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Purpose: We investigate fertility and sexual function in patients following orchiectomy and adjuvant cisplatin based chemotherapy for high risk, stage I nonseminomatous germ cell tumor of the testis., Materials and Methods: Between 1985 and 1994, 59 patients with stage I nonseminomatous germ cell tumor and poor prognostic factors were treated with 2 cycles of cisplatin, vinblastine and bleomycin, or bleomycin, etoposide and cisplatin after orchiectomy. At least 32 months following treatment all patients were contacted and asked to complete a questionnaire regarding fertility and sexual activity, and to volunteer for a semen and hormonal analysis., Results: Of the 59 patients 49 (83%) completed the questionnaire. Before chemotherapy 18 (37%) patients had fathered children, 6 (12%) were involuntarily childless and none had a major sexual dysfunction. After treatment 11 (22%) patients fathered children, and 5 (10%) were involuntarily childless, with 4 involuntarily childless before chemotherapy. There were no significant alterations in sexual function. Semen analysis in 27 patients was normal in 23, and revealed mild oligospermia in 2 and azoospermia in 2. In 18 patients with hormone analysis median values for luteinizing hormone and free testosterone were normal but median value for follicle-stimulating hormone was slightly increased., Conclusions: Two cycles of cisplatin based adjuvant chemotherapy do not seem to affect adversely fertility or sexual activity.

Purpose: We propose that patients with high risk, clinical stage I nonseminomatous germ cell tumors receive 2 cycles of chemotherapy initially, instead of undergoing surgery or observation., Materials and Methods: A total of 59 patients with high risk, clinical stage I nonseminomatous germ cell tumor received risk adapted adjuvant chemotherapy. Until June 1987, 20 patients were treated with 2 courses of adjuvant cisplatin, vinblastine and bleomycin at 3-week intervals. After June 1987 another 39 patients were treated with 2 cycles of bleomycin, etoposide and cisplatin., Results: Long-term results with this treatment strategy have been excellent with limited morbidity., Conclusions: Adjuvant chemotherapy may be of particular value in patients with compromised followup.

Purpose: We determine the efficacy and safety of 2 cycles of adjuvant chemotherapy after orchiectomy in patients with high risk clinical stage I nonseminomatous germ cell tumor of the testis as an alternative to retroperitoneal lymphadenectomy or watchful waiting., Materials and Methods: A total of 60 consecutive patients with clinical stage I nonseminomatous germ cell tumor of the testis and 1 or more risk factors were entered into this prospective study. Criteria for high risk were embryonal cell carcinoma, tumor invasion of blood or lymph vessels, or tumor stage pT2 or greater. Chemotherapy consisted of 2 cycles of cisplatin, vinblastine and bleomycin or bleomycin, etoposide and cisplatin., Results: Of the 60 patients 1 refused chemotherapy and 1 was lost to followup 1.5 years after treatment. The remaining 58 patients have been followed for a median of 93 months (range 32 to 146). World Health Organization grade 4 toxicity was observed in 9 of the 116 chemotherapy cycles, and consisted mainly of transient neutropenia and thrombocytopenia. No significant long-term sequelae were detected. There was 1 relapse after 22 months in a patient with adult teratoma in the ipsilateral region of the iliac vessels who remained disease-free 85 months after surgical excision of the lesion. Another patient had a seminoma in the contralateral testicle with interaortocaval lymph node metastases 7.5 years after adjuvant chemotherapy. The remaining 56 men are without relapse or contralateral tumor to date., Conclusions: We recommend adjuvant chemotherapy as an efficient therapeutic alternative to retroperitoneal lymphadenectomy for high risk nonseminomatous germ cell tumor of the testis.

