John M. Kirkwood

Comparison of Intramuscular and Intravenous Recombinant Alpha-2 Interferon in Melanoma and Other Cancers

In two phase I-II trials, 33 patients were given recombinant interferon alpha-2 daily at dosages of 3, 10, 30, 50, or 100 MU/d for up to 4 weeks by intramuscular or intravenous routes. Dose-limiting toxicities, including neutropenia, elevated hepatocellular enzyme levels, fatigue, and disturbed mentation, correlated with differing serum pharmacokinetics of interferon in the two trials. In the intramuscular study, dose-limiting toxicity occurred at all dosages greater than 10 MU/d, at a median of 6 to 9 days of treatment. In the intravenous dose-study, limiting toxicity was seen only at dosages of 100 MU/d, at a median of day 8. Twenty-three patients had metastatic melanoma and 4 had objective partial or complete responses at dosages of 10 to 50 MU/d in the first month. Two patients with complete responses are free of tumor after 2.5 years of follow-up. A fifth patient had delayed complete regression, requiring 1 year to achieve maximum response, but remains free of disease at 26 months since entry to the trial. Interferon had antitumor activity against melanoma by both routes tested, at dosages of 10 to 50 MU/d.

Gangliosides of normal and neoplastic human melanocytes

The major ganglioside component isolated from diploid human melanocytes is sialosyllactosylceramide (GM3 86-91% of total sialic acid). The corresponding disialo derivative (GD3) is found as a minor component (2-6% of total sialic acid) in the membranes of these cells. In human melanoma cells, grown in tissue culture, GD3 is the predominant ganglioside component (48-63% of total sialic acid). Withdrawal of TPA from the culture medium of normal melanocytes or addition of TPA to the medium of melanoma cells had no significant effect on GM3/GD3 ratios. We conclude that the difference between the composition of gangliosides is related to the normal vs transformed phenotypes of melanocytes.

Randomized phase III trial of vinblastine, bleomycin, and cis-dichlorodiammine-platinum versus dacarbazine in malignant melanoma.

A randomized phase III study was carried out in 57 patients with metastatic melanoma treated with either dacarbazine (DTIC) given intravenously (IV) daily for 10 days using light protection, or a combination of vinblastine IV on days 1 and 2, bleomycin by continuous IV infusion during days 1-5, and cisplatin by IV infusion on day 5 (VBD). Objective response rates were similar: 14% for dacarbazine and 10% for VBD. However, dacarbazine responses were associated with a trend toward longer progression-free intervals and longer survival. Toxicity was significantly greater in the VBD arm, and fatal in two patients. Dacarbazine was also associated with severe toxicity by the 10-day light-protected schedule used here. VBD is not as effective as previously reported, and dacarbazine remains a standard of therapy for metastatic melanoma.

High-dose fraction radiation therapy for intracranial metastases of malignant melanoma: A comparison with low-dose fraction therapy

Malignant melanoma is considered unresponsive to conventional radiation therapy when it is delivered at a daily dose rate of 130–300 rad/fraction. Previous studies have suggested that this is in part due to a large shoulder on the radiation survival curve and that higher dose fractions might be beneficial. High‐dose fraction therapy is effective for local control of cutaneous, lymph node, and soft‐tissue metastases. Results in 46 patients treated with high‐ or low‐dose fractions for intracranial metastases over the last decade in the Melanoma Unit and Department of Radiotherapy at Yale have been examined. Twenty‐six patients received high‐dose fraction therapy, generally 600 rad/fraction/week to 2400–3600 rad; 20 patients received low‐dose fraction radiotherapy with 125–400 rad/fraction daily. All patients were given steroids, and most received chemotherapy. Results in both groups were similar. Comparison of high‐ and low‐dose fraction patients revealed: improvement in 38 and 35%, respectively, stability in 23 and 25%, and deterioration in 38 and 40%. Median survival was three months in the high‐dose fraction group and 21/2 months in the low‐dose fraction group. Presence of hepatic metastases had no significant influence upon median survival in patients who received high‐dose fraction radiotherapy. In patients receiving low‐dose fraction, survival was 21/4 months with and three months without hepatic metastases. Death in most patients resulted from progression of central nervous system disease. Side effects, especially headache, were more prominent in the high‐dose fraction group. However, in no instance did side effects require discontinuation of therapy. The greater ease of delivery for weekly high‐dose fraction radiotherapy outweighed any other difference between the regimens.

