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A pilot study investigating intraoperative electron beam irradiation in the treatment of ovarian malignancies
GYNECOLOGIC
ONCOLOGY
38,
121-124 (1990)
A Pilot Study Investigating lntraoperative Electron Beam Irradiation in the treatment of Ovarian malignancies ANDRE
A. KONSKI, M.D.,* JAMES NEISLER, M.D.,? GARTH PHIBBS, M.D.,? DONALD G. BRONN, M.D., PH.D.,* RALPH R. DOBELBOWER, JR., M.D.,
Ilppartrnents
of *Radiation
Therapy and tObstetrics
and Gynecology.
Medical
AND
PH.D.*
College of Ohio, .WW Arlingrm
,4vgmw, To/&o,
O/-Go 43514
Received December 28, 1989
Intraoperative electron beam radiation therapy (IOEBRT) in the treatment of ovarian malignancies was investigated at the Clement 0. Miniger Radiation Oncology Center (COMRW). Nine patients were operated in the COMROC IOEBRT operating amphitheater and five were found to have disease sufficiently limited to allow for IOEBRT. The patients’ ages ranged from 13 to 80 (median 53) years. Five patients had serous cystadenocarcmoma, one papillary adenocarcinoma, one mixed germ cel1 tumor, one squamous cell carcinoma, and one granular cell tumor of the ovary. The median survival of the non-IOEBRT group was 13 (range 12-29) months, while the IOEBRT group’s median survival was 14 (range 18-46) months. All of the patients tolerated IOEBRT well without addition to the surgical morbidity. 0 IWO Academic
Press, Inc.
INTRODUCTION The American Cancer Society estimates that ovarian tumors will account for 4% of new cancers and 5% of all cancer deaths in females in 1989 [ 11. The majority of the patients will present with advanced disease because of the insidious growth and vague presenting symptoms of ovarian cancer [2,3]. Despite aggressive multiple surgical procedures, combination chemotherapy, and whole-abdomen irradiation, improvements in survival have been less than encouraging 14-161. Newer modalities
including
intraperitoneal
chemotherapy and radiolabeled antibodies are being investigated at this time 117-191. The pattern of failure continues to be primarily in the abdomen despite ail of the intensive regimens employed to date [l I,ZO-221. The dose of external-beam radiation that can be delivered to the abdomen is limited because of the tolerance of the kidney, liver, and small intestine to irradiation. We report our experience utilizing intraoperative elec-
tron beam radiation therapy (IOEBRT) in the treatment of ovarian malignancies at the Medical College of Ohio. METHODS AND MATERIALS Hospital, clinic, and radiation therapy records were retrospectively reviewed. Nine patients underwent exploratory laparotomy in the Clement 0. Miniger Radiation Oncology Center (COMROC) IOEBRT surgical suite. All of the patients had histologic confirmation of an ovarian malignancy prior to exploratory laparotomy. Presurgical evaluation found them to be without metastatic disease. All patients had failed previous therapy prior to evaluation for IOEBRT. After the surgeon explored the abdomen and intraoperative consuitation was obtained with the radiation oncologist, a determination was made if IOEBRT could be performed. Patients were considered eligible for intraoperative irradiation if all presurgical evaluation revealed no evidence of distant spread or diffuse abdominal disease. If extensive and unresectable disease was found at the time of surgery no irradiation was given. Maximal tumor resection was obtained prior to moving the patient from the operating side of the COMROC IOEBRT room to under the treatment machine. After the appropriate applicator was selected, an adaptor was placed onto the treatment machine and mated to the applicator. The applicator size, electron energy, and delivered dose were selected based upon the area and depth of the residual disease. With increasing depth of tumor, higher electron energies and doses were used. The higher the electron energy, the greater the penetrating power of the treatment beam. The tumor or the tumor bed was marked with clips for subsequent external-beam irradiation, The size of the applicator was selected by determining which
121 oo90-8258190$1.50 Copyright 0 I!390 by Academic Press, Inc. All rights of reproduction in any form reserved.
