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GYNECOLOGIC ONCOLOGY 39, 47-55 (1990)

Radiation Therapy in Stage III Ovarian Cancer following Surgery and Chemotherapy: Prognostic Factors, Patterns of Relapse, and Toxicity:

A Preliminary Report

KARIN S. ARIAN-SCHAD, M.D.,“,’ DANIEL S. KAPP, PH.D., M.D.,t ARNULF HACKL, M.D. ,* FREYJA M. JUETTNER, M.D. .* HUBERT LEITNER, PH.D. ,* G~NTER PORSCH, M.D. ,* MANFRED LAHOUSEN, M.D. ,$

AND HELLMUTH PICKEL, M.D.+

*University Clinic of Radiology/Department of Radiotherapy; #University Clinic of Gynecology and Obstetrics, Graz, Austria; and TStanford University, Department of Radiation Oncology, Stanford, California

Received January 3 1, 1990

Twenty patients with FIG0 stage III epithelial ovarian cancer who had undergone maximum cytoreductive surgery (including pelvic and paraaortic lymph node dissection) and combination chemotherapy (4-10 cycles, median 6) were treated with irradiation to the abdomen and pelvis with 30 Gy followed by diaphragmatic/paraaortic and pelvis boost fields to 42 and 51.6 Gy, respectively. Second-look laparotomy was not performed. Sev- enteen of 20 patients completed the planned course of radiation. In 2 cases, failure to complete treatment was related to acute hematologic toxity, and 1 patient refused further treatment. Five patients (29%) required treatment breaks ranging from 8 to 16 days (median, 12 days) due to pancytopenia. Actuarial overall survival and relapse-free survival at 3 years for the 17 patients who completed radiation was 69 and 47%, respectively, with follow-up ranging from 19 to 53 months (median: 24, mean: 27.6 months). Seven patients (41%) relapsed within the abdomen alone and 2 patients developed extraabdominal lymph node metastasis as their sole site of failure. The prognostic factors evaluated for correlation with relapse-free survival included histologic subtype, grade, amount of residual disease at the time of surgery, and nodal involvement; only residual tumor at surgery (none vs ~2 cm or >2 cm) was found to be statistically significant (P < 0.01). Three-year overall survival correlated with amount of residual disease following the initial cytoreductive surgery. It was 100% for patients with no residual disease, 66.7% for s2 cm, and 26.7% for those with >2 cm residual disease, respectively. Radiation treatment was well tolerated, with only one patient developing treatment-related bowel obstruction 7 months after radiation therapy. The results of this planned trimodality treatment approach compare favorably with those reported following surgery and

’ To whom reprint requests should be addressed at University Clinic of Radiology, Department of Radiotherapy, Auenbruggerplatz, A-8036 Graz, Austria.

chemotherapy, particularly in patients who have been maximally cytoreduced. 0 1990 Academic Press, Inc.

INTRODUCTION

Despite combined treatment approaches, the survival rates in advanced stage ovarian cancer have shown little improvement in the last decade. Management with more radical surgery [l-3], new chemotherapy combinations utilizing cis-platinum [4,5], second-look operations, and varying radiation treatment techniques have been evaluated [6-101. Several prognostic factors including stage, histological subtype, grade, and extent of residual tumor after debulking surgery have been shown to be predictive for recurrence of disease and survival [8,10-221.

The benefit of radiation therapy as an adjuvant to chemotherapy in advanced stage ovarian cancer has not yet been clearly defined but its curative potential as postoperative first-line therapy has been demonstrated in a selected subgroup of patients [23,24]. Poor tolerance to large-field radiation in patients previously treated with combined chemotherapy regimens including c&platinum has been documented in literature [8,18,20,25-281. We retrospectively reviewed 20 patients with FIG0 stage III epithelial ovarian cancer, who had been treated in a uni- form manner with radical surgery, multidrug chemotherapy, and whole abdominal pelvic radiation (WAP) with additional boost to the subdiaphragmatic area, the paraaortic lymph nodes, and the true pelvis. The aims of this study were to evaluate pretreatment and treatment factors predictive of recurrence-free survival; sites of recurrent disease; treatment-related toxicities; and complications due to the addition of radiotherapy.

