Mediastinal germ cell tumors. A continuing odyssey.

Mediastinal germ cell tumors are rare, and in the past they were uniformly lethal. A high index of suspicion leading to early diagnosis combined with modern interdisciplinary management can now prolong comfortable survival and produce many cures. The development of Cis-Platinum based combination chemotherapy, and its early use, has been the major factor in the improvement of treatment results.

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.

Toxicity comparisons between two chemotherapy regimens as adjuvant or salvage treatment in nonseminomatous testicular cancer.

The Testicular Cancer Intergroup Study was initiated to evaluate the efficacy of adjuvant chemotherapy in Stage II and salvage therapy in Stage I nonseminomatous testicular carcinoma. Chemotherapy regimens of cisplatin, vinblastine, and bleomycin (PVB) or the same drugs plus cyclophosphamide and dactinomycin (VAB) were used at institution or cooperative group preference. A comparison of the toxicities of these two regimens shows that VAB caused significantly more mucosal, dermatologic, and otologic toxicity than PVB, and PVB caused more leucopenia. Both regimens were equally effective in controlling cancer. Either regimen could be used as chemotherapy in testicular cancer, and the decision about which one to use could be based on their differences in toxicity and degree of patient convenience.

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.

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.

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.

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.

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.

Changes in serum alpha-fetoprotein and chorionic gonadotropin in response to cancer therapy.

The usefulness of measuring both alpha-fetoprotein and hCG in following the progress of patients with testicular cancers and germ cell tumors is demonstrated. In almost half the cases of testicular cancers studied, only one tumor marker was elevated; in at least one instance, the source of alpha-fetoprotein was eliminated while the source of hCG persisted. A comparison of the hCG method in use at Memorial Sloan-Kettering Cancer Center ( MSKCC ) with a commercial kit (Corning) showed that the methods were equivalent for monitoring both testicular cancers and gestational trophoblastic disease. All 17 patients with hepatocellular carcinoma had elevated levels of alpha-fetoprotein.

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.

Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I. Treatment by hepatic resection.

In the United States, there are an estimated 5000 to 6000 new patients annually who might be candidates for major hepatic resection to treat their recurrent colon cancer. Since 1971, the program reported here has evaluated various factors that might influence the curative potential of such an approach. Sixty-five patients had a major hepatic resection from March 1971 through May 1982. Using a stepwise proportional hazard analysis, all data that had been stored in CLINFO (a data analysis system by Bolt, Beranek and Newman; Boston, MA) were evaluated for the effect of multiple variables on the survival of patients with resected hepatic metastases. Twenty-seven had a right hepatic lobectomy; 14 had extended right hepatectomy with one having the caudate lobe also removed; ten had left lobectomy, nine had left lateral segmentectomy; and five had a major hepatic resection with three-dimensional wedge excision of a metastatic deposit in the contralateral lobe. The 30-day operative mortality rate was 7% (4/58) for patients undergoing the standard major hepatic resection. It was 14% for seven patients in whom the isolation-hypothermic perfusion technique was used early in the series. In ten patients, wedge excision only was required to remove the tumor. Stage I disease is defined as tumor confined to the resected portion of the liver without invasion of major intrahepatic vessels or bile ducts. Stage II disease is regional spread and Stage III disease is metastasis to lymph nodes or extraregional sites. The 3-year survival estimate was 66% for the 37 patients with Stage I disease. The 3-year survival estimate for 13 patients with Stage II disease was 58%. Five of the nine patients with Stage III disease are presently alive from 3 to 23 months; one of the other four died at 35 months of disease. The stage of liver disease was the most significant variable in this survival analysis (p = 0.02); Dukes' classification of colorectal primary was significant at p less than 0.05. Those factors found not to be significant determinants of survival were: number of metastatic hepatic deposits, site of colon primary, age, sex, preoperative liver function tests, and CEA.

Multivariate analysis of a personal series of 247 patients with liver metastases from colorectal cancer. II. Treatment by intrahepatic chemotherapy.

One hundred and seventeen patients with colorectal hepatic metastases had insertion of catheters for infusional chemotherapy. The two-year survival estimate of patients with less than 50% hepatic replacement and no other adverse factors was 37%. Nine of 39 patients in this group are alive at 24 months. The catheters were placed into the hepatic artery (HA), 23; into the portal venous system (PV), 18; into both HA and PV, 64; or into an accessory HA following ligation, 12. Fifty-nine patients had ligation of the common HA also. The 30-day postoperative mortality rate was 1.7% (2/117) and morbidity was 37.6%. The majority of complications were related to fever (61%, 27/44). Over the past 2 years, 87% of patients have been discharged within 10 days following surgery. Preoperative CEA ranged from 0.5-12,150 ng/ml (median 165 ng/ml); 93% (78/84) had plasma CEA levels exceeding 5 ng/ml. All patients had careful intraoperative staging: per cent hepatic replacement (PHR) ranged from 5-95% (median 60%); portal, celiac, or periaortic lymph node metastases were observed in 31% (36/117). Initial intrahepatic chemotherapy programs consisted of either CAMF (9 patients), MAFL (60 patients), BFS (22 patients), continuous infusion FUDR (14 patients), or miscellaneous drugs (4 patients). Median survival time of 109 evaluable patients was 11.5 months. The effect of 20 variables on the observed survival time was analyzed using a multivariate proportional hazard model. Three variables were found to have influenced survival: PHR emerged as the most significant, p = 0.000001. Increased PHR was associated with decreased survival time. Lymph node metastases and prior chemotherapy were prognostic factors also, p = 0.0006 and p = 0.03, respectively. No patient with PHR greater than 80% lived more than 8 months. Utilization of these variables would appear to be necessary for accurate stratification and evaluation of future chemotherapy trials in patients with colorectal hepatic metastases.

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.

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.

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.

Interrelationships of histopathology and other clinical variables in patients with germ cell tumors of the testis.

Possible relationships between histopathologic cell type and several clinical variables were examined in 253 patients with Stage III nonseminomatous germ cell tumors of the testis. No statistically significant associations were found between cell type and either the side of primary tumor or cryptorchidism. The presence of elements of choriocarcinoma was associated with the presence of retroperitoneal tumor (P less than 0.03) but no other association between cell type and site of metastasis was encountered. Elevated serum levels of human chorionic gonadotropin were found in patients with elements of choriocarcinoma but serum levels of alphafetoprotein, lactate dehydrogenase and carcinoembryonic antigen were not correlated with a specific cell type. No statistically significant association was found between cell type and either complete response to combined modality therapy or survival. These results would indicate that cell type is probably not an important prognostic variable in patients with Stage III nonseminomatous tumors of the testis.

Cytologic diagnosis of metastatic germ-cell tumors.

The clinical, pathologic and cytologic findings were correlated in 86 cases of metastatic germ-cell tumors. Although the cytologic features of malignant germ-cell tumors are sufficiently characteristic to make specific cytologic diagnosis possible, the diagnostic accuracy can be augmented with cytochemical stains. It was found that due to recent advances in therapy, cytologic detection of metastases does not necessarily indicate a fatal outcome.