Between April 1984 and May 1989, 77 eligible patients with invasive, nonmetastatic (stage M0) transitional cell carcinoma of the bladder were stratified after radical cystectomy and pelvic lymph node dissection on the basis of nodal status (stage pN0 versus pN1-2) and were randomly assigned to either observation or postoperative cisplatin chemotherapy (3 courses of 90 mg./m.2 cisplatin given for 3 consecutive days at monthly intervals). Patient eligibility included a creatinine clearance of greater than 60 ml. per minute. There were 40 eligible patients in the control group (median age 61 years) and 37 in the cisplatin group (median age 64 years). In regard to postoperative tumor stage and nodal status, there was no statistical difference between the 2 patient groups. In the cisplatin group 21 patients received the full dose, 9 required dose reduction and 7 refused treatment. Median followup was 5 years 9 months (range 3 to 8 years). Survival analysis showed no significant difference (log rank p = 0.65) between the 40 patients in the control group and the 37 in the cisplatin group. The survival rate at 5 years was 54% (95% confidence interval 39 to 69%) in the control group and 57% (95% confidence interval 40 to 74%) in the treatment group. Patients with cancer confined to the bladder wall (stage pT3a or less) had a 5-year overall survival rate of 70% and those with tumor growth in the perivesical fat or into the prostate (stages pT3b plus pT4a) had a 5-year overall survival rate of 40%. This difference in survival between the low stage subgroup (stages pT3a or less) and the high stage subgroup (pT3b plus pT4a) is highly significant (p = 0.0043). However, no difference between the controls and the cisplatin group was found within either the low or high stage subgroups. The reasons for failing to show a survival benefit from adjuvant high dose cisplatin monotherapy after radical cystectomy are discussed.

The aim of this prospective study was to examine the prognostic pathomorphological factors in urothelial cancer of the urinary bladder. Clinical and morphological variables were evaluated by univariate and multivariate analysis in 70 patients with invasive transitional-cell carcinoma of the bladder (pTI-pT4a). The patients were treated according to a prospective program consisting of radical cystectomy and pelvic-node dissection, either alone or followed by adjuvant cisplatinum chemotherapy. Nodal status was pN0 in 89% of the patients. The median follow-up time was 5.75 years and the 5-year survival was 58%. Among the morphologic variables, deep invasion of the bladder wall and squamous differentiation indicated a poorer prognosis. Differentiation grade, pattern of growth (infiltrating versus expanding), angioinvasive growth, glandular differentiation and concomitant prostate carcinoma (pT1) were not significative factors for survival. By contrast, a significant reduction in mortality rate was found in patients with concomitant carcinoma in situ. Multivariate analysis confirmed that depth of invasion is an independent prognostic factor of outcome. The results confirm the primary importance of tumor stage in the prediction of survival after radical cystectomy.

In patients with clinical stage I non-seminomatous germ cell tumor the relapse rate seen after orchiectomy alone is approximately 30%. If retroperitoneal lymph node dissection is adopted the relapse rate in patients with histologically negative retroperitoneal nodes is reduced to approximately 10%. Nevertheless, follow-up is still mandatory and 70-80% of clinical stage I patients undergo unnecessary surgery. Metastases and relapses are mostly seen in patients with histological evidence of vascular invasion, growth beyond the testicular capsule and/or embryonal carcinoma in the primary tumor. We conducted a prospective trial of two cycles of cisplatin-based adjuvant chemotherapy for 43 patients with clinical stage I non-seminomatous germ cell tumors and at least one of these risk factors (vascular invasion n = 5, pT > 1 n = 21, embryonal carcinoma n = 42). After a median follow-up of 42 months (12-82 months) 40/41 patients (97.5%) who received the planned chemotherapy remain relapse-free. One patient had surgical excision of a mature teratoma in the ipsilateral iliac region 26 months after orchiectomy and is now disease-free without further treatment after 25+ months. No life-threatening toxicity from chemotherapy was encountered. Two patients who refused the chemotherapy relapsed. In patients with high-risk clinical stage I non-seminomatous testicular cancer two cycles of adjuvant chemotherapy are highly effective in preventing relapses and may be used as an alternative to a 'wait and watch' program or retroperitoneal lymph node dissection, particularly in patients with a compromised follow-up.

Thirty-eight pretreated patients with Hodgkin's disease (HD) and malignant non-Hodgkin's lymphoma were given combination chemotherapy with VM-26, Adriamycin, bleomycin, and prednisone. Four of 15 evaluable patients with HD achieved a partial remission (PR), with a median duration of 8 months. Of 12 patients with diffuse poorly differentiated lymphocytic lymphoma, one achieved a complete remission (30+ months) and five achieved a PR (median, 6 months). One of three patients with histiocytic lymphoma had a PR of 1.5 months. There was one drug-related death. Five patients developed life-threatening hematologic toxicity. Two HD responders died of acute nonlymphocytic leukemia.

