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Sandwich Therapy in Testis Tumor: Current Experience
0022-534 7/78/1194-0612$02. 00/0 Vol. 119, May Printed in U.SA.
TIQl JOURNAL OF, UROLOGY Copyright © 1978 by The Williams & Wilkins Co.
SANDWICH THERAPY IN TESTIS TUMOR: CURRENT EXPERIENCE DONALD F. LYNCH, JR.,* LARRY P. MCCORD, THOMAS C. NICHOLSON,t JEROME P. RICHIE:j: AND C. ROLLAND SARGENTS§ From the Department of Urology, Naval Regional Medical Center, San Diego, California
ABSTRACT
Sandwich therapy, a regimen of lymphadenectomy combined with preoperative and postoperative cobalt teletherapy, yielded a survival rate of 84 per cent in 13 patients with stages A and B non-seminomatous testis tumor. This statistic is consistent with the previously reported survival rate of 83 per cent achieved among 35 patients treated with this regimen from 1958 to 1970 at our institution. Bone marrow depression, retroperitoneal fibrosis and possible induction of a second malignancy were important side effects of radiation therapy. The superior survival rates with fewer severe side effects of treatment obtained by other investigators using either lymphadenectomy alone or lymphadenectomy combined with chemotherapy have prompted us to discontinue sandwich therapy as standard treatment for non-seminomatous testis tumors at our institution. Sandwich therapy, that is lymphadenectomy preceded and followed by radiation, has been the standard method of treatment at our institution for stages A and B embryonal cell carcinoma and teratocarcinoma of the testis. In 1958 Dykhuizen and associates reported a survival rate of 93 per cent in a series of 15 patients. 1 Nicholson and associates, summarizing their experience with 35 patients treated between 1958 and 1970, reported a 3-year survival of 83 per cent. 2 Thirteen additional patients form the basis for our report. The value of sandwich therapy has been reassessed in the light of recent advances in surgery and adjuvant chemotherapy. MATERIAL AND METHODS
The 13 patients were treated between December 1970 and November 1973, with a followup of 3 to 6 years. Testis tumors were classified according to the criteria of Friedman and Moore as either seminoma, teratoma, teratocarcinoma, embryonal cell carcinoma or choriocarcinoma. 3 After radical orchiectomy each patient was evaluated based on results obtained with lymphangiography, excretory urography, chest roentgenogram, urinary or serum gonadotropins and scalene node biopsy when indicated clinically. Patients were staged clinically as stage A-those with tumor confined to the testis, stage B- those with tumor metastases limited to the retroperitoneal lymph nodes and stage C - those with distant metastases. No patient who survived 3 years free of tumor died subsequently of the disease; therefore, all patients alive at least 3 years post-therapy are included as survivors. All cases were considered resectable. Preoperatively, all patients received an average of 2,000 rads to the entire abdomen during a 28-day period, 1 which was followed within 1 week by bilateral retroperitoneal lymphadenectomy. Limits of the dissection included the diaphragm superiorly, the ureters laterally, the inguinal ring inferiorly on the ipsilateral side and the aortic bifurcation inferiorly on the contralateral side. Approximately 3 weeks postoperatively an average of 2,500 rads was delivered through a restricted abdominal port that excluded the kidneys. The mediastinum and supraclavicular areas were irradiated with a dosage Accepted for publication July 1, 1977. Read at annual meeting of Western Section, American Urological Association, San Francisco, California, March 13-17, 1977. * Requests for reprints: Department of Urology, Naval Regional Medical Center, San Diego, California 92134. t Current address: 9844 Genesee Ave., La Jolla, California 92037. :j: Current address: Peter Bent Brigham Hospital, Boston, Massachusetts 02115. § Current address: 5450 Lea St., San Diego, California 92105. 612
averaging 4,200 rads several weeks after the completion of abdominal radiation therapy. RESULTS
