Role of radiotherapy in the treatment of cancer of the ovary

Seminars in Surgical Oncology 10305-312 (1994)

Role of Radiotherapy in the Treatment of Cancer of the Ovary

GERARD MORTON, MD, AND GlLLlAN M. THOMAS, MD

From the Toronto-Bayview Regional Cancer Centre, Department of Radiation Oncology, University of Toronto, North York, Ontario, Canada

The initial management of carcinoma of the ovary is surgical. The need for further treatment is determined by a consideration of tumor stage, grade, and the presence of residual disease. Approximately one-third of patients are suitably managed by primary post-operative radiotherapy directed to the entire abdomen and pelvis with curative intent. Patients are mainly derived from stages I and 11. Stage I11 patients are also included if the tumor is of low grade and there is no pelvic residuum. The dose which can be safely delivered to the upper abdomen is limited by normal tissue tolerance. Curative radiation is inappropriate for patients with upper abdominal disease and/or more than small volume residuum in the pelvis. These patients are best managed with chemotherapy. Suitably selected patients have a ten-year relapse-free survival of 68Yo following radiotherapy. Acute gastrointestinal symptoms are common during the treatment, but are usually amenable to symptomatic management. Long term morbidity is infrequent, and with modern techniques the incidence of treatment-related small bowel obstruction is around 5%. Radiotherapy to the abdomen and pelvis has also a potential role as consolidative treatment in patients with advanced disease, following a favourable response to chemotherapy. 0 1994 WiIey-~iss, Inc.

KEY WORDS: abdominopelvic, open field, prognosis, adjuvant, consolidative

INTRODUCTION Carcinoma of the ovary is the fourth leading cause

of cancer death in North American women, after carcinoma of the lung, breast, and large bowel [l]. There has been a slight improvement in overall five-year survival from 32% in 1960 to the present 39%. It is usually metastatic at presentation, being confined to the ovar- ies in only 23% of cases.

Ovarian cancer has a unique pattern of dissemination compared with other solid tumors. Clinical experience in staging studies has shown that transperitoneal spread is the most common route of dissemination and that, at first relapse regardless of therapy, the tumor is confined to the abdominal cavity in approximately 85% of patients [2,3]. Meticulous systematic intra-abdominal exploration reveals previously unsuspected extra-pelvic metastases in up to 3 0 % ~ Twenty-one percent of patients referred to the

National Cancer Institute with stage I and 11 ovarian cancer were upstaged to stage I11 on the basis of dia- phragmatic metastases detected by laparoscopy [4]. Eleven percent of presumed stage I and 23%) of stage I1 patients referred to Roswell Park were also upstaged on the basis of previously unsuspected dia- phragmatic metastases [2]. Both gross and occult in- traperitoneal disease is common at presentation.

The standard initial management of ovarian carcinoma is surgical. As might be predicted from the transperitoneal relapse pattern and studies detecting occult upper abdominal disease in apparent stage I and I1 situations, the practice of pretreatment surgical staging is supported. The procedure requires partial omentectomy, visualization of the entire visceral and

Address reprint requests to Gillian M. Thomas, M.D., Toronto- Bayview Regional Cancer Centre, 2075 Bayview Avenue, North York, Ontario, Canada M4N 3M5.

0 1994 Wiley-Liss, Inc.

