Hypovitaminosis C in patients treated with high-dose interleukin 2 and lymphokine-activated killer cells.

Patients (n = 15) with metastatic malignant melanoma, hypernephroma, and colon carcinoma received a three-phase adoptive immunotherapy protocol: phase 1, 10(5) units (high-dose) interleukin-2 (IL-2) iv every 8 h or 1 mg/m2 continuous intravenous infusion; phase 2, 6.5 d rest + leukapheresis; phase 3, 4 d of high-dose IL-2 plus three infusions of autologous lymphokine-activated killer cells. Toxicities of treatment included fever, chills, tachycardia, hypotension, vomiting, diarrhea, and fluid retention. Patients entering the trial were not malnourished, and mean plasma ascorbic acid concentrations before therapy were normal (36.3 +/- 14.2 mumol/L). Mean concentrations dropped by 80% after the first phase of treatment with high-dose IL-2 alone (to 7.4 +/- 4.5 mumol/L). Mean plasma ascorbic acid concentrations remained severely depleted (between 4.5 and 7.4 mumol/L) throughout the remainder of the 15-d treatment. Ascorbic acid concentrations became undetectable (less than 2.8 mumol/L) in 12/15 patients during this time. Blood pantothenate and plasma vitamin E concentrations remained within normal limits in all patients tested throughout the phases of therapy.

Long-term biopsychosocial effects of interleukin-2 therapy.

This three-year project evaluates the biopsychosocial effects of interleukin-2 (IL-2) therapy on the first 45 patients treated with the therapy at the Moses Division of the Montefiore Medical Center in Bronx, NY, starting in April 1986. Therapy with IL-2 and lymphokine-activated killer (LAK) cells is a promising new development but requires an extensive amount of supportive care. Various important issues must be considered in planning the care of patients being treated with IL-2, including the effects of the treatment on quality of life, the cost of resources necessary for providing therapy, and the emotional effects of treatments. The instruments used to measure the various aspects of quality of life were the Sickness Impact Profile, the Inventory of Current Concerns, the Symptom Distress Scale, the Acute Physiology and Chronic Health Evaluation Scale, and the Therapeutic Intervention Scoring System. The researchers believe that, in addition to tumor response, the biopsychosocial and financial effects of treatment should be understood.

Testing hypotheses derived from the Roy Adaptation Model.

This study investigated the role of perception and biopsychosocial adaptation in patients with cancer entering an aggressive cancer treatment program. The Roy adaptation model provided the framework from which hypotheses were derived and tested. The hypotheses proposed that physiological stimuli are translated by the cognator through perception that alters the biopsychosocial responses. Forty-five patients were tested as they entered into the chemotherapy program. The APACHE II was used to measure actual physiological status; the Symptom Distress Profile was used to measure subjects' perceived physiological discomfort, and the Sickness Impact Profile was used to measure subjects' perceived effect of the cancer on their psychosocial adaptation. The results supported the theoretical predictions that perception of symptoms is positively correlated with psychosocial adaptation and not with actual physiological status. In addition, perception of symptoms and psychosocial adaptation were correlated with survival at six months and not with actual physiological status. Discussion of findings addresses theoretical and practice issues.

A phase I-II trial of 4'-deoxydoxorubicin (esorubicin) in refractory or relapsed acute leukemia.

In a phase I-II study, 21 patients with relapsed or refractory acute leukemia were treated with 4'-deoxydoxorubicin (esorubicin), the 4'-deoxy derivative of doxorubicin. Four of 14 evaluable patients with acute nonlymphocytic leukemia (ANLL) in relapse or refractory to other anthracyclines achieved partial response (28.5%). Pharmacokinetics were similar to those of the parent compound, doxorubicin. Esorubicin has activity in ANLL and has pharmacologic properties comparable to those of other anthracyclines. Dose-limiting toxicity occurs in the form of mucositis, which may limit its use in combination with other antileukemic drugs.

Severe hypovitaminosis C occurring as the result of adoptive immunotherapy with high-dose interleukin 2 and lymphokine-activated killer cells.

