Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1·5 mm without clinically detectable node metastases

Grob, Jean-Jacques; Dréno, Brigitte; Salmonière, Pauline de La; Delaunay, M.; Cupissol, Didier; Guillot, B.; Souteyrand, P; Sassolas, B.; Césarini, Jean-Pierre; Lionnet, Sylvie; Lok, C.; Chastang, Claude; Bonerandi, J. J.

doi:10.1016/s0140-6736(97)12445-x

Cited by 404 publications

(143 citation statements)

References 7 publications

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“…However, the administration of relatively high doses of cytokine appears to be required (Agarwala and Kirkwood, 1996;Grob et al, 1998;Keilholz and Eggermont, 2000), frequently resulting in severe toxic side effects, ranging between flu-like symptoms, severe neuro-hepato-toxicity and myelosuppression (Vial and Descotes, 1994). Clinical, immunological or molecular features enabling a targeted selection of patients likely to take advantage of this therapy have not been identified so far (Kirkwood, 1998).…”

Section: Discussionmentioning

confidence: 99%

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

et al. 2001

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Summary Interferon alpha (IFN-α) represents an adjuvant therapy of proven effectiveness in increasing disease-free interval and survival in subgroups of melanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. Furthermore, naturally occurring insensitivity to IFN-α may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential responders have not been identified so far. To explore the molecular basis of IFN-α responsiveness, we analysed the expression pattern of about 7000 genes in IFN-α sensitive and resistant cell lines and we compared the transcription profiles of cells cultured in the presence or absence of the cytokine using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction upon IFN-α treatment by standard 3H-thymidine incorporation and flowcytometry. The study of 4 sensitive and 2 resistant cell lines allowed the identification of 4 genes (RCC1, IFI16, hox2 and h19) preferentially transcribed in sensitive cells and 2 (SHB and PKC-ζ) preferentially expressed in resistant cells. IFN-α stimulation resulted in the expression of a panel of 19 known inducible genes in sensitive but not in resistant cells. Moreover a group of 30 novel IFN-α inducible genes was identified. These data may provide a useful basis to develop diagnostic tools to select potential IFN-α responders eligible for treatment, while avoiding unnecessary toxicity to non-responders. Furthermore, by extending the knowledge of the polymorphic effects of IFN-α on gene expression, they offer novel clues to the study of its pleiotropic toxicity.

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Section: Discussionmentioning

confidence: 99%

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

et al. 2001

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“…As treatment, however, is associated with significant toxicity and many patients still do not benefit, there is a great need for predictive tests identifying patients with a high probability of response. In the adjuvant setting also, immunotherapy has shown important results on relapse-free (Pehamberger et al, 1998;Grob et al, 1998;Kirkwood et al, 2000) and overall survival (Kirkwood et al, 1996). Today, several different studies are undertaken, where immunotherapy is given to high-risk patients.…”