306 Morton and Thomas

parietal peritoneal surfaces (including diaphragm, dome of liver, the entire bowel surfaces, and paracolic gutters), biopsy of any palpable or suspicious lesions, and cytologic examination of ascites or peritoneal washings from the diaphragm, paracolic gutters, and pelvis. Para-aortic and pelvic lymph nodes should be sampled if they are palpable, if the lesion is grade 2 or 3, and possibly if no postoperative treatment is con- templated. Nodal spread occurs in less than 5% of well differentiated stage I and stage I1 tumors, in up to 1O0/u of poorly differentiated stage I and stage I1 tumors, and in about 20% to 50% of stage 111 and stage IV tumors. Many studies have recognized that median and long term survival rates worsen as a function of increasing residual tumor volume, both for radiotherapeutic and chemotherapeutic management [5- 1 11. Cytoreductive surgery with maximum tumor reduction is therefore recommended as a standard approach, since the viewpoint is held that maximum tumor reduction confers a beneficial effect on outcome. In a review article by Hoskins [12], optimal cytoreduction could only be achieved in about one- third of 177 patients in seven published articles. The better outcome of patients with optimum cytoreductive surgery has previously been attributed to the therapeutic effects of surgery, but it may also reflect that patients in whom optimal surgery is possible have biologically less aggressive or more responsive disease. Even in the situation of maximally debulked tumor, cure is generally unlikely because even reduction to an “optimal” minimal residuum of < 1 cm leaves approximately loy tumor cells. Currently the most effective chemotherapy available will effectively reduce the residual cells by only approximately three logs. How- ever, because cure is rarely achieved in patients with stage 111 disease who have residuum over 1 cm, it is usually worthwhile attempting to accomplish optimal cytoreduction before commencing treatment, in the hope that this will increase the chances of cure. The need for further adjuvant treatment is determined by a consideration of postoperative prognostic factors, including residuum, grade, stage, and pathological subtype, which will be discussed subsequently.

The use of radiation therapy in the management of ovarian cancer remains a controversial subject despite extensive data in support of its use. Controversy has resulted from a number of factors. including the early use of inappropriate techniques and doses of radiation, and the selection of inappropriate patients for such therapy. Cisplatin-containing chemotherapy gave initial promise for a curative benefit, fostered by high initial response rates. Unfortunately, cure rates in ovarian cancer have not changed appreciably with the use of cisplatin. Thus, it is important that the thera-

peutic benefits of radiation in ovarian cancer be recognized and integrated into management schemes for ovarian cancer that allow maximum exploitation of its benefits.

Radiation therapy has been used as postoperative management for patients with a wide variety of stages and extents of residual disease after initial surgery. Evidence that radiation therapy is curative in some stages and extents of ovarian cancer comes from multiple series in which long-term survival has been proven in patients with known residual disease. Five series in the literature document the use of abdominal pelvic irradiation for stage I1 and 111 disease, where the amount of residual disease has been described in detail, and the outcome for patients with residuum separated from those without apparent residuum [13- 171. The mature data on these studies provides 10-year relapse-free survival rates and clearly constitute a close estimate of cure rates, since the majority of relapses occur within five years of initial treatment (Table I ) . The results of these studies concur and show similar long term failure-free survival among patients with known macroscoic residual disease < 2 cm with long-term relapse-free rates between 30% and 62%. The proportion of disease-free survivors appears to be determined by the presenting stage and site and volume of residual disease, as documented by the largest diameter of the remaining lesions postoperatively. The curative benefit of radiation is dependent on the number of residual clonogenic cells and the radiation dose that can be safely delivered. Given the restriction of dose that must be applied to treat the upper abdomen safely, cure rates are low when there is macroscopic residual disease in the upper abdomen. The pelvis, however, may be boosted safely to higher doses, thus

TABLE 1. Ovarian Cancer: Evidence for Cure by Abdominopelvic Radiotherapy: Long-Term Outcome in Stages I1 and 111 With Macroscopic Residuum*

Size of residuum

< 2 c m > 2cni Centre and reference End-voint

Princess Margaret %J 10 yr RFR (n) 38 (91) 6 (91)

Stanford [ 141 %, 15 yr FFR (n) 50 (42) 14 (54) Salt Lake City [I51 ‘% 10 yr RFS (n) 62 (12) 0 (10) Walter Reid Hospital ‘%I 10 yr S (n) 42 (24) 10 (20)

Yale [ 171 = 6 yr surv fract .41 (27)

*RFR = relapse free rate; FFR = failure free rate; S = survival rate; RFS = relapse free survival rate; surv fract = surviving fraction; n = number of patients. (Reprinted from Int J Radiat Oncol Biol Phys 225335-845, Dembo AJ, Epithelial ovarian cancer, 1992, with permission from Elsevier Science. Ltd., Kidlington, U.K. )

Hospital [ 131

_ _ [I61

Radiotherapy in Ovarian Cancer 307

providing an increased probability of tumor control for larger residual masses in the pelvis (up to 2 cm) than in the upper abdomen.