122
KONSKI
applicator covered the tumor or tumor bed with a l-cm margin. All of the radiation-sensitive structures were moved out of the field if possible. The area of the treatment was verified by use of a right-angle illuminating telescope which permitted the operator to view the tumor or tumor bed as if he were looking down the central ray of the treatment beam. Utilization of remote monitoring of the patient’s heart rate and respirations by the anesthesiology team permitted all personnel to be evacuated from the COMROC IOEBRT surgical room while the radiation was delivered. Midway through the irradiation, the treatment was interrupted and the applicator was inspected to verify its position in the patient. At the completion of the irradiation, the operating team carefully moved the patient back to the operating area of the IOEBRT room for the completion of the surgical procedure. Postoperative external-beam irradiation was delivered with parallel opposed fields with 6- or lo-meV X rays at 1.8 or 2.0 Gy. Posterior kidney blocks were utilized to reduce the dose to the kidneys. All nine patients had surgery as initial treatment and eight of nine patients had chemotherapy before consideration of IOEBRT. Five patients had serous cystadenocarcinoma, one papillary adenocarcinoma, one mixed germ cell tumor, one squamous cell carcinoma of the ovary, and one granulosa cell tumor. Seven patients had greater than 2 cm of residual disease, one patient had less than 5 mm of residual disease, and one patient had no residual disease after the initial operation. Two patients had IOEBRT after the initial operation and one patient had IOEBRT after a “second-look” operation. Three patients had external-beam irradiation after the second-look operation. Of the five patients having second-look laparotomies, four had greater than 2 cm of residual disease and one patient had less than 2 cm of residual disease. Patients were considered for whole-abdomen irradiation after the IOEBRT if this was not given prior to the IOEBRT since most of these patients had stage II or III disease. Survival was calculated from the time of IOEBRT. This time was selected because all of the patients had previous treatment and the effect of the IOEBRT would not be accurately reflected if survival was calculated from the time of diagnosis. RESULTS Extensive and unresectable disease was found at surgery in four patients even though the preoperative evaluation determined these patients to be candidates for surgery; hence, IOEBRT was not delivered. Four of the five patients receiving IOEBRT had a single field irradiated intraoperatively while the other pa-
ET AL.
tient had three fields irradiated. The patients’ ages ranged from 13 to 80 (median 53) years. Two patients had stage II disease and seven, stage III. Two patients receiving IOEBRT had disease that recurred in the pelvis; in one patient the cancer recurred in the abdomen and lung; and in one patient, cancer recurred in the anterior abdominal wall. One patient died 8 months after treatment without any evidence of disease at autopsy. She was found to have a fistula between a pelvic abscess and a blood vessel which also communicated with the vagina. Two of the four patients not receiving IOEBRT had disease in the pelvis and abdomen at the time of death, one had disease in the abdomen and lung, and one had disease in the abdomen and liver. The applicator size, radiation dose, beam energy, residual disease, and treatment outcome are listed in Table 1. The median survival for the entire group was 14 (range 2-46) months. The median survival for the four patients not receiving IOEBRT was 13 (range 2-29) months, while it was 14 (range 8-46) months for the patients receiving IOEBRT. Two of the patients not receiving IOEBRT survived 20 and 29 months from the day of surgery for the proposed IOEBRT. They both received systemic chemotherapy but had evidence of recurrent disease at 15 and 19 months. DISCUSSION The cure rates for epithelial malignancies of the ovary remain poor despite aggressive multimodality treatment. Patients initially presenting with stage II disease have 5year survival in the 50% range, while patients presenting with stage III disease have 5-year survival in the 2030% range, even when combination chemotherapy, aggressive surgical debulking, and whole-abdomen irradiation is employed [5-12,14,15,23,24]. The results of attempts at salvaging those patients whose disease relapses or who are found to have residual tumor at second-look laparotomy are dismal [ 13,161. The amount of residual disease after laparotomy remains one of the most important prognostic factors in epithelial ovarian malignancies. Those patients having greater than 2 cm of tumor remaining have significantly worse survival than those patients with less than 2 cm or no residual tumor [25]. Whether the poor prognosis in these patients is due to drug resistance or the inability to deliver adequate doses of radiation is not known at this time. The amount of radiation which can be delivered to the abdomen is limited because of the volume and radiation sensitivity of the tissue irradiated. The radiation sensitivity of the small intestine, liver, and kidney limits
