sufficient to allow this classification. Likewise, stage lic was added to encompass cases with either ascites or malignant cells in the pentoneal washings. The definition of stage IV disease has been expanded to include cases with parenchymal liver metastases or a pleural effusion containing malignant cells. Every analysis of survival in ovarian cancer has demonstrated the prognostic significance of accurate staging at the time of the initial operation, yet studies in the United States have indicated that staging by the primary physician is rarely complete. For example, Piver, Lele and Barlow,5 analysing 100 consecutive referrals to Roswell Park Memorial Institute in Buffalo, New York, reported that the preoperative and intraoperative evaluation of patients undergoing exploratory laparotomy for ovarian cancer was often inadequate for staging and even for excluding the possibility of metastases in the ovary from other primary tumours: 33% of the patients had had

Staging The 5-year survival of persons with ovarian cancer has been shown to correlate inversely with the FIGO stage of the disease.3 The FIGO staging classification, as revised in January 1975,. is shown in Table I. With the revision, stages Ia and lb disease have been further subdivided according to whether extracapsular excrescences are found or intraoperative rupture of the tumour occurs. Support for the prognostic importance of this change is provided from studies at the Mayo Clinic: investigators reported that for 250 CMA JOURNAL/AUGUST 12, 1978/VOL. 119

only a physical examination and routine laboratory studies prior to the operation, and 11 % had not had a pelvic examination; the incision was inadequate for evaluation of the upper abdomen (liver, diaphragm and para-aortic lymph nodes) in 83%; and a biopsy of the ovary was not obtained in 33%. Clearly, thorough initial surgical exploration is vital to accurate assessment of the extent of tumour spread. Recent studies have indicated that lymphangiography may now be considered an extremely useful part of the staging evaluation of ovarian cancer. The main lymphatics draining the ovary ascend bilaterally along the ovarian blood vessels and terminate in the para-aortic lymph nodes between the bifurcation of the aorta and the renal pedicles.6 A second, but slightly less common, route of lymphatic drainage ends in the external iliac and hypogastric lymph nodes. Several centres have demonstrated that approximately 30% to 50% of persons with ovarian cancer have abnormalities in th'.se areas on lymphangiograms.74 Features that usually indicate metastatic ovarian tumour in lymphatics are filling defects not traversed by lymphatics and often associated with lymphatic obstruction. The areas of replacement in the nodes are usually peripheral, with the residual node appearing to have a crescent-shaped defect. These de-

fects have been found in the lymphangiograms of persons with many other solid tumours; hence they are specific only when the primary tumour is known.101' In studies performed at Stanford University in ?alo Alto, California, 21 % of patients classified at laparotomy as having stage I or II ovarian cancer had abnormal lymphangiograms indicating more extensive disease.1' Although further studies correlating histologic with lymphangiographic abnormalities are required, spread of ovarian cancer into the retroperitoneal lymph nodes undoubtedly accounts for some intra-abdominal recurrences in persons with stage I or II disease. Another approach that has yielded important new information on the pattern of spread of ovarian cancer is peritoneoscopy. This procedure also appears to be useful in the accurate staging of ovarian cancer. For several years, as a part of the staging work-up of patients with ovarian cancer referred to us, we have performed peritoneoscopy within 1 month of exploratory laparotomy as part of pretreatment evaluation. Details of the procedure as used in 49 patients referred consecutively have been published;14 the findings are summarized in Table II. Of the 16 patients in whom a diagnosis of stage I or II disease had been made from the laparotomy findings 9 (56%) were found to have advanced disease (stage III) at peritoneoscopy and therefore had their treatment programs modified. Seven of these patients had diaphragmatic metastases; the other two had metastases to the omentum or the peritoneum or both. Since six of these nine patients had negative results of physical, laboratory and roentgenologic examinations, peritoneoscopy afforded the sole followable findings. Of the 33 patients whose disease was classified as stage III or IV from the laparo-

