Preoperative radiation therapy in advanced carcinoma of the

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1 Radiotherapy and Oncology, 4 (1985) Elsevier 329 RTO Preoperative radiation therapy in advanced carcinoma of the ovary Kerstin Sj6vall 1 and Nina Einhorn 2 Departments of 1Obstetrics and Gynaecology, Karolinska Hospital and ZGynaecological Ontology, Radiumhemmet, Karolinska Hospital, S-104 Ol Stockholm, Sweden (Received 31 January 1985, revision received 14 April 1985, accepted 16 July 1985) Key words: Preoperative radiation; Advanced ovarian cancer Summary Preoperative radiotherapy in advanced ovarian carcinoma was evaluated. The overall 5-year survival rate in the irradiated group was 27%. When tumour mass remaining after operation was less than 2 cm in diameter, this figure rose to 52%. Comparison was made between those in whom operation became feasible only after preoperative irradiation and patients in advanced stages who were primarily successfully operated to less than 2 cm and with a 5-year survival rate of 44%. Selection of the cases for preoperative radiotherapy is obviously necessary. Fixed, bulky turnouts in the pelvis, with or without metastases, may be suitable for preoperative radiotherapy. Introduction The role of radiation therapy in ovarian carcinoma has been controversial since the introduction of cytotoxic drugs for treatment of this disease. Reports for and against radiotherapy in ovarian cancer have been published [1,10,12,13]. Radiotherapy can be used preoperatively, postoperatively and in the management of local recurrence or distant metastases. As radical surgery and effective debulking of tumour seem to be an important prognostic factor for survival in ovarian cancer [4,8], preoperative radiotherapy should invite interest for attemtps to heighten surgical success rates. This concept relatively seldom receives support in the literature. As early as 1961, Kottmeier [5] emphasized the usefulness of preoperative irradiation, which led to successful surgery in about 20% of advanced cases of ovarian carcinoma. Consequently, this method is used at Radiumhemmet. The aim of the present study is to evaluate preoperative irradiation for advanced ovarian carcinoma in cases of large inoperable tumour volume fixed to the surrounding tissues and pelvic walls planned according to a protocol. Patients and methods In the period , 770 women were treated at Radiumhemmet for ovarian carcinoma. This /85/$ Elsevier Science Publishers B.V. (Biomedical Division)

2 330 TABLE I Carcinoma of the ovary, distribution by stage of disease. Stage No. of cases % of series IA IB IC I0 1.3 IIA IIB IIC III IV Total 770 material represents a total coverage of the disease in a region of 1.6 million inhabitants. The tumour was classified as stage IIB-IV in 584 patients. Borderline cases were excluded. The stage distribution of the 770 turnouts is shown in Table I and the distribution by histology of the advanced cases in Table II. Of the 584 patients with advanced cancer, 1 I0 underwent successful primary operation. In the remaining 474 cases, large tumour masses remained after primary surgery or after diagnosis by fineneedle biopsy only. In 59 patients the inoperable largest tumour volume was localized to the pelvis and was judged to be suitable for preoperative irradiation. The decision of preoperative radiotherapy was based either on laparotomy finding or TABLE II Carcinoma of the ovary, distribution by histologic class in advanced cases and number of patients treated with preoperative irradiation. Class Stages IIB-IV No. of patients treated no. % Serous Mucinous Endometrioid Mesonephroid Undifferentiated Mixed epithelial tumours Tot~ examination in anaesthesia. The criteria for patient selection was large tumour volume fixed to the surrounding tissue and pelvic walls localized below lumbar 3 and with none or small tumour volumes above this point. According to the primary planning, the surgery was supposed to be performed days after fulfilment of preoperatively given 30 Gy. Three among the 59 patients were found after irradiation and clinical examination not to be operable. Fifty-six patients could, according to the protocol, be operated after 30 Gy. When decision of preoperative radiotherapy was made in 29 patients chemotherapy had already been given, and in 12 of them more than one course. Thirty patients had preoperative radiotherapy alone. Radiotherapy Preoperative radiotherapy was given in two different situations. One was without laparatomy, diagnosed from fine-needle biopsy (28 cases) and clinical examination. The other group (31 cases) had undergone primary laparotomy, at which the turnour was found to be inoperable and only biopsy was performed. A low abdominal field was used for the irradiation and a dose of 30 Gy. Megavoltage therapy was given, using 6~ or accelerators with 4-6 MVe. The upper margin of the radiation field was located between the third and fourth lumbar vertebrae and the lower border was below the obturator foramina. The field covered the entire lower peritoneal cavity. The aims of this treatment were to decrease the tumour volume and to produce oedema round the turnout. In 12 patients with metastases to the endometrial mucosa, pouch of Douglas or the serosa of uterus or bladder, intracavitary irradiation was added, with the aim of increasing the intrapelvic dose. Radium sources were used, with a treatment dose of ~2.200 mg/h. Surgery In ovarian carcinoma there is a tendency to for-