INTRAOPERATIVE
IRRADIATION TABLE
Patient
OF OVARIAN 1
Applicator
Beam energy WV)
Dose (GY)
No IOEBRT No IOEBRT I % in., 15” bevel 2% in., 15” bevel 4 in., 15” bevel No IOEBRT No 1OEBRT 2 in., flat 2 in., flat 2% in., 15” bevel 2 in., flat
N/A N/A 9 12 12 N/A N/A 15 6 9 18
N/A N/A 20 20 20 N/A N/A 2.5 20 I5 26.64
the whole-abdomen dose to 20-25 Gy [26]. The radiation dose estimated, however, to be necessary to eradicate macroscopic deposits of tumor is in the range of 50 to 60 Gy, while microscopic deposits of tumor require 22.5 to 30 Gy [27,28]. It is obvious that the dose required to sterilize macroscopic deposits of tumor exceeds the tolerance of the structures in the external-beam treatment field. Intraoperative electron-beam radiation therapy has the advantage of delivering a single high dose of radiation to the tumor without treating radiation-sensitive structures. This method has been used in the treatment of other abdominal tumors [29-3 11. The majority of the patients in this small pilot study had previous resections and chemotherapy and the cancer had relapsed. In general, the patients tolerated the treatment well without any addition to the acute surgical morbidity. One patient died of a hemorrhage from a fistulous tract between an abscess and an artery. Whether this was secondary to her previous surgery, subsequent irradiation, or IOEBRT was not discovered at autopsy and is open to conjecture. Two patients treated with IOEBRT doses of 20 and 25 Gy developed permanent back and leg pain starting within 3 weeks of treatment. Both these patients received chemotherapy prior to the IOEBRT. Patient 3 received 4 months of chemotherapy consisting of vincristine, actinomycin D, and Cytoxan. The intraoperative dose was directed at the obturator fossa. Patient 9 received 10 courses of c&platinum, Cytoxan, and hexamethylmelamine prior to receiving the radiation. She received an intraoperative dose of 26.64 Gy. Postoperatively she received intraperitoneal &-platinum and whole-abdomen and pelvic irradiation. The abdomen received 7.5 Gy and the pelvis, 43.40 Gy. She developed pain in the lumbosacral plexus and left sciatic nerve area which was in the intraoperative field. It was unknown whether the pain was secondary to the treatment or recurrent disease.
123
TUMORS
Residual before IOEBRT
Survival from surgery for IOEBRT (months)
N/A N/A None None >2 cm N/A N/A
2 29 9 46 8 (NED) 20 6
None
14
<2 cm
24
These two cases raise the possibility that the chemotherapy the patients received could have sensitized the neural tissues to the radiation. No firm conclusions of the efficacy of IOEBRT in the treatment of ovarian malignancies can be drawn by reviewing the data from this small pilot study with varied histologies. By using IOEBRT, however, after the initial operation before whole-abdomen irradiation, macroscopic tumor deposits could be given higher doses, presumably with a greater chance of cure without unduly increasing treatment morbidity. ACKNOWLEDGMENT The authors thank Susan Bannister for her technical assistance in the typing of this manuscript.
REFERENCES 1. Silverberg, E., and Lubera, J. A. Cancer statistics, 1989, CA 39, 3-20 (1989). 2. Richardson, Cl. S., Scully, R. E., Nikrui, N., and Nelson, J. H. Common epithelial cancer of the ovary (first of two parts), N. Engl. J. Med. 312, 415-424 (1985). 3. Richardson, G. S., Scully, R. E., Nikrui, N., and Nelson, J. H. Common epithelial cancer of the ovary (second of two parts), N. Engl. J. Med. 312, 474-483 (1985). 4. Belinson, J. T., McClure, M., Ashikoga, T., and Karadhof, I. H. Treatment of advanced and recurrent ovarian carcinoma with cyclophosphamide, doxorubicin and cisplatin, Cancer 64, 1983-1990 (1984). 5. Dembo, A. J. Abdominopelvic radiotherapy in ovarian cancer, Cancer 55, 2285-2290 (1985). 6. Dembo, A. J. Radiotherapeutic management of ovarian cancer, Semin. Oncol. 11, 238-250 (1984). 7. Fuks, Z., Rizel, S., Anteby, S. O., and Brian, S. The multimodality approach to the treatment of stage III ovarian carcinoma, Int. J. Radiut.