Diagnosis of the dysplastic nevus in different populations

Because of the relationship of the dysplastic nevus to melanoma, physicians are being encouraged to identify the clinical features of this newly defined entity. However, the dysplastic nevus was originally characterized in the familial setting, and application of equivalent criteria to the general population will be disappointing. The ability of the clinician to diagnose the presence of dysplastic nevi will be markedly influenced by the true underlying prevalence of dysplastic nevi in the population subjected to the examination. Even with superlative (and perhaps unattainable) examining skills (e.g., sensitivity and specificity both 90%), the positive predictive value in the general population will be relatively low (less than one third). Grading the severity of clinical dysplasia, obtaining serial observations, and improving specificity of clinical examination are important but irrelevant to this problem because these items focus only on examining skills. Consideration given to the epidemiologic and referral characteristics of the person undergoing examination will substantially improve the ability to predict dysplastic nevi on clinical evaluation. Although comprehensive recommendations must await further research, some priorities in the diagnosis and management of patients with presumptive dysplastic nevi are suggested.

Increased therapeutic index using moderate dose methotrexate and leucovorin twice weekly vs. weekly high dose methotrexate‐leucovorin in patients with advanced squamous carcinoma of the head and neck: A safe new effective regimen

A new intensive methotrexate regimen for the treatment of advanced squamous carcinoma of the head and neck is presented, employing twice‐weekly parenteral low‐moderate doses of methotrexate and a single parenteral dose of leucovorin 24 hours following methotrexate. Toxicity and therapeutic results in 20 patients treated with this regimen compare favorably with results of weekly high‐dose methotrexate‐leucovorin in 36 patients treated immediately before initiation of the new regimen. Moderate nephrotoxicity and mild gastrointestinal/mucosal toxicity were common to both, while myelotoxicity was rarely seen with the low dose regimen and was more frequent with the high‐dose regimen. Partial response was observed in 60% of patients treated on the intensive low‐moderate dose schedule, and 50% of patients previously untreated with methotrexate on the weekly high‐dose schedule. None of 12 patients previously failing low‐moderate doses of methotrexate responded to high doses administered in this trial. The characteristics of antitumor response with low‐moderate and high‐dose schedules were similar except for the median dose required to attain response (50 mg/m2 vs. 3 g/m2) and the lesser toxicity of intensive lower dose therapy with leucovorin.

Vitiligo and melanoma: Can genetically abnormal melanocytes result in both vitiligo and melanoma within a single family?

We found twelve families with melanoma who had close family members with halo nevi, early graying of hair, a halo primary melanoma, or ordinary vitiligo. On the basis of these findings and the observation of others in fish, horses, and pigs with melanomas, we suggest that the melanocytes of people with vitiligo or with a genetic background for vitiligo are predisposed to undergo a malignant transformation. The presence of vitiligo appears as a manifestation of host suppression of malignant melanocytes.

Analysis of granulocyte-macrophage progenitor cells in patients treated with recombinant interferon alpha-2.

The most common dose-limiting toxicity of alpha interferon has been leukopenia. It is well documented that interferon inhibits human multipotential, erythroid, and granulocyte-macrophage progenitor cells in vitro. Granulocyte-macrophage progenitor cells were evaluated by a colony-forming assay in patients treated with recombinant interferon alpha-2, and results of the assay were correlated with histologic findings in the same bone marrow aspirates and biopsy specimens from the same patients. Eleven patients received 10 million units/m2 interferon subcutaneously thrice weekly for three months. The bone marrow was evaluated on Day-3 (pretreatment) and Day 10 of treatment. Colony-forming granulocyte-macrophage cell count fell from 40.9 +/- 7.6 colonies per 10(5) cells before treatment to 9.3 +/- 1.2 at Day 10 (mean +/- SE, p less than 0.001). It is concluded that the leukopenia induced by interferon is caused by inhibition of maturation of marrow progenitor cells preventing the repopulation of the peripheral blood.

Reproducibility and Validity in the Clinical Diagnosis of the Nonfamilial Dysplastic Nevus: Work in Progress

An exciting development in recent years has been the documentation of a clinical syndrome characterized by familial clusters of cutaneous melanoma (CM), with members at risk for CM having multiple atypical moles (Clark et al. 1978; Greene et al. 1978; Lynch et al. 1978; Reimer et al. 1978). Persons affected by the familial dysplastic nevus syndrome (formerly known as the BK mole syndrome) have more than a 100-fold increased risk for the development of CM (Greene 1984).

Initial adjuvant weekly high dose methotrexate with leucovorin rescue in advanced squamous carcinoma of the head and neck

Abstract Despite aggressive local therapy, advanced head and neck cancer continues to have a poor prognosis. In an attempt to improve survival in this disease, the Joint Center for Radiation Therapy and the Sidney Farber Cancer Institute instituted a pilot study employing high dose methotrexate with leucovorin rescue (3.5−27.5 g/m 2 ) as an adjuvant to aggressive radiotherapy and surgery. A high response rate of 60% ( 9 15 ) with no compromise of definitive therapy indicates such cooperation multimodality trials may hold promise for an increase in cure rates in these patients.