Of the 13 patients 11 (84 per cent) have survived at least 3 years without recurrence of disease. One patient with stage B teratocarcinoma died of metastatic disease and 1 patient died of peritonitis following lymphadenectomy. Another patient died of complications of thrombocytopenic purpura 3 years after therapy but an autopsy revealed no evidence of tumor. The 3-year survival rate by stage and histologic type is summarized in table 1. In 1 patient a scrotal abscess developed during postoperative radiation and 1 patient experienced chylous ascites that persisted several months postoperatively. An additional patient, not included in these data, required discontinuation of postoperative abdominal radiation because of severe leukopenia. A total of 48 patients has now been treated with sandwich therapy from 1958 to 1974. Forty patients (83 per cent) survived at least 3 years (table 2). Eight patients have died of metastases or as a direct result of complications of treatment and 2 have died subsequently of causes other than tumor. Commonly encountered complications have included ejaculatory impotence, bone marrow depression, prolonged ileus, superficial wound infections and weight loss. Serious complications have required the discontinuation of sandwich therapy in at least 5 patients. We currently are evaluating 11 additional patients treated with sandwich therapy for whom followup ranges from 4 to 21 months. Of this group 1 patient is dead of metastatic disease and 1 of complications of anesthesia. A third patient has recent pulmonary metastases following a complicated postoperative course in which reoperation and ureterostomy were required to relieve ureteral obstruction secondary to postoperative, post-radiation, non-malignant retroperitoneal fibrosis. In another patient treated during this time leukopenia developed and required discontinuation of sandwich therapy. DISCUSSION
The combined results of the 2 series,from our institution provide an over-all survival rate of 83 per cent for 48 patients. All were treated in a uniform manner with the sandwich therapy protocol during a 16-year period. The 3-year survival rate of 84 per cent obtained with the present series of 13 patients is consistent with earlier observations. Maier and Mittemeyer report an over-all survival rate of 90 per cent using a similar protocol with a group of 51 patients. 4
613
SANDWICH THERAPY IN TESTIS TUMOR TABLE
1. 3-year survival rates-current series Pathologic Stage
A
B
No. Pts.
No. Pts.
3/3 4/4
2/4 _Jj'!:._
7/7
4*/6
Teratoca. Embryonal cell Ca
Total No. Pts.
11/13
* Includes l operative death. TABLE
2. 3-year survival rates-total series (1958-1974) Pathologic Stage A
B
No. Pts. (%)
No. Pts. (%)
15/16 (93) 15/18 (83)
6*/9 (67)
30/34 (88)
10*/14 (71)
Teratoca. Embryonal cell Ca
Total No. Pts. (%)
4/5 (80) 40/48 (83)
* Includes 1 operative death. our results continue to be satisfactory recent developments in the treatment of stages A and B non-seminomatous testis tumors have prompted reassessment of our treatment regimen. With the use of lymphadenectomy alone Staubitz and associates have obtained an over-all survival rate of 87 per cent. 5 Skinner recently has demonstrated an over-all survival rate of 90 per cent using a regimen of lymphadenectomy in combination with a program of chemotherapy.G Skinner has demonstrated that 2 advantages attributed to sandwich therapy, that is the control of lymph node metastases inaccessible to operation and the reduction of local and systemic seeding during surgical manipulation, can be accomplished successfully with intraoperative and postoperative chemotherapy. Furthermore, chemotherapy theoretically would be effective against microscopic tumor metastases in those areas of the lung outside of the irradiated mediastinal zone. This feature may be significant since most of the treatment failures have recurred as pulmonary metastases. The disadvantages of sandwich therapy are considerable. 1) The period of treatment averages a lengthy 20 weeks from orchiectomy to completion of cobalt therapy, with complications prolonging hospitalization. Discontinuation of treatment to complications is not infrequent. 2) Depression of bone 111.arrow has limited the use of tumoricidal dosage of chemoin with recurrent tumor following treatment.