Thus, approximately 40% to 50% of patients with small residual lesions are cured. Most of these have stage I1 lesions with tumor residuum confined to the pelvis. Patients with bulky residuum (BSOH incomplete or residual disease > 2 cm) or any macroscopic upper abdominal disease are not cured by radiotherapy and are best treated with chemotherapy [18]. Radiotherapy has a less established role as consolidative treatment in patients who obtain complete response to chemotherapy.

RATIONALE FOR WHOLE ABDOMINAL RADIOTHERAPY

Because of the transperitoneal pattern of spread, potentially curative radiotherapy for ovarian carcinoma must encompass the entire peritoneal cavity, including the whole abdomen and pelvis. Treatment of the entire peritoneal cavity results in a greater cure rate than treatment of the pelvis or lower abdomen alone. In a prospective three arm trial from the Prin- cess Margaret Hospital [ 19,201, 190 postoperative patients were randomized to receive either pelvic radiotherapy alone (then taken as standard), pelvic radiotherapy plus chlorambucil, or pelvic radiotherapy followed by irradiation of the upper abdomen. In patients with small or no residuum (132 cases), there was a significant survival advantage to pelvic plus upper abdominal irradiation over the other two arms. Patients with small or no residuum treated to the whole abdomen had five and ten-year survival rates of 78% and 64%, respectively, as compared to 50% and 40% in the pelvic radiotherapy plus chlorambucil group (P = 0.0007). Other non-randomized studies confirm the superiority of radiotherapy directed to the whole abdomen over pelvic radiotherapy alone. Reports from both the M.D. Anderson Hospital [21] and Salt Lake City [ 151 report improved five-year survival with whole abdominal treatment over pelvic only or subtotal abdominal irradiation, respectively. Pa- tients treated only to the pelvis or to the lower abdomen have an increased abdominal relapse rate. In the latter study, patients with no or small residuum had a ten-year relapse-free survival of 7 1% when the whole abdomen was irradiated as opposed to 48% with subtotal abdominal techniques. The positive survival advantage with whole abdominal radiotherapy, however, is only found in patients “optimally” debulked. In the Princess Margaret Hospital study, in patients with extensive residuum, there was no advantage to whole abdominal radiotherapy (WAR) over the other treatment arms (12% versus 10%).

Even in stage I epithelial ovarian cancer, pelvic radiation therapy alone is inadequate postoperative therapy because relapses occur throughout the abdomen. Two randomized studies have compared postoperative pelvic radiation therapy with observation in stage I disease, and both were null in outcome [22,23]. Where radiation therapy is to be used, abdominopelvic treatment is superior to pelvic or lower abdominal therapy alone.

RADIOTHERAPY TECHNIQUE AND TOXICITY

The aim of treatment is to administer a therapeutic dose of radiation to the entire peritoneal cavity with a boost dose to the pelvis, while limiting toxicity to normal structures (bowel, liver, kidneys, marrow). The radiation fields extend from above the domes of the diaphragm at their maximal excursion to below the obturator foramina. Laterally, the fields extend beyond the skin of the flanks to cover the peritoneal reflection. The dose to the kidneys is limited to between 1,800 and 2,000 cGy. This may be accomplished by inserting a renal shield to attenuate the dose. The dose to the liver should generally be kept below 2,500 to 2,750 cGy. To avoid exceeding liver tolerance, the dose to the upper abdomen is usually limited to 2,250 to 2,500 cGy, given over 22 to 25 fractions. The pelvis, where residuum may be up to 2 cm in diameter, may be treated to a higher dose, usually to a total dose of 4,500 to 5,100 cGy. Some investigators have also given a boost dose to the para-aortic nodes and medial diaphragm, although the benefit of this is uncertain and complications may be increased [24].

