Monfardini S

Clinical trials with bleomycin in lymphomas and in solid tumors

Abstract The authors report the results of Phase I and Phase II evaluation of intravenous bleomycin (BLM) in 176 patients. During the trial different doses and schedules were employed. The less toxic regimen was that of 15 mg/m2 × 2/week per 4 weeks. Irrespective of the schedules, the side effects are represented by sclerotic changes of the skin of hands (88%), skin hyperpigmentation (78%), fever (70%), loss of hair (68%), stomatitis (47%) pulmonary toxicity (42%), gastro-intestinal symptoms (20%). No significant myelo-suppression was observed. Pulmonary toxicity occurred after 4–10 weeks from starting therapy and was detected on clinical bases (fine crepitations at the base), radiologically (reticulonodularity mostly at the lower lung zones) and histologically (edema of alveoli, hyaline membranes formation, collagen deposition). Upon prompt discontinuation of BLM, the signs of pulmonary damage remained unchanged or regressed in the majority of cases. Lower total doses of BLM produced a lesser incidence of lung toxicity. However, in about 5% of cases the presumptive cause of death could be related to extensive pulmonary drug-induced lesions. The incidence of lung toxicity was not found to be significantly related to the age of patients, to the total dose of BLM or to the presence of chronic pulmonary disease. BLM produced significant regression in all types of malignant lymphomas (40%), in epidermoid carcinomas of the head and neck (57%) and of the esophagus (60%). No significant responses were observed in epidermoid carcinomas of the lung. Regressions were prompt but usually short-lived with or without maintenance therapy. Because of its toxic and therapeutic properties BLM appears suitable for therapeutic trials either in short courses alone in or in combination with myelosuppressive agents.

LYMPHORETICULAR SARCOMAS WITH PRIMARY INVOLVEMENT OF WALDEYER'S RING. CLINICAL EVALUATION OF 225 CASES.

A total of 225 consecutive untreated patients with lymphoreticular sarcomas with primary involvement of Waldeyers ring was evaluated (151 without lymphography and 74 with lymphography). On admission, the anatomical distribution of the primary growth within Waldeyers ring was as follows: tonsil, 40%; nasopharynx, 27.5%; base of tongue, 2.7%; soft palate, 2.7%; oropharynx, 0.9%; other sites, 26.2%. In the group studied without lymphography, the disease was confined to Waldeyers ring in 22.5% of cases and had spread to the cervical nodes in 62.3% and to distant nodes in 15.2%. In the group studied more recently with lymphography, these figures were 13.5%, 41.9%, and 44.6%, respectively. At the time of initial evaluation, the lymphoma involved extranodal sites in only 24 of 225. In the 74 cases evaluated with lymphography, the mode of spread was studied by observing the first site of recurrence after radiotherapy. New manifestations occurred in most patients within 2 years from the end of treatment and preferentially in extranodal sites. The involvement of the gastointestinal tract, either at the time of admission or early in the follow‐up, was 20% in the group studied with lymphography. The possibility that a certain number of lymphoreticular sarcomas could arise concomitantly in Waldeyers ring and in the gastrointestinal tract is discussed.

Clinical Trials with Adriamycin in Leukemia and Solid Tumors

Adriamycin is a new antitumor antibiotic of the anthracycline group. Its chemical structure is very close to that of daunorubicin. Pharmacological studies demonstrated that adriamycin has a higher therapeutic index (1.21) than daunorubicin (0.67). Adriamycin was given intravenously to 53 patients with different types of leukemia and cancer (13 children and 40 adults). Three doses were used: 0.4 mg/kg (pretreated patients), 0.65 mg/kg (untreated adults), 0.8 mg/kg (children). Three different schedules were also employed regardless of the single dose/kg (table 1): A) Loading-dose schedule: treatment for 4 consecutive days followed by a 3 day interval: the drug was then restarted 1–2 times a week; B) Alternate day-dose schedule: treatment every other day for 4–6 doses followed by a 3 day interval; the drug was then restarted 1–2 times a week; C) Intermittent-dose schedule: two treatments for 3 consecutive days separated by two intervals of 4 days; the drug was then restarted 1–2 times a week. The chief evidence of toxicity was a triad of symptoms: stomatitis, bone marrow depression and alopecia (table 2). The oral ulcerations where the first sign of toxicity in more than 50 % of cases. The first sign of toxicity usually precedes the other side effects by 1–3 days. Fever, gastroenteritis and phlebitis at the site of injection were toxic signs of minor importance. However, to avoid phlebitis the drug should be injected through a tube of a free-running intravenous infusion. Adriamycin seems from the present series to be devoid of significant cardiac toxicity. As expected, children tolerated higher doses than adults and all pretreated patients became rapidly intoxicated with small doses. The less toxic schedule appears to be the intermittent one (C). Prompt and consistent responses were observed in many cases (table 4), but they were usually short lived. The drug appears therefore to be a potent growth-inhibiting compound more useful for inducing the first remission than for mantaining it. Acute lymphoblastic and chronic myelogenous leukemias as well as malignant lymphomas, neuroblastomas and soft tissue sarcomas were the diseases most sensitive to adriamycin.