tomy findings 70% were found to have diaphragmatic metastases at peritoneoscopy, and for 45% pentoneoscopy provided the sole followable findings. A complete staging evaluation is important for reasons other than prognostic. In many instances it is responsible for the detection of disease outside the pelvis that would have been inadequately treated if irradiation had been directed only to the pelvis. Often metastases are identified on the right diaphragm - an area customarily shielded during total abdominal irradiation because of the risk of liver injury. In situations such as this a complete staging evaluation not only provides prognostic information to the patient and physician but also alters the therapeutic approach, increasing the likelihood of success. Restaging after treatment may also be useful.. The detection of residual tumour following therapy has been notoriously difficult in ovarian cancer, and "second-look" laparotomy has been advocated.15 We have used peritoneoscopy as a restaging approach with considerable success: with this technique residual tumour was detected in 7 (39%) of 18 patients with apparently complete clinical remission; therapy was continued and they were spared another laparotomy. However, negative results of peritoneoscopy do not eliminate the possibility of residual tumour, especially deep within the pelvis - an area difficult to evaluate with this technique. Two of our four patients with apparently complete clinical remission confirmed by repeat peritoneoscopy were found to have small foci of residual tumour at secondlook laparotomy. Histologic grading Epithelial ovarian tumours, which account for more than 85% of all

ovarian cancers, have been classified pathologically as serous, mucinous, endometroid, mesonephroid or undifferentiated adenocarcinomas. Although the epithelial tumours display similar patterns of spread and overall behaviour, the mucinous and endometroid types tend to present earlier and hence have a somewhat better prognosis.' Recently investigators at the Mayo Clinic have suggested that the degree of anaplasia may be a better determinant of prognosis than the cell type in ovarian cancer.16 They used Broders' classification,17 which grades malignant tumours according to the percentage of undifferentiated cells - that is, 0 to 25%, grade 1; 25% to 50%, grade 2; 50% to 75%, grade 3; and 75% to 100%, grade 4. The overall 5-year survival for treated stage II serous cystadenocarcinoma was 38%; however, the rate was 80% for grade 1 lesions, 47% for grade 2 lesions and 10% for grades 3 and 4 lesions combined. For each stage the same trend was observed: patients having tumours with lower grades of anaplasia had a better survival than those having tumours with higher grades of anaplasia. Day and Smith's data supported these conclusions.' Future clinical trials should consider stratification of patients by histologic grade as well as stage of disease. Radiotherapy Radiotherapy has been used for many years as an adjuvant to surgical treatment of localized disease and as palliative therapy for advanced disease. However, its precise place in the management of ovarian cancer is difficult to establish. Radiotherapy equipment and the fields irradiated have varied from study to study; most centres have used open- or stationary-field techniques, though some have used the moving-strip technique. Fazekas and Maier18 conducted a randomized trial of radiotherapy in 50 persons with all stages of ovarian cancer; the patients received a biologically similar dose of either 1060 or 1400 ret (radiation equivalent therapy units) by either the openfield technique (4000 rad in 40 fractions over 56 days) or the movingstrip technique (3000 rads in 8 frac-

CMA JOURNAL/AUGUST 12, 1978/VOL. 119 251

tions over 10 days). Although the moving-strip technique gave superior results early in the trial, there was no difference in survival between the two groups at 4 years. The value of adjuvant radiotherapy for localized disease (FIGO stage I) has not yet been established, partly because of defects in study design. Among the various series staging was not uniform. Furthermore, patients were often referred to radiotherapists after surgery because of apparently poor prognostic signs. Few studies have assigned postoperatively all patients to receive at random either radiotherapy or no adjuvant therapy. No definite benefit from postoperative radiotherapy in patients with stage I disease has been demonstrated from early studies (Table III). The mean 5-year survival as determined from a number of series of patients was 67% (range 32% to 78%) for those treated by surgery alone and 60% (range 40% to 71%) for those treated by surgery and pelvic irradiation.3'13 With persons having stage Ia or lb disease the Gynecologic Oncology Group since June 1971 has given at random after surgery no further treatment, pelvic irradiation or melphalan for 18 months. A preliminary communication analysed the data for 56 evaluable cases,1 and the most recently published update includes an analysis of the data for 111 patients. Rates of recurrence were 17.5%, 14.3% and 7.1 % respectively - not significantly different. Table lll-Five.year survival of persons with ovarian cancer . Treatment; weighted mean and range (%) FICO Surgery and stage Surgery only radiotherapy .1 67(32-78) 60(40-71) II 24(0-33) 39(2749) Ili.rIV. 1 (-3) 9 (3-.30)