The simplest technique to deliver WAR is the open fieZd technique, which treats the entire target volume each day with large opposed anterior and posterior fields to minimize the late complications of radiation therapy. The dose per fraction is kept low, usually within 100 cGy to 150 cGy. An alternative technique is the moving strip, in which the abdomen is treated by an anterior and posterior 10 cm long field which sequentially moves down the abdomen in 2.5 cm steps. The prescribed dose (typically 2,500 cGy to 2,800 cGy in 10 to 12 fractions) is completely delivered to each point within the abdomen, as the area being treated gradually descends from the diaphragm to the pelvic floor. This technique is associated with a longer overall treatment time and has the potential disadvantage of allowing reimplantation of tumor cells as the treatment field sequentially moves down the abdomen. The dose per fraction is relatively high and theoretically may be biologically more effective, although a randomized comparison [25] of the two techniques has shown them to be of equal efficacy. The moving strip.


however, was found to have a higher incidence of late side effects than the open field technique.

Whole abdominal radiotherapy is generally well tolerated with a low incidence of long term sequelae. Of 598 patients treated at the Princess Margaret Hospital [26] between 1971 and 1985, nausea and vomiting occurred in 61% and was severe in 6%. Diarrhea occurred in 62%, severe in 6%. Myelosuppression was infrequent, with leukocyte count falling below 2.0 X

109/litre in only 11%. Treatment interruptions occurred in 23%. most commonly due to low blood counts. The most frequently reported late sequela of treatment was chronic diarrhea requiring intermittent medica- tion in 14%. Small bowel obstruction occurred in 25 patients (4%). Symptomatic basal pneumonitis occurred in 4%, almost exclusively in patients treated with a moving strip technique. Using similar doses, only one case of small bowel obstruction occurred in 84 patients treated at Ingolstadt, Germany [27]. The Yale experience [17] is comparable with 7% of 74 patients experiencing late small bowel obstruction, although acute nausea and vomiting occurred in 95%. In Am- sterdam [28], the risk of bowel obstruction was signifi- cantly related to the extent of surgery. Small bowel obstruction occurred in 13% (6/45) of patients with prior retroperitoneal lymph node dissection, whereas no serious toxicity occurred in 39 patients without. At Stanford [24], a higher abdominal and pelvic dose was administered and a para-aortic boost employed. Of 77 patients treated to the whole abdomen, 79% suffered acute gastrointestinal toxicity, but 90% had reason- able symptomatic control. Treatment was interrupted in 27‘Yo due to hematological toxicity. The three-year actuarial risk of developing a treatment related bowel obstruction was calculated at 9%. Using a similar technique and dose, 7% of patients (3/42) treated at Salt Lake City [15] developed bowel obstruction.

Therefore, although acute gastrointestinal symptoms are common during therapy, they are generally tolerable and amenable to symptomatic management. Symptoms generally settle on completion of radiotherapy, but mild chronic or recurrent diarrhea is not uncommon. The most serious potential side effect is small bowel obstruction, the risk of which is related to radiotherapy technique, dose, and fractionation in addition to prior abdominal surgery, particularly retroperitoneal lymph node dissection. With modern radiation technique and appropriate patient selection, the incidence is < 5%.

PATIENT SELECTION FOR RADIOTHERAPY Whole abdominal radiotherapy is generally em-

ployed only with curative intent. While it has been used over the past 15 years in all states and extents of

ovarian cancer, analysis of both randomized trials and non-randomized data have yielded considerable infor- mation on the patient and tumor factors that will predict for cure after the use of adjuvant abdominopelvic radiation therapy. These factors are discussed below. It may also have a potential role as a consolidative treatment in patients who initially had advanced or inoperable disease following a favourable response to chemotherapy. Patients who relapse following chemotherapy or who are unresponsive to chemotherapy have a very poor prognosis with any treatment and have been treated with radiotherapy in the past. The results are disappointing and novel combination treat- ments or techniques need to be explored. Finally, limited field radiotherapy may play a palliative role in the management of symptomatic metastatic disease or for pelvic sidewall recurrences in which chemotherapy is no longer a useful option.

RADIOTHERAPY AS AN ADJUVANT TREATMENT

Optimally debulked [I 31 postoperative patients are selected for whole abdominal radiotherapy by relapse risk, based on consideration of prognostic factors.

