Multivariate analysis of prognostic variables in patients with metastatic testicular cancer.

A majority of patients with metastatic testicular cancer achieve a complete remission as a result of current treatment programs. However, patients who fail to achieve a complete remission have a very poor prognosis, and nearly all die of their disease. A multivariate logistic regression analysis of several clinical variables associated with prognosis was performed using data from 171 patients treated for metastatic testicular cancer at Memorial Hospital between September 1975 and February 1981. A mathematical model was identified which correctly predicted 94% of complete remissions and 83% of all outcomes. The variables achieving statistical significance were the logarithm of the serum values of lactate dehydrogenase (p less than 0.001) and human chorionic gonadotropin (p less than 0.001) and the total number of sites of metastasis (p less than 0.001). The model was tested against 49 patients with metastatic testicular cancer treated at the University of Minnesota Hospitals, and it correctly predicted 86% of complete remissions and 84% of all outcomes. In a highly curable disease such as testicular cancer, mathematical modeling may enable the clinical investigator to anticipate those patients who are least likely to do well. Alternate treatment strategies would be appropriate for such patients.

Randomized trial of combined modality therapy with and without thymosin fraction V in the treatment of small cell lung cancer.

A randomized trial of thymosin fraction V (60 mg/m2 s.c. twice weekly) given during induction chemotherapy and radiation therapy was performed in 91 patients with small cell carcinoma of the lung. Induction chemotherapy consisted of four cycles of an alternating combination of drugs (cyclophosphamide/Adriamycin/vincristine and cisplatin/etoposide). Radiation to the primary complex was given to patients with limited disease. All patients received prophylactic cranial irradiation. There were 35 patients with limited disease (18 randomized to thymosin and 17 to no thymosin) and 56 with extensive disease (28 thymosin and 28 no thymosin). Pretreatment immunological parameters were comparable between the two groups. For limited disease patients the overall response rate was 100%, including 66% (21 of 32) complete responders. The median duration of response was 19 mo (range, 5-57 mo) and survival 21 mo (range, 4 days to 57 mo). The 3-yr survival was 32%. For ED patients the overall response rate was 95% with 29% (13 of 48) complete. The median duration of response was 10 mo and the median duration of survival 12 mo with 13% alive at 2 yr. A comparison of the thymosin-versus no thymosin-treated patients revealed no difference in response rate, response duration, or survival whether analyzed as a whole or by extent of disease. An analysis based on pretreatment immune function and total white blood cell and absolute lymphocyte count revealed no difference in the survival distributions. No differences in the pattern of toxicity were observed between the thymosin- versus no thymosin-treated patients. The addition of thymosin fraction V during induction chemotherapy and consolidation radiotherapy did not alter outcome.

The results of chemotherapy for extragonadal germ-cell tumors in the cisplatin era: the Memorial Sloan-Kettering Cancer Center experience (1975 to 1982).

Thirty-eight patients with extragonadal germ-cell tumors treated at Memorial Sloan-Kettering Cancer Center (New York) between 1975 and 1982 received high-dose cisplatin-based chemotherapy. Complete response was achieved in 89% of patients with pure seminoma and all complete responders are alive without evidence of disease (median follow-up time, 29+ months). Complete response was achieved in only 41% (12 of 29) of patients with extragonadal nonseminomatous germ-cell tumors; only four patients are alive and free of disease (median survival time, 18 months). Although patients with extragonadal seminoma respond well with current cisplatin-based chemotherapy, minimal improvement in CR rates has been achieved in patients with extragonadal nonseminomatous tumors. Patients with extragonadal nonseminomatous germ-cell tumors have a relatively poor prognosis when compared to patients with primary testicular tumors and investigational trials of innovative therapy should be considered.

The treatment of extragonadal seminoma.

Primary extragonadal seminoma (EGS) is a rare tumor of young adults that often presents with bulky primary tumors and metastatic disease. Long-term survival is inadequate with conventional therapy consisting of radiotherapy with or without surgery. The charts of 21 patients with EGS treated initially either with conventional therapy (group I) or with multimodality therapy including initial chemotherapy with high doses of cisplatin followed by either radiotherapy or surgery or both (group II) were reviewed. Five of the ten patients in group I developed recurrent disease and four of them eventually died of disease. Only one of 11 patients in group II died of metastatic disease and the remaining patients are free of disease with 19+ to 46+ months of follow-up. Of the six patients from group II who underwent surgical resection of apparently residual disease after chemotherapy but prior to radiotherapy, five were found to have completely necrotic tumor and one had microscopic disease on histologic examination, proving the efficacy of chemotherapy. Combined modality therapy including initial chemotherapy containing high doses of cisplatin provided rapid reduction in tumor burden and the results appeared superior to treatment that did not include initial chemotherapy.

Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy.

