Search

12 patients with metastatic cancer were treated with the substituted indazole carboxylic acid Lonidamine at oral daily doses of 270 mg/m2. Toxicity, consisting mainly of myalgias, somnolence, hyperesthesia, anorexia and vomiting, generally decreased or disappeared over time despite continuing drug administration at unmodified dosage. Myalgias and hyperesthesias were markedly relieved with prednisone 5 mg twice daily. No laboratory abnormalities were seen. Partial responses were observed in a patient with hypernephroma and in a patient with breast cancer. Disease-oriented phase II studies with this new anticancer agent are warranted.

The concept of chemoprevention is generating increasing attention among oncologists. This article discusses the issue of dose of chemopreventive agents in relation to the stages of tumor development. Vitamin A-deficient animals have an increased susceptibility to cancer development, and epidemiologic studies have shown an inverse relationship between intake of food rich in vitamin A and/or beta-carotene and cancer risk. These data suggest that physiologic levels of these natural substances exert a protective effect against cancer development. In the presence of precursor lesions, however, this protective effect has been overwhelmed and pharmacologic doses of chemopreventive agents are required to induce regression or to arrest the progression of these lesions. Phase I pharmacologic and toxicologic studies, and Phase II dose-intensity investigation of chemopreventive agents in patients having precancerous lesions need to be carried out. Such studies would enable to select the least toxic effective chemopreventive dose for intervention trials in high-risk populations, which could then be undertaken based on evidence of activity.

15 patients with metastatic cancer were treated with Lonidamine, a substituted indazole carboxylic acid active against the Lewis lung and Sarcoma 180 tumors. Single doses of 600 mg (350-400 mg/m2) mostly induced somnolence and gastro-intestinal side effects. Toxicity occurring during chronic administration of Lonidamine at doses ranging between 45 and 275 mg/m2 twice daily, mainly consisted of somnolence, myalgias, hyperesthesia and mild hair loss. Myalgias and hyperesthesias were markedly relieved with prednisone 5 mg twice daily. No laboratory abnormalities were seen. In 1 patient with breast cancer resistant to standard chemotherapeutic agents, a 30% reduction of measurable tumor masses was seen. In view of the lack of overlapping toxicity between Lonidamine and other chemotherapeutic drugs, and of its potential activity, it is suggested that phase II studies of Lonidamine be initiated at a dose of 135 mg/m2 twice daily.

Patients with advanced breast carcinoma and no prior chemotherapy were prospectively evaluated to assess the induction capabilities of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), Adriamycin and vincristine (AV), and CMF plus prednisone (CMFP). The crossover responsiveness from CMF or CMFP to AV and of AV to CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF and 86 on CMFP induction. One hundred and twelve patients were evaluated on crossover. Induction response rates were similar with 56% on AV, 57% on CMF and 63% on CMFP. Crossover response rates ranged from 32% to 41%. CMFP and AV were superior to CMF in terms of response duration (P = 0.05), and CMFP was superior to either in terms of time to treatment failure (P = 0.04), and survival (P = 0.03). Treatment failures occurred in only the on-study organ sites of disease in 73% of the patients and did not appear to be related to the response achieved. CMF was associated with more thrombocytopenia than either AV or CMFP (P = 0.03). AV was associated with fewer infections than CMFP (P = 0.02), less diarrhea than CMFP (P = 0.04), more emesis than CMF (P = 0.02), and more neurologic toxicity than either CMF or CMFP (P less than 0.0001). There was also more emesis with CMF than with CMFP (P = 0.006). CMFP was associated with greater delivery of CMF than was the CMF regimen despite a similar day 1 leukocyte distribution. These results strongly suggest that CMF(P) and AV are clinically noncross-resistant regimens, that AV and CMF are essentially equivalently active induction regimens, and that CMFP is superior to CMF and AV.