The first detailed multivariate analysis of prognostic factors in ovarian cancer was performed on a series of 430 postoperative patients [18], with all stages of disease studied on prospective treatment protocols at the Princess Margaret Hospital. Univariate analysis revealed that five variables-stage, residuum, grade, age (above or below 50), and pathology subtype-were predictive for survival. Log-rank test revealed residual disease and tumor grade to be the two most important independent variables ( P < 0.001), followed by stage ( P = 0.002), age ( P = 0.004), and pathology subtype ( P = 0.058). It was possible to crudely divide the patients into a poor and good prognosis group. The former comprised patients with stage IV disease or stages I1 and I11 with large residual disease. The five- year relapse-free survival was under 5%. The good prognosis group consisted of patients with stage I, 11, and 111 with no or small residuum, having had com- pleted BSO. Approximately one-half of patients treated at the Princess Margaret Hospital between 1971 and 1985 fell into this category [29]. The overall five-year survival for this group was 61%. It was possible to further subdivide the “good prognosis” group on the basis of stage, grade, the presence of residual disease, and pathology subtype into a low, intermediate, and high risk category, with six-year actuarial survivals of 1 1%, 67%, and 27%, respectively, when treated with postoperative radiotherapy (Fig. 1). The prognostic classification has been validated on patients treated in the last seven years and the complexity

Radiotherapy in Ovarian Cancer 309

Fig. 1. Prognostic subgroupings according to stage, residuum, and grade in patients with stages 1 through 111, small, or no tumor residuum. Abdominopelvic radiation therapy is recommended as the sole post-operative treatment in the intermediate-risk group. (Reprinted from Int J Radiat Oncol Bjol Phys 22:835-845, Dembo AJ, Epithelial ovarian cancer, 1992, with permission from Elsevier Science, Ltd., Kidlington, U.K.)

of the system, which previously categorized patients by combinations of grade and cell type, has been sim- plified, since grade emerged as a significant prognostic factor in all pathology subtypes [29]. The validity of the prognostic groups was confirmed (Fig. l), and currently forms the basis on which we select patients for postoperative radiation therapy and on which we base treatment recommendations. These data and identification of groups likely to have a curative benefit from radiation therapy have been confirmed in series from other centres. At Stanford [14], grade, stage, residuum, histology, and age, similarly emerged as independent prognostic factors for survival among patients treated with irradiation as the sole postoperative therapy. By combining prognostic factors, it was possible to divide the population into a favourable group with a 15-year failure free rate (FFR) of 62% and an unfavourable group with a rate of 14%. The former comprised patients with stages I through 111 with no residuum or residuum < 2 cm. The unfavourable group are patients with stages I1 and I11 with large residuum. These are very similar to the Princess Mar- garet Hospital good and poor prognosis groups, respectively. Similar groups were identified at Salt Lake City [15].

From the Princess Margaret Hospital data, a low risk group consisting of 103 patients with stage I, grade 1 tumors of all histological types was identified with a five-year relapse-free rate of 96%. The favourable prognosis of this group was confirmed in a sepa- rate analysis of patients treated at the Norwegian Ra- dium Hospital [30], where an identical five-year relapse-free survival of 96% was reported in a further 103 patients with stage I, grade 1 ovarian carcinoma.

Apart from tumor grade, dense adherence and large volume ascites emerged as the only other prognostic variables within stage I. Patients with dense adherence are more correctly classified as stage I1 and should be treated accordingly. In the absence of these other risk factors, patients with grade 1 carcinoma had a five- year relapse-free survival of 980/. With such an excel- lent prognosis, no benefit was found from any postoperative therapy, and adjuvant radiotherapy may safely be withheld. In contrast, the high risk group within the good prognosis category have a 23% to 35% relapse- free rate at five years and 18% at ten years when treated with WAR (Fig. 1). Patients in this group have stage 111, grade 2 or 3 disease, or high grade stage I1 with postoperative residuum. Similar findings were reported from Ingolstadt [27] and Yale [17] with a five- year survival of 20% and ten-year survival of 7%, respectively, in high risk patients treated with post-operative radiotherapy. Adjuvant radiotherapy alone is not curative for the majority of these patients and is therefore not indicated as the sole primary postoperative treatment. The addition of chemotherapy should be considered and in a further study at the Princess Margaret Hospital [3 1],44 patients with high risk postoperative features received six cycles of cisplatin-based chemotherapy prior to whole abdominal radiotherapy. Compared with a historical matched control treated with radiotherapy alone, median survival was extended from 2.4 to 5.7 years and 5-year relapse-free survival increased from 21.6% to 42.6% in the combined treatment modality group. Although i t is possible that the improvement in survival was due to the chemotherapy alone, there is evidence that the radiotherapy may have been additive.


