Lucien Israel

Clinical phase II trial of recombinant dna interferon (interferon alfa 2b) in patients with metastatic malignant melanoma

Twenty‐four patients with historically proven metastatic malignant melanoma were included in a Phase II trial of human DNA recombinant interferon (rDNA IFNα2). They were given 10 × 106 IU of IFNα2 subcutaneously three times a week until progression of disease or major intolerance developed. Twenty‐ two patients were evaluable for toxicity and response. General manifestations of intolerance were seen in all the patients. Hematologic toxicity was seen in six patients and therapy had to be interrupted in one patient. Mild liver toxicity was seen in most patients after 2 weeks of treatment. These manifestations disappeared within 2 weeks after treatment was discontinued. A partial response was seen in four cases lasting 2, 4, 4, and 5 months, respectively. There were two complete responses (one skin, one lymph node metastasis) lasting 20 and 6 weeks, respectively. These results indicate a potential role for rDNA IFNα2 in treating patients with metastatic malignant melanoma. However, further trials are required to determine the optimal dose and schedule of administration and modalities of combination. Cancer 58:215–218, 1986.

Two years of high-dose cyclophosphamide and 5-fluorouracil followed by surgery after 3 months for acute inflammatory breast carcinomas. A phase ii study of 25 cases with a median follow-up of 35 months

Twenty‐five consecutive cases of inflammatory breast carcinoma were treated with high‐dose cyclophosphamide and 5‐fluorouracil in 5‐day courses every 3 weeks for 2 years, with totalMastectomy performed after the third course. The toxicity was high but acceptable in 24 of the patients, provided the doses were decreased. Tumor was found at surgery in all 24 patients, and the lymph nodes were involved in 19 of 24 cases. The median follow‐up was 35 months (range, 16–76 months). Thirteen relapses were observed, three of which were exclusively locoregional. The median disease‐free survival was 46 months. The expected median survival is greater than 6 years. Six patients were treated with radiotherapy for regional recurrences. The good results obtained with this severe form of the disease confirm: (1) that chemotherapy is highly effective in primary tumors and (2) that initial radiotherapy is not necessary in theManagement of this disease.

Immunosuppressive effect of acute-phase reactant proteins in vitro and its relevance to cancer

SummaryAcute-phase reactant proteins reach abnormally high levels in patients with cancer, and correlate with the extent of disease. In this study, several acute-phase glycoproteins, and serum albumin as a control, were tested at different concentrations for their ability to modify the blastogenic response of lymphocytes from 30 normal donors to PHA and the chemotactic response of monocytes from 15 normal donors to casein. In high concentrations approximating those found in cancer patients, but not in normal concentrations, haptoglobin and fibrinogen inhibited both functions to different degrees. Orosomucoid inhibited only monocyte chemotaxis, while ceruloplasmin and α1-antitrypsin affected neither function.Increasing concentrations of PHA did not overcome the blocking effect of haptoglobin and fibrinogen on blastogenesis, suggesting that PHA-protein interaction was not responsible for the effect observed. The three proteins that did not suppress blastogenesis individually did so strongly when combined.It is suggested that these glycoproteins, synthesized by the liver in response to an inflammatory stimulus, may act as ‘non-specific blocking factors’ protecting tumors against the hosts immunological attack. This non-specific blocking activity of the acute-phase proteins may contribute to the ‘immune escape’ of the tumor.

Adjuvant chemotherapy in the management of primary malignant melanoma

In a prospective randomized study, the effect of chemotherapy (either systemic or combined intraarterial and systemic) was studied in 117 patients undergoing a curative resection of Clarks level III, IV or V malignant melanoma. Systemic chemotherapy was started one month after surgery one week courses with an I.V. injection of Vinblastin 6 mg/m2, Thiotepa 6 mg/m2, Rufocromomycine 60 μg/m2, Methotrexate 15 mg/m2 on day one with procarbazine 30 mg/m2 orally daily were given every other week for three months and later every four weeks. Intraarterial chemotherapy of DTIC 80 mg/kg/day for ten days was given 28 days prior to surgery. 65 patients with limb malignant melanoma were treated either by surgery only (27 patients), or by systemic chemotherapy (23 patients) or by preoperative intraarterial chemotherapy and systemic chemotherapy (15 patients): 52 patients with non limb malignant melanoma were treated either by surgery only (28 patients) or by systemic chemotherapy (24 patients). We drew curves of disease free survival following surgery and studied the levelling off of the curves, 24 months after surgery 65% of the patients treated by surgery alone were alive and free of disease whereas 81% of the patients treated by surgery and chemotherapy were alive and free of disease (p < 0.05) suggesting a possible benefit of adjuvant chemotherapy. Intraarterial preoperative chemotherapy has not proved of additional benefit to date.