From October 1973 to October 1977 the ECOG prospectively evaluated cyclophosphamide, methotrexate, and fluorouracil (CMF) versus CMF plus fluoxymesterone (CMFH) maintenance therapies in responders to 6 months of induction therapy which consisted of either CMF, CMF plus prednisone (CMFP), or adriamycin plus vincristine (AV). Following the maintenance randomization 12% of the patients converted from a PR to a CR status. The median time from randomization to treatment failure was 9.5 months for CMFH and 6.7 months for CMF (p = 0.03). This difference was observed only for partial responders (p = 0.01) and not for complete responders. Patients receiving CMFH tended to maintain higher hemoglobin, leukocyte, and platelet levels, and receive a higher dosage of each of the cytotoxic drugs. The results are taken as evidence that the addition of fluoxymesterone to a maintenance CMF regimen provides a therapeutic advantage. It is hypothesized that this effect is due at least in part to fluoxymesterone associated maintenance of improved marrow function resulting in greater myelosuppressive drug delivery.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of lonidamine, given in an escalating oral daily schedule to a maximum dose of 450 mg/m2 in patients with previously treated advanced breast cancer. Five responses were seen in 30 evaluable patients (17%). Treatment was discontinued because of toxicity in seven patients. Toxicity generally consisted of myalgia, nausea, vomiting, skin hyperesthesia, somnolence, and ototoxicity. All side effects were reversible and no hematologic toxicity was observed. The absence of myelosuppression and the suggestive lack of cross-resistance between lonidamine and standard chemotherapeutic drugs warrant further studies of lonidamine in breast cancer, particularly in combination with other agents.

A wide variety of approaches are being applied to the therapy of breast cancer. Treatment begins with a biopsy followed by mastectomy to remove the primary tumor. The risk category must be determined and, at present, an axillary dissection appears to be required; in the future, tumor cell markers may replace the role of an axillary dissection in the determination of risk category (TORMEY et al., 1975). If the nodes are positive, adjuvant chemotherapy and possibly immunotherapy should be considered. A positive estrogen receptor assay suggests that patients may also benefit from endocrine treatments. If it is negative, the chances of responding to hormonotherapy are very limited, except, perhaps, for anti-estrogens (McGUIRE, et al., 1975). Adjuvant therapy for patients with negative nodes is not recommended at this time; this view may have to be modified as the results of current adjuvant studies become available. We have at hand the means to improve the cure rate of patients with breast cancer. We are getting better diagnostic methods and find more patients with negative nodes. We know more about the primary treatment and have systemic modalities that are effective in the adjuvant situation. The immediate problem is to learn how to put these treatments together, and this task has been undertaken by on-going clinical trials. We are anticipating the results with optimism.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of lonidamine, given in an escalating oral daily schedule in patients with measurable advanced renal cell carcinoma. Two responses were seen in 25 evaluable patients. Toxicity was mild or moderate in most patients and included myalgia, nausea, vomiting, somnolence, and testicular pain. Lonidamine was not myelosuppressive. This agent had only minimal activity against renal cell carcinoma when given in this oral schedule.

A prospective randomized clinical trial was undertaken in 184 patients with metastatic breast carcinoma to compare single drug chemotherapy with L-phenylalanine mustard (L-PAM) and intermittent combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluourouracil (CMF). All patients had not been previously treated with cytotoxic drugs and all had objectively measurable visceral of soft tissue disease. Of the 93 patients who received CMF, 49 (53%) achieved a complete (14 patients) or partial (35 patients) regression of measurable tumor, for a median duration of 25 weeks. Eighteen of the 91 patients (20%) treated with L-PAM responded, for a median duration of 13 weeks. The toxicity was primarily hematologic, and greater in the CMF group, which also received more cycles of therapy because of the higher rate and duration of response. The overall survival of CMF-treated patients was superior to that of the single drug group. The differences were even greater when the patients were subclassified according to the presence of liver involvement or nonambulatory performance status. The superior antitumor effect of CMF over L-PAM suggests that it may be a more effective drug regimen to be used as an adjuvant to primary therapy.