Sewa S. Legha

Phase II study of thalidomide in patients with metastatic melanoma.

The aim of this study was to determine the antitumour activity and toxicity of thalidomide in patients with metastatic melanoma. Between July 1999 and July 2001, 20 patients with metastatic melanoma were enrolled into this study. Patients were required to have progressive disease following standard therapies (unless there was a known contraindication for their usage) and to be free from symptomatic brain metastases. Thalidomide was administered orally at a starting dose of 200u2009mg/day, with increments of 100u2009mg every 7 days to a maximum dose of 800u2009mg/day. Patients experiencing intolerable side effects had their dose reduced to the maximum tolerated dose. Response and tolerance to treatment were assessed at 4 week intervals and therapy was continued until progression of disease or development of intolerable side effects despite appropriate dose reduction. All 20 patients were assessable for response. No objective response (complete or partial remission) was observed. In seven patients (35%), stable disease with a duration of 12–32 weeks (median 16 weeks) was seen. The median time to progression for all patients was 8 weeks (range 5–32 weeks) and the median overall survival was 20 weeks (range 7–130+ weeks). Treatment was generally well tolerated. Nine patients (45%) were able to tolerate the maximal planned dose of thalidomide (800u2009mg/day). Constipation, fatigue, somnolence and dryness of skin or mouth were the most common side effects. Thalidomide appears to possess cytostatic activity in patients with metastatic melanoma. Further studies of thalidomide in melanoma are warranted.

Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma.

Interleukin‐2 (IL‐2) has activity in metastatic melanoma when given in high doses by the intravenous (IV) route, but its side effects and effectiveness when given in intermediate to high doses by the subcutaneous (SC) route have not been studied adequately. This study sought to determine the maximum tolerated dose (MTD) of IL‐2 administered once daily by the SC route.

A randomized phase III trial of biochemotherapy versus interferon-α- 2b for adjuvant therapy in patients at high risk for melanoma recurrence

The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-&agr;-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy. Patients who had undergone lymphadenectomy for melanoma metastatic to regional lymph nodes were randomly assigned to either biochemotherapy or IFN, and IFN patients were further randomized to either high-dose IFN (HDI) or intermediate-dose IFN (IDI). The primary end point was relapse-free survival (RFS); the secondary end point was overall survival (OS). The planned enrollment was 200 patients, the number required to have 80% power to detect, at a significance level of 5%, an improvement in median RFS from 18 to 36 months and an improvement in median OS from 40 to 80 months between the IFN and biochemotherapy groups. A futility analysis was performed because of slow accrual. One hundred and thirty-eight patients were enrolled – 71 in the biochemotherapy group, 34 in the HDI subgroup, and 33 in the IDI subgroup. No significant differences in median RFS or OS between the HDI and IDI subgroups were observed. With a median follow-up of 49.3 months, neither the biochemotherapy nor IFN group had reached median RFS or OS, and there were no significant differences in estimated median RFS or OS (P=0.86 and 0.45, respectively) between the two groups. Biochemotherapy is not more effective than IFN as adjuvant therapy for melanoma. These findings support early termination of this trial.

A phase II study of 'decrescendo' interleukin-2 plus interferon-α-2a in patients with progressive metastatic melanoma after chemotherapy

The authors tested a biotherapy regimen involving recombinant interferon‐α‐2a (rIFN‐α‐2a) and recombinant human interleukin‐2 (rhIL‐2), given in a “decrescendo” schedule over 5 days, for its activity and toxicity in 21 patients who previously had received chemotherapy for advanced melanoma.

Pilot study of intra-arterial cisplatin and intravenous vinblastine and dacarbazine in patients with melanoma in-transit metastases

For melanoma, in-transit metastases (ITMs) are a harbinger of systemic disease in over 70% of patients and thus warrant a systemic approach to management. In this study, previously untreated patients with ITMs (n=15) received a systemic regimen of CVD in 21 day cycles (median, three cycles) as follows: dacarbazine 800 mg/m2 intravenously (i.v.) on day 1, vinblastine 1.6 mg/m2 i.v. on days 1-5, and cisplatin (CDDP) 100 mg/m2 by 24 h intra-arterial (i.a.) infusion in 1l of heparinized saline via the iliac or subclavian artery on day 3. There were three clinical complete responses (CRs) in patients with a modest burden of ITMs (< 3 cm in size) and seven partial responses (PRs), yielding a 67% response rate (95% confidence interval, 38-88%). One of the clinical CRs had microscopic residual disease at surgery (a pathological PR). The times to progression (TTP) for the CRs were 5, 21 and 38+ months; the median TTP for the PRs was 4.5 months (range, 2-10 months). Overall median survival was 31 months. Systemic toxicities were similar to those induced by i.v. CVD. However, patients noted more pronounced paraesthesia in the infused extremity. Also, two patients experienced severe CDDP-induced burns, one patient developed brachial plexopathy, and one patient had a haemorrhage in an occult brain metastasis. The high clinical activity of this regimen will have to be confirmed in more patients before a first-pass i.a. advantage can be claimed. Furthermore, the dose, schedule and technique of i.a. CDDP delivery must be further refined before it can be routinely incorporated in regimens as an alternative to isolated regional hyperthermic perfusion, which is technically more difficult and is not readily available in community-based hospitals.

Basic Science of Cancer

Kruh GG, Tew KD, eds. 282 pages. Philadelphia: Current Science; 2000.

Biochemotherapy using interleukin-2 + interferon alpha-2a (IFN) in combination with cisplatin (C), vinblastine (V) and DTIC (D) in patients with metastatic melanoma: 113

79.99. ISBN 1573401439. Order phone 215-574-2266. Field of Medicine: Medical oncology, radiation oncology, and surgical oncology. Format: Hardcover book. Audience: Physicians, clinical researchers, and trainees. Purpose: To provide an extensive review of the molecular processes involved in the development of human cancer and its treatment. Content: The books 13 chapters cover the techniques for identifying cancer genes and the role of oncogenes and tumor suppressor genes in carcinogenesis. Cell cycle control, signal transduction, transcriptional regulation, and DNA repair are discussed. Clinically relevant topics, such as apoptosis, pharmacology of anticancer drugs, drug resistance, approaches to discovery of new drugs, and pharmacogenetics, are also included. Highlights: The first 8 chapters, which discuss the pathogenesis of cancer, are well written and are the major strength of the book. The numerous tables, figures, and charts enhance the text. Limitations: The last 5 chapters are less comprehensive, especially the chapter on the pharmacology of anticancer drugs; it is primarily devoted to mechanisms of action but lacks information on pharmacokinetics of commonly used anticancer drugs. Some of the tables contain outdated information and lack up-to-date clinical data. Information on angiogenesis and metastases is omitted. Related reading: Tannocks The Basic Science of Oncology (McGraw-Hill, 1998) and Mendelsohn and colleagues The Molecular Basis of Cancer (WB Saunders, 2001) deal with the fundamental processes of cancer. Although topics covered in these two books and Basic Science of Cancer overlap considerably, the latter complements rather than competes with the former two. Reviewer: Sewa S. Legha, MD, Baylor College of Medicine, St. Lukes Episcopal Hospital, Houston, Texas.