Minority cancer patients and their providers: pain management attitudes and practice.

BACKGROUND: The goals of the current studies were: 1) to determine the pain treatment needs of socioeconomically disadvantaged African-American and Hispanic patients with recurrent or metastatic cancer and 2) to assess the attitudes of health care professionals who treat them. METHODS: In the first study 108 African-American and Hispanic patients with metastatic or recurrent cancer and pain completed a survey about their pain intensity, pain interference, and attitudes toward analgesic medications. Physicians also rated their patients' pain and the adequacy of the patients' current analgesic prescriptions was assessed. In the second study 55 physicians and nurses who treat these patients completed a questionnaire regarding cancer pain and its management in their practice settings. RESULTS: Approximately 28% of the Hispanic and 31% of the African-American patients received analgesics of insufficient strength to manage their pain. Although the majority of patients received appropriate analgesics, 65% reported severe pain. Physicians underestimated pain severity for 64% of the Hispanic and 74% of the African-American patients. Physicians were more likely to underestimate the pain severity of female patients than male patients. Inadequate pain assessment, patient reluctance to report pain, and lack of staff time were perceived as barriers to pain management. CONCLUSIONS: Although the data suggest recent improvements in analgesic prescribing practices for African-American and Hispanic cancer patients, the majority of patients reported high levels of pain and limited pain relief from analgesic medications. Inadequate pain assessment remains a major barrier to optimal cancer pain treatment.

A Phase II trial of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of patients with locally advanced breast carcinoma.

BACKGROUND: Traditionally, primary surgical therapy is considered unsuitable for the treatment of patients with locally advanced breast carcinoma (LABC). Multiple reports have documented the efficacy of primary chemotherapy in this group of patients. The purpose of this study was to investigate the efficacy of a multimodality treatment program in reducing distant and local disease relapses in patients with LABC. METHODS: Fifty-five patients with large operable or inoperable Stage III breast carcinoma, median tumor greatest dimension 7 x 8 cm, were treated with neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) to achieve maximum clinical response, followed by modified radical mastectomy, adjuvant MVAC for six courses, and chest wall radiation. Of these patients, 37 had Stage IIIA disease and 18 had Stage IIIB or inflammatory breast carcinoma. RESULTS: Forty-nine patients achieved overall responses to the neoadjuvant chemotherapy, including 16 complete clinical remissions. Histopathologic evaluation was performed for all patients; nine were pathologically free of disease and six had residual intraductal carcinoma only. After a median follow-up of 47 months (range, 8-76 months), 24 patients had relapsed: 6 locoregional and distant, and 18 distant only. The median disease free and overall survival have not been reached; the 5-year disease free and overall survival rates are 51% and 63%, respectively. The number of lymph nodes with metastases was found to be an independent predictor of relapse in univariate and multivariate analyses. CONCLUSIONS: This multidisciplinary approach produced an excellent local control rate and a respectable 5-year distant relapse free rate. Axillary lymphadenectomy after primary chemotherapy provides crucial prognostic information, which can be important in planning multimodality treatment of patients with LABC.

Phase II trial of low-dose N-(phosphonacetyl)-disodium L-aspartic acid and high-dose 24-hour infusional 5-fluorouracil in advanced gastric adenocarcinoma. A Southwest Oncology Group study.

N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) followed 24 hours later by a 24-hour infusion of 5-FU (2600 mg/M2) for an initial period of 8 weeks. No objective responses were noted. PALA and 5-FU is inactive against gastric adenocarcinoma at the doses and schedule used in this trial.

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.

A phase II trial of continuous-infusion recombinant interleukin-2 in patients with advanced renal cell carcinoma: a Southwest Oncology Group study.