An early study, though not randomized, was designed to establish whether the intraperitoneal instillation of radioactive gold (140 mCi) in patients with stage I disease and rupture of a cyst at laparotomy was beneficial in preventing recurrence.30 The 5-year survival rates for the 25 treated patients and the 22 well matched patients who received surgical treatment only were* 80% and

43% respectively. This significant difference in survival supports the need for additional therapy in such patients. Whether intraperitoneal instillation of radioactive gold is the optimal therapy is unknown. A trial recently completed at the Princess Margaret Hospital in Toronto compared the benefits of postoperative radiotherapy and chemotherapy.21 Patients with stage Ia disease were randomly assigned to observation or pelvic irradiation following surgery; since only 30 such patients had been entered into the trial their data could not be analysed. Owing to a prior retrospective study that had shown similar survival in patients with stage lb or II disease, data for these two groups were pooled for the prospective study. Stratification was by the patient's age and by the stage, histologic type and histologic grade of the tumour. Staging by laparoscopy or repeat laparotomy, however, was not done in most of the referred patients. The 125 patients with stage lb or II disease were randomly allocated to receive pelvic irradiation (4500 rad to the midpelvis) alone, pelvic irradiation (4500 rad to the midpelvis) and abdominal-strip irradiation (2250 rad to the midplane), or pelvic irradiation (4500 rad to the midpelvis) and chlorambucil (6 mg/d for 24 months) immediately thereafter. No significant difference was seen between the three groups; however, among the patients who had had a total abdominal hysterectomy and bilateral salpingo-oophorectomy (most of whom would have a residual mass less than 2 cm in diameter) recurrence or progression of disease was less frequent among those who had received abdominal irradiation or chemotherapy. For persons with stage II ovarian cancer some benefit from postoperative radiotherapy is generally accepted. Five-year survival rates have averaged 24% (range 0 to 33%) for persons undergoing surgery and 39% (range 27% to 69%) for those undergoing surgery and radiotherapy.3'13 Persons with stage III ovarian cancer have generally received only palliative therapy after irradiation, and 5-year survival rates have ranged from 0 to 17%. Johnson and colleagues22 randomly allocated 50 patients with advanced ovarian cancer to receive surgery and cyclophos-

252 OMA JOURNAL/AUGUST 12, 1978/VOL. 119

Librax (chiordiazepoxide HOI clidinium bromide 'Roche') Rx Summary Indications Adjunctive management of irritable bowel syndrome, peptic ulcer and other gastrointestinal disorders associated with hypersecretion, hypermotility and spasm and accompanied by anxiety or tension states. Contralndlcatlons Hypersensitivity to chlordiazepoxide and/ or clidinium bromide. Glaucoma, prostatic hypertrophy and benign bladder neck obstruction. Precautions In elderly or debilitated patients limit the initial dose to the smallest effective to preclude the development of oversedation or ataxia. Use with caution in severely depressed patients and in those who may increase the dosage on their own accord. Advise patients against concomitant ingestion with alcohol or other CNS depressants and caution against engaging in activities requiring complete mental alertness or physical coordination. Use only in women who are or who may become pregnant when benefits have been weighed against possible hazards to mother and fetus. Use with caution in patients with impaired renal or hepatic function; periodic blood counts and liver and renal function tests may be advisable during prolonged therapy. Adverse Effects As for chlordiazepoxide. In addition, clidinium bromide may cause dryness of the mouth, blurred vision, urinary hesitancy; constipation particularly when combined with other spasmolytics and/or low residue diet. Dosage Adults-ito 2 capsules 3 or 4 times daily, before meals and at bedtime. Supply Each capsule contains chlordiazepoxide HOI -5 mg, and clidinium bromide 2.5 mg; green opaque body and cap with ROCHE and LI (black ing betweenBRAX body and cap.ink) alternatBottles of 100 and 500. Complete prescribing information available on request. ROCHE * Vaudreuil, Hoffmann-La RocheJ7V Limited Quebec 6B3

