Inhaled IL-2 for Malignant Melanoma: A Breath of Fresh Air?
June 1, 2000 4 minutes read
Inhaled IL-2 for Malignant Melanoma: A Breath of Fresh Air?
ABSTRACT & COMMENTARY
Source: Enk A, et al. Cancer 2000;88:2042-2046.
All of us would welcome an effective and nontoxic treatment alternative for patients with malignant melanoma. High-dose interleukin-2 (IL-2) given systemically has a response rate of about 20% and was approved by the FDA because of the potential for durable complete responses. However, the toxicity of this approach limits its routine application in the community setting.
In this report by Enk and colleagues from Germany, 27 patients with Stage IV malignant melanoma with "mostly" pulmonary metastases were treated with intravenous dacarbazine and inhaled IL-2. The dacarbazine dose was 850 mg/m2 on day 1 of a four-week cycle up to a maximum of four doses. The IL-2 was started on day 2 and was given by a special inhaler in a solution of 5% glucose and 2% albumin. After a daily dose escalation the first week, patients received 36 million units of IL-2 each day. The IL-2 was given each day in 3-to-5 fractions.
Patients were selected based on a pattern of metastases that predominantly involved the lungs, although this was not strictly defined. About one-half of the patients had disease outside the lungs, although brain metastases were excluded. Because there were no responses outside the lungs, results refer ONLY to the pulmonary responses. There was a complete response rate of 18.5% and a partial response rate of 29.6%. Including stable disease, two-thirds of patients benefited from inhaled IL-2. This response rate is particularly noteworthy because all patients had failed one prior regimen with the majority having been exposed to dacarbazine either alone or in combination.
Those patients who had a complete response maintained their response for a median of 12 months. Most patients with a partial response or stable disease progressed within six months. Toxicity was manageable on an outpatient basis with cough (85%) being the most common side effect and no severe toxicities noted.
COMMENT BY KENNETH L. KOTZ, MD
While the responses and toxicity of inhaled IL-2 are promising, it should be kept in mind that the data presented are for the pulmonary metastases only. A responding pulmonary metastasis could coexist with progressing extra-pulmonary disease. The contribution from the dacarbazine was probably minimal because most patients had been previously treated with it and there were no peripheral responses. Whether there is some synergistic effect in the lungs could only be determined by a trial of inhaled IL-2 without chemotherapy. With a high early relapse rate, Enk et al suggest indefinite inhaled IL-2 for responding patients.
With its low toxicity and promising response rate, inhaled IL-2 would be reasonable to consider in the palliative setting. IL-2 administered by inhalation would be most appropriate for patients whose metastatic disease is restricted to the lungs, or patients with symptomatic pulmonary metastases who are too ill to receive systemic therapy. Certainly, patients eligible for systemic IL-2 should not receive inhaled IL-2 instead because systemic IL-2 has a proven role in allowing patients with metastatic melanoma to achieve long-term disease-free survival. Whether the addition of inhaled IL-2 to systemic therapy improves the outcome for patients with malignant melanoma confined to the chest has not been studied.
An overview of inhalation IL-2 therapy has been recently published.1 In this overview, Enk et al review their 10-year experience of using inhaled IL-2 in 300 patients; most of whom had metastatic renal cell carcinoma, but also patients with melanoma, breast cancer and, ovarian cancer. Both pulmonary and mediastinal metastases have been controlled with inhaled IL-2.1 Frequent daily applications seem to be more effective than a single daily dose, and the IL-2 appears to act through local mechanisms rather than through systemic absorption.1 A consistent finding of inhaled IL-2 is its excellent toxicity profile with a dose-dependent cough being the major adverse event. Long-term pulmonary fibrosis has not been reported.1 These preliminary results of IL-2 delivered by inhalation will need to be confirmed, but may provide a breath of fresh air for cancer patients with pulmonary metastases.
Reference
1. Huland E, et al. Cancer J Sci Am 2000;6:S104-S112.
Which of the following is true?
a. Inhaled IL-2 provides high blood levels of IL-2 with minimal toxicity.
b. Inhaled IL-2 is effective only for hepatic and pulmonary metastases.
c. Inhaled IL-2 must be given with dacarbazine to be effective.
d. The most frequent side effect of inhaled IL-2 is cough.
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