47

0090-8258/90 $1.50 Copyright 0 1990 by Academic Press, Inc.

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MATERIAL AND METHODS was initiated. The radiation therapy fields employed were similar to those described previously by Schray et al.

Between May 1985 and December 1987, 20 patients [81, but the sequence of treatment of the various fields ages 43-68 years (median, 59 years), with FIG0 stage differed. WAP radiation was delivered with an 8-MeV III epithelial ovarian cancers, were treated with maxi- photon beam through open AP/PA fields. The daily frac- mum cytoreductive surgery followed by chemotherapy tion was 1.5 Gy, five times a week, both fields treated and, if no measurable disease progression was docu- daily to a total dose of 30 Gy. After a scheduled 2-week mented, with external beam radiation therapy. Patient break, a diaphragmatic boost field at a daily dose of 1.5 selection criteria for surgery and chemotherapy included Gy at the midplane was employed up to a total of 42 Gy age ~70 years; Karnofsky performance status ~80%; no through individually shaped fields with the patient treated radiologic evidence of extraperitoneal metastases; nor- in the prone position. If either positive pelvic or para- mal renal and hepatic functions (serum creatinine co.15 aortic lymph nodes were found at surgery, the diaphrag- nmole liter or 1.5 mg/lOO ml, serum bilirubin ~20 mi- matic field was extended to include the paraaortic lymph cromole/liter or 1.5 mg/lOO ml); normal blood counts (WBC *4000/mm3, platelets 2 100,000/mm3); no history

nodes. An AP/PA shaped true pelvic field was added to the diaphragmatic or diaphragmatic/paraaortic field and

of previous malignant disease, aside from basal or squa- simultaneously treated with 23-MeV photons with a daily mous cell carcinoma of the skin; and no serious con- fraction of 1.8 Gy to a total of 5 1.6 Gy. current medical illness. Pretreatment evaluation included Other modifications to the method described by Schray full history and physical examination. Radiological et al. [8] included enlargement of the width of the upper workup consisted of chest X-ray, CT scan of the ab- portion of the diaphragmatic boost fields to 18 to 20 cm domen and pelvis, and intravenous pyelogram (IVP). In and shielding of both kidneys and liver from both the selected cases, ultrasound of the liver was performed to AP and the PA fields with 3% cerrobend transmission help rule out hepatic metastases. blocks placed at 15 and 19.5 Gy, respectively. Using a

Surgery included hysterectomy, bilateral salpingo- CT-aided treatment planning system, calculations in oophorectomy, omentectomy, exploration of the dia- three defined planes were obtained for every treatment phragmatic surfaces, pelvic and abdominal washings, and field. Special care was taken to cover the entire peri- attempted radical pelvic and paraaortic lymph node dis- toneal surface. Blood counts were obtained once a week, section with maximum tumor debulking. If infiltration or more frequently if indicated. If WBC fell to into adjacent organs was confirmed intraoperatively, low <2000/mm3, or platelets were <80,000/mm3, radiation anterior bowel resection (LAR), abdomino-perineal re- was interrupted for at least 1 week and treatment was section (APR), or partial bladder resection was per- resumed when repeat counts indicated bone marrow re- formed. Frozen sections for histopathological confir- covery. Total dose of radiation was then increased to mation were taken from the tumor, the enlarged nodes, compensate for the prolongation of the treatment course and any adjacent organs that appeared to be macroscopi- [29,30]. tally involved. Surgical specimens were histopatholog- Follow-up examinations were scheduled on a 3-month ically evaluated to determine stage, lymph node involve- basis and included CT scan, chest X-ray, IVP, and ul- ment, tumor subtype, and grade. trasound of the abdomen. Second-look surgery was not

Chemotherapy was started 2 to 3 weeks after surgery performed. Physical examinations and close observation with the aim of delivering at least six cycles of a mul- of blood chemistries and tumor markers were carried out tidrug regimen. Several drug combinations were utilized at the Clinic of Gynecology. The results of those marker in this patient series. These included a modified PAC studies have been published in detail elsewhere [31]. regimen, replacing c&platinum by JM8 and Adriamycin by 4’-epidoxorubicin in 12 patients, and epirubicin-JM8 with chlorambucil-prednisolone ester in 7 patients. One Statistical Analysis

patient was treated with a cyclophosphamide-mitoxan- The Kaplan-Meier product limit method [32] was used trone combination only. for survival curves with onset of survival measured from

the date of surgery. Alternatively, survival from the date

Radiation Therapy of initiation of radiotherapy was analyzed. The Cox pro- portional hazard model was used to evaluate the factors

