The Toxicity and Benefit of Various Dosing Strategies for Interleukin-2 in Metastatic Melanoma and Renal Cell Carcinoma

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Abstract

Interleukin-2 (IL-2) therapy has been used with success in curing metastatic renal cell carcinoma and melanoma in a small minority of patients. However, the benefits can be accompanied by severe toxicity. This review of the literature discusses varying doses of IL-2 and their associated response rates and the toxicities associated with treatment. The review also explores the maximally beneficial dose with the most tolerable side effects. Although the higher-dose regimens with a more frequent dosing schedule produce higher-grade toxicity, they were found to deliver the most durable and complete responses. It is recommended to use a higher-dose regimen (720,000 IU/kg every 8 hours for a maximum of 15 doses) and provide supportive care for toxicity, so patients can have maximal benefit from therapy.

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High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

Janice Dutcher, Douglas Schwartzentruber, Howard L. Kaufman … (2014)

Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as "cures". Recent publications have suggested improved efficacy, perhaps due to improved patient selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998. Electronic supplementary material The online version of this article (doi:10.1186/s40425-014-0026-0) contains supplementary material, which is available to authorized users.

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Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group.

Jessie Hsu, Britt L Flaherty, Sandra Lee … (2008)

Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup. Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and interferon alfa-2b (BCT). Treatment cycles were repeated at 21-day intervals for a maximum of four cycles. Tumor response was assessed after cycles 2 and 4, then every 3 months. Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001). Although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma.

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Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.

Nicholas Papadopoulos, Feng Zhan, Agop Y. Bedikian … (2002)

The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b. Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks. Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P =.001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P =.008); median survival was 11.9 and 9.2 months, respectively (P =.06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects. Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.

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Author and article information

Journal

Journal ID (nlm-ta): J Adv Pract Oncol

Journal ID (iso-abbrev): J Adv Pract Oncol

Journal ID (publisher-id): JADPRO

Title: Journal of the Advanced Practitioner in Oncology

Publisher: Harborside Press

ISSN (Print): 2150-0878

ISSN (Electronic): 2150-0886

Publication date (Print): May-Jun 2015

Publication date (Electronic): 1 May 2015

Volume: 6

Issue: 3

Pages: 212-221

Affiliations

University of Texas MD Anderson Cancer Center, Houston, Texas

Author notes

Correspondence to: Laura A. Pachella, RN, MSN, AGPCNP-BC, AOCNP®, Department of Nursing, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1489, Houston, TX 77030. E-mail: lpachella@mdanderson.org

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Other ID: jadpro.v06.i03.pg212

DOI: 10.6004/jadpro

PMC ID: 4625627

PubMed ID: 26557408

SO-VID: 2f300e60-5cdc-43e8-beb4-5ed44711d16b

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited and is for non-commercial purposes.

The Toxicity and Benefit of Various Dosing Strategies for Interleukin-2 in Metastatic Melanoma and Renal Cell Carcinoma

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Regulatory T cell (Treg) therapy

Most cited references 14

High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.

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