To determine the frequency and prognostic importance of pretreatment clinical characteristics in patients currently undergoing treatment for stage III non-small-cell lung cancer (NSCLC), data were collected on 378 patients receiving high-dose (120 mg/m2) cisplatin plus vinca alkaloid combination chemotherapy regimens since 1978. Variables analyzed included age, sex, weight loss, performance status, histologic subtype, presence of extrathoracic metastases, number of metastatic organ sites, presence of liver, bone, or brain involvement, prior radiation or surgery, and serum lactate dehydrogenase (LDH). The effect of a major response to chemotherapy on survival was also investigated. Using multivariable analyses, the following were found to be associated with outcome: initial performance status, with patients having a performance status of 80% to 100% having an increased major objective response rate and survival; bone metastases, which were adversely predictive of response rate and survival; elevated serum LDH and male sex, both of which were associated with shortened survival and remission duration; and the presence of two or more extrathoracic metastatic organ sites, which was associated with shorter survival. When major objective response with chemotherapy was included in a conditional multivariable analysis, it was strongly associated with longer median survival. Information from this analysis may be useful when comparing the response data of completed studies in similar patients, in designing future trials, and in the selection of cisplatin plus vinca alkaloid therapy for individual patients with advanced NSCLC.

VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors.

One hundred sixty-six patients with germ-cell tumors (GCT) of the testis, retroperitoneum, and mediastinum were treated with cyclophosphamide, vinblastine, bleomycin, dactinomycin, and cisplatin (VAB-6), with and without maintenance chemotherapy. The overall complete response (CR) rate was 78%, 67% to chemotherapy alone, and 11% after chemotherapy and resection of viable residual cancer. The CR rate in all patients with seminoma was uniformly high, while the CR rate of patients with testicular nonseminomatous germ-cell tumors (79%) was superior to that of similar tumors of extragonadal origin (60%). The overall relapse rate was 12%, and was greater in tumors of extragonadal origin (21%) than in those of testicular origin (11%). Three relapses occurred after 2 years. Maintenance chemotherapy did not prolong either relapse-free or total survival. Toxicity was tolerable, and there were no treatment deaths. No Raynaud's phenomena have occurred, with a minimum duration since start of therapy of 36 months. VAB-6 is an effective chemotherapy regimen in patients with GCT with no treatment-related deaths and a majority of patients requiring only 3 months of treatment.

Orchiectomy alone in the treatment of clinical stage I nonseminomatous germ cell tumor of the testis.

Forty-five patients with clinical stage I nonseminomatous germ cell tumor of the testis (NSGCTT) were entered in a prospective clinical trial to receive no treatment other than orchiectomy until clinical evidence of relapse. Of this group, 36 patients (80%) have been continuously free of disease for a median duration of 19.5 months after orchiectomy. Nine patients (20%) have relapsed, eight within seven months of orchiectomy. Seven of nine relapsing patients have been rendered free of disease with chemotherapy and/or surgery for a median duration of seven months (range, one to 33 months) after completion of treatment; the other two patients are presently under treatment although one has progressive disease. The relapse rate was higher in patients with embryonal carcinoma than in those with teratocarcinoma, 57% versus 17%. These preliminary results imply that the omission of routine lymphadenectomy or lymph-node irradiation in clinical stage I NSGCTT deserves further trial.

VAB-6 as initial treatment of patients with advanced seminoma.

Thirty patients with advanced seminoma were treated with VAB-6. Eighteen patients were previously untreated, eight had relapsed after radiation therapy, and four had persistent disease following chemotherapy and radiation therapy. Two patients had received prior high-dose cisplatin. Twenty-four (86%) of 28 evaluable patients achieved a complete remission. Four patients had relapsed. The median disease-free follow-up of patients achieving complete remission was 32+ months. VAB-6 is effective treatment for patients with advanced seminoma, and chemotherapy is recommended as the initial therapy in all patients with stage II seminoma with disease larger than 5 cm, extragonadal seminoma, and stage III seminoma.

A randomized trial of etoposide + cisplatin versus vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin in patients with good-prognosis germ cell tumors.

Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynaud's phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm, the total, relapse-free, and event-free survival distributions were similar in the two arms. Patients receiving EP experienced less emesis (P = .05), higher nadir WBC (P = .06) and platelet counts (P = .01), less magnesium wasting (P = .0001), less mucositis (P = .09), and no pulmonary toxicity. No treatment-related mortality was observed. EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT.

Role of etoposide-based chemotherapy in the treatment of patients with refractory or relapsing germ cell tumors.