Two to 3 weeks after completion of chemotherapy, a correlating with actual or relapse-free survival [33]. Sta- complete radiologic restaging was performed. If no mea- tistical differences between factors influencing survival surable disease was documented and repeat of WBC and were determined by the Mantel-Haenszel test [32]. The platelet counts showed at least 3000/mm3 leukocytes and parameters analyzed included extent of residual disease 100,00O/mm’ platelets, respectively, radiation therapy at the time of surgery (none vs ~2 cm vs >2 cm), his-

48 ARIAN-SCHAD ET AL.

TABLE 1 1 oo-

Patient Parameters 80 overall survival

No. of patients Percentage

Stage III 20 100

Histologic subtype 20 t

Serous 12 60 Endometroid 3 15 Mutinous 2 10 Clear-cell 2 10 FIG. 1. Overall and recurrence-free survival from date of surgery Undifferentiated I 5 for 17 patients, FIG0 stage III, who completed the planned course of

Histologic grades radiation.

Well differentiated 5 25 Moderately differentiated 7 35 Poorly differentiated 7 35 differentiated, 7 moderately differentiated, 7 poorly dif- Undifferentiated I 5 ferentiated, and 1 undifferentiated carcinoma. No mac-

Residual at initial surgery roscopic residual disease was present in 40% (8/20) of No visible disease 8 40 the patients, and residual disease ~2 cm was present in Residual ~2 cm 3 15 Residual >2 cm 9 45

15% (3/20) and >2 cm in 45% (9/20) of the patients. Radiation therapy was well tolerated. Seventeen of 20

Nodal involvement None 5 25

patients were able to complete the planned course of

Pelvic nodes only 3 15 radiation. Two patients could not complete their radia-

Paraaortic nodes only 1 5 tion treatments because of persistent bone marrow de- Pelvic and paraaortic nodes II 55 pletion and 1 patient refused to continue treatment.

Overall and relapse-free-3-year survival from date of surgery (Fig. 1) for the 17/20 patients who have com-

tologic subtype (serous, mutinous, endometroid, clear- pleted the full course of irradiation was 69% (median: cell, undifferentiated), tumor grade (well vs moderate vs 24, mean: 27.6 months) and 47% (median: 22, mean: poorly vs undifferentiated), and lymph node status (none 25.3), respectively, with a follow-up from 19 to 53 months vs pelvic vs paraaortic vs pelvic plus paraaortic for overall survival. Time to recurrence ranged from 17 involvement). to 37 months (median: 20, mean: 22.1). The overall and

relapse-free survival from onset ofradiation (Fig. 2) was

RESULTS 71.8% (median: 16, mean: 19.6, range: lo-45 months) and 23.8%, respectively, with recurrences observed be-

Radical surgery, including pelvic and paraaortic lymph tween 9 and 29 months after initiation of radiation node dissection, was carried out in all but two patients, therapy. in whom only retroperitoneal sampling was performed. The overall relapse rate was 53%. Seven of 17 irra- Tumor debulking included a partial bladder resection and diated patients (41%) failed in the abdomen. One patient APR in one case and a LAR in another patient because developed at 20 months a histologically verified left su- of macroscopic infiltration of the bladder and bowel with tumor. Chemotherapy was administered in all patients ranging from 4 to 10 cycles (median, 6). A dose reduction

too*

in the last cycle of the chemotherapy course to 75% of 80 overall survival

the planned drug dose was necessitated due to hematologic toxicity in five patients and hepatitis in one case.