Adoptive immunotherapy of human cancer was investigated in our institution as part of a National Cancer Institute extramural group study. This treatment, for patients with metastatic malignant melanoma, hypernephroma, and colon carcinoma, consisted of three phases: (a) 5 days of i.v. high-dose (10(5) units/kg every 8 h) interleukin 2, (b) 6 1/2 days of rest plus leukapheresis; and (c) 4 days of high-dose interleukin 2 plus three infusions of autologous lymphokine-activated killer cells. Toxicities included fever, chills, tachycardia, hypotension, vomiting, diarrhea, and fluid retention. Ascorbic acid is known to be important to cell-mediated immunity, and it has been reported to be depleted during physiologically stressful events. Therefore, we determined plasma ascorbic acid levels in patients (n = 11) before adoptive immunotherapy and before and after Phases 1, 2, and 3 of treatment. Patients entering the trial were not malnourished. Mean plasma ascorbic acid levels were normal (0.64 +/- 0.25 mg/dl) before therapy. Mean levels dropped by 80% after the first phase of treatment with high-dose interleukin 2 alone (0.13 +/- 0.08 mg/dl). Mean plasma ascorbic acid levels remained severely depleted (0.08 to 0.13 mg/dl) throughout the remainder of the treatment, becoming undetectable (less than 0.05 mg/dl) in eight of 11 patients during this time. Values obtained from 24-h urine collections on two of two patients indicated that ascorbate was not excreted in the urine. Plasma ascorbic acid normalized in three of three patients tested 1 mo after the completion of treatment. Unlike the results for ascorbic acid, blood pantothenate and plasma vitamin E remained within normal limits in all 11 patients throughout the phases of therapy. Responders (n = 3) differed from nonresponders (n = 8) in that plasma ascorbate levels in the former recovered to at least 0.1 mg/dl (frank clinical scurvy) during Phases 2 and 3, whereas levels in the latter fell below this level.

Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma.

Taxol, a plant product, has significant activity against certain rodent and human xenograft tumors. It promotes microtubule assembly in vitro, in contrast to vinca alkaloids, which inhibit assembly. In this phase I study, taxol was administered as a 24-hour continuous intravenous (IV) infusion in 65 courses to 26 patients. A premedication regimen of dexamethasone, cimetidine, and diphenhydramine was used to prevent the acute hypersensitivity reactions observed in previous studies of taxol. Only one episode of mild stridor occurred in this study. Peripheral neuropathy was the dose-limiting toxicity and was observed in 40% of patients treated at a dose of 250 mg/m2. Significant neutropenia of brief duration was also common. Pharmacokinetic studies by a high-performance liquid chromatography (HPLC) method demonstrated that drug plasma concentrations increased during the 24-hour infusion and then declined rapidly. Peak plasma concentrations correlated with dose, and less than 5% of taxol was excreted in the urine. Most of the drug was bound to serum components. Partial responses of more than 3 months' duration were observed in four of 12 melanoma patients treated. The recommended phase II dose of taxol on this schedule is 250 mg/m2. Priority should be given to the study of taxol in melanoma.

Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia.

Mitoxantrone is a synthetic aminoanthraquinone we have previously reported to be effective for patients with acute leukemia in relapse. We presently report the results of a trial of mitoxantrone in combination with cytosine arabinoside (ara-C) in patients with refractory or relapsed acute myelocytic leukemia (AML). Forty-nine patients, 24 males and 25 females, with a median age of 56, of whom 32 were in first relapse, four were in second relapse, and 13 had primarily refractory AML, were treated with mitoxantrone 10 mg/m2 daily for 3 days and ara-C 100 mg/m2 daily by continuous infusion for 7 days. Twenty patients (62.5%) with first relapse AML achieved M1 marrow, whereas only two of 13 patients with refractory AML did; none of four patients with more than one prior remission responded. Marrow recovery was observed in a median of 32 days. Remissions were maintained with monthly ara-C plus mitoxantrone alternating with ara-C plus 6-TG; median duration of remission was 8 months and two patients are in continuing remission at 8 and 16 months. Treatment was well tolerated, with minimal nausea and vomiting, diarrhea, drug-induced mucositis. Treatment-related cardiac toxicity was not observed. Transient hepatic dysfunction was observed in greater than 50% of courses. Mitoxantrone plus ara-C is an active combination with great promise for the therapy of previously untreated patients with AML.

Phase I clinical and pharmacokinetic study of taxol.

Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooperative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at the first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 2 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grades 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was biphasic; half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respectively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred immediately postinfusion, was approximately 8 microM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carcinoma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.