Davor Vugrin

Autopsy findings in 154 patients with germ cell tumors of the testis.

Autopsy findings are reviewed in 154 patients treated for germ cell tumors of the testis. Of the patients with apparently pure seminoma, 44% had autopsy evidence of nonseminomatous metastases. For all tumor types, the most common sites of distant metastasis were lung (89%), liver (73%), brain (31%), and bone (30%). There was a high incidence of brain metastases in choriocarcinoma and of bone metastases in seminoma. Brain, liver, and bone metastases were late occurrences in the course of the disease and were almost always associated with involvement of other sites. Recurrences in the retroperitoneal area after lymph node dissection occurred mainly in those who had had retroperitoneal lymph node metastases. No difference in site or frequency of metastases was apparent in autopsied patients treated before or after introduction of platinum containing regimens. Respiratory failure, secondary to lung metastases, was the most common cause of death. Of the autopsied patients, 6% died of iatrogenic causes.

VAB-6 Combination Chemotherapy in Disseminated Cancer of the Testis

Twenty-nine men with stage III or unresectable stage II malignant germ cell tumors and no previous chemotherapy received treatments with the VAB-6 protocol. The VAB-6 regimen is a 1-year program beginning with three successive inductions at 3-to-4-week intervals: day 1--cyclophosphamide, 600 mg/m of body surface area intravenously, bleomycin, 30 mg intravenously, dactinomycin, 1 mg/m2 intravenously, and vinblastine, 4 mg/m2 intravenously; days 1 through 3--bleomycin, 20 mg/m2 . d by continuous infusion; and day 4--cisplatin, 120 mg/m2 intravenously. Bleomycin is omitted from the third induction. One month after the third induction, any residual disease is resected. If the resected specimen contains malignant tissue, an additional two inductions are given before maintenance with vinblastine, 6 mg/m2 intravenously, and dactinomycin, 1 mg/m2 intravenously, every 3 weeks. Of 25 patients with evaluable records, 23 achieved complete remission, and 21 remain in complete remission (median follow-up, more than 16 months). Myelosuppression is the major toxicity. With VAB-6 response rate is high, and treatment is short and better tolerated than with previous VAB protocols.

Combined chemotherapy and surgery in treatment of advanced germ‐cell tumors

Forty‐eight selected patients with GCT who were suspected of having residual disease after two or three chemotherapy inductions underwent an attempt at resection of this residual tumor. In 37 patients all gross disease was resected: 11 had malignant tissue, eight adult teratoma, and 18 no residual neoplasm, and 9, 7 and 17, respectively, remain free of disease. Patients in whom complete resection was not possible generally did poorly. Elevated serum tumor markers following the completion of preoperative chemotherapy indicated residual malignant disease and poor probability for complete resection. Twenty‐nine percent of patients with negative preoperative markers had malignancy at the time of surgery, but disease was resectable in most of these patients. The key for success is, first, the response to chemotherapy and, second, complete resection of residual disease. It is recommended that patients with initially bulky metastases (diameter > 5 cm) be first managed by chemotherapy, employing successive close inductions, and subsequently explored with intent to resect residual disease. When the resected specimen shows malignant elements, the patients should receive additional inductions, otherwise, maintenance chemotherapy is employed.

VAB–4 combination chemotherapy in the treatment of metastatic testis tumors

Forty‐two patients with advanced testis carcinoma without previous chemotherapy were treated with VAB‐4, and 41 were evaluable. The program consisted of three in‐hospital inductions 16 weeks apart, and outpatient treatments every three weeks. Of the patients, 80% achieved complete remissions (CR). Chemotherapy alone induced CR in 61%, partial remissions (PR), in 24% and minor response (MR), in 15%. An additional 20% of patients (six PRs and 2 MRs) achieved CR following resection of residual tumor deposits. With a median follow‐up of 27 months, the median duration of CR has not been reached. Of those achieving CR to chemotherapy alone, 12% had relapses. Bulk and extent of metastatic disease, histology of primary tumor, and tumor markers at the beginning of therapy influenced the frequency of CR. Of those with minimal disease, 90% achieved CR. The CR rate was 67% for those with advanced thoracic disease and 29% for those with advanced abdominal disease. Patients who had embryonal carcinoma and those who had no elevation of alpha‐fetoprotein had a higher frequency of CRs. Myelosuppression with a leukocyte count drop < 1000/mm3 occurred in three patients, and no patient had chronic renal failure or pulmonary fibrosis. One patient died from sepsis while in complete remission. Cancer 47:833–839, 1981.