Table IY-Druga used singly In chemotherapy for advanced ovarian cancer No. of Drug patients Melphalan' 494 5-fluorourecil" 102 Flexamethyhuelainine" 53 Doxorublcin'6 51 Cls.dlchiorodIaanmfnepletluwn (1 t)fl 34 Methotrexate" 16

% with objective response 47 32 41 33 27 33

In prospective studies at Mount Sinai Hospital in New York cis-platinum, used alone and in. combination with doxorubicin, has been compared with a combination of thiotepa and methotrexate.33 The patients were not stratified; as a result a greater percentage of older patients received thiotepa and a greater percentage of patients with poorly differentiated tumour cells received cis-platinum plus doxorubicin. Responses were determined clinically only. The rates of response were: cis-platinum alone 41 % (7 of 17), cis-platinum plus doxorubicin 67% (12 of 18) and thiotepa plus methotrexate 35% (6 of 17). Again, the results are preliminary, and the completeness of remission was not assessed by a restaging evaluation, but the combination cis-platinum and doxorubicin appears to result in a better response than cis-platinum used alone or thiotepa plus methotrexate. At our institute previously untreated patients with stage III or IV ovarian cancer have been randomly assigned to treatment with melphalan or the hexa-CAF regimen, a combination of hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil.. A review of data for the first 80 patients indicated a rate of overall response of 76% for the combination, as compared with 54% for melphalan. In addition, the combination has yielded a higher proportion of complete responses (33% v. 16%) and longer overall survival (29 v. 17 months). Complete remission, as documented by a restaging evaluation, has been associated with long survival; the median exceeds 3 years, with 15 of 19 patients surviving. The hexa-CAF regimen and newer chemotherapeutic combinations may begin to alter the discouraging results of treatment of advanced ovarian cancer, for they show promise as both primary and adjuvant therapeutic agents. References 1. SEIDMAN H, SILVERBERO E, HOLLEB

Al: Cancer statistics, 1976. Cancer 26: 2, 1976 2. DAY TG, SMITH JP: Diagnosis and staging of ovarian cancer. Semin Onccl 2: 217, 1975 3. BAGLEY CM JR, YOUNG RC, CANELLOS

GP, et al: Treatment of ovarian carcinoma: possibilities for progress. N Engi J Med 287: 856, 1972

4. WEBB MJ, DECKER DG, MUSSEY E, et al: Factors influencing survival in stage I ovarian cancer. Am J Obstet Gynecol 116: 222, 1973

20. DECKER DG, WEBB MJ, HOLBROOK MA: Radiogold treatment of epithelial cancer of the ovary: late results. Am J Obstet Gynecol 115: 751, 1973

5. PIVER MS, LELE 5, BARLOW JJ: Preoperative and intraoperative evaluation in ovarian malignancies. Obstet

21. BUSH RS, ALLT WEC, BEALE FA, et

Gynecol 48: 312, 1976 6. PLENTL A, FRIEDMAN EA: Lymphatic System of the Female Genitalia, Saunders, Philadelphia, 1971, pp 16896 7. ATHEY PA, WALLACE 5, JING BS, et

al: Lymphangiography in ovarian cancer. Am J Roentgenol Radium Ther Nucl Med 123: 106, 1975 8. MUSUMECI R, BANFI A, CANADIANI

GB, et al: Lymphographic evaluation in ovarian carcinoma of epithelial origin. Tumori 61: 151, 1975 9. PARKER BR, CASTELLINO RA, FUKS ZY, et al: The role of lymphography in patients with ovarian cancer. Cancer 34: 100, 1974 10. CASTELLINO RA, RAY G, BLANK N,

et al: Lymphangiography in prostatic carcinoma. Preliminary observations. JAMA 223: 877, 1973