Severe leukopenia has twice necessitated discontinuance sandwich therapy midway in treatment. 3) Radiation may cause or exacerbate retroperitoneal fibrosis or gastric ulcer disease. 4 4) The possibility exists of a radiation-induced second malignancy. One patient reported by Nicholson and associates died of metastatic reticulum cell sarcoma 12 years after treatment for stage A embryonal cell carcinoma, 2 and other reports have suggested that radiation-induced malignancies may occur as a possible late side effect ofradiation therapy. a We have concluded that in the treatment of stages A and B non-seminomatous testis tumors sandwich therapy now has been superseded by more effective approaches that yield if not superior survival rates and fewer potential serious side effects. Therefore, sandwich therapy has been discontinued as the standard method of treatment for this disorder at our institution. A new protocol, based on thorough retroperitoneal lymphadenectomy in conjunction with chemotherapy, is designed, with radiation therapy reserved for adjunctive treatment of recurrent tumor or non-resectable retroperitoneal. metastases. REFERENCES
L Dykhuizen, R. F., George, F. W., III, Kurohara, S., Rotner, M., Sargent, C. R. and Varney, J. K.: The use of cobalt 60 telecurietherapy or x-ray therapy with and without lymphad enectomy in the treatment of testis germinal tumors: a 20year comparison study. J. UroL, lllll: 321, 1968. 2. Nicholson, T. C., Walsh, P. C. and Rotner, M. B.: Lymphadenectomy combined with preoperative and postoperative cobalt 60 teletherapy in the management of embryonal carcinoma and teratocarcinoma of the testis. J. Urol., 112: 109, 1974. 3. Friedman, N. B. and Moore, R. A.: Tumors of the testis: a report of922 cases. Mil. Surg., 99: 573, 1946. 4. Maier, J. G. and Mittemeyer, B. T.: Carcinoma of the testis. Cancer, 39: 981, 1977. 5. Staubitz, W. J., Early, KS., Magoss, I. V. and Murphy, G. P.: Surgical management of testis tumor. J. UroL, 111: 205, l.974. 6. Skinner, D. G.: Non-seminomatous testis tumors: a plan of management based on 96 patients to improve survival in all stages by combined therapeutic modalities. J. Urol., H5: 65, 1976. 7. Arseneau, J.C., Sponzo, R W., Levin, D. L., Schnipper, L. E., Bonner, H., Young, RC., Canellos, G. P., Johnson, R. E. and DeVita, V. T.: Nonlymphomatous malignant tumors complicating Hodgkin's disease. Possible association with intensive therapy. New Engl. J. Med., 287: 1119, 1972. 8. Senyszyn, J. J., Johnston, A. D., Jacox, H. W. and Chu, F. C. H.: Radiation-induced sarcoma after treatment of breast cancer. Cancer, 26: 394, 1970.
TIQl JOURNAL OF, UROLOGY Copyright © 1978 by The Williams & Wilkins Co.
SANDWICH THERAPY IN TESTIS TUMOR: CURRENT EXPERIENCE DONALD F. LYNCH, JR.,* LARRY P. MCCORD, THOMAS C. NICHOLSON,t JEROME P. RICHIE:j: AND C. ROLLAND SARGENTS§ From the Department of Urology, Naval Regional Medical Center, San Diego, California
ABSTRACT
Sandwich therapy, a regimen of lymphadenectomy combined with preoperative and postoperative cobalt teletherapy, yielded a survival rate of 84 per cent in 13 patients with stages A and B non-seminomatous testis tumor. This statistic is consistent with the previously reported survival rate of 83 per cent achieved among 35 patients treated with this regimen from 1958 to 1970 at our institution. Bone marrow depression, retroperitoneal fibrosis and possible induction of a second malignancy were important side effects of radiation therapy. The superior survival rates with fewer severe side effects of treatment obtained by other investigators using either lymphadenectomy alone or lymphadenectomy combined with chemotherapy have prompted us to discontinue sandwich therapy as standard treatment for non-seminomatous testis tumors at our institution. Sandwich therapy, that is lymphadenectomy preceded and followed by radiation, has been the standard method of treatment at our institution for stages A and B embryonal cell carcinoma and teratocarcinoma of the testis. In 1958 Dykhuizen and associates reported a survival rate of 93 per cent in a series of 15 patients. 1 Nicholson and associates, summarizing their experience with 35 patients treated between 1958 and 1970, reported a 3-year survival of 83 per cent. 2 Thirteen additional patients form the basis for our report. The value of sandwich therapy has been reassessed in the light of recent advances in surgery and adjuvant chemotherapy. MATERIAL AND METHODS