Histopathological lymph node staging revealed nodal t involvement in 75% (15/20) of the patients. In 3 cases \ rec.-free survival

positive nodes were limited to the pelvis, in 1 case paraaortic involvement only was noted, and 11 patients (55%) had both pelvic and paraaortic involvement (Table 1). Distribution by histologic types showed 12 serous, 3 endometroid, 2 mutinous, 2 clear-cell, and 1 undiffer- FIG. 2. Overall and recurrence-free survival from onset of radio- entiated adenocarcinoma. Tumor grades included 5 well- therapy for 17 patients, who completed the planned course of radiation.

MULTIPLE MODALITY TREATMENTS IN OVARIAN CARCINOMA 49


TABLE 2 Residual Disease at Surgery and Sites of Failure of 20 Patients with FIG0 Stage III Ovarian Carcinoma

Patient No.

1 <2 cm

2 None

3 >2 cm

4 >2 cm

5 >2 cm

6 c2 cm

7 >2 cm

8 None

9 >2 cm

10 >2 cm

II None

12 None

13 >2 cm

14 <2 cm

15 >2 cm

16 None

17 None

18 None

19 None

20 >2 cm

Amount of residual disease

Site of residual

Diaphr.

Diaphr.

Aorta1 + caval Ln

Diaphr.

Aortocaval

Diaphr.

Diaphr. pelvis

Diaphr.

Diaphr.

Pelvis

Pelvis

Diaphr.

Treatment outcome

NED

NED

Relapse

Relapse

NED

NED

Relapse

NED

Relapse

NED *

NED

Relapse

Relapse

Relapse

NED

*

Relapse

Relapse

Relapse

Pattern of relapse

Diaphr.

Aortal+ caval Ln

Diaphr. liver

Diaphr. pelvis

Ln met. supraclav.

Diaphr.

Pelvis

Pelvis

Ln met. supraclav.

Pelvis

Liver

Diaphr. liver

XRT

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

1

Note. Definitions and abbreviations: residual disease: no macroscopic (None); equal or less than 2 cm (~2); more than 2 cm (>2); no clinical or radiological evidence of disease (NED); dome of diaphragm (Diaphr.); no abdominal disease: (*): XRT: radiation treatment completed (+ ); not completed (-); Ln: lymph node; met: metastasis, supraclav: supraclavicular.

praclavicular lymph node metastasis and another relapsed in both supraclavicular lymph node regions at 38 months, as sole sites of disease. In both cases no macroscopic residual had been noted following the initial operation. In contrast, the 7 patients who relapsed in- traabdominally had postsurgical residual tumors >2 cm (6 patients) and 1 patient had a ~2 cm residual mass. There were no abdominal failures among the 6 patients who had no visible residual disease after surgery and had completed full course of radiation therapy (follow up 28 to 53 months, median: 30, mean: 34.5 months).

The most frequent sites of relapse were at locations where the tumor had not been grossly removed at surgery (Table 2). These included the right dome of the diaphragm in three cases, paraaortic and caval lymph nodes in one patient, and the pelvis in two cases. One patient recurred at the diaphragm and the pelvic wall simultaneously. Abdominal failures occurred with a median follow-up time of 23 months (range, 17-25 months). The

survival from detection of intraabdominal recurrence was short, ranging from 1 to 8 months (median: 3).

Univariate analysis showed that only the amount of residual disease at the time of surgery (none vs ~2 cm or >2 cm) was significantly correlated with overall and relapse-free survival (P < 0.01). Three-year overall sur-

FIG. 3. Survival according to the amount of residual disease at initial surgery for 17 patients, who completed radiotherapy.


1 oo-

overall survival

abd. rec.- free survival k

FIG. 4. Overall and abdominal recurrence-free survival for 17 patients, who completed radiotherapy.

viva1 as a function of the amount of residual disease was 100% for none, 66.7% for ~2 cm residual, and 26.7% for >2 cm residual, respectively (Fig. 3). The 3-year abdominal recurrence-free survival after surgery was 54.4% (Fig. 4). The amount of residual disease was the only statistically significant factor found in the Cox pro- portional hazard model predictive of recurrence-free survival (P < 0.05). Neither histopathological subtype, nor grade, nor nodal involvement showed significant impact on relapse-free survival.

Radiation Treatment Toxicity and Complications

All patients experienced some degree of discomfort during radiation therapy, such as fatigue, anorexia, and meteorism. Intestinal cramps and diarrhea developed after an average dose of 20 Gy in 16/17 patients, but were successfully treated with diet and administration of loperamide-hydrochloride. Nausea without vomiting was a common complaint and was the reason for early ces- sation of treatment in 1 case.

