Vol. 131, March
JOURNAL OF UROLOGY
Copyright © 1984 by The Williams & Wilkins Co.
Printed in U.S.A.
SURVEILLANCE ALONE FOR PATIENTS WITH CLINICAL STAGE I NONSEMINOMATOUS GERM CELL TUMORS OF THE TESTIS: PRELIMINARY RESULTS DOUGLAS K JOHNSON,* RICHARD K. LO, ANDREW C_ DAVID A. SWANSON
From the Department of Urology, University of Texas, M. D. Anderson Hospital and Tumor Institute, Houston, Texas
A total of 31 men with clinical stage I nonseminomatous germ cell tumors of the testis was followed for 2 to 18 months (median 10 months) after inguinal orchiectomy. Of the patients 26 (84 per cent) have been continuously free of disease. Relapse occurred in 5 patients (16 per cent) at 2, 2, 4, 4 and 6 months, respectively, but they were rendered free of disease with combination chemotherapy_ The results suggest that careful surveillance following orchiectomy is all that is required for patients who have nonseminomatous germ cell testicular tumors but no obvious regional or visceral metastases_ Attitudes about surgery and radiotherapy for testicular cancer are changing as a result of improved detection of early metastatic foci and the availability of chemotherapy regimens that eradicate metastases effectively. Now that cure can be expected for all types and stages of testicular cancer emphasis currently is being directed toward how best to achieve cure and, at the same time, limit the morbidity and long-term sequelae of therapy. Although radiotherapy or retroperitoneal lymphadenectomy had a major role in the treatment of stage I nonseminomatous germ cell testicular tumors in the past, 1 recent reports suggested that careful surveillance may be sufficient for patients who have no obvious regional or visceral metastases. 2- 4 Consequently, in October 1981 we began a pilot study to evaluate the feasibility of a post-orchiectomy surveillance program in a carefully controlled setting for patients with nonseminomatous germ cell tumors of the testis. MATERIALS AND METHODS
We studied 31 patients with stage I nonseminomatous germ cell tumors of the testis (19 with teratocarcinoma, 10 with embryonal carcinoma and 2 with teratoma) who were evaluated in our department of urology from October 1981 through January 1983. Metastatic disease was judged to be absent in each patient on the basis of normal physical findings, normal levels of t-human chorionic gonadotropin and a-fetoprotein, and negative chest x-rays, computerized tomography (CT) of the retroperitoneum, abdomen and pelvis, and bilateral pedal lymphangiograms. Patients were excluded from the study if the tumor markers failed to decrease at a rate consistent with their known metabolic decay or half-life, even if all other findings were negative. The surveillance program consisted of periodic examinations plus radiographic and serum studies (table 1). Plain radiographs of the abdomen were obtained at 2-month intervals as long as sufficient contrast material was retained in the retroperitoneal lymph nodes to allow adequate examination_ If the patient remained free of disease after 12 months he was placed on a routine followup program of examinations every 3 months for 2 years and every 6 months for another 2 years. Annual checkups are recommended after 5 years. Accepted for publication September 2, 1983. * Requests for reprints: Department of Urology, M. D. Anderson Hospital, 6723 Bertner Ave., Houston, Texas 77030.