3 331 mation of adhesions between the tumour and pelvic structures, and in many cases the tumour is fixed to adjacent tissues. The oedema that forms in response to preoperative irradiation helps to separate the neoplastic tissue from healthy organs. This effect can be achieved days after preoperative irradiation is terminated [5]. Routine surgery was in cases of ovarian carcinoma bilateral salpingo-oophorectomy, total hysterectomy and during part of the period infracolic omentectomy. For assessment of the outcome of surgery, patients with less than 2 cm in diameter tumour mass left in the abdomen were defined as successfully operated. Chemotherapy Melphalan was used in a dose of 1 mg/kg body weight intravenously, to a maximum dose of 60 mg. Postoperative chemotherapy was given usually for a year, with a minimum interval of 4 weeks. Results As mentioned, 110 of the 584 patients with advanced ovarian cancer (stages IIB-IV) underwent surgery without preceding radiotherapy and has residual tumour mass not exceeding 2 cm in diameter. Among them were 65 in stage IIB, 8 in stage IIC, 29 in stage III and 8 in stage IV. The 5-year survival rate among these 110 patients was 52% in stage IIB and IIC and 31% for stage III with a total survival of 44% [2,3]. Of the 59 cases planned for preoperative irradiation surgery could be performed according to protocol in 56 cases. In spite of the preoperative irradiation three patients were considered still not to be operable and no surgery was performed at this point. The 5-year survival rate among the total group of 59 patients with preoperative irradiation was 27%, with 46 and 50% survival rate in stage lib and IIC, respectively, 22 in stage III and 0 in stage IV (Table III). In 29 of 59 patients successful debulking could be achieved, in 18 of them after radiotherapy alone. Of the 29 suc- TABLE III Five-year survival rate after surgery preceded by irradiation. Stage Survivors/total Rate (%) IIB 6/13 46 IIC 2/4 50 III 8/37 22 IV 0/5 0 Total 16a/59 27 a One patient not successfully debulked. cessfully operated patients, 9 were in stage lib, 4 in stage IIC, 14 in stage III and 2 in stage IV. Among them 15 are still alive 5 years postoperatively, all disease-free. The differentiation grade for the 15 survivors was equally distributed; 5 had well, 5 moderate and 5 poor differentiated turnouts. The overall survival rate in this group thus was 52%, with 67 and 50% survival rate for stage lib and IIC, respectively, 50% for stage III and 0 for stage IV (Table IV). Table II demonstrates the distribution according to histology, and showing that preoperative irradiation was not selected for any specific histological group. In the 29 cases where preoperative radiotherapy was preceded by chemotherapy the 5-year survival rate was 29%, which can be compared with a survival rate of 33% in the group of 30 patients with preoperative irradiation alone. In the 12 patients who received more than one course of chemotherapy before radiotherapy, only TABLE IV Five-year survival rate after successful debulking (2 cm residual tumour) preceded by irradiation. Stage Survivors/operations Rate (%) IIB 6/9 67 IIC 2/4 50 III 7/14 50 IV O/2 0 Total 15/29 52