A multicenter, phase II trial of continuous-infusion interleukin 2 (IL-2) was done in the Southwest Oncology Group to evaluate the efficacy and safety of this treatment in a broad-based population of patients with metastatic renal-cell carcinoma. Forty-seven patients from 11 different institutions were entered in this study, with 43 eligible. Two technically ineligible patients who received treatment and for whom records are available are included in the data analysis. Thus, there are 45 analyzable patients. Of these patients, performance status was 0 in 58% and 1 in 42%. Thirty-one patients had a prior nephrectomy, and 12 patients had received prior therapy. IL-2 was initially given at a dose of 4.5 x 10(6) Roche U/m2/day, 4 days a week, for 4 weeks in a row, followed by a 3-week rest period. Because of the difficulty in obtaining reimbursement for the hospitalization required on the days of IL-2 administration, after 10 patients had been entered, the treatment regimen was changed to 6 x 10(6) Roche U/m2/day for 4 days as an inpatient, followed by 2 weeks of potential outpatient treatment at a dose of 3 x 10(6) Roche U/m2/day for 4 days each week. This was followed by a 2-week rest period. Within the 45 analyzable patients, there were 0 complete responses and 6 partial responses, for a response rate of 13% (95% confidence interval 5.1-27%). Responses occurred in lung metastases, nodal disease, and in one patient with bone metastases and the primary kidney tumor. Response durations were 1 month, 1 month, 14+ months, 19 months, 26+ months, and 27 months. Of 12 patients with a nephrectomy and only lung metastases, 4 showed partial responses. Medial survival for all analyzable patients is 15 months (95% confidence interval 8-20 months). Toxicity was significant, with nausea and vomiting, diarrhea, fever and chills, dermatologic changes, and fatigue the most frequent. There were 18 instances of grade 4 toxicity, with the most common grade 4 toxicity, respiratory, found in 8 patients. There were two early deaths of probable heart-related causes while receiving treatment. A continuous-infusion IL-2 regimen that allows some potential outpatient treatment shows effectiveness and toxicity similar to that in other multicenter IL-2 infusion trials and high-dose intravenous bolus regimens.

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.

Phase II trial of trimetrexate in untreated advanced gastric carcinoma. A Southwest Oncology Group study.

Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8-12 mg/m2 intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0-22%). Hematologic toxicities of grade > or = 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease.

Phase II trial of piroxantrone in patients with recurrent and metastatic squamous cell carcinoma of the head and neck. A Southwest Oncology Group trial.

Twenty-two patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with piroxantrone 150 mg/m2 intravenously every 21 days. There were no objective responses. The 95% upper confidence bound for response is 15%. Primary toxicity was hematologic.

Phase II trial of 4'-0-tetrahydropyranyladriamycin (pirarubicin) in head and neck carcinoma.

BACKGROUND: 4'-0-tetrahydropyranyladriamycin (Pirarubicin, Meiji Seika (USA) Inc., New York, NY) may be less toxic than doxorubicin. METHODS: A Phase II trial of Pirarubicin was done in 26 patients who had not previously had chemotherapy and who had measurable and incurable head and neck carcinoma. All patients received an intravenous bolus dose of 60 mg/m2 Pirarubicin in the first cycle without any prophylactic antiemetic. The cycles were repeated every 3 weeks. Based on tumor response, nadir counts, or complications of myelosuppression, the doses were escalated or de-escalated by 10 mg/m2, if necessary, in the second cycle to achieve mild leukopenia (3000-4000 leukocytes/microliters). RESULTS: Leukopenia was mild, moderate (2000-2999 leukocytes/microliters), severe (1000-1999 leukocytes/microliters), and life threatening (less than 1000 leukocytes/microliters) in 13%, 31%, 27%, and 9% of the first two courses, respectively. The median interval to nadir leukopenia was 13 days (range, 7-21 days), with a median of 8 days (range, 5-13 days) to recover to normal. One patient with a leukocyte count of 800/microliters and an absolute granulocyte count (AGC) of 488/microliters died of sepsis 15 days after the first course. All patients had at least one course that resulted in leukopenia. One episode each of mild (100,000-150,000 platelets/microliters) and severe (25,000-49,999 platelets/microliters) thrombocytopenia occurred in the first two courses. Leukocyte, granulocyte, and platelet counts were not done routinely after the second cycle. Six patients who received four or more courses with cumulative doses of 310, 610, 340, 260, 660, and 550 mg/m2 had decrements of 0%, 1%, 7%, 10%, 12%, and 13%, respectively, in radionuclide left ventricular ejection fraction (LVEF). All other toxic effects were mild. CONCLUSIONS: In the 24 patients with disease evaluable for response to Pirarubicin therapy, 1 had a complete response that lasted 5 months and 4 had a partial response of 2, 3, 6, and 8 months. The median survival time in patients with disease that responded to Pirarubicin therapy was 27 months; in patients with disease that did not respond to Pirarubicin therapy, the median survival time was 4 months, and in the total cohort, it was 5 months. Pirarubicin was well tolerated and was an active agent in head and neck squamous cell carcinoma.

