Phase 2 study with Baker's Antifol in solid tumors.

One hundred thirty-eight adults with advanced cancers were treated with Baker's Antifol. The complete response + partial response rate was only 10%. Best responses were obtained in 31 patients with lung adenocarcinoma (complete response + partial response, 13%), in 25 patients with colorectal carcinoma (partial response, 16%), and in 6 patients with renal cell carcinoma (partial response, 50%). Two partial responses occurred in 15 patients with squamous cancer. No significant responses were seen in 27 patients with other adenocarcinomas, 13 with sarcomas, 14 with melanomas, and 8 with miscellaneous tumors. The most frequent toxicities were dermatitis, stomatitis, gastrointestinal symptoms, and mild myelosuppression. The incidence of dermatitis was significantly decreased by shortening the schedule of Baker's Antifol administration from 5 to 3 days. Baker's Antifol has some degree of antitumor activity, and studies of combination of this agent with other effective chemotherapeutic agents are indicated.

Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia.

PURPOSE: This multicenter, double-blind, randomized trial was performed to determine the efficacy and safety of pamidronate disodium (APD) in comparison to etidronate disodium (EHDP) in the treatment of cancer-related hypercalcemia. PATIENTS AND METHODS: Sixty-five male and female adult patients with cancer and corrected calcium levels of greater than or equal to 12.0 mg/dL after 24 hours of hydration were randomized to receive either 60 mg APD given as a single 24-hour infusion or 7.5 mg/kg EHDP given as a 2-hour infusion daily for 3 days. RESULTS: APD normalized corrected calcium levels in 70% (21 of 30) of patients, whereas EHDP did so in 41% (14 of 34) of patients (P = .026). The mean corrected serum calcium level decreased from 14.6 to 10.5 mg/dL in the APD-treated group and from 13.8 to 11.6 mg/dL in the EHDP-treated group within the first week of treatment. There was no difference in response to APD in patients without versus those with bone metastases (78% v 67%). Both drugs were well tolerated. CONCLUSION: This study demonstrated that a single 60-mg infusion of APD is safe and more effective than EHDP given at the dose of 7.5 mg/kg for 3 days in the treatment of cancer-related hypercalcemia.

Combination chemotherapy with cis-diamminedichloroplatinum and vinblastine in advanced non-small cell lung cancer.