Sweat gland carcinoma with bone and visceral metastases. Prolonged complete remission lasting 16 months as a result of chemotherapy

Sweat gland carcinoma is a rare malignant tumor considered to be radio‐ and chemo‐resistant. A case affecting a labium majorum recurred after surgical resection and was accompanied by bone and visceral metastases. After four cycles of combination chemotherapy consisting of doxorubicin, mitomycin C, vincristine and cisplatin, complete remission lasting 16 months and prolonged survival (50 months) were obtained. A review of the literature also is presented.

HORMONES AS CANCER GROWTH FACTORS

It is postulated that some hormones may regulate proliferation of cancer cells in the same way as growth factors produced by cellular oncogenes. The gene coding for the hormones specific receptor would also act as a cellular oncogene. Normal adult breast cells show few if any oestrogen receptors. In the model put forward the oestrogen receptors in breast cancer cells should not be regarded as a marker of differentiation but as a survival advantage for the tumour when oestrogens are present. Prolactin and somatomedin may also behave as growth factors. In relation to the antitumour effects of hormone antagonists such as tamoxifen, it is postulated that cancer cells are immortalised and prevented from full differentiation by the presence of growth factors and their receptors. If receptor genes are re-expressed through the process of neoplastic transformation, their presence in cancers from unresponsive normal tissues should be regarded as a common event.

Fibrocystic disease of the breast in premenopausal women: Histohormonal correlation and response to luteinizing hormone releasing hormone analog treatment

Sixty-six patients with fibrocystic mastopathy were enrolled in the trial after being selected according to clinical, radioultrasonographic, and histologic criteria. No characteristic hormonal profile was noted in most patients (52%). Estrogen receptors or progesterone receptors, or both, were found in 57% of patients. Hormone receptor levels were correlated with atypical proliferative mastopathy (87.5%). Mastopathy was associated with a uterine fibroma or a fibromatous uterus in 73% of cases. All patients received intramuscular injections of a sustained delivery system (microcapsules) of luteinizing hormone releasing hormone agonist [D-Trp6]-LHRH, Ipsen-Biotech, Paris) for 3 to 6 months. In case of partial response at 3 months, an antiestrogen (tamoxifen, 40 mg/day, for estrogen receptor-predominant lesions) or a progestin (cyproterone acetate, 50 mg/day, for progesterone receptor-predominant lesions) was added to the luteinizing hormone releasing hormone agonist. A complete response was observed in more than half of the patients (n = 35, 53%) treated by [D-Trp6]-LHRH alone (n = 29) or associated with tamoxifen (n = 4) or cyproterone acetate (n = 2). A significant partial response was observed in 30 other patients (45%). Additionally, half of them received inhibitory drugs. The best responses were seen with cyst reformation (complete response, 100%) and fibrous block. Clinical responses to treatment with [D-Trp6]-LHRH alone were independent of hormone receptor status, but synergistic effects occurred with concomitant use of the corresponding inhibitory drugs. We conclude that chronic mastopathy, particularly when associated with uterine fibroma, can be successfully treated by luteinizing hormone releasing hormone analogs in premenopausal women.

Combination chemotherapy for 418 cases of advanced cancer

Chemotherapy was instituted in 418 cases of advanced cancer. A 5‐drug regimen was administered, without interruption, for periods of from one month to 3 years. Side effects were not prohibitive. There was maintained reduction in size of the tumors for more than 6 months in 54% of the total group; 29.6% of the patients have been on therapy for over a year. The median survival times from the onset of treatment ranged from 5 to 16.5 months according to site of the primary. These results are discussed in the light of what is known about clinical resistance to drugs and studies on tumor growth. It is concluded that combinations of cytostatic agents without cross resistance are necessary to achieve acceptable results and that randomized trials should be performed with a single drug in measurable tumors as a first step in order to gain quantitative information about the effectiveness of, and the tumor resistance against, available drugs.

High-dose cyclophosphamide and high-dose 5-fluorouracil. A new first-line regimen for advanced breast cancer.

Thirty consecutive patients with metastatic breast cancer previously untreated by chemotherapy were given high‐dose cyclophosphamide (Cytoxan) and high‐dose 5‐fluorouracil (5‐FU) as first‐line therapy. Cyclophosphamide, 1200 mg/m2 was administered intravenously (IV) on day I and 5‐FU, 600 mg/m2 IV on days 1 through 5. Cycles were repeated every 21 days or on hematologic recovery. Twenty‐eight of the 30 patients achieved a remission (16 partial, and 12 complete). i.e., a response rate of 93%, and a complete response rate of 40%. The actuarial survival rate at 43 months was 52% for the population as a whole, and 68% for patients who achieved a complete response. Hematologic toxicity was relatively severe and the initial doses had to be reduced by 20% in all patients between the second and fifth courses. No deaths due to either infection or bleeding were seen due largely to intensive supportive care. It is concluded that increasing the doses of a small number of drugs of proven efficacy may be more useful than increasing the number of drugs given in lower doses. Furthermore, this approach spares other effective drugs for second‐line therapy.

Retinoid Chemoprevention Timing and Dose Intensity

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.