At present there are no firm data for the routine use of adjuvant chemotherapy in stage II testicular cancer after retroperitoneal lymph node dissection. The possible advantage of adjuvant chemotherapy in terms of reduced relapse rate and continuously disease free survival have to be weighed against the increasing cure rates with modern chemotherapy regimen, applied at the time of advanced and recurrent disease. About 10-15% of stage I and 40-50% of stage II patients relapse after RPLND. Depending on risk factors such as total tumor burden, histology and disease sites and symptoms at the time of presentation, 30-90% of these patients are brought into complete remission with modern chemotherapy (overall between 50 and 70%). Based on these results, a subgroup of patients with a low risk of relapse and a more than 90% chance of cure with salvage chemotherapy may be defined. They do not need adjuvant chemotherapy with its associated toxicity. On the other hand, in a high risk group, which demonstrates poor results with salvage chemotherapy, adjuvant chemotherapy seems to have the potential to significantly improve the cure rate. A third group of patients, presenting with bulky abdominal disease may need immediate postdiagnostic intensive chemotherapy, with surgical exploration only at the time of maximum response. The question of definition of optimal treatment strategies in the various subgroups of patients with testicular cancer can only be solved by ongoing and future randomized clinical trials.

53 patients with advanced and measurable cancerr were treated with vindesine in doses of 3 mg/m2 (pretreated) and 4 mg/m2 (non pretreated) i.v. once weekly. 48 patients are evaluable for response: of 14 patients with squamous cell carcinoma of the lung, 1 partial remission (PR), 1 minor response (MR) and 1 no change (NC) were observed. In 5 patients with large cell carcinoma of the lung: 1 NC. In 3 with adenocarcinoma of the lung: 1 MR. One patient with nasopharyngeal carcinoma had progressive disease. Stable disease was observed in a patient with carcinoma of the tongue and in a patient with adenocarcinoma of the esophagus. Four patients with colorectal carcinoma had progressive disease. One MR was observed in a patient with breast cancer, while all of the other 3 patients had progressive disease. One carcinoma of the penis was stable. One MR was observed in a patient with Hodgkin's disease. One PR was observed in a case with no-Hodgkin's lymphoma. A patient with acute leukemia had progressive disease. Among 9 patients with malignant melanoma, 3 had an MR and 1 patient had stable disease. A patient with fibrosarcoma had progressive disease. Observed toxicity included leukopenia, thrombocytopenia, anemia, paresthesias, constipation, jaw pain, nausea, stomatitis, alopecia, loss of taste, pruritus and skin rash, weakness and fatigue.

In an ongoing cooperative study of the Cancer and Acute Leukemia Group B, 21 evaluable patients with advanced malignant lymphomas were treated with 70 mg/m2 of cis-dichlorodiammineplatinum(II) (cis-platinum) once every 3 weeks. All patients had received extensive prior therapy. Partial remission was obtained in two of seven patients with Hodgkin's disease, for 1+ and 7 months, and in three of 14 patients with non-Hodgkin's lymphoma, for 2, 2+, and 2.5 months. In another ongoing trial, 11 patients with advanced, pretreated small cell cancer of the lung received 80 mg/m2 of cis-platinum once every 3 weeks. Four patients achieved partial remissions. These lasted 2+ and 2.5 months in the two patients evaluable for duration of response. Two further clear-cut tumor regressions were noted. The major toxic effects were myelosuppression and vomiting. In the second trial, one case of probable drug-related fatal nephrotoxicity was encountered despite optimal forced diuresis with mannitol and furosemide. cis-Platinum definitely warrants further evaluation in these diseases because of significant effectiveness even after extensive prior treatment.

Cis-diamminedichloroplatinum(II) (DDP) represents a new class of platinum compounds with cytostatic activity. Although the exact mechanism of action remains unknown, it is the most widely studied of these agents to date. The toxicology, metabolism, mode of application and clinical experience with this drug are presented and discussed. The value of DDP as monotherapy as well as in combination with other cytostatic agents, especially in the treatment of testicular cancer, as well as the possibilities of controlling its nephrotoxic effects are presented in greater detail.

Three prospectivelyly planned and controlled cooperative clinical studies in the use of combination drug therapy for metastatic breast cancer are reported. Each study contained two drug regimen arms. A total of 326 evaluable patients were treated with one of the five various drug combinations employed. As the number of drugs used in each regimen was increased from two to five, a concommitant increase in remission rates from 50% to 75% was observed. Remission duration of approximately 8 months and survival from the onset of treatment, however, remained relatively constant at 13 to 16 months in all drug regimens. Patients achieving tumor remission survived an average of three times longer than those with progressive disease under therapy. The results are correlated to patient age and predominant metastatic type. Subjective improvement was definitely related to objective tumor regression or stabilization. Treatment was relatively well tolerated and well applicable to outpatient care. Dosage adjustments were often necessary during the initial phases of therapy. Combined cystostatic drug therapy is highly effective in the prognostically worst forms of metastatic breast cancer, and is the treatment of choice for younger patients with visceral type metastases.

