Martin S. Blumenreich

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 D51/2NS 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 × 103/mm3 were seen following two courses and between 2.0 and 3.0 × 103/mm3 following three courses. Platelet nadir counts below 50 × 103/mm3 were recorded after four courses and between 50 and 100 × 103/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 × 103/mm3 followed four courses and between 2.0 and 3.0 followed one course. Nadir platelet counts below 50 × 103/mm3 were seen after three courses; two patients required prophylactic platelet transfusions. Nadirs between 50 and 100 × 103 platelets/mm3 followed three further courses. Ototoxicity and nephrotoxicity did not occur at level III. Responses were seen in all three dose levels in patients with prostate carcinoma, non‐small cell lung cancer, adenocarcinoma of the esophagus, and malignant fibrous histiocytoma. It was concluded that CDDP at a dose of 200 mg/m2, divided in five daily fractions, is tolerable and can be introduced into Phase II trials.

Intravesical cisplatin for superficial bladder tumors

Cisplatin, 50–150 mg in a maximum concentration of 1 mg/ml, was administered intravesically each week to 24 patients with multiple, recurrent carcinoma in situ and/or bladder tumors confined to the mucosa and lamina propria. All patients had a history of multiple transurethral resections and four had received prior chemotherapy. Response was evaluated by urinary cytology, cystoscopy, and biopsy. In a total of 237 weekly doses, toxicities included mild dysuria, pruritus, rash and in one patient, acute anaphylaxis. Only three (13%) patients were classified as achieving complete remission. Cisplatin, in the dose and schedule employed, is ineffective in controlling superficial bladder cancer.

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)

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial

Background. Hydroxyurea is an S‐phase specific drug. Constant exposure of tumor cells with a low S‐phase fraction to the agent may result in improved cell kill. Because of its short half‐life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses.

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.

Hepatic Perfusion with FUdR Utilizing an Implantable System in Patients with Liver Primary Cancer or Metastatic Cancer Confined to the Liver

Nineteen patients with colorectal adenocarcinoma, three with cholangiocarcinoma, two with hepatocellular carcinoma, and one with carcinoid were treated with hepatic artery infusion chemotherapy. An implantable pump system was used to deliver floxuridine (FUdR), starting at 400 mg for 2 weeks with 2 weeks of rest. Eleven of 15 (73%) measurable patients with colorectal carcinoma responded. Of 6 complete responses, 4 were documented by laparotomy, including 1 with cholangiocarcinoma. Toxicity included dyspepsia and elevated liver function tests in all patients, gastric ulcer in 2, cholecystitis in 2, and sclerosing cholangitis in 3. Overall median survival for the colon cancer patients has not been reached at 16 months. Regional disease was controlled in the majority of patients treated with this regimen with acceptable toxicity and good quality of life.

High-dose chlorambucil and dexamethasone for relapsed non-Hodgkin's lymphomas

Twenty patients with relapsed or refractory non-Hodgkins lymphoma were treated with high-dose chlorambucil (14 mg/m2 every 6 hours for 6 doses) and dexamethasone (40 mg/day for 5 days). There was a 45% response rate with 17% complete responses. The median duration of complete response was 7 months. The regimen was well tolerated and had minimal toxicity.

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 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 × 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 <1000 cells/mm3 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, lausea, 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 × 5 days (total dose 2.5 mg/m2) for further studies.

Phase II trial of 5-fluorouracil, folinic acid, and N,N1,N11-triethylenethiophosphoramide (thiotepa) in patients with advanced breast cancer.

A total of 35 women with advanced, metastatic breast cancer were treated with combination chemotherapy consisting of folinic acid 500 mg/m2 over 2 hours administered with 600 mg/m2 of 5FU at the midpoint of the folinic acid infusion weekly for 6 weeks, plus 60 mg/m2 of thiotepa on day 1 and day 28. The cycle was repeated every 8 weeks. Patients were evaluated for toxicity weekly. Response was evaluated at the end of each 8-week cycle. The median age was 55 years (range: 34–67). Prior to this study 30 patients had received chemotherapy; 13 had 1 regimen; 17 had 2 or more regimens; 8 had 5FU treatment; 18 had hormonal therapy; and 15 had radiation treatment. The overall response rate was 40% (1 complete and 13 partial); median duration of response was 4 months. Four of 8 patients with prior 5FU responded. Hematologic toxicity was significant: nadir WBC count: < 1,000/mm3 (10 patients); 1,000–1,999/mm3 (13 patients); nadir platelet count: < 20,000/mm3 (8 patients); 20,000–49,000/mm3 (8 patients); 50,000–99,000/mm3 (10 patients). We conclude that the combination of thiotepa, 5FU, and leucovorin has significant myelotoxicity and do not recommend its routine use in the treatment of metastatic breast cancer.