Oncol. Biol. Phys. 8, 903-908 (1982).
8. Glatstein, E., Fuks, Z., and Bagshaw, M. A. Diaphragmatic treatment in ovarian carcinoma: A new radiotherapeutic technique, lnt. .I. Radiat.
0~01.
Biol. Phys. 2, 357-362 (1977).
124
KONSKI ET AL.
9. Martinez, A., Schray, M. F., Howes, A. E., and Bagshaw, M. A. Postoperative radiation therapy for epithelial ovarian cancer: The curative role based on a 24-year experience, .I. Clint. Oncol. 3, 901-911 (1985). 10. Young, R. C., Decker, D. G., Wharton, J. T., Piver, S., Sindelar, W. F., Edwards, B. K., and Smith, J. P. Staging laparotomy in early ovarian cancer, J. Amer. Med. Assoc. 250,3072-3076 (1983). 11. Schray, M. M., Cox, R. S., and Martinez. Lower abdominal radiotherapy for stages I and II and selected III epithelial ovarian cancer: 20 years experience, Gynecol. Oncol. 15, 78-87 (1983). 12. Kuten, A., Stein, M., Steiner, M., Rubinov, R., Epelbaum, R., and Cohen, Y. Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma, Int. J. Radiat. Oncol. Biol. Phys. 14, 273-280 (1988).
13. Ozols, R. F., and Young, R. C. Chemotherapy of ovarian cancer, Semin. Oncol. 11, 251-263 (1984).
14. Fuks, Z., and Bagshaw, M. A. The rationale for curative radiotherapy for ovarian carcinoma, Int. J. Radial. Oncol. Biol. Phys. 1, 21-32 (1985).
15. Young, R. C., Decker, D. G., Wharton, J. T., Piver, S., Sindelar, W. F., Edwards, B. K., and Smith, .I. P. Staging laparotomy in early ovarian cancer, J. Amer. Med. Assoc. 250,3072-3076 (1983). 16. Neijt, J. P., Ten Bookel Hinuniuh, W. W., and Van der Burg, M. Complete remission at laparotomy: Still gold standard in ovarian cancer? Lancet 1, 1028 (1986). 17. Stewart, J. S. W., Hird, V., Snook, D., Sullivan, M., Hooker, G., Courtenay, Luch, N., Sevalapenko, G., Griffiths, M., Myers, M. J., Lambert, H. E., Munro, A. J., and Epenetos, A. A. Intraperitoneal radioimmunotherapy for ovarian cancer: Pharmacokinetics, toxicity, and efficacy of I-131 labeled monoclonal antibodies, Znt. J. Radiat. Oncol. Biol. Phys. 16, 405-414 (1989). 18. Lopez, J. A., Krikorian, J. G., and Reich, S. D. Intraperitoneal cisplatinum therapy of ovarian cancer, Clin. Res. 29, 684-689 (1982). 19. Ozak, R. F., Young, R. C., and Speyer, J. L. Phase I and pharmacologic studies of Adriamycin administered intraperitoneally, Cancer Res. 40, 567-572 (1980). 20. Piver, S. M., Barlow, J. J., Yazigi, R., and Blumenson, L. E. Melphalan chemotherapy in advanced ovarian carcinoma, Obstet. Gynecol.
51, 352-356 (1988).