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.

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.

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.

A phase I study of 4'-0-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics.

A Phase I study of intravenous (IV) bolus 4'-0-tetrahydropyranyladriamycin (Pirarubicin) was done in 55 patients in good performance status with refractory tumors. Twenty-six had minimal prior therapy (good risk), 23 had extensive prior therapy (poor risk), and six had renal and/or hepatic dysfunction. A total of 167 courses at doses of 15 to 70 mg/m2 were evaluable. Maximum tolerated dose in good-risk patients was 70 mg/m2, and in poor-risk patients, 60 mg/m2. The dose-limiting toxic effect was transient noncumulative granulocytopenia. Granulocyte nadir was on day 14 (range, 4-22). Less frequent toxic effects included thrombocytopenia, anemia, nausea, mild alopecia, phlebitis, and mucositis. Myelosuppression was more in patients with hepatic dysfunction. Pharmacokinetic analyses in 21 patients revealed Pirarubicin plasma T 1/2 alpha (+/- SE) of 2.5 +/- 0.85 minutes, T beta 1/2 of 25.6 +/- 6.5 minutes, and T 1/2 gamma of 23.6 +/- 7.6 hours. The area under the curve was 537 +/- 149 ng/ml x hours, volume of distribution (Vd) 3504 +/- 644 l/m2, and total clearance (ClT) was 204 + 39.3 l/hour/m2. Adriamycinol, doxorubicin, adriamycinone, and tetrahydropyranyladriamycinol were the metabolites detected in plasma and the amount of doxorubicin was less than or equal to 10% of the total metabolites. Urinary excretion of Pirarubicin in the first 24 hours was less than or equal to 10%. Activity was noted in mesothelioma, leiomyosarcoma, and basal cell carcinoma. The recommended starting dose for Phase II trials is 60 mg/m2 IV bolus every 3 weeks.

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.

A phase I trial of chlorambucil administered in short pulses in patients with advanced malignancies.

We carried out a phase I trial with chlorambucil. Thirty patients with advanced cancer were entered in six dose levels: 36, 48, 60, 84, 108, and 144 mg/m2. The drug was given in six divided oral doses every 6 hours and the regimen was repeated every 3 weeks. The median age was 62 years (31-84), median Karnofsky performance status (KPS) 60 (40-90). All patients but one had received prior radiation therapy, chemotherapy, or both. Central nervous system toxicity was dose limiting, occurring in 5 of 6 patients at 144 mg/m2. It was characterized by transient seizures, hallucinations, lethargy, stupor, and coma. Metoclopramide was successful in controlling nausea and vomiting, which was severe if the antiemetic was not used. Leukopenia (3 patients) and thrombocytopenia (2 patients) were mild. One patient with colorectal carcinoma had a minor response, and two patients with non-small cell lung cancer had stable disease. A safe dose for phase II trials is 108 mg/m2 in six 6-hourly oral doses.

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.