The 31 patients ranged from 18 to 47 years old, with a median age of 27 years. The initial clinical characteristics were fairly uniform, including testicular mass in 90 per cent of the patients and testicular pain in 42 per cent. Serum measurements for afetoprotein and t-human chorionic gonadotropin were available for all patients and 1 or both markers were elevated initially in 55 per cent (52 and 35 per cent, respectively). Both measurements initially were elevated in 32 per cent of the patients. The markers returned to the normal range postoperatively in all but 1 patient, in whom the a-fetoprotein level was believed to be decreasing at the expected rate but on subsequent followups began increasing. This patient was treated for metastatic disease. Followup for the 31 patients ranged from 2 to 18 months, with a median of 10 months (see figure). Five patients had relapse at 2, 2, 4, 4 and 6 months, respectively. Relapse occurred in the lung in 3 patients and the retroperitoneum in 1. In the remaining patient the only indication of metastatic disease was an increasing titer for both tumor markers. All 5 patients have received combination chemotherapy and are in complete remission after 6, 8, 15, 15 and 15 months, respectively. DISCUSSION
Once the diagnosis of nonseminomatous germ cell tumor of the testis has been established by inguinal orchiectomy and a careful evaluation has excluded metastatic disease (stage I) the physician can choose between several treatment options, including observation alone, retroperitoneal lymphadenectomy, radiotherapy and chemotherapy alone or in combination with lymphadenectomy or radiotherapy. 5 Early in this century, when observation alone was used, only 25 per cent of the patients survived. 6 This unacceptable survival rate led to the routine use of retroperitoneal lymphadenectomy or radiotherapy. Although similar results were reported with both treatments retroperitoneal lymphadenectomy became the standard therapy for patients with clinical stage I nonseminomatous germ cell tumors of the testis. 1 Unfortunately, although operative mortality has been negligible and immediate postoperative complications have been infrequent (7 to 15 per cent) and minor ,7· 8 the operation results frequently in loss of seminal emission. This loss of fertility has proved to be a major problem, since these patients usually are young and have not completed their families. A few studies have suggested satisfactory resto-
JOHNSON AND ASSOCIATES TABLE
2. Summary of current surveillance programs
Continuously Free of Disease (%)
Memorial Sloan-Kettering Cancer Center Royal Marsden Hospital M. D. Anderson Hospital and Tumor Institute Totals
..c E ::::,
1. Program of clinical surveillance for patients with stage I
nonseminomatous testis tumor Interval (mos.)
Physical examination Lymphangiogram CT scan Chest x-ray Plain film of the kidneys, ureters and bladder a-fetoprotein /J-human chorionic gonadotropin SMA-12
X X X X X
X X X
X X X
ration of ejaculation with sympathomimetic drugs9 • 10 but our experience with such therapy has been disappointing. Attempts to circumvent this complication by cryopreservation of semen have not proved practical. 11 Understandably, therefore, with the development of newer diagnostic studies (ultrasonography, CT and radioimmunoassays) and the general availability of effective chemotherapy programs to salvage patients who have relapse despite careful clinical staging the possibility of terminating active treatment after orchiectomy for patients with stage I disease is being reappraised. Preliminary reports in several surveillance studies have demonstrated the feasibility of conservative treatment after orchiectomy for patients with nonseminomatous germ cell tumors of the testis (table 2). 3 • 12• 13 Relapse rates have ranged from 16 to 22 per cent but it is noteworthy that all patients who have metastases have become free of disease with chemotherapy. Skeptics have criticized the relapse rates reported in surveillance studies and argued that survival rates following retroperitoneal lymphadenectomy are too high to justify abandoning the procedure. 5• 14 However, one should not forget that metastatic disease develops subsequently at other sites in 10 to 15 per cent of the patients in whom normal retroperitoneal lymph nodes have been proved by lymphadenectomy. 15• 16 Although recent studies by Raghavan and associates have suggested no association between histologic subtypes and metastatic rates, 17 previous analyses of pathologic stage I nonseminomatous germ cell tumors of the testis managed by retroperitoneal lymphadenectomy have shown that embryonal carcinoma has a much greater propensity for spread to other sites without involvement of the regional lymph nodes. 1• 8 Among 72 patients at our hospital who had pathologic stage I disease and who underwent lymphadenectomy alone only 10 per cent of those with teratocarcinoma suffered metastases at other sites compared to 25 per cent of those with embryonal carcinoma. 15 Therefore, it is not surprising that Peckham and associates
found a much higher relapse rate after orchiectomy alone for patients with embryonal carcinoma (37 per cent) than for those with teratocarcinoma (3 per cent). 12 Likewise, we noted later metastases in 11 per cent of patients with teratocarcinoma and 30 per cent of those with embryonal carcinoma. As a result of the different frequencies of histologic subtypes among patient populations, relapse rates and sites of metastases can be expected to vary somewhat among studies. It is disappointing that despite recent advances in diagnostic procedures 10 to 15 per cent of the patients believed to be free of nodal metastases will have retroperitoneal disease later. 8 • 16 However, initial lymphangiography and CT examination of the retroperitoneal lymph nodes, serial abdominal radiographs and periodic CT scans to monitor changes within the nodes should detect early metastatic disease in the retroperitoneum. The majority of the metastases in patients with nonseminomatous germ cell tumors of the testis are evident ~12 months postoperatively. 18 Consequently, it is imperative that these patients be examined frequently during the first year of surveillance. It has been suggested that these young patients often are unreliable about returning for followup examinations and may escape early diagnosis of metastases, thereby reducing the likelihood of cure with chemotherapy. 14 However, our experience is similar to that of Peckham and associates 12 in that if these patients are informed fully about the reasons for close surveillance they experience less mental anguish and attend followup examinations conscientiously. In summary, our preliminary experience with surveillance alone after orchiectomy in patients with clinical stage I nonseminomatous germ cell tumors of the testis has proved that a wait and watch policy is safe. The morbidity and long-term sequelae that result from lymphadenectomy or radiotherapy are eliminated and all patients with relapse have been rendered free of disease by chemotherapy. REFERENCES
1. Babaian, R. J. and Johnson, D. E.: Management of stages I and II
nonseminomatous germ cell tumors of the testis. Cancer, 45: 1775, 1980.