21. Raju, K. S., McKinna, J. A., Barker, G. H., Wiltshaw, E., and Jones, J. M. Second look operations in the planned management of advanced ovarian carcinoma, Amer. J. Obstet. Gynecol. 122, 355-357 (1982). 22. Dauplat, J., Feniere, J., Gorbinet, M., Legros, M., Challet, P., Giraud, B., and Plagne, R. Second-look laparotomy in managing epithelial ovarian carcinoma, Cancer 5, 1627-1631 (1986). 23. Terada, K. Y., Morley, G. W., and Roberts, J. A. Pelvic irradiation for stage II ovarian carcinoma, Gynecol. Oncol. 29, 26-31 (1988). 24. Dembo, A. J., and Bush, R. S. Choice of postoperative therapy based on prognostic factors, Int. J. Radiat. Oncol. Biol. Phys. 8, 893-897 (1982). 25. Weiser, E. B., Burke, T. W., Heller, P. B., Woodward, J., Hoskins, W. J., and Park, R. C. Determinants of survival of patients with epithelial ovarian carcinoma following whole abdominal irradiation (WAR), Gynecol. Oncol. 30, 201-208 (1988). 26. Rubin, P., Cooper, R., and Phillips, T. L. Radiation biology and radiation pathology syllabus, American College of Radiology, Chicago (1975). 27. Delclos, L., and Smith, J. P. Tumors of the ovary, in Textbook of radiotherapy (G. Fletcher, Ed.), Lea & Febiger, Philadelphia, pp. 6%-702 (1973). 28. Dembo, A. J. The sequential multiple modality treatment of ovarian cancer, Radiat. Oncol. 3, 187-192 (1985). 29. Bagne, F. R., Dobelbower, R. R., Milligan, A. J., and Bronn, D. G. Treatment of cancer of the pancreas by intraoperative electron beam therapy: Physical and biological aspects, Int. J. Radial. Oncol. Biol. Phys. 16, 231-242 (1989).
30. Hoechstra, H. J., Sindelar, W. F., and Kinsella, T. J. Surgery with intraoperative radiotherapy for sarcomas of the pelvic girdle: A pilot experience, Znt. J. Radiat. Oncol. Biol. Phys. 15, 1013-1016 (1988). 31. Dobelbower, R. R., Howard, J. M., Bagne, F. R., Eltaki, A., and Merrick, H. W. Treatment of cancer of the pancreas by precision high dose (PHD) external photon beam and intraoperative electron beam radiation therapy (IOEBT), Int. J. Radial. Oncol. Biol. Phys. 16, 205-209 (1989).
ONCOLOGY
38,
121-124 (1990)
A Pilot Study Investigating lntraoperative Electron Beam Irradiation in the treatment of Ovarian malignancies ANDRE
A. KONSKI, M.D.,* JAMES NEISLER, M.D.,? GARTH PHIBBS, M.D.,? DONALD G. BRONN, M.D., PH.D.,* RALPH R. DOBELBOWER, JR., M.D.,
Ilppartrnents
of *Radiation
Therapy and tObstetrics
and Gynecology.
Medical
AND
PH.D.*
College of Ohio, .WW Arlingrm
,4vgmw, To/&o,
O/-Go 43514
Received December 28, 1989
Intraoperative electron beam radiation therapy (IOEBRT) in the treatment of ovarian malignancies was investigated at the Clement 0. Miniger Radiation Oncology Center (COMRW). Nine patients were operated in the COMROC IOEBRT operating amphitheater and five were found to have disease sufficiently limited to allow for IOEBRT. The patients’ ages ranged from 13 to 80 (median 53) years. Five patients had serous cystadenocarcmoma, one papillary adenocarcinoma, one mixed germ cel1 tumor, one squamous cell carcinoma, and one granular cell tumor of the ovary. The median survival of the non-IOEBRT group was 13 (range 12-29) months, while the IOEBRT group’s median survival was 14 (range 18-46) months. All of the patients tolerated IOEBRT well without addition to the surgical morbidity. 0 IWO Academic
Press, Inc.