Patients with metastatic nonseminomatous testicular cancer received an induction regimen consisting of bleomycin in 24-hour infusions and bolus iv doses of vinblastine followed by an Adriamycin and cis-dichlorodiammineplatinum(II) combination. Patients achieving complete remission after one or two cycles of this induction chemotherapy were then randomized to receive either radiotherapy (RT) to the previously involved tumor areas or maintenance chemotherapy (MCT) with CCNU, methotrexate, and vinblastine for 2 years. Among 62 evaluable patients, induction chemotherapy achieved 15 (24%) partial remissions and 35 (56%) complete remissions. Two patients with partial remission and single pulmonary metastases were rendered disease-free by surgical resection of residual tumor. Twenty patients received MCT and 15 received RT. To date, median survival is 10,8+ months in the MCT group with five relapses and 12.5 months in the RT group with two relapses. Toxicity in the induction phase was moderately severe with two drug-related deaths.

We reviewed 16 patients treated for primary extragonadal germ cell tumors whose testes were initially negative for cancer at palpation. Residues compatible with an occult testicular primary, overlooked at the pretreatment examination, were found in 10 of 12 patients with retroperitoneal germ cell tumors, whereas the testes in all 4 patients with mediastinal germ cell tumors showed no pathological signs. Therefore, we conclude that mere palpation to exclude a testicular primary is not sufficient and the testes of patients with so-called extragonadal germ cell tumors should be examined by all available means, at least by high frequency ultrasound. Orchiectomy is advisable if a focal lesion is found.

Thirty patients with bronchogenic carcinoma were treated with an 8-week induction therapy consisting of cyclophosphamide, methotrexate, vincristine and VP 16-213 (NSC 141 540). Those who achieved objective remission of tumor stabilization were then placed on an intermittent treatment schedule with the same drugs. Of the 30 patients, 17 had an objective response, 5 remained without change, and 8 progressed. Responses were more frequent among anaplastic (13/19) than epidermoid or adenocarcinoma (4/11). The toxicity consisted mainly of leucopenia, thrombopenia, alopecia, nausea and vomiting. The implications of these findings in the planning of further chemotherapeutic programs are discussed.

Adriamycin (doxorubicin, Adriblastin) and cis-diammine-dichloro-platinum (II) (DDP, NSC 119 875) were used in the treatment of 18 patients with ovarian carcinoma, usually after intensive pre-treatment, both in a dosage of 50 mg/m2 once every 4 weeks. Forced diuresis was initiated at the same time. On average three such treatments were given. Six patients showed partial remission defined as decrease of tumour mass by more than 50% or as almost complete disappearance of ascites during more than two months without concomitant diuretic treatment. The remission time was 2+, 3, 3+, 3.5, 7+, and 9+ months. In all patients severe gastrointestinal toxicity occurred, however the myelosuppressive action was only moderate. Nephrotoxicity was negligible. Combined chemotherapy with Adriblastin and DDP thus seems effective even in intensively pretreated patients with ovarian carcinoma.

Bleomycin and its combinations have a definite place in the treatment of metastatic testicular carcinomas other than seminomas and may also prove to be effective, when given as adjuvant postoperative therapy in state II disease. A study, using the combination of Bleomycin and CCNU in 17 patients with metastatic testicular teratoma, is reported. A remission rate of 59% has been observed. Only patients with a complete remission had a satisfactory remission duration. Sequential combinations, using all drugs effective in this disease, may be the most promising way to further improve therapeutic results in terms of remission rate and survival.

Modern polychemotherapy has decisively changed the spontaneous course and median survival in metastatic stages of breast cancer. The prognosis for patients with the rather unfavorable type of visceral metastatic spread is definitely better now than 10 years ago. The influence of modern polychemotherapy on the survival and course of cases with mainly osseous metastases, however, is more limited. It seems that, in contrast to hormonal therapy, modern polychemotherapy alters the course of more aggressive types of metastases with a poor prognosis into a more favorable form of disease.