Persistent hematologic toxicity was a problem in 2 of the 20 patients, who could not complete radiation because of leukocyte counts below 2000/mm3 and platelets counts below 80,000/mm3 after 12 and 13.5 Gy of WAP radiation. They had received 6 and 10 cycles of chemotherapy, respectively, with subsequent dose reduction to 75% in their last chemotherapy treatment course because of hepatitis in 1 patient and myelosuppression in the other patient. Subsequently, both patients failed in the abdomen at 20 and 32 months. At the time of their initial surgery there was no residual disease documented in 1 and >2 cm residual at the diaphragm in the other.

Due to pancytopenia, five patients (29%) required treatment breaks ranging from 8 to 16 days (median, 12) while undergoing WAP irradiation. However, they were all finally able to receive the prescribed dose. In three of them only five courses of chemotherapy had been employed with dose reduction to 75% in the last cycle because of acute hematologic toxicity. The only serious

complication was a bowel obstruction (laparotomy confirmed) in one patient at 7 months after radiation treatment. In addition three of six patients with progressive intraabdominal disease ultimately developed symptoms of intestinal obstruction.

DISCUSSION

The role of radiation therapy in the treatment of stage III ovarian cancer following surgery and chemotherapy remains difficult to define. Reported series have included patients with differing surgical and chemotherapy treatments (including the extent of surgery, choice of chemotherapy regimens, dose intensity, and numbers of cycles) and varying criteria for evaluation of response (imaging methods versus second-look laparotomy) and a range of radiation techniques and doses have been employed [lo,1 1,20,26,27,34-441. This lack of uniformity including the differing sequences of therapeutic modal- ities applied contributes to the variations in treatment results. Prospective randomized trials comparing postsurgical use of chemotherapy alone with chemotherapy plus radiation are lacking.

Although the number of patients in our series is small, careful attention was paid to selection criteria for patients entering this protocol. All cases presented with bulky stage III disease. Maximum tumor debulking was attempted, including radical pelvic and paraaortic lymph node dissection up to the renal pedicle, in order to minimize possible residual disease. Despite this attempt, residual tumors of >2 cm in 45% of the patients and palp- able residuals ~2 cm in 15% of the patients were left in the abdomen. In only 40% of the cases could macroscopic disease be completely resected. The pattern of intraabdominal spread in patients with extensive abdominal disease has revealed metastases at the subpleural diaphragmatic surface in 70% of cases [45]. In our series, 9 of 20 patients showed involvement of the diaphragmatic surface, and in none of these cases could the tumor be completely removed.

The finding of nodal involvement in 75% of patients in our series confirms the necessity for radical lymph node dissection rather than a sampling procedure in order to assure maximum cytoreduction. Although the incidence of nodal involvement is known to increase with stage, up to 25% of patients with untreated otherwise stage I and II disease have been found to have biopsy- proved positive paraaortic nodes [6]. The detection of retroperitoneal lymph node involvement by bipedal lym- phangiogram was limited due to the high false negative rates and it is felt, in agreement with reports from Chen et al [2] and Wu et al. [3], that the true incidence of involvement can best be determined by surgical resection.


Chemotherapy has been demonstrated to eradicate residual disease with clinical response rates reaching 90% and pathological complete responses (pCR’s) of about 30-40% reported with &-platinum containing regimens. However, up to 50% of patients will ultimately relapse, despite laparotomy-confirmed complete responses [5,18,19,36,41,46-511. Second-look laparotomy (SLL) has proven useful in assessing the response to different chemotherapy protocols and has been considered helpful in the selection of subgroups of patients, in whom adjunctive treatment for consolidation of response might be indicated [ 10,16,20,36-38,47,52]. However, for patients refractory to first-line chemotherapy the lack of efficient second-line treatments represents a major problem. The extent of residual disease following the initial radical surgical debulking procedure seems to be a major prognostic factor for a favorable course of disease. The rate of pCR’s achieved with multidrug regimens is reported to be 68% in patients with minimal or no residual disease after initial surgery in contrast to 17% pCR in patients with large residual masses [53]. This raises the question whether SLL should be performed routinely or be restricted to patients on investigational protocols studying the efficacy of second-line therapy after additional surgical debulking is carried out.