Twenty-seven patients (25 males and 2 females) with histologically confirmed, unresectable, or metastatic non-small cell lung cancer were entered on a combination chemotherapy protocol including cisplatinum and vinblastine sulfate (DDP)(VLB). Patients had to have measurable disease as defined by the presence of two clearly measurable perpendicular diameters, be untreated with either chemotherapy or radiation therapy, and give informed consent to be eligible for study entry. The median age was 57 yr and the median performance status was 70 (Karnofsky scale); 10 patients had epidermoid carcinoma, 9 adenocarcinoma, 4 large cell carcinoma, and 4 undifferentiated carcinoma. All patients had intrathoracic disease, 12 also had extrathoracic lymph node involvement, 8 bone involvement, 2 liver metastasis, and 2 central nervous system metastasis prior to beginning chemotherapy; 9 patients had involvement of one site, 12 of two sites, 5 of three sites, and 1 of four sites. Cisplatinum was given as a short intravenous infusion of 120 mg/m2 on days 1 and 28, and then every 6 wk. Vinblastine was administered as an intravenous injection of 8 mg/m2 on days 1, 14, and 28, and then every 3 wk. Patients were evaluated prior to each course of cisplatinum. If progression occurred, therapy was discontinued. If stabilization or response was noted, then therapy was continued until intolerable toxicity or progression supervened. Every patient entered is considered evaluable for toxicity and response. There were no complete remissions; 14 patients achieved a partial response, 3 had a minimal response, 5 had stabilization of their disease, 1 had disease progression, and 4 are considered to have had drug deaths. Responses were seen after the first cisplatinum course in 13 patients and after the second in 1. Toxicities seen were universal nausea and vomiting; elevation of creatinine occurred in 6 patients, ranging from 2.1 to 14.6 mg/dl, and was clinically significant in 2 patients. Myelosuppression, with a leukocyte nadir of less than 3.0 X 10(9)l in 10 cases and platelet nadir of less than 100.0 X 10(9)l was seen in 5 cases and partial hearing deficit occurred in 2 patients. Median survival was 22 wk for the whole group (24 wk for the whole group if the 4 early drug deaths are excluded). Median survival was 26 wk for responding patients and 13 wk for nonresponding patients (remains the same if the early deaths are excluded from the latter group).(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose cisplatin and vinblastine infusion with or without radiation therapy in patients with advanced non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) patients with locally advanced or metastatic measurable disease were given a combination of cisplatin, 200 mg/m2 divided in five daily doses, and simultaneously, vinblastine, 7.5 mg/m2 as a continuous intravenous (IV) infusion over five days. Five courses of chemotherapy were planned. Afterwards or on progression, patients were randomized to receive maximally tolerated radiation to all sites of disease v observation only. Forty males and seven females were entered. Median age was 60 years (range, 37 to 74), median Karnofsky performance status was 70 (range, 30 to 90). Five patients had previous brain radiation therapy for metastatic disease, all others were previously untreated. Side effects in the 87 courses of chemotherapy administered included leukopenia (WBC less than 1,000/microL following nine courses) and thrombocytopenia (platelets less than 20,000/microL following four courses). Ten patients became septic, nine of them while leukopenic. Elevations of serum creatinine followed eight courses; in all cases the level was less than 3.0 mg/dL. Nausea and vomiting were mild to moderate. Five patients experienced mild hypoacusis and six had sensory polyneuropathy. The deaths of three patients were considered drug-related. The response rate was 28%. The median survival for the group was 22 weeks, 63.2 weeks for responders and 17.9 weeks for nonresponders. Twenty-six patients received radiation therapy, 16 randomized to this arm as planned, ten to palliate symptoms. Median survival of all irradiated patients was 24.8 weeks. Seven responders to chemotherapy were randomized to receive radiotherapy; their median survival was 25 weeks. In six responders randomized not to receive radiation, the median survival was 77.8 weeks (P greater than .3). Among nonresponding patients, the median survival of those radiated was 22.2 weeks, while that of nonradiated patients was 11 weeks. This regimen is cumbersome and toxic. It has offered no major survival benefits, or improvement in response rates, therefore, we do not recommend it for the standard treatment of NSCLC.

Systemic therapy of malignant melanoma.

To date, the therapeutic challenge of improving the poor prognosis of malignant melanoma has not been met by adjuvant therapy for disseminated disease. But the tedious determination of ineffective therapy has closed some lines of research and opened others. Disseminated melanoma is a fertile field for application of new drugs and phase II studies. An effective drug for advanced disease is the key to defining adjuvant therapy. In the next years, clinical application of antimelanoma monoclonal antibodies will be feasible to determine efficacy. Viral oncolysate, a new and promising agent, will also be studied in prospective randomized trials. Continuing research to define an effective systemic therapy for malignant melanoma is warranted.

Phase II trial of recombinant interferon-alpha with BCNU, cisplatin, DTIC and tamoxifen in advanced malignant melanoma.

Since cytotoxic chemotherapy (BCNU, DTIC and cisplatin, tamoxifen) and interferon-alpha (IFN-alpha) have each produced responses in advanced malignant melanoma, a phase II trial was conducted to evaluate the response and toxicity of simultaneous administration of both therapies. Of 33 assessable patients, two (6%) had complete response (CR) and 12 patients (36%) had partial response (PR), for a total response rate (CR+PR) of 42% (95% confidence interval 26-58). Four patients had minor response (12%). Mixed responses occurred in five patients (15%). The remaining patients had progressive disease. The duration of CR was 3, 7 and 17 (+) months and the duration of PR was 3+ to 19+ months (median 6 months). The median overall survival for all patients entered into the study was 5 months. Main toxicities included myelosuppression and fatigue. Combined simultaneous cytotoxic chemotherapy and IFN produced a high response rate (42%) which is comparable to that reported for chemotherapy alone. Further studies are needed to determine the optimal schedule for combining chemotherapy and immunotherapeutic agents as well as the impact of biological agents on survival in the treatment of melanoma.