The 13 patients were treated between December 1970 and November 1973, with a followup of 3 to 6 years. Testis tumors were classified according to the criteria of Friedman and Moore as either seminoma, teratoma, teratocarcinoma, embryonal cell carcinoma or choriocarcinoma. 3 After radical orchiectomy each patient was evaluated based on results obtained with lymphangiography, excretory urography, chest roentgenogram, urinary or serum gonadotropins and scalene node biopsy when indicated clinically. Patients were staged clinically as stage A-those with tumor confined to the testis, stage B- those with tumor metastases limited to the retroperitoneal lymph nodes and stage C - those with distant metastases. No patient who survived 3 years free of tumor died subsequently of the disease; therefore, all patients alive at least 3 years post-therapy are included as survivors. All cases were considered resectable. Preoperatively, all patients received an average of 2,000 rads to the entire abdomen during a 28-day period, 1 which was followed within 1 week by bilateral retroperitoneal lymphadenectomy. Limits of the dissection included the diaphragm superiorly, the ureters laterally, the inguinal ring inferiorly on the ipsilateral side and the aortic bifurcation inferiorly on the contralateral side. Approximately 3 weeks postoperatively an average of 2,500 rads was delivered through a restricted abdominal port that excluded the kidneys. The mediastinum and supraclavicular areas were irradiated with a dosage Accepted for publication July 1, 1977. Read at annual meeting of Western Section, American Urological Association, San Francisco, California, March 13-17, 1977. * Requests for reprints: Department of Urology, Naval Regional Medical Center, San Diego, California 92134. t Current address: 9844 Genesee Ave., La Jolla, California 92037. :j: Current address: Peter Bent Brigham Hospital, Boston, Massachusetts 02115. § Current address: 5450 Lea St., San Diego, California 92105. 612
averaging 4,200 rads several weeks after the completion of abdominal radiation therapy. RESULTS
Of the 13 patients 11 (84 per cent) have survived at least 3 years without recurrence of disease. One patient with stage B teratocarcinoma died of metastatic disease and 1 patient died of peritonitis following lymphadenectomy. Another patient died of complications of thrombocytopenic purpura 3 years after therapy but an autopsy revealed no evidence of tumor. The 3-year survival rate by stage and histologic type is summarized in table 1. In 1 patient a scrotal abscess developed during postoperative radiation and 1 patient experienced chylous ascites that persisted several months postoperatively. An additional patient, not included in these data, required discontinuation of postoperative abdominal radiation because of severe leukopenia. A total of 48 patients has now been treated with sandwich therapy from 1958 to 1974. Forty patients (83 per cent) survived at least 3 years (table 2). Eight patients have died of metastases or as a direct result of complications of treatment and 2 have died subsequently of causes other than tumor. Commonly encountered complications have included ejaculatory impotence, bone marrow depression, prolonged ileus, superficial wound infections and weight loss. Serious complications have required the discontinuation of sandwich therapy in at least 5 patients. We currently are evaluating 11 additional patients treated with sandwich therapy for whom followup ranges from 4 to 21 months. Of this group 1 patient is dead of metastatic disease and 1 of complications of anesthesia. A third patient has recent pulmonary metastases following a complicated postoperative course in which reoperation and ureterostomy were required to relieve ureteral obstruction secondary to postoperative, post-radiation, non-malignant retroperitoneal fibrosis. In another patient treated during this time leukopenia developed and required discontinuation of sandwich therapy. DISCUSSION
The combined results of the 2 series,from our institution provide an over-all survival rate of 83 per cent for 48 patients. All were treated in a uniform manner with the sandwich therapy protocol during a 16-year period. The 3-year survival rate of 84 per cent obtained with the present series of 13 patients is consistent with earlier observations. Maier and Mittemeyer report an over-all survival rate of 90 per cent using a similar protocol with a group of 51 patients. 4
613
SANDWICH THERAPY IN TESTIS TUMOR TABLE
1. 3-year survival rates-current series Pathologic Stage
A
B
No. Pts.
No. Pts.
3/3 4/4
2/4 _Jj'!:._
7/7
4*/6
Teratoca. Embryonal cell Ca
Total No. Pts.