However, the impact of such secondary debulking also seems to be unclear [46,50]. Haie et al. [34] found residual disease after SLL to be the only significant prognostic factor in terms of relative risk of death and local or distant failure. This is in contrast to a series from Rizel et al. [41], who reported on 12 patients with secondary complete removal of tumor, of which only 4 patients remained free of disease. Ho et al. [50] suggested a reassessment of the role of SLL. His study failed to demonstrate a significant improvement in survival comparing two groups of patients with and without SLL. Nine of 17 patients relapsed despite pCR compared to 5/l 1 patients who had not undergone repeat laparotomies. Because of the controversies in terms of benefit, the relatively inefficient current second-line treatment options, and the increase in morbidity and in the gas- trointestinal complication rate, SLL was omitted in our current study.

An analysis of patterns of intraabdominal failures in our series demonstrated that all patients recurred at sites of initial macroscopic residual disease. In agreement with most reports, the extent of residual disease significantly correlated with survival [20,25,34,37,38]. Best results were obtained in patients with no visible residual tumor. In our series, there were no abdominal failures in the six patients without macroscopic residual disease who had completed radiation therapy.

The 3-year overall survival rate of 69% achieved in our study compares favorably with other reports in lit-

erature [35,411. Mencer ef al. [37] reported a 64.1% overall survival in 18 patients with stage II-IV ovarian cancer, who underwent surgery, chemotherapy, and adjunctive WAP radiotherapy. Survival correlated with the amount of residual disease; it was 87.5% for patients with no residual disease and 34.3% for patients with limited residual. Kuten et al. [38] have reported on the survival of 43 patients (stages I-IV) who had received surgery, chemotherapy, and radiation. The 3-year actuarial survival of 5 patients with negative findings at SLL was lOO%, as compared to a 5-year survival of 66% in 18 patients with microscopic residual disease, and a 3-year survival of only 5% in 14 patients with macroscopic disease. These results are very similar to our observed survival rates. Furthermore, Fuks et al. [47] reported an approximate 57% 3-year survival rate in patients who were microscopically free of tumor at SLL and Haie et al. [34] reported a 63% 6-year freedom for disease rate in patients with negative SLL.

The specific role that either chemotherapy or radiotherapy contributed in our series as well as those reported by others remains unclear. Recent data from Fuks et al. [47] showed no improvement of cure rate using adjuvant WAP following surgery and chemotherapy. Nineteen of 25 patients failed within the abdomen after a pathologically confirmed complete response; yet 11 of those patients were debulked at SLL and might have represented a group with a biologically different and prognostically unfavorable disease behavior. The results obtained in patients with no clinically detected tumors at initiation of radiotherapy were identical to those obtained by Neijt er al. [51] with chemotherapy alone. Pod- ratz et al. [I71 also were not able to demonstrate an advantage for adjunctive irradiation following chemotherapy compared with studies employing postsurgical chemotherapy alone.

However, radiation treatment following chemotherapy appears to be of potential value in patients with microscopic disease or no residual disease as documented at second-look operations following chemotherapy [8,10,20,25,28,36-38,41,43,53]. This suggests the need for a prospective study randomizing patients with negative or microscopic disease to no additional treatment versus whole abdominal radiation thereapy.

Several possible mechanisms may help explain the failure of radiotherapy to control bulky residual disease. First is the relatively low dose of radiation that can be safely delivered due to the limited tolerance of the bowel, kidney, and liver. Extrapolating from clinical experience in the management of epithelial tumors at other sites, doses of 30 to 50 Gy would be unlikely to control bulky residual disease [54-561. The second mechanism which may limit the effectiveness of postchemotherapy radiation treatment is the possible development of cross-re-


sistance of the chemotherapeutically treated residual tumor to radiation [57]. In fact, Ensley er al. [58] reported a strong correlation between +-platinum resistance and radiation resistance in head and neck tumors. Wallner et al. [59] stated that cross-resistance of tumors between c&platinum and radiation might be a result of the tumor microenvironment rather than a cellular phenomenon. In contrast, Schwartz et al. noted in human tumor cell lines tested in vitro a strong association of radioresistance and resistance to cis-platinum [60]. Similarly, Louie et al. [61] reported the simultaneous acquisition of drug and radiation resistance after exposure of human ovarian cancer cell lines to &-platinum.