Forty-nine patients with metastatic germ cell tumors were treated with etoposide 100 mg/m2 and cisplatin 20 mg/m2 intravenously each day for five days as "salvage" chemotherapy. Forty-seven patients had received standard induction regimens for metastatic germ cell tumors before receiving etoposide and cisplatin. Four patients were treated after surgical resection of a single site of relapse (Group I). Forty-five patients had measurable or evaluable disease at the time of treatment. In 17 patients with evaluable disease who had either achieved a prior complete remission or received no prior cisplatin (Group II), eight (47 percent) complete and four (24 percent) partial remission were observed. In 28 patients who had never achieved a prior complete remission (Group III), no complete and five (18 percent) partial responses were observed. Seven of 21 patients in Groups I and II and none of 28 patients in Group III remain alive and free of disease. Assuming prior treatment with cisplatin-based chemotherapy, these data and a review of the published experience with similar salvage regimens for patients with relapsing or refractory germ cell tumors suggest that combination chemotherapy based on etoposide and cisplatin is effective primarily in those patients who achieved a prior complete remission. Such therapy is ineffective in the absence of a prior complete remission probably because the patients have tumors that are largely resistant to cisplatin. Observed responses are probably due to etoposide alone. Investigational therapies should be pursued in those patients whose disease is refractory to current induction regimens.

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.

Therapy and prognosis of testicular carcinomas in relation to TNM classification.

Eight-hundred and thirty-one patients with testicular carcinomas, either teratocarcinoma (405), embryonal carcinoma (406) or pure choriocarcinoma (20), treated mainly at our center from 1950 to 1976, were clinicopathologically staged according to the TNM Classification. The cancer was confined to the body of testis alone (T1 N0 M0) or extended to paratesticular structures (T2-4 N0 M0) in 37% of all patients. Para-aortic lymph nodes were found involved (N1-3) in 33% and juxtaregional lymph nodes (N4) in 9% of patients; distant metastases were detected initially in the lung alone (M1) and other distant organs (M2) in 21% of the patients. Postorchiectomy treatment was retroperitoneal lymphadenectomy with or without regional-juxtaregional irradiation and systemic chemotherapy in 470 patients; the other 361 patients received external irradiation and/or adjuvant chemotherapy. Survival determined at 5 years was 58% in teratocarcinoma cases, 41% in embryonal carcinoma cases and 0% in pure choriocarcinoma cases. Rates of 5-year survival according to the TNM staging were 81% for T1 N0 M0 tumors, 58% for T2-4 N0 M0 tumors, 44% for N1-3 M0 tumors, 33% for N4 M0 tumors and 10% for N0-4 M1 or 2 tumors. In patients who underwent lymphadenectomy with or without external irradiation, the 5-year survival rates with and without adjuvant chemotherapy, respectively, were 96% and 86% for T1 N0 M0 tumors, 100% and 60% for T2-4 N0 M0 tumors, 66% and 42% for N1-3 M0 tumors, 54% and 40% for N4 M0 tumors and 38% and 0% for N0-4 M1 tumors. In patients treated by external irradiation alone or following lymphadenectomy the rates of 5-year survival with versus without adjuvant chemotherapy were 100% versus 66% for T1-4 N0 M0 tumors, 44% versus 18% for N1-3 M0 tumors, 41% versus 22% for N4 M0 tumors and 3% versus 4% for N0-4 M1-2 tumors.

Spontaneous pneumothorax as a result of intensive cytotoxic chemotherapy.

Spontaneous pneumothorax occurring as a complication of the antitumor effect of cytotoxic chemotherapy has been reported in occasional cases of osteogenic sarcoma. Its occurrence in other tumors has not been described. This report describes two cases of this complication in patients with germinal tumors and discusses possible pathophysiologic mechanisms.

Impact of symptomatic interval on prognosis of patients with stage III testicular cancer.

In patients with testicular cancer, the interval from the onset of symptoms to histologic diagnosis has been correlated with extent of disease. To determine whether or not the symptomatic interval was related to response to chemotherapy and extent of disease in patients presenting with metastatic disease, the charts of 253 patients treated with chemotherapy were reviewed. In the 123 patients presenting with metastatic disease, for whom the symptomatic interval was known, complete response was significantly associated with the symptomatic interval (P = 0.039). A trend was noted between the symptomatic interval and the extent of retroperitoneal metastases (P = 0.065). The survival of patients with testicular cancer in all stages may be improved by heightening public awareness through educational programs.

Phase II trial of VP16-213 in non-small cell lung cancer (NSCLC).

Fifty-one patients with non-small cell lung cancer (NSCLC) were treated, during a phase II trial, with 4'demethylepipodophyllotoxin-beta-D-ethylidene glucoside (VP16-213). Forty-nine were evaluable for response, and of these two (4%) had partial responses lasting 5 and 6 months. Prior treatment with chemotherapy may have adversely affected response rate; none of the 24 previously treated patients had a major response. Myelosuppression was the dose limiting toxicity. Anorexia, nausea and vomiting, partial alopecia, and chills plus hypotension during drug infusion were the other toxic effects. We conclude that VP16-213 has only minimal activity as a single agent in NSCLC.