11/13
* Includes l operative death. TABLE
2. 3-year survival rates-total series (1958-1974) Pathologic Stage A
B
No. Pts. (%)
No. Pts. (%)
15/16 (93) 15/18 (83)
6*/9 (67)
30/34 (88)
10*/14 (71)
Teratoca. Embryonal cell Ca
Total No. Pts. (%)
4/5 (80) 40/48 (83)
* Includes 1 operative death. our results continue to be satisfactory recent developments in the treatment of stages A and B non-seminomatous testis tumors have prompted reassessment of our treatment regimen. With the use of lymphadenectomy alone Staubitz and associates have obtained an over-all survival rate of 87 per cent. 5 Skinner recently has demonstrated an over-all survival rate of 90 per cent using a regimen of lymphadenectomy in combination with a program of chemotherapy.G Skinner has demonstrated that 2 advantages attributed to sandwich therapy, that is the control of lymph node metastases inaccessible to operation and the reduction of local and systemic seeding during surgical manipulation, can be accomplished successfully with intraoperative and postoperative chemotherapy. Furthermore, chemotherapy theoretically would be effective against microscopic tumor metastases in those areas of the lung outside of the irradiated mediastinal zone. This feature may be significant since most of the treatment failures have recurred as pulmonary metastases. The disadvantages of sandwich therapy are considerable. 1) The period of treatment averages a lengthy 20 weeks from orchiectomy to completion of cobalt therapy, with complications prolonging hospitalization. Discontinuation of treatment to complications is not infrequent. 2) Depression of bone 111.arrow has limited the use of tumoricidal dosage of chemoin with recurrent tumor following treatment.
Severe leukopenia has twice necessitated discontinuance sandwich therapy midway in treatment. 3) Radiation may cause or exacerbate retroperitoneal fibrosis or gastric ulcer disease. 4 4) The possibility exists of a radiation-induced second malignancy. One patient reported by Nicholson and associates died of metastatic reticulum cell sarcoma 12 years after treatment for stage A embryonal cell carcinoma, 2 and other reports have suggested that radiation-induced malignancies may occur as a possible late side effect ofradiation therapy. a We have concluded that in the treatment of stages A and B non-seminomatous testis tumors sandwich therapy now has been superseded by more effective approaches that yield if not superior survival rates and fewer potential serious side effects. Therefore, sandwich therapy has been discontinued as the standard method of treatment for this disorder at our institution. A new protocol, based on thorough retroperitoneal lymphadenectomy in conjunction with chemotherapy, is designed, with radiation therapy reserved for adjunctive treatment of recurrent tumor or non-resectable retroperitoneal. metastases. REFERENCES
L Dykhuizen, R. F., George, F. W., III, Kurohara, S., Rotner, M., Sargent, C. R. and Varney, J. K.: The use of cobalt 60 telecurietherapy or x-ray therapy with and without lymphad enectomy in the treatment of testis germinal tumors: a 20year comparison study. J. UroL, lllll: 321, 1968. 2. Nicholson, T. C., Walsh, P. C. and Rotner, M. B.: Lymphadenectomy combined with preoperative and postoperative cobalt 60 teletherapy in the management of embryonal carcinoma and teratocarcinoma of the testis. J. Urol., 112: 109, 1974. 3. Friedman, N. B. and Moore, R. A.: Tumors of the testis: a report of922 cases. Mil. Surg., 99: 573, 1946. 4. Maier, J. G. and Mittemeyer, B. T.: Carcinoma of the testis. Cancer, 39: 981, 1977. 5. Staubitz, W. J., Early, KS., Magoss, I. V. and Murphy, G. P.: Surgical management of testis tumor. J. UroL, 111: 205, l.974. 6. Skinner, D. G.: Non-seminomatous testis tumors: a plan of management based on 96 patients to improve survival in all stages by combined therapeutic modalities. J. Urol., H5: 65, 1976. 7. Arseneau, J.C., Sponzo, R W., Levin, D. L., Schnipper, L. E., Bonner, H., Young, RC., Canellos, G. P., Johnson, R. E. and DeVita, V. T.: Nonlymphomatous malignant tumors complicating Hodgkin's disease. Possible association with intensive therapy. New Engl. J. Med., 287: 1119, 1972. 8. Senyszyn, J. J., Johnston, A. D., Jacox, H. W. and Chu, F. C. H.: Radiation-induced sarcoma after treatment of breast cancer. Cancer, 26: 394, 1970.