2. Stout, R. and Hunter, R. D.: Orchidectomy alone for stage I testicular teratoma. Brit. Med. J., 283: 885, 1981. 3. Read, G.: Follow-up policy in stage I teratoma of testis-first year's experience. In: Germ Cell Tumours. Edited by C. K. Anderson, W. G. Jones and A. Milford Ward. London: Taylor & Francis, p. 289, 1981. 4. Peckham, M. J. and Barrett, A.: Radiotherapy in testicular teratoma. In: The Management of Testicular Tumours. Edited by M. Peckham. Chicago: Year Book Medical Publishers, chapt. 13, pp. 174-201, 1981. 5. Williams, S. D. and Einhorn, L. H.: Clinical stage I testis tumors: the medical oncologist's view. Cancer Treat. Rep., 66: 15, 1982. 6. Higgins, C. C. and Buchert, W. I.: Malignant tumors of the testicle: a review of eighty-three cases. Amer. J. Surg., 43: 675, 1939. 7. Babaian, R. J., Bracken, R. B. and Johnson, D. E.: Complications of transabdominal retroperitoneal lymphadenectomy. Urology, 17: 126, 1981. 8. Whitmore, W. F., Jr.: Surgical treatment of adult germinal testis tumors. Semin. Oncol., 6: 55, 1979. 9. Kelly, M. E. and Needle, M. A.: Imipramine for aspermia after lymphadenectomy. Urology, 13: 414, 1979. 10. Nijman, J. M., Jager, S., Boer, P. W., Kremer, J., Oldhoff, J. and
STA.GE I l\J0i'-'J8£:tv_nt~OTh11AT0US GERM CELL TUt1lORS OF TESTIS
Koops, I-I. S.: The treatrr1ent of ejaculation disorders .after retroperitoneal lymph node dissection. Cancer, 50: 2967, 1982. Bracken, R. B. and Smith, K. D.: Is semen cryopreservation helpful in testicular cancer? Urology, 15: 581, 1980. Peckham, M. J., Barrett, A., Husband, J. E. and Hendry, W. F.: Orchidectomy alone in testicular stage I non-seminomatous germ-cell tumours. Lancet, 2: 678, 1982. Sogani, P. C., Whitmore, W. F., Jr., Herr, H., Bos!, G., Golbey, R., Watson, R. and DeCosse, J.: Orchiectomy alone in treatment of clinical stage I non-seminomatous germ cell tumor of testis (NSGCTT). Proc. Amer. Soc. Clin. Oneal., abstract C-547, 2: 140, 1983. Pontes, J. E.: Place of radical node dissection in testicular tumour therapy. Lancet, 2: 1404, 1982. Johnson, D. E., Bracken, R. B. and Blight, E. M.: Prognosis for pathologic stage I non-seminomatous germ cell tumors of the testis managed by retroperitoneal lymphadenectomy. J. Urol., 116: 63, 1976. Whitmore, W. F., Jr.: Surgical treatment of clinical stage I nonseminomatous germ cell tumors of the testis. Cancer Treat. Rep., 66: 5, 1982. Raghavan, D., Vogelzang, N. J., Bos!, G. J., Nochomovitz, L. E., Rosai, J., Lange, P. H., Fraley, E. E., Goldman, A., Torkelson, J. and Kennedy, B. J.: Tumor classification and size in germcell testicular cancer: influence on the occurrence of metastases. Cancer, 50: 1591, 1982. Glatstein, E.: Optimal management of clinical stage I nonseminomatous testicular carcinoma: one oncologist's view. Cancer Treat. Rep., 66: 11, 1982. EDITORIAL COMMENTS
These data would be more relevant in another 2 years. Studies from Memorial Sloan-Kettering Cancer Center and Royal Marsden Hospital have indicated similar results in a larger patient population and with longer followup. It is intriguing to abandon retroperitoneal lymphadenectomy in patients with clinical stage I disease. However, that can be done only when we have a realistic appraisal of the relapse rate and, more importantly, information on whether all relapses are cured with chemotherapy. This study concerns only 31 patients with brief followup (2 to 18 months) and 5 (16 per cent) have had a relapse. More patients will have a relapse with longer followup. Although all 5 patients with a relapse presently are free of disease the followup is brief. Lawrence H. Einhorn Department of Urology Indiana University Medical Center Indianapolis, Indiana At a time when the cure rate for nonseminomatous germ cell tumors of the testis approaches 100 per cent for all patients with stage A or B disease it is logical to question the role of any part of the therapy that produces morbidity. Although one cannot question the mortality (O per cent) or complication rate (3 to 5 per cent) for retroperitoneal lymphadenectomy the issue of infertility resulting from the operation and the success of combination chemotherapy in curing patients with a relapse have led to pilot studies, such as this, in which patients with clinical stage A disease are observed closely without an operation and then treated by intensive combination chemotherapy at the first evidence of relapse. To date 4 centers have reported early results. There is an average 18