INTRODUCTION The American Cancer Society estimates that ovarian tumors will account for 4% of new cancers and 5% of all cancer deaths in females in 1989 [ 11. The majority of the patients will present with advanced disease because of the insidious growth and vague presenting symptoms of ovarian cancer [2,3]. Despite aggressive multiple surgical procedures, combination chemotherapy, and whole-abdomen irradiation, improvements in survival have been less than encouraging 14-161. Newer modalities
including
intraperitoneal
chemotherapy and radiolabeled antibodies are being investigated at this time 117-191. The pattern of failure continues to be primarily in the abdomen despite ail of the intensive regimens employed to date [l I,ZO-221. The dose of external-beam radiation that can be delivered to the abdomen is limited because of the tolerance of the kidney, liver, and small intestine to irradiation. We report our experience utilizing intraoperative elec-
tron beam radiation therapy (IOEBRT) in the treatment of ovarian malignancies at the Medical College of Ohio. METHODS AND MATERIALS Hospital, clinic, and radiation therapy records were retrospectively reviewed. Nine patients underwent exploratory laparotomy in the Clement 0. Miniger Radiation Oncology Center (COMROC) IOEBRT surgical suite. All of the patients had histologic confirmation of an ovarian malignancy prior to exploratory laparotomy. Presurgical evaluation found them to be without metastatic disease. All patients had failed previous therapy prior to evaluation for IOEBRT. After the surgeon explored the abdomen and intraoperative consuitation was obtained with the radiation oncologist, a determination was made if IOEBRT could be performed. Patients were considered eligible for intraoperative irradiation if all presurgical evaluation revealed no evidence of distant spread or diffuse abdominal disease. If extensive and unresectable disease was found at the time of surgery no irradiation was given. Maximal tumor resection was obtained prior to moving the patient from the operating side of the COMROC IOEBRT room to under the treatment machine. After the appropriate applicator was selected, an adaptor was placed onto the treatment machine and mated to the applicator. The applicator size, electron energy, and delivered dose were selected based upon the area and depth of the residual disease. With increasing depth of tumor, higher electron energies and doses were used. The higher the electron energy, the greater the penetrating power of the treatment beam. The tumor or the tumor bed was marked with clips for subsequent external-beam irradiation, The size of the applicator was selected by determining which
121 oo90-8258190$1.50 Copyright 0 I!390 by Academic Press, Inc. All rights of reproduction in any form reserved.
122
KONSKI
applicator covered the tumor or tumor bed with a l-cm margin. All of the radiation-sensitive structures were moved out of the field if possible. The area of the treatment was verified by use of a right-angle illuminating telescope which permitted the operator to view the tumor or tumor bed as if he were looking down the central ray of the treatment beam. Utilization of remote monitoring of the patient’s heart rate and respirations by the anesthesiology team permitted all personnel to be evacuated from the COMROC IOEBRT surgical room while the radiation was delivered. Midway through the irradiation, the treatment was interrupted and the applicator was inspected to verify its position in the patient. At the completion of the irradiation, the operating team carefully moved the patient back to the operating area of the IOEBRT room for the completion of the surgical procedure. Postoperative external-beam irradiation was delivered with parallel opposed fields with 6- or lo-meV X rays at 1.8 or 2.0 Gy. Posterior kidney blocks were utilized to reduce the dose to the kidneys. All nine patients had surgery as initial treatment and eight of nine patients had chemotherapy before consideration of IOEBRT. Five patients had serous cystadenocarcinoma, one papillary adenocarcinoma, one mixed germ cell tumor, one squamous cell carcinoma of the ovary, and one granulosa cell tumor. Seven patients had greater than 2 cm of residual disease, one patient had less than 5 mm of residual disease, and one patient had no residual disease after the initial operation. Two patients had IOEBRT after the initial operation and one patient had IOEBRT after a “second-look” operation. Three patients had external-beam irradiation after the second-look operation. Of the five patients having second-look laparotomies, four had greater than 2 cm of residual disease and one patient had less than 2 cm of residual disease. Patients were considered for whole-abdomen irradiation after the IOEBRT if this was not given prior to the IOEBRT since most of these patients had stage II or III disease. Survival was calculated from the time of IOEBRT. This time was selected because all of the patients had previous treatment and the effect of the IOEBRT would not be accurately reflected if survival was calculated from the time of diagnosis. RESULTS Extensive and unresectable disease was found at surgery in four patients even though the preoperative evaluation determined these patients to be candidates for surgery; hence, IOEBRT was not delivered. Four of the five patients receiving IOEBRT had a single field irradiated intraoperatively while the other pa-
ET AL.
