Robert B. Golbey

High dose Cis‐platinum diammine dichloride. Amelioration of renal toxicity by mannitol diuresis

A clinical trial was undertaken to improve the therapeutic index of cis‐plati‐num diammine dichloride with a concomitantly administered mannitol induced diuresis. Sixty patients, heavily pretreated, were entered; fifty‐one are evaluable. The technique of concomitant osmotic diuresis and CPDD administration is described in detail. Doses ranged from 3mg/kg to 5mg/kg. At 5mg/kg, dose‐limiting renal, marrow and ototoxicity were seen, and resulted in one drug death. Marrow toxicity was moderate. Renal toxicity was limited to transient elevations in serum creatinine levels, except in some patients who had renal impairment prior to CPDD treatment. These patients had moderate renal toxicity. Serial treatments as frequently as once every 3 weeks were used to maintain responses. Serial high dose CPDD produced only mild renal dysfunction. Ototoxicity, usually subclinical, was quantitated audiometrically, and found to be dose related, but not clinically prohibitive at 4mg/kg or less. The overall response rate (PR/MR) was 42%. Clinically significant responses in epidermoid carcinoma of the head and neck, adenocarcinoma of the ovary, and germ cell tumors of the testis were seen. All six responding patients with germ cell tumor of the testis, had been resistant to low dose (1mg/kg) CPDD. Two responding patients with ovarian adenocarcinoma had been resistant to alkylating agents.

Cisplatin and vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules

Eighty-five patients with advanced squamous carcinoma or adenocarcinoma of the lung were randomly assigned to receive vindesine with either high dose (120 mg/m2 of body surface area) or low dose (60 mg/m2) cisplatin. All patients had measurable disease and had not previously received chemotherapy. The response rate was similar with both treatments (43% complete and partial remission rate), but the high dose cisplatin regimen was superior to the low dose in median duration of response (12 versus 5.5 months; p = 0.05) and in median survival for responding patients (21.7 versus 10 months; p = 0.02). Myelosuppression was generally not a treatment problem; peripheral neuropathy and moderate azotemia were the major dose-limiting toxicities. With improved survival and response rates over those reported for conventional regimens, this combination of new agents supports the approach of new drug investigation in patients with lung cancer and the importance of the incorporation of active new agents into initial chemotherapy regimens.

Malignant schwannoma--clinical characteristics, survival, and response to therapy.

One hundred and sixty‐five cases of malignant schwannoma were reviewed. Sixty‐five (40%) of the patients had evidence of disseminated neurofibromatosis. Patients with neurofibromatosis were younger, had malignant schwannomas that were centrally rather than peripherally located, and had a shorter five‐year survival (23%) than patients with solitary malignant schwannomas (47%). Histologically, tumors developing in patients with neurofibromatosis had a collagenous appearance, while tumors in patients without neurofibromatosis were undifferentiated and highly cellular. The clinical course of both groups of patients tended to be that of multiple local recurrences, although local recurrence had a more ominous prognosis in patients with neurofibromatosis. Chemotherapy responses in all these patients were extremely poor; however, the results of adjuvant therapy after surgery appeared encouraging. Fourteen patients (8.5%) had a malignant schwannoma in an area of prior radiation therapy and died of disease a median of 14 months after diagnosis. Malignant schwannoma should be considered in the differential diagnosis of tumors developing in areas previously treated with radiation.

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.

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 Raynauds 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.

Malignant mesothelioma of the pleura: Review of 123 patients

One‐hundred‐twenty‐three cases of malignant pleural mesothelioma were reviewed. Exposure to asbestos or to other industrial dusts or chemicals was an important etiologic factor with 24% of patients relating such a history. A history of prior irradiation or previous lung disease was also occasionally noted. Diagnosis was most often made by exploratory thoracotomy, with pleural biopsy or cytology rarely helpful. Except for nine patients, tumor was confined to the chest at the time of diagnosis, but in 33 of the remaining 114 patients, spread to the abdomen or distant metastasis was seen during the course of disease. Surgery and radiotherapy were ineffective in preventing local recurrence. There were only three major responses to chemotherapy in 111 trials. Median survival was 12 months, and only seven patients (5.6%) lived more than five years. Patients with epithelial mesothelioma and Stage I disease had the most favorable prognosis.

Extraosseous osteogenic sarcoma: A review of 48 patients

The clinical records and histologic material of 48 patients with extraosseous osteogenic sarcoma were reviewed. Most patients developed their tumors in the fifth or sixth decades of life. Five patients (10%) developed neoplasms in an area of prior radiation therapy, a median of 15 years after their exposure. Six patients (13%) related a history of trauma to the area where their extraosseous osteogenic sarcoma developed. The course of most patients was that of multiple local recurrences (69%) followed by pulmonary metastases (80%) and death (76%). Amputation or wide resection followed by irradiation appeared to be the most effective types of therapy, with median survivals greater than 60 months for patients receiving these treatments, compared to 28 months for patients initially treated with resection alone. Chemotherapy was not effective for patients with advanced disease; however, adjuvant chemotherapy after surgery may have been of value. Four of five patients who received adjuvant chemotherapy after surgery are alive and disease‐free; the only two survivors after development of pulmonary metastases received adjuvant chemotherapy after surgical resection of visible pulmonary metastases.

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 Raynauds 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 evolution of mature teratoma from malignant testicular tumors.

During the period 1969‐1976 twelve cases of malignant germ cell tumor of the testis were seen in which the diagnosis was associated with the subsequent development of one or more metastases composed histologically of fully mature teratoma. These patients had a variety of primary germ cell tumors in the testis and were treated with radiation therapy and/or chemotherapy in addition to surgery, prior to the development of mature teratomas in different anatomic sites. The development of mature teratoma in this clinical setting seems to be a favorable prognostic sign, inasmuch as only one of the 12 patients has died with known persistent cancer. Since the incidence of this phenomenon seems to be increasing, the mechanism is probably related, directly or indirectly, to therapy. Cancer 40:2987‐2992, 1977.

Primary mediastinal germ cell tumors

Thirty patients with germ cell tumors originating in the mediastinum are reviewed and analyzed (20 embryonal carcinomas and 10 seminomas). Local control of the disease was successful by resection and/or external radiation in patients with seminoma; 50% were alive and well at 10 years. Patients with embryonal carcinoma were poorly controlled with surgery, radiation, or chemotherapy. However, early aggressive chemotherapy did seem to improve survival in embryonal carcinoma. Death by local recurrence was characteristic of embryonal carcinoma, whereas distant spread of disease, usually to bone and lymph nodes, was the cause of death in seminoma.