A phase I trial of dactinomycin intravenous infusion in patients with advanced malignancies.

Eighteen patients with advanced malignancies refractory to other forms of treatment were given dactinomycin (Act D) as continuous intravenous infusions. Their median age was 51 years (range, 36-67); their median performance status was 50 (range, 40-90) on the Karnofsky scale. Act D was administered continuously for 5 days, utilizing a central venous line and a perfusion pump. The starting dose was 0.1 mg/m2/24 hours X 5 days (total dose, 0.5 mg/m2) and was escalated according to a modified Fibonacci scale to 0.2, 0.33, and 0.5 mg/m2/24 hours X 5 days, respectively. Three, three, four, and eight patients were entered, respectively, in each dose level. Toxicities observed were: leukopenia in four patients (nadir leukocyte count less than 1000 cells/nm3 in one patient and 2000-3000 cells/mm3 in 3 patients); thrombocytopenia, with nadir platelet counts between 50,000 and 100,000 platelets/mm3 in 2 patients; stomatitis in four patients; and nausea in three patients. Vomiting was not observed during the infusions. Two patients may have had a radiation recall phenomenon. Blood count depression, nausea, and mucositis were transient, resolving after a few days. One patient at level IV died of sepsis, which was diagnosed on the fourth day of the infusion, before leukopenia intervened. No objective responses were seen. It was concluded that a higher dose of Act D can be given by continuous infusion than by a bolus injection; the authors recommended 0.5 mg/m2/day X 5 days (total dose, 2.5 mg/m2) for further studies.

High-dose cisplatin in patients with advanced malignancies.

A study was conducted to determine if cisplatin (CDDP) can be given at higher doses than usual, utilizing aggressive supportive measures. Twelve patients were entered into three dose levels of CDDP: level I, 180 mg/m2 given as a short infusion; level II, 220 mg/m2 also given as a short infusion; level III, 200 mg/m2 divided in five daily doses, each infused over 6 hours. In all cases, CDDP was dissolved and given in 250 ml of a 5% saline solution. For levels I and II, intravenous hydration with 200 to 250 ml/hour D5 1/2NS with potassium and magnesium supplements, was started 24 hours before therapy and continued for 3 to 4 days after, longer if nausea persisted. Mannitol was given before (25% solution, 50 ml bolus) and after (20% solution, 500 ml over 3 hours) CDDP. At level III hydration with the same intravenous (IV) fluids was begun the day before therapy and continued without interruption at 200 to 250 ml/hour for a minimum of 24 hours after the completion of the 5 days of chemotherapy. Each daily dose of CDDP was preceded by injection of mannitol (25% solution, 50 ml bolus) and accompanied by a 6-hour infusion of 1000 ml 20% mannitol. Three patients received five CDDP courses at level I; 4 patients, seven courses at level II; and 5 patients, seven courses at level III. Ototoxicity was dose-limiting in three patients at level II. Transient elevation of serum creatinine was seen following two courses at level I and two courses at level II. The renal impairment was asymptomatic in all cases; dialysis was not needed. At level II, leukocyte nadir counts between 1.0 and 2.0 X 10(3)/mm3 were seen following two courses and between 2.0 and 3.0 X 10(3)/mm3 following three courses. Platelet nadir counts below 50 X 10(3)/mm3 were recorded after four courses and between 50 and 100 X 10(3)/mm3 after one course. Nausea and vomiting occurred frequently, but were tolerable. At level III, myelosuppression was dose-limiting. Nadir leukocyte counts between 1.0 and 2.0 X 10(3)/mm3 followed four courses and between 2.0 and 3.0 followed one course. Nadir platelet counts below 50 X 10(3)/mm3 were seen after three courses; two patients required prophylactic platelet transfusions. Nadirs between 50 and 100 X 10(3) platelets/mm3 followed three further courses. Ototoxicity and nephrotoxicity did not occur at level III.(ABSTRACT TRUNCATED AT 400 WORDS)