tient had three fields irradiated. The patients’ ages ranged from 13 to 80 (median 53) years. Two patients had stage II disease and seven, stage III. Two patients receiving IOEBRT had disease that recurred in the pelvis; in one patient the cancer recurred in the abdomen and lung; and in one patient, cancer recurred in the anterior abdominal wall. One patient died 8 months after treatment without any evidence of disease at autopsy. She was found to have a fistula between a pelvic abscess and a blood vessel which also communicated with the vagina. Two of the four patients not receiving IOEBRT had disease in the pelvis and abdomen at the time of death, one had disease in the abdomen and lung, and one had disease in the abdomen and liver. The applicator size, radiation dose, beam energy, residual disease, and treatment outcome are listed in Table 1. The median survival for the entire group was 14 (range 2-46) months. The median survival for the four patients not receiving IOEBRT was 13 (range 2-29) months, while it was 14 (range 8-46) months for the patients receiving IOEBRT. Two of the patients not receiving IOEBRT survived 20 and 29 months from the day of surgery for the proposed IOEBRT. They both received systemic chemotherapy but had evidence of recurrent disease at 15 and 19 months. DISCUSSION The cure rates for epithelial malignancies of the ovary remain poor despite aggressive multimodality treatment. Patients initially presenting with stage II disease have 5year survival in the 50% range, while patients presenting with stage III disease have 5-year survival in the 2030% range, even when combination chemotherapy, aggressive surgical debulking, and whole-abdomen irradiation is employed [5-12,14,15,23,24]. The results of attempts at salvaging those patients whose disease relapses or who are found to have residual tumor at second-look laparotomy are dismal [ 13,161. The amount of residual disease after laparotomy remains one of the most important prognostic factors in epithelial ovarian malignancies. Those patients having greater than 2 cm of tumor remaining have significantly worse survival than those patients with less than 2 cm or no residual tumor [25]. Whether the poor prognosis in these patients is due to drug resistance or the inability to deliver adequate doses of radiation is not known at this time. The amount of radiation which can be delivered to the abdomen is limited because of the volume and radiation sensitivity of the tissue irradiated. The radiation sensitivity of the small intestine, liver, and kidney limits
INTRAOPERATIVE
IRRADIATION TABLE
Patient
OF OVARIAN 1
Applicator
Beam energy WV)
Dose (GY)
No IOEBRT No IOEBRT I % in., 15” bevel 2% in., 15” bevel 4 in., 15” bevel No IOEBRT No 1OEBRT 2 in., flat 2 in., flat 2% in., 15” bevel 2 in., flat
N/A N/A 9 12 12 N/A N/A 15 6 9 18
N/A N/A 20 20 20 N/A N/A 2.5 20 I5 26.64
the whole-abdomen dose to 20-25 Gy [26]. The radiation dose estimated, however, to be necessary to eradicate macroscopic deposits of tumor is in the range of 50 to 60 Gy, while microscopic deposits of tumor require 22.5 to 30 Gy [27,28]. It is obvious that the dose required to sterilize macroscopic deposits of tumor exceeds the tolerance of the structures in the external-beam treatment field. Intraoperative electron-beam radiation therapy has the advantage of delivering a single high dose of radiation to the tumor without treating radiation-sensitive structures. This method has been used in the treatment of other abdominal tumors [29-3 11. The majority of the patients in this small pilot study had previous resections and chemotherapy and the cancer had relapsed. In general, the patients tolerated the treatment well without any addition to the acute surgical morbidity. One patient died of a hemorrhage from a fistulous tract between an abscess and an artery. Whether this was secondary to her previous surgery, subsequent irradiation, or IOEBRT was not discovered at autopsy and is open to conjecture. Two patients treated with IOEBRT doses of 20 and 25 Gy developed permanent back and leg pain starting within 3 weeks of treatment. Both these patients received chemotherapy prior to the IOEBRT. Patient 3 received 4 months of chemotherapy consisting of vincristine, actinomycin D, and Cytoxan. The intraoperative dose was directed at the obturator fossa. Patient 9 received 10 courses of c&platinum, Cytoxan, and hexamethylmelamine prior to receiving the radiation. She received an intraoperative dose of 26.64 Gy. Postoperatively she received intraperitoneal &-platinum and whole-abdomen and pelvic irradiation. The abdomen received 7.5 Gy and the pelvis, 43.40 Gy. She developed pain in the lumbosacral plexus and left sciatic nerve area which was in the intraoperative field. It was unknown whether the pain was secondary to the treatment or recurrent disease.