Clinical evaluation of procarbazine and fluorouracil in advanced lung cancer

Procarbazine and 5-fluorouracil were given to 69 untreated patients with inoperable or metastatic lung cancer. 62 were adequately evaluable. The patients were divided into 3 groups: A) 26 cases received procarbazine (250 mg/day i.v. for 4 weeks); B) 24 cases received procarbazine in association with 5-fluorouracil given by rapid single i.v. injection (10 mg/kg on alternate days for 4 weeks); C) 12 cases received procarbazine in association with 5-fluorouracil which was given by 2 hour i.v. infusion on alternate days for 4 weeks. No maintenance treatment was given. The objective responses were evaluated following the categories of Karnofsky. Considering only the category 1 responses, 15 % of patients of group A showed objective improvement, in comparison to 43 % and 16 % of patients of group B and C respectively. Therefore, it seems that the combination of procarbazine and 5-fluorouracil (rapid i.v. injection) is better than procarbazine alone, and that the combined treatment is more successful when 5-fluorouracil is given by single i.v. injection rather than through slow i.v. infusion. Regressions were observed in all histologic types. However, in the group of cases with adenocarcinoma none (0/5) responded to procarbazine alone but 5/6 to procarbazine plus 5-fluorouracil. It is likely that procarbazine is more effective in the oat-cell type and 5-fluorouracil in adenocarcinomas. Toxicity consisted in nausea and vomiting during the first 7–10 days in the group treated with procarbazine alone (15/26 cases), while only 2/26 patients had transient leukopenia. In group B the side-effects were diarrhea (13 cases) and leukopenia (9 cases), both possibly due to 5-fluorouracil. Only 2/12 patients of group C showed side-effects (1 vomiting and 1 diarrhea). The fact that no patients of this group showed signs of bone marrow depression confirms what is already known, i.e. that when 5-fluorouracil is given by slow i.v. infusion toxicity rarely occurs. The conclusion is that the association of procarbazine with 5-fluorouracil can produce consistent regressions in patients with advanced carcinoma of the lung, although unmaintained remissions are almost always short lived.

Clinical Evaluation of High Intermittent Intravenous Doses of Methotrexate in Advanced Lung Cancer

Methotrexate (MTX) was given by weekly intravenous injections to 43 patients with inoperable or metastatic lung cancer (32 cases were untreated while 11 received radiotherapy or chemotherapy prior to administration of MTX). In 35 cases the dose was 40 mg/m2/week and in 8 cases 60 mg/m2/week. 36 patients were adequately evaluable. In most cases it was possible to continue the administration of MTX for 6–8 weeks (table 1). In responsive cases maintenance treatment was given at the dose of 15 mg/m2 every 4 days either orally or intramuscularly. Response to treatment was evaluated according to Karnofskys scale. Considering only the category I responses 12/30 patients adequately treated with 40 mg/m2 showed objective improvement and 2/6 of those given 60 mg/m2. Regressions were short-lived and in no case did they last longer than 5 months (table 2). Regressions were seen in practically all histologic types (table 3). Of 43 patients receiving MTX 30 (70%) had one or more side-effects: 27 showed oral or gastrointestinal toxicity, 8 varying degrees of bone marrow depression, 6 hepatic and 4 renal toxicity. Four patients died because of toxicity, renal damage being present in all cases (table 4). The relatively small number of consistent objective regressions (about 40%), their short duration and the high incidence of severe toxicity, as observed in the present series, indicate that weekly high-dose intravenous MTX is of moderate therapeutic usefulness in lung cancer.