per cent relapse rate with a median followup of 10 months among the 3 centers discussed in table 2. Toronto has reported a 40 per cent reiapse rate among 20 patients with a median followup of 14 months. Several points of perspective should be emphasized. M. D. Anderson Hospital and Tumor Institute, and Royal Marsden Hospital, in particular, are known to have outstanding skills in interpretation of lymphangiograms and CT scans, with accuracy in predicting the presence or absence of nodal disease far better than that reported elsewhere. The median followup of 10 months suggests further erosion in the percentage of patients continuously free of disease, inasmuch as the median interval to relapse in patients with surgical stage A disease is 13 months, with a range to 24 months. We probably cannot assume a continued 100 per cent salvage by combination chemotherapy for patients who have a relapse, given the reported morbidity and mortality of combination chemotherapy (1 to 2 per cent for cisplatinum, vinblastine and bleomycin). In addition, patient compliance and followup may not be perfect and some may return with more advanced relapse, in which case cure with drugs and an operation is less certain (50 to 80 per cent). Whitmore has reported that 1 of his patients had brain metastases and subsequently died. Einhorn has reported on 2 patients who were treated as outlined in the paper and subsequently failed cisplatinum, vinblastine and bleomycin therapy. Both patients are failing salvage VP-16 combination chemotherapy. These 3 failures have not been reported previously. The reader should recognize that this is a preliminary report. It is a carefully controlled, monitored experimental alternative approach but far from state-of-the-art therapy. The ultimate value of this or similar protocols will not be known for 2 to 3 years. In the meantime, the following arguments support the continued use of retroperitoneal dissection. Those series in which retroperitoneal lymph node dissection has been the principal treatment have produced the best over-all survival rate for patients with stages A and B cancer (nearly 100 per cent at 3 years). The operation is extremely well tolerated by patients without operative mortality and with <5 per cent morbidity. The issue of infertility may be overstated. To date, no patient has been reported to have lost the ability to achieve a satisfactory erection and to experience orgasm as a result of a properly performed retroperitoneal dissection. Modification of the operation for patients with minimal disease allows nearly 50 per cent to achieve antegrade ejaculation postoperatively. In addition, many patients with testicular cancer have impaired fertility even before therapy. Finally, an operation has the fewest long-term side effects. The late sequelae of combination chemotherapy are entirely unknown and many more nonsurgical patients will be subjected to intensive platinum-containing combination chemotherapy. How many will suffer late pulmonary, vascular or renal complications? Will there be an increased risk of chemotherapy-induced second cancers? These are legitimate questions that remain unanswered. Thus, while it is quite proper to question the need for an operation and to study nonoperative alternatives, retroperitoneal dissection should remain a part of the treatment for nonseminomatous germ cell tumors of the testis until or unless carefully controlled clinical trials stand the test of time and prove that patients can be managed just as effectively and efficiently by other means. Donald G. Skinner Division of Urology University of Southern California Medical Center Los Ange/,es, California