Approximately one-third of the entire population belongs to an intermediate risk group [29], for whom abdominopelvic radiotherapy is indicated as the sole postoperative treatment modality. With radiotherapy, patients have an overall survival of 75% at five years and 68% at ten years [13,29]. Patients within this group are mainly derived from stages I and 11. Stage 111 patients are included if there is no or minimal ( < 2 cm) residual disease, which is confined to the pelvis and the tumor is grade 1. Primary postoperative abdominopelvic radiotherapy is therefore only indicated [32] in patients with stages I to 111 with no residual disease or small volume pelvic disease, who belong to this intermediate risk group. Over two-thirds of patients so treated will be alive and disease-free, with minimal late morbidity.

A difficult and unresolved question is the relative benefit of abdominopelvic radiotherapy over chemotherapy as the primary adjuvant treatment in the intermediate risk group. Cisplatin-based combination therapy is mainly reported in patients with stage 111 or IV disease, with emphasis on response rates and negative second-look rates. There is as yet very little informa- tion on long-term survival. The radiotherapy series are generally older with survival data at five, ten, and even fifteen years [13-17, 27-29]. Most patients were treated without rigorous modern staging which, if anything, would tend to underestimate the benefits from radiotherapy. It is therefore very difficult to com- pare the results of radiotherapy with that of modern chemotherapy within the intermediate risk group. Piver et al. [33] reported disappointing results in stage I1 carcinoma treated with cisplatin, Adriamycin, and cyclophosphamide, with a five-year estimated progression-free survival of only 45’/0. This is inferior to the results expected with abdominopelvic radiotherapy .

Two large cooperative groups have been unable to complete randomized clinical trials comparing optimally administered whole abdominal radiotherapy with cisplatin-based chemotherapy. Early study clo- sure due to lack of patient accrual may be a result of strong investigator biases against one or the other therapies, or the widely divergent treatment methods. The results in the literature support the use of radiotherapy as postoperative treatment in patients from the “intermediate risk” group.

RADIOTHERAPY AS CONSOLIDATIVE TREATMENT

Patients with advanced ovarian carcinoma are managed with primary chemotherapy. Second-look laparotomy following cisplatin-based chemotherapy will reveal 33% to 48% of patients with macroscopic disease. 13% to 24% with microscopic disease, and

25% to 48% with no evidence of disease [34]. The risk of subsequent recurrence may be as high as 50% in patients rendered disease-free, and whole abdominal radiotherapy has been used in an attempt at “con- solidating” the response to chemotherapy.

Several European centres have investigated this sequential multimodality approach to advanced ovarian cancer. A Swiss study [35] performed second-look pro- cedures on 158 patients with advanced disease following cisplatin-based chemotherapy. Forty-five patients (28%) had obtained a complete response, 24 of whom subsequently received abdominopelvic radiotherapy and 21 no further treatment. Although not a randomized comparison, fewer relapses occurred in the radiotherapy arm (5 / 24 versus 9 / 2 l), with a progression- free rate at three years of 83% versus 49%. At Institut Gustave-Roussy [36], 65 patients had residual disease < 2 cm at second-look laparotomy following chemotherapy for advanced disease. Patients then received consolidative whole abdominal radiotherapy with three- and six-year disease-free survival rates of 60% and 33%, respectively. The only significant prognostic factor was the presence of any residual disease, either microscopic or macroscopic at second-look, with a relative risk for survival and disease-free survival of 4.2. Patients who had been rendered disease-free by the primary chemotherapy had a six-year relapse-free survival of 63% versus 18% if any residual disease was present. There is evidence that site, as well as presence or absence of residual disease, is also prognostic. Reddy [37] reported a four-year disease-free survival of 56% when the residual disease was confined to the pelvis versus OYO when the upper abdomen was involved.