VAB-3 combination chemotherapy of metastatic testicular cancer

The initial response and long‐term follow‐up of 74 evaluable patients who received combination chemotherapy for metastatic nonseminomatous testicular cancer are reported. Patients were treated with a protocol (VAB‐3) including vinblastine, actinomycin‐D, bleomycin, and cis‐dichlorodiammine platinum (DDP). VAB‐3 alone caused complete remission (CR) in 54% (40/74) and partial remission (PR) in 26% (19/74). Five patients with less than CR to chemotherapy achieved CR following surgical excision of residual mature teratoma after starting VAB‐3 protocol, resulting in an overall CR rate of 61% (45/74). With a minimum follow‐up of 24+ months, and a median follow‐up of 35+ months for those still living, 45% (33/74) of the patients are living free of evidence of disease, 4% (3/74) are living with disease, and 51% (38/74) are dead. Response to VAB‐3 protocol was examined with respect to performance status, histology, prior therapy, extent of disease, tumor markers, and duration of disease from diagnosis. No one died because of toxicity of VAB‐3, and life‐threatening toxicity was uncommon. Long survival is significantly associated (P < 0.001) with achievement of CR. The treatment goal for metastatic testicular cancer is cure. The achievement of CR, using aggressive combination chemotherapy and surgery, is essential in reaching this goal.

Serum tumor markers in patients with metastatic germ cell tumors of the testis: A 10-year experience

The serum values of alphafetoprotein, human chorionic gonadotropin, lactate dehydrogenase, and carcinoembryonic antigen in patients with metastatic testicular cancer were reviewed for the period 1972 to 1982. All values were obtained before chemotherapy was begun. Elevated values of alphafetoprotein were present in 47 percent of patients tested, of human chorionic gonadotropin in 60 percent, of lactate dehydrogenase in 64 percent, and of carcinoembryonic antigen in 11 percent. The frequency of elevated values of alphafetoprotein, human chorionic gonadotropin, and lactate dehydrogenase decreased during the study period. Inverse relations between elevated values of alphafetoprotein, human chorionic gonadotropin, and lactate dehydrogenase and both complete remission rate and survival rate were noted in some of the chemotherapy trials. Carcinoembryonic antigen was believed not to be useful as a marker in this disease. It is concluded that assays of alphafetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are important both clinically and prognostically in patients with testicular cancer.

Recurrences in Surgical Stage I Nonseminomatous Germ Cell Tumors of the Testis

A retrospective analysis of patients with surgical stage I nonseminomatous germ cell tumors of the testis was done in an attempt to define the pathogenesis of treatment failure. Of 138 patients 126 (91 per cent) remain free of disease, with a median followup of 5 or more years, and 12 (9 per cent) suffered relapse an average of 9 months after orchiectomy and retroperitoneal lymph node dissection. The majority of recurrences were in the lungs. Of 12 patients who had recurrence 6 were salvaged and are alive without evidence of disease 3 or more years after the second complete remission. A history of scrotal surgery or scrotal violation, the extent of the primary tumor and the presence of sarcomatous elements in the primary were not statistically significant risk factors in this study. A higher recurrence rate with embryonal carcinoma than with teratocarcinoma was not statistically significant.

Adjuvant chemotherapy combination of vinblastine, actinomycin D, bleomycin, and chlorambucil following retroperitoneal lymph node dissection for stage II testis tumor

In an attempt to reduce recurrence of nonseminomatous germ cell tumors of testis stage II, 62 patients were treated with vinblastine, actinomycin D, bleomycin, and chlorambucil after retroperitoneal lymph node dissection. Of the patients, 84% have remained in complete remission with median follow‐up of three years: 33/33 stage II‐A (N‐1,N‐2A) and 19/29 (66%) stage II‐B (N‐2B,N‐3). The relapse rate in patients who had histologic evidence of extranodal extension of the tumor (N‐3) was 54% (7/13). This program did not cause any serious toxicity. Adjuvant chemotherapy is effective in reducing relapses. More recently, with the current availability of chemotherapy with a high efficacy for control of disseminated disease, patients with resected stage II‐A (N‐1,N‐2A) have been followed closely and treated only if they developed evidence of recurrence. Patients with resected stage II‐B (N‐2B,N‐3) have been placed on a more aggressive adjuvant program. Cancer 47:840–844, 1981.

Adjuvant chemotherapy with VAB‐3 of stage II‐B testicular cancer

A recent report from the Memorial Sloan‐Kettering Cancer Center has indicated that patients with resected Stage IIB (N‐2B and N‐3) testicular cancer are at significant risk for relapse. Of patients with resected Stage IIB disease (N‐2B, 19%; N‐3, 54%), 34% relapsed after having undergone relatively mild adjuvant chemotherapy consisting of vinblastine, actinomycin D, bleomycin, and chlorambucil (VAB). In this study, 29 patients with resected Stage IIB testicular cancer underwent treatment with adjuvant VAB‐3 which has been used as primary treatment for Stage III disease. All patients have remained in complete remission with a median follow‐up time of 24 months. Three patients received broad spectrum antibiotics when fever and leukopenia developed. No patient experienced renal failure. The results of this study demonstrate the capability of aggressive adjuvant chemotherapy to prevent recurrence in the high‐risk setting of resected Stage II (N‐2B and N‐3) disease. Optimal adjuvant treatment remains to be defined.

Sequential Bilateral Germ Cell Tumors of the Testis Despite Interval Chemotherapy

We report on 3 patients who had a second primary germ cell tumor of the testis despite prior or ongoing systemic chemotherapy for the original tumor. Evidence favoring the designation of the tumors as separate primary lesions is presented. The clinical and theoretical implications of this phenomenon are discussed.