4 332 in two the haematological toxicity with a low white cell count interfered with the treatment; in one patient the radiotherapy was postponed 2 weeks and in another the treatment was interrupted after 16 Gy. In all the 10 remaining patients the haematological status caused no difficulties during the irradiation period or at surgery. Of the 14 patients successfully operated, but later dead in the disease, 6 developed recurrence even in the irradiated area and 8 patients outside the treated area. Discussion In analysing the literature concerning radiotherapy in ovarian carcinoma, most authors have dealt with the method as adjuvant in resectable tumour cases or postoperatively for incompletely resectable tumours. Only a few authors have been concerned with the usefulness of radiotherapy as a preoperative measure. Kottmeier [5,6] was the first to advocate preoperative radiotherapy for cases in which radical surgical removal of a bulky tumour is not feasible. In one review of the literature [9] the point was made that only 8% of the authors used irradiation before radical surgery, and some found this treatment to be valuable. Similar findings were reported from other studies [6,7,11]. The philosophy underlying this therapeutic approach nowadays, when chemotherapy is extensively used in ovarian carcinoma, may be open to question. Despite the proven usefulness of chemotherapy, however, preoperative irradiation should not be completely disregarded for advanced cases. Such treatment may help to make the surgical procedure more radical. One may discuss the fact that only 110 of 584 patients were primarily successfully debulked. It has, however, to be stressed that the material presented represents a total coverage of all ovarian carcinoma of all ages in a total region. When the survival rates in the presented material were compared with cases primarily successfully operated, the 5-year survival rate was rather in fa- vour of the preoperatively treated group. It has to be kept in mind that the group selected for preoperative irradiation belonged from the beginning to an unfavourable surgical material. Even with a primarily more aggressive surgery it is not likely that the result could be better than in the primarily more favourable group, comprising about twice as many patients in less advanced stages (stage [IB and IIC), than in the preoperatively irradiated patient group. Of our total 59 patients with inoperable bulky tumours planned for preoperative irradiation and surgery after 2 weeks, in half of these cases the operation was successful, considerable raising the 5-year survival rate for each stage of malignancy. Selection of the cases for preoperative radiotherapy is obviously necessary. Advanced ovarian cancer is not an entity, and individualized programmes probably are a prerequisite for optimum results. The wide variety within the same stage of ovarian carcinoma makes strictly randomized treatment protocols of doubtful usefulness. A step-bystep philosophy would seem to have greater validity. It is then important to keep in mind that patients with fixed, bulky tumours in the pelvis, with or without metastases, may be suitable for preoperative radiotherapy. References 1 Dembo, A. J., Van Dyk, J., Japp, B., Bean, H. A., Beale, F. A., Pringle, J. F. and Bush, R. S. Whole abdominal irradiation by a moving-strip technique for patients with ovarian cancer. Int. J. Radiat. Oncol. Biol. Phys. 5: , Einhorn, N. and Sjrvall, K. Radiotherapy and chemotherapy as combined treatment in carcinoma of the ovary. 13th International Congress of Chemotherapy, Vienna, Einhorn, N., Nilsson, B. and Sjrvall, K. Prognostic factors in cancer of the ovary. Cancer, 55: , Griffiths, C. T., Parker, L. M. and Fuller, A. F. Role of cytoreductive surgical treatment in the management of advanced ovarian cancer. Cancer Tret. Res. 63: , Kottmeier, H. L. Radiotherapy in the treatment of ovarian carcinoma. Clin. Obstet. Gynecol. 4: , Kottmeier, H. L. Ovarian cancer. Diagnosis and treatment. Medical College of Virginia Q. 3" 47-53, Long, R. T. J. and Sala, J. M. Radical surgery combined with radiotherapy in the treatment of advanced ovarian carcinoma. Surg. Gynecol. Obstet. 117: , 1963.

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