Section: Discussionmentioning

confidence: 99%

Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes

Håkansson

Gustafsson²,

Krysander

et al. 2001

Br J Cancer

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SummaryThe therapeutic efficacy of biochemotherapy in metastatic malignant melanoma still carries a low remission rate, but with some durable responses. It would therefore be of considerable importance if patients with a high probability of responding could be identified using predictive tests. The response to interferon-alpha (IFN-α) correlates with the occurrence of CD4 + lymphocytes identified by fine-needle aspirates from melanoma metastases (Håkansson et al, 1996). The present investigation studies a possible correlation between tumourinfiltrating CD4 + lymphocytes in malignant melanoma metastases and the therapeutic effect of biochemotherapy. A total of 25 patients with systemic and 16 with regional metastatic melanoma were analysed before initiation of biochemotherapy (cis-platinum 30 mg/m 2 d.1-3, DTIC 250 mg/m 2 d.1-3 i.v. and IFN-α2b 10 million IU s.c. 3 days a week, q. 28d.). A monoclonal antibody, anti-CD4, was used to identify tumourinfiltrating lymphocytes in fine-needle aspirates before start of treatment. The presence of these lymphocytes was correlated to response, time to progression and overall survival. A statistically significant correlation (P = 0.01) was found between the occurrence of CD4 + lymphocytes and tumour regression during biochemotherapy in patients with systemic disease. Out of 14 patients with moderate to high numbers of infiltrating CD4 + lymphocytes, 12 achieved tumour regression. In contrast, among patients with low numbers of these cells in metastatic lesions, 8 out of 11 had progressive disease. We also found a significantly longer time to progression (P < 0.003) and overall survival (P < 0.01) among patients with moderate to high numbers of these cells compared to patients with low numbers of these cells before initiation of biochemotherapy. Furthermore, in patients with regional disease, we found a significantly longer time to progression (P = 0.01) and a trend toward a longer overall survival time (P = 0.09). Based on these results and as previously shown with IFN-α therapy alone, there seems to be a need for CD4 + lymphocytes infiltrating the tumours before the start of biochemotherapy to make the treatment successful. Determination of these cells in fine-needle aspirates seems to be a method to predict responders to biochemotherapy, thus increasing the cost-benefit of this treatment strategy considerably, both in terms of patient adverse reactions and health care costs. The aim of the present investigation was therefore to study whether the presence of tumour-infiltrating CD4 + lymphocytes identified by fine-needle aspirates of melanoma metastases before treatment is started also correlates with the response to biochemotherapy. MATERIALS AND METHODS Study populationThis report describes 41 patients with metastatic malignant melanoma, 26 males and 15 females. The median age was 61 years (range 36-77) and Karnofsky performance status was 70 or more. Recurrences were cytologically verified by fine-needle aspirates before start of treatment. Two groups of patients were st...

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“…The studies that have reported since the Scottish study was closed to recruitment consistently demonstrate a clear improvement in disease-free survival for treatment with interferon-α, and furthermore 2 studies, one each with low-and high-dose interferon-α, report an improvement in overall survival with a two-sided P value between 0.05 and 0.06 (Kirkwood et al, 1996;Grob et al, 1998). Furthermore, the magnitudes of these improvements are well within the confidence intervals for the observed disease-free and overall survival rates in the current study.…”

Section: Discussionmentioning

confidence: 93%

“…In contrast, 2 studies have reported a disease-free survival advantage for prolonged low-dose interferon. A French study randomized 489 eligible patients with stage II disease between observation and 18-months of 3 MU interferon-α given subcutaneously 3 times a week (Grob et al 1998). There was a significant disease-free survival advantage for the patients who received interferon-α, and a trend for an improvement in overall survival with a two-sided P value between 0.05 and 0.06.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study

et al. 2001

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In 1989, the Scottish melanoma group initiated a randomized trial, comparing observation alone with 6 months' therapy with low dose interferon α (given subcutaneously 3 MU day –1 , thrice weekly), for patients with primary melanomas of at least 3 mm Breslow thickness, or with evidence of regional node involvement. The trial was closed in 1993 with only 95 eligible patients randomized. There were no toxic deaths, and no patient failed to complete the treatment for reasons of toxicity. 6 months' treatment with low-dose interferon-α resulted in a statistically significant improved disease-free survival for up to 24 months after randomization ( P < 0.05). However, at a median follow-up of over 6 years, although there was an apparent improvement in disease-free survival (from 9 to 22 months), and overall survival (from 27 to 39 months), consistent with larger studies powered to detect such differences, these differences were not statistically significant. The data therefore suggest that 6 months of low-dose interferon is active, and confirm the importance of the large randomized studies, such as the UKCCCR AIM-High and EORTC trials, that seek to confirm a possible survival advantage for low or intermediate dose interferon. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1·5 mm without clinically detectable node metastases

Cited by 404 publications

References 7 publications

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

High density oligonucleotide array analysis of interferon-α2a sensitivity and transcriptional response in melanoma cells

Biochemotherapy of metastatic malignant melanoma. Predictive value of tumour-infiltrating lymphocytes

Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study

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