Chemotherapy of seminoma.

1. Seminoma may occasionally be rapidly growing, aggressive, radioresistant, and chemotherapy-resistant tumor. 2. Alkylating agents have had the greatest number of trials and have produced the best response rates in the management of seminoma, but a wide range of other agents warrants trials. 3. Adjunct chemotherapy is a logical consideration in patients with stage II and stage III seminoma.

Clinical and pathological evaluation of response to chemotherapy in patients with esophageal carcinoma.

Pretreatment clinical staging, radiographic response to chemotherapy, and posttreatment pathological staging were assessed in 39 patients with epidermoid carcinoma of the esophagus. Thirty patients received combined modality therapy with cisplatin, vindesine, and bleomycin followed by surgery; nine patients were treated with the same chemotherapy with or without radiation therapy. Using barium esophagrams as the measure of response, radiographic objective regressions were quantitated and considered as complete (CR), partial (PR), and minor or no radiographic response. Sixty percent of patients had CR or PR. However, surgical or endoscopic restaging showed residual microscopic or macroscopic disease in nine patients, with complete radiographic regression. Downstaging of the primary tumor following chemotherapy (pretreatment clinical staging as compared to posttreatment pathological staging) was common. Chemotherapy-induced objective regressions in esophageal carcinoma can be achieved frequently and can be quantitated, using serial barium esophagrams. Complete radiographic regressions should be confirmed by repeat endoscopy or surgery. Downstaging of the primary tumor is commonly noted in responding patients, but it is too soon to determine whether or not this will effect their long-term prognosis.

VP-16-213 and cisplatin in the treatment of patients with refractory germ cell tumors.

Twenty-two patients with progressive or relapsing germ cell tumors and one patient without prior treatment received VP-16-213 (etoposide) 100 mg/m2 on days 1-5 and cisplatin 20 mg/m2 days 1-5 every 4 weeks. Three complete remissions and one partial remission were seen in five patients who previously achieved a complete remission to a cisplatin-based regimen. A partial remission was observed in a previously untreated patient with widely metastatic extragonadal choriocarcinoma. No complete remissions and two partial remissions were seen in 14 patients who did not achieve a previous complete remission to cisplatin-based combination chemotherapy. Four patients remain free of disease, including one complete responder and three patients treated after resection of a solitary recurrence. Myelosuppression was universal and two very heavily pretreated patients died with leukopenia and presumed infection. VP-16-213 plus cisplatin may be an effective salvage regimen for patients relapsing after a complete remission, but is probably ineffective if the patient has not achieved a prior complete remission.

Phase II trial of VP-16-213 in non-small-cell lung cancer.

Fifty-one patients with metastatic non-small-cell lung cancer (NSCLC) were treated with VP-16-213 (4'-demethylepipodophyllotoxin) during a phase II trial. Of the 49 patients who had adequate trials, 2 patients achieved a partial response (PR), for an overall 4% major response rate. The median Karnofsky performance status (PS) was 80%; 85.7% of patients had adenocarcinoma and 14.2% had epidermoid carcinoma. Prior treatment with chemotherapy may have adversely affected response rate; the two responses occurred among the 25 previously untreated patients, while no responses were seen in patients who had previously received chemotherapy. Myelosuppression was the most frequent side effect and two drug-related deaths due to septicemia occurred. Other toxic effects noted included anorexia, nausea and hypotension during drug infusion. We conclude that VP-16-213 has minimal activity as a single agent in NSCLC.

Pharmacokinetics of cisplatin regional hepatic infusions.

Cisplatin (DDP), a potent antineoplastic agent, is usually administered via a peripheral vein. Recently, there has been considerable interest in intraarterial regional infusions of DDP. The pharmacokinetics of DDP when administered by this technique have not been explored in detail. We studied DDP pharmacokinetics in dogs given DDP by infusion and bolus injection in the hepatic artery (H.A.), portal vein (portal V), and peripheral vein (P.V.). Blood and biliary platinum concentrations ([Pt]) were assayed by flameless atomic absorption spectrophotometry. During an infusion into the H.S., peak [Pt] in the vessel were markedly higher (mean value 19 micrograms/ml) than those found, simultaneously, in the portal V or superior vena cava. Following a bolus injection of DDP into the H.A., higher H.A. [Pt] were also seen, but [Pt] rapidly (within 5-10 minutes) equilibrated in all sites sampled. During the H.A. infusion, most [Pt] was in its free (active) form. Bile and hepatic tissue were also sampled. Hepatic artery infusions of DDP give high drug concentrations in the perfusing blood, while systemic [Pt] are much lower. During the infusion, the majority of DDP is in its active (unbound) state.