Fuks [38] reports on 25 patients with no residual disease following CHAD chemotherapy, who received consolidative abdominopelvic radiotherapy. Fourteen of the patients had been rendered disease-free by the chemotherapy. A further 11 were debulked to no residuum at second-look prior to the administration of the radiotherapy. Nineteen of the 25 failed within the abdomen. A further difficulty is that radiotherapy is often poorly tolerated following prior chemotherapy with many patients failing to complete the planned treatment due to myelosuppression. While consolidative radiotherapy may have a role in patients who obtain a pathological complete response to chemotherapy, it appears to have no role if the response is incomplete.

A number of studies have compared abdominopelvic radiotherapy with further consolidative chemotherapy in patients who have obtained a favourable response to initial chemotherapy. One randomized trial from Genoa [39] demonstrated a progression-free

Radiotherapy in Ovarian Cancer 31 1

survival advantage in favour of continued platinum- based chemotherapy over consolidative radiotherapy. The two treatment arms, however, were not well bal- anced for prognostic factors, with fewer patients in the radiotherapy arm having had a complete response to primary chemotherapy. A larger study was recently reported from the North Thames Ovary Group [40] which compared carboplatin with WAR as consolidation. All patients underwent second-look surgery after five cycles of carboplatin, and 117 patients with no or residual disease < 2cm throughout the abdomen were then randomized to receive either consolidative abdominopelvic radiotherapy or a further five courses of carboplatin. The study revealed no difference in survival or disease-free survival between the two arms. No difference in outcome was noted when the analysis was restricted to the smaller subset of patients without disease at second look. The study, although indicating therapeutic equivalence between the two arms, does not demonstrate an advantage to either treatment over observation alone.

Several possible explanations may be given for the identified apparent lack of efficacy for sequential chemotherapy and radiation [41]. Methodological prob- lems exist in the interpretation of the multiple phase I1 trials. No randomized trials have compared “consolidative” radiotherapy to no further therapy and the numbers of patients on these trials who are likely to benefit from the sequential strategy are small. Several studies document the poor results with radiotherapy following anything other than a complete response to chemotherapy [42-451. It is also likely that the biology of cancers rendered disease-free by chemotherapy is very different from that of tumors rendered disease- free only by secondary debulking. Cross resistance between cisplatin and radiotherapy may occur. With advancing tumor age, spontaneous mutation to resistance to therapy may develop.

Available data suggest that long-term survivals may occur where consolidative WAR is used for patients with microscopic residuum or no residual disease who are at high risk for relapse after negative second-look laparotomy [41]. It may be valid to explore the use of WAR in these settings.

CONCLUSIONS AND FUTURE DIRECTIONS Postoperative radiotherapy to the abdomen and

pelvis is a curative treatment modality in selected patients with epithelial ovarian cancer. By a consideration of prognostic factors in optimally debulked patients (residuum, grade, stage, pathology) it is possible to identify a group with a 68% ten-year survival following abdominopelvic radiotherapy. The treatment is well tolerated and associated with very little long-

term toxicity. Abdominopelvic radiotherapy may also have a role as consolidative treatment in patients with advanced disease who obtain a complete response to primary chemotherapy .

Patients with residual or recurrent intra-abdominal disease following chemotherapy pose a therapeutic challenge. It is possible that altered fractionation may improve control [46] by allowing the delivery of a more effective dose. This, in itself, is unlikely to have a major impact on cure, and combined modality therapy needs further study. The combination of radiotherapy with sensitizing drugs, such as 5-fluorouracil [47] or cisplatin [48], should be explored, in addition to methods of overcoming possible platinum-induced radiation resistance. Taxol has shown in vitro ability to sensitize ovarian cancer cells to the effects of radiotherapy [49,50] and, if this also happens in the clinic, offers exciting therapeutic possibilities for the future.

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Role of radiotherapy in the treatment of cancer of the ovary