123
TUMORS
Residual before IOEBRT
Survival from surgery for IOEBRT (months)
N/A N/A None None >2 cm N/A N/A
2 29 9 46 8 (NED) 20 6
None
14
<2 cm
24
These two cases raise the possibility that the chemotherapy the patients received could have sensitized the neural tissues to the radiation. No firm conclusions of the efficacy of IOEBRT in the treatment of ovarian malignancies can be drawn by reviewing the data from this small pilot study with varied histologies. By using IOEBRT, however, after the initial operation before whole-abdomen irradiation, macroscopic tumor deposits could be given higher doses, presumably with a greater chance of cure without unduly increasing treatment morbidity. ACKNOWLEDGMENT The authors thank Susan Bannister for her technical assistance in the typing of this manuscript.
REFERENCES 1. Silverberg, E., and Lubera, J. A. Cancer statistics, 1989, CA 39, 3-20 (1989). 2. Richardson, Cl. S., Scully, R. E., Nikrui, N., and Nelson, J. H. Common epithelial cancer of the ovary (first of two parts), N. Engl. J. Med. 312, 415-424 (1985). 3. Richardson, G. S., Scully, R. E., Nikrui, N., and Nelson, J. H. Common epithelial cancer of the ovary (second of two parts), N. Engl. J. Med. 312, 474-483 (1985). 4. Belinson, J. T., McClure, M., Ashikoga, T., and Karadhof, I. H. Treatment of advanced and recurrent ovarian carcinoma with cyclophosphamide, doxorubicin and cisplatin, Cancer 64, 1983-1990 (1984). 5. Dembo, A. J. Abdominopelvic radiotherapy in ovarian cancer, Cancer 55, 2285-2290 (1985). 6. Dembo, A. J. Radiotherapeutic management of ovarian cancer, Semin. Oncol. 11, 238-250 (1984). 7. Fuks, Z., Rizel, S., Anteby, S. O., and Brian, S. The multimodality approach to the treatment of stage III ovarian carcinoma, Int. J. Radiut.
Oncol. Biol. Phys. 8, 903-908 (1982).
8. Glatstein, E., Fuks, Z., and Bagshaw, M. A. Diaphragmatic treatment in ovarian carcinoma: A new radiotherapeutic technique, lnt. .I. Radiat.
0~01.
Biol. Phys. 2, 357-362 (1977).
124
KONSKI ET AL.
9. Martinez, A., Schray, M. F., Howes, A. E., and Bagshaw, M. A. Postoperative radiation therapy for epithelial ovarian cancer: The curative role based on a 24-year experience, .I. Clint. Oncol. 3, 901-911 (1985). 10. Young, R. C., Decker, D. G., Wharton, J. T., Piver, S., Sindelar, W. F., Edwards, B. K., and Smith, J. P. Staging laparotomy in early ovarian cancer, J. Amer. Med. Assoc. 250,3072-3076 (1983). 11. Schray, M. M., Cox, R. S., and Martinez. Lower abdominal radiotherapy for stages I and II and selected III epithelial ovarian cancer: 20 years experience, Gynecol. Oncol. 15, 78-87 (1983). 12. Kuten, A., Stein, M., Steiner, M., Rubinov, R., Epelbaum, R., and Cohen, Y. Whole abdominal irradiation following chemotherapy in advanced ovarian carcinoma, Int. J. Radiat. Oncol. Biol. Phys. 14, 273-280 (1988).
13. Ozols, R. F., and Young, R. C. Chemotherapy of ovarian cancer, Semin. Oncol. 11, 251-263 (1984).
14. Fuks, Z., and Bagshaw, M. A. The rationale for curative radiotherapy for ovarian carcinoma, Int. J. Radial. Oncol. Biol. Phys. 1, 21-32 (1985).
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