11. DOLAN PA, HUGNES RR: Lymphography in genital cancer. Surg Gynecol Obstet 118: 1286, 1964 12. RAY B, HAJDU SI, WHITMORE WF

JR: Distribution of retroperitoneal lymph node metastases in testicular germinal tumors. Cancer 33: 340, 1974 13. FUKS Z: External radiotherapy of ovarian cancer: standard approaches and new frontiers. Semin Oncol 2: 253, 1975 14. ROSENOFF SH, DEVITA VT, HUBBARD 5, et al: Peritoneoscopy in the staging and follow-up of ovarian cancer. Ibid, p 223

al: Treatment of epithelial carcinoma of the ovary. Surgery, irradiation and chemotherapy. Am J Obstet Gynecol (in press) 22. JOHNSON

CE,

DECKER

DG,

VAN

HERICK M, et al: Advanced ovarian cancer: therapy with radiation and cyclophosphamide in a random series. Am J Roentgenol Radium Ther Nuci Med 114: 136, 1972 23. HINTZ BL, FUKS Z, KEMPSON RL, et

al: Results of postoperative megavoltage radiotherapy of malignant surface epithelial tumors of the ovary. Radiology 114: 695, 1975 24. FUKS Z, BAGSHAW MA: The rationale for curative radiotherapy for ovarian

carcinoma. mt i Radiat Oncol Bid Phys 1: 21, 1975 25. YOUNG RC, Hunn.uID SH, DEVITA VT: The chemotherapy of ovarian carcinoma. Cancer Treat Rev 1: 99, 1974 26. YOUNG RC: Chemotherapy of ovarian cancer: past and present. Se,nin Oncol 2: 267, 1975 27. WILTSHAW E, KRONER T: Phase II study of cis-dichlorodiammineplatinum (II) in advanced adenocarcinoma of the ovary. Cancer Treat Rep 60: 55, 1976 28. SULLIvAN RD, MILLER E, ZUREK WZ, et al: Re-evaluation of methotrexate as an anticancer drug. Surg Gynecol

Obstet 125: 819, 1967 29. ANSFIELD FJ, SHROEDER JM, CURRERI AR: Five years clinical experience with 5-fluorouracil. JAMA 181: 295, 1962

15. WALLACH RC, KARAKOW B, JEREZ E,

et al: The importance of second-look surgical procedures in the staging and treatment of ovarian cancer. Ibid, p 243 16. MALKASIAN GD, DECKER DG, WEBB MJ: Histology of epithelial tumors of the ovary: clinical usefulness and prognostic significance of the histologic classification and grading. Ibid, p 191

30. MALKASIAN GD JR, DECKER DG, MUSSEY E, et al: Observations on gynecologic malignancy treated with

17. BRoDu.s AC: Carcinoma: grading and practical application. Arch Pathol 2: 376, 1926

32. SMITH JP: Report of the Ovarian Cancer Contract, National Cancer In-

18. FAZEKAS JT, MAIER JG: Irradiation of ovarian carcinomas: a prospective comparison of the open-field and moving-strip techniques. Am J Roentgenol Radium Ther Nucl Med 120: 118, 1974 19. HRESHCHYSHYN MM: Results of the Gynecologic Oncology Group trials on ovarian cancer: preliminary reports. Natl Cancer Inst Monogr 42: 115, 1975

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5-fluorouracil. Am J Obstet Gynecol 100: 1012, 1968 31. DE PALO GM, DE LENA M, Di RE F, et al: Melphalan versus adriamycin

in the treatment of advanced carcinoma of the ovary. Surg Gynecol Obstet 141: 899, 1975

stitute, Jan 1, 1976 33. BRUCKMAN HW, COHEN CJ, GUSBERG SB, et al: Chemotherapy of ovarian cancer with adriamycin and cis-

platinum. Proc Am Soc Clin Oncol 17: 287, 1976 34. YOUNG RC, CHABNER BA, HUBBARD

SP, et al: Preliminary results of trials of chemotherapy in advanced ovarian carcinoma. Nati Cancer Inst Monogr 42: 145, 1975