Results of BCG adjuvant immunotherapy in 100 patients with epidermoid carcinoma of the head and neck.

One hundred patients with advanced, recurrent, or metastatic squamous cell carcinoma of the head and neck were treated with chemotherapy and BCG as adjuvant immunotherapy. The overall response rate was 35 per cent, and the median duration of response was seventeen weeks. BCG does not prolong duration of remission or survival time.

Lung carcinoma in 1,336 patients.

Characteristics of 1336 successive lung cancer patients diagnosed between 1977 and 1986 according to the Tumor Registry of the University of Miami and Jackson Memorial Hospitals were 92% smokers, 69% men, and 68% white. The histologic subtypes were 32% squamous cell carcinoma, 26% adenocarcinoma, 19% small-cell carcinoma, 12% large-cell carcinoma, 8% adenosquamous carcinoma, and 3% bronchioalveolar carcinoma. Age distribution was as follows: younger than 45, 8%; 45-54, 21%; 55-64, 36%; 65-74, 25%; and 75 years or older, 10%. Local stage constituted 15%; regional, 26%; and distant 60%. Women had a higher number of nonsmokers and adenocarcinoma. Black patients presented with lung carcinoma at a younger age than white patients. Younger patients and black patients presented with more advanced stages than older patients and white patients. The significant factors predictive of better survival were local stage and white race. Patients with bronchioloalveolar carcinoma had a better survival rate (p less than 0.02) than the other histologic subtypes, probably because of a higher incidence of local stage. There were no differences in survival between the other histologic subtypes. There were significant increases in adenocarcinoma (p less than 0.01) and adenosquamous histologies (p less than 0.025) and in distant stage (p less than 0.0001); but there were no significant changes in the age and sex distribution, smoking history, and survival rate at our center over the 10-year study period.

Phase II trial of mitoxantrone in head and neck carcinoma.

Nineteen patients with measurable and incurable head and neck carcinoma (17 squamous cell and two adenoid cystic) received intravenous bolus doses of 14 mg/m2 mitoxantrone in the first course. The doses were escalated or de-escalated by 2 mg/m2 in subsequent courses, based on leukocyte nadir, to achieve mild (3,000-3,999/mm3) or moderate (2,000-2,999/mm3) toxicity and response. The courses were repeated every 3 weeks. All 60 courses were evaluated for toxicity. Leukopenia was mild, moderate, severe (1,000-1,999/mm3), and life-threatening (less than 1,000/mm3) in 17%, 23%, 42%, and 2% of courses, respectively. Mild thrombocytopenia (100,000-129,999/mm3) occurred in two courses. The median interval to nadir leukopenia was 14 days (range 7-36) with a median of 13 days (range 3-50) to recover to normal. After the first course, leukopenia was mild in 16%, moderate in 32%, severe in 26%, and life-threatening in 5%. One patient died of pulmonary embolism 8 days after the first course and had concomitant leukocyte count of 700/mm3. Eighteen patients had at least one course resulting in leukopenia. Three of six patients receiving greater than or equal to 4 courses (cumulative dose 56-102 mg/m2) had an asymptomatic decrement of 14%, 17%, and 29%, respectively, in radionuclide left ventricular ejection fraction. The other toxicities were mild. In the 16 patients with squamous cell carcinoma that could be evaluated for response, one had a partial response lasting 8 months, and six had stable disease. One of the two patients with parotid adenoid cystic carcinoma had a minor response lasting 16 months. Mitoxantrone on a bolus schedule has minimal activity and is not indicated in head and neck squamous cell carcinoma.

Effect of microbial fractions and vehicle on survival of mice bearing Lewis lung carcinoma.

Mice bearing pulmonary metastases of the Lewis lung carcinoma were treated iv with a nonviable microbial vaccine following amputation of the primary inoculation site. The vaccine consisted of BCG cell wall skeleton, trehalose, dimycolate, and endotoxin attached to mineral oil microdroplets. Single and repeated doses ranging from 15 to 675 micrograms were tested. Survival was modestly but consistently prolonged by vaccination. A portion of the activity appeared to be due to the Tween saline-oil vehicle. A single low dose (15 micrograms) was as efficacious as higher or repeated doses.