We were unable to confirm the prognostic value of histological subtype or grade as reported by others [15,17,20,43,47], possibly because of the small patient numbers in our study. We also failed to demonstrate a significant impact of nodal involvement on survival. This might have been related to the association of extensive bulky intraabdominal disease with lymph node involvement. However, lymph node status might be a prognostic indicator in patients with stage III disease if there is only nodal involvement [54]. Such patients may do better than those with other sites of intraabdominal disease.

Radiotherapy was well tolerated in the face of radical retroperitoneal dissection and chemotherapy in our series. Only 2 of 20 patients failed to complete the planned radiation course because of acute hematologic toxicity. One patient developed bowel obstruction after radiation treatment. Episodes of pancytopenia, necessitating interruptions in treatment, occurred in 5 patients. This incidence appears comparatively low. Schray et al. [8] reported that 9 of 35 patients failed to complete therapy. Hacker et al. [25] noted that 30% of their 30 patients were unable to complete radiation therapy and Hains- worth et al. [26] reported that only 7/17 patients were able to complete the planned course of radiation. Treat- ment interruptions in 42% of patients were observed by Fuks et al. [47]. In their study, however, the average number of chemotherapy treatment cycles exceeded the number used in our patients. This suggests that hematologic toxicity is strongly dependent on the number of chemotherapy cycles employed [S].

The relatively high rate of radiation-induced bowel obstruction reported in other series is most likely related to the higher incidence of second-look surgery or other preradiation laparotomies [8]. Peters et al. [39] noted bowel obstruction in 4/l 1 patients who had received a pelvic boost. Thirty percent chronic bowel morbidity was reported by Hacker et al. [25], and 21% in a series from Schray and co-workers [20]. The highest incidence of bowel complications was described by Shelley et al. [27], who noted a 48% complication rate.

New approaches are necessary to improve the results

of current treatment for advanced epithelial ovarian cancer. The delivery of a single high dose radiation fraction intraoperatively to sites of bulky disease while shielding or positioning normal tissues from the field might prove to be of value. Additional efforts need to be directed toward identifying more effective routes of administration of chemotherapy (or radioisotopes) for tumors pri- marily confined to the peritoneal cavity. The preliminary results of intraperitoneal cis-platinum chemotherapy appeared promising [62,63]. Best results were obtained in patients with small-volume disease, with complete remission rates of as high as 69% reported [62]. Further clinical studies will be needed to evaluate the feasibility and curative potential of such an approach. Also, one can attempt to minimize the potential development of drug and radiation resistance by integrating the radiation therapy earlier in the treatment course. A ping-pong-type technique, alternating several cycles of chemotherapy and radiation, would be worth considering. This approach has been of value in the treatment of Hodgkin’s disease [64]. Alternatively radiation therapy could be administered during the course of chemotherapy and used as an additional “chemotherapeutic agent.”

CONCLUSION

In conclusion, this study has demonstrated the feasibility of a planned course of debulking surgery (including radical pelvic and retroperitoneal lymph node dissection), chemotherapy, and aggressive radiation therapy. The treatment was well tolerated with a comparatively low toxicity and complication rate. Seventeen of 20 patients were able to complete the radiation treatment. In only 2 was the interruption related to hematologic toxicity. Three-year overall and recurrence-free survival rates of 69 and 47%, respectively, were obtained with an abdominal-recurrence-free survival of 54.4%. These results compare favorably to those reported previously, particularly considering that only patients with initially widespread intraabdominal disease were included in this study. However, this approach appeared to be most effective in patients with no visible disease after initial surgery. A randomized controlled study with a larger number of patients and longer follow-up will be necessary to confirm the value of radiation therapy as an ad- junct to chemotherapy and surgery in this subgroup of patients. Innovative approaches will need to be considered for patients with macroscopic postsurgical residual disease.

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