Cancer immunotherapy.

Important contributions that stimulated studies in cancer immunotherapy included: (1) the discovery of tumour-associated antigens; (2) the observation that infection with bacille Calmette-Guérin (BCG) in animals was protective against tumour challenge; and (3) the observation that immunodepression due either to malignant disease or to treatment of the disease, was, in some instances, related to prognosis. Immunotherapy trials with microbial agents have involved attempts to obtain a local effect by injecting the agent into the tumour or into the region of the tumour and to obtain a "systemic" effect distant from the site of injection. Trials with active specific immunotherapy involving tumour cells or tumour cell extracts have frequently involved the combination of these specific agents with a nonspecific adjuvant such as BCG. Recent studies with thymosin and levamisole in patients with lung cancer and other types of malignant disease have shown prolonged survival in the groups receiving immunotherapy.

Epilesional scarification. Preliminary report of a new approach to local immunotherapy with BCG.

Because of the serious toxicity of intralesionally injected BCG, including high fever, local ulceration, chronic drainage, and disseminated BCG disease, 13 patients received local BCG immunotherapy by the new approach of epilesional scarification. Three patients had complete responses, four had partial responses, and six had no response. Toxic reactions were minimal compared to those reported for intralesionally given BCG.

Clinical features of adenosquamous lung carcinoma in 127 patients.

There has been increased recognition of adenosquamous lung carcinoma since the 1982 modification of World Health Organization (WHO) histologic criteria. However, data on clinical features of this histologic subtype were nonexistent. Medical records of 127 patients with adenosquamous lung carcinoma were reviewed to determine the clinical features, namely, age, race, sex, smoking history, asbestos exposure, symptoms present at the time of diagnosis, stage, treatments, and survival. The age distribution was: less than 40 yr, 3%; 40 to 49, 17%; 50 to 59, 28%; 60 to 69, 32%; 70 to 79, 18%; greater than or equal to 80, 2%. Men constituted 72%, and 90% were smokers. Four smokers had documented asbestos exposure. The symptoms in order of decreasing frequency were cough, weight loss, expectoration, anorexia, chest pain, dyspnea, weakness, hemoptysis, pneumonia, fever, nausea, vomiting, dizziness, and chills. Stage could be ascertained in 120 (95%) patients. Local stage constituted 10%, regional constituted 30%, and distant constituted 60%. Local stage had the best survival, with a projected 5-yr survival of 62%. Median survivals in regional and distant stages were 8 and 4 months, respectively. Symptoms of adenosquamous lung carcinoma were similar to other histologies. Most patients present in regional or distant stages. Local-stage patients had a good long-term survival after surgical excision of the tumor.

Phase I trial of low dose N-phosphonacetyl-L-aspartic acid and high dose 5-fluorouracil administered concomitantly with radiation therapy for unresectable localized adenocarcinoma of the pancreas.

BACKGROUND: Preclinical and clinical data suggest that N-phosphonacetyl-L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. METHODS: Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. RESULTS: All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose-limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. CONCLUSIONS: PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

A phase II multi-institutional trial of low-dose N-(phosphonacetyl)-L-aspartate and high-dose 5-fluorouracil as a short-term infusion in the treatment of adenocarcinoma of the pancreas. A Southwest Oncology Group study.

Adenocarcinoma of the pancreas is a highly lethal malignancy and chemotherapy has had little impact on the natural history of this disease. PALA, used to potentiate 5-fluorouracil (5-FU), has been shown to have synergy in vivo and in vitro. Twenty-seven patients were treated with an intravenous push dose of PALA (250 mg/m2) followed 24 hours later with a 24-hour infusion of 5-FU (2600 mg/m2). This regimen was repeated weekly. There was one partial response of 21 eligible patients with an estimated response rate of 5%. Toxicity was severe with one toxic death and four patients experiencing Grade 4 toxicity. 5-Fluorouracil and PALA, given in the schedule described, do not appear to be effective against adenocarcinoma of the pancreas.