Interferon alpha for the adjuvant treatment of cutaneous melanoma

  • Review
  • Intervention

Authors


Abstract

Background

Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists.

Objectives

To assess the disease-free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma.

Search methods

We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials.

Selection criteria

We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II).

Data collection and analysis

Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates of treatment efficacy.

Main results

Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta-analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease-free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between-study heterogeneity (disease-free survival: I² statistic = 16%, Q-test P value = 0.27; overall survival: I² statistic = 6%; Q-test P value = 0.38).

Considering that the 5-year overall survival rate for TNM stage II–III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.

Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no-one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation.

Authors' conclusions

The results of this meta-analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high-risk (AJCC TNM stage II-III) cutaneous melanoma in terms of both disease-free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.

Plain language summary

Interferon for the treatment of melanoma patients after surgical removal of their tumour

Cutaneous melanoma is one of the deadliest types of skin cancer, and its incidence is rising in all Western countries. Furthermore, melanoma is one of the solid tumours most resistant to treatment with chemotherapy, which means that the outlook for people whose cancer has spread through their body (distant metastatic disease) is dismal, with only 10% of these patients surviving longer than 5 years.

After surgical removal of the primary tumour and in the absence of distant metastatic disease, people with melanoma have variable prognosis: In fact, between 40% to 90% of these patients are alive after 5 years. Therefore, adjuvant (i.e. postoperative) therapy has been proposed to reduce the risk of death in patients with high-risk melanoma who have more aggressive tumours that are identified according to pathological features, such as the primary tumour thickness and regional lymph node status (disease stage).

The only compound that has shown some positive therapeutic effects in this patient group is interferon alpha, which is a protein produced by human macrophages (one type of white blood cell) and is known for its antiviral and antitumour activities.

In this review, we gathered evidence from 18 randomised controlled trials, enrolling more than 10,000 participants, testing the hypothesis that interferon treatment can improve the survival of people with melanoma at high risk of spreading after surgical removal of the tumour.

Whereas not all single studies demonstrated a survival benefit for patients treated with interferon, combining the available evidence, we found that the use of postoperative interferon improves the survival of those with high-risk melanoma. On average, the toxicity associated with interferon administration (such as fever and fatigue) is limited; moreover, it is reversible when the treatment is stopped. Since interferon alpha is the only approved drug after surgery for those with high-risk melanoma, efforts to identify those who might benefit most from this treatment are very important in order to avoid unnecessary toxicity for those who would not benefit from interferon alpha treatment. Combination of interferon with novel drugs is another field of ongoing research to improve the life expectancy of people with high-risk melanoma.

Laički sažetak

Interferon za poboljšavanje preživljenja oboljelih od melanoma nakon kirurškog uklanjanja tumora

Kožni melanom je jedan od najsmrtonosnijih oblika karcinoma kože, i njegova učestalost se povećava u svim zapadnim zemljama. Osim toga, melanom se ubraja u solidne tumore koji su najotporniji na liječenje kemoterapijom, što znači da je prognoza osoba čiji se karcinom proširio po tijelu (bolest s udaljenim metastazama) vrlo loša, jer svega 10% oboljelih preživi dulje od 5 godina.

Nakon kirurškog uklanjanja primarnog tumora, ako nema udaljenih metastaza, osobe oboljele od melanoma imaju različitu prognozu. Između 40 i 90% pacijenata nakon pet godina i dalje su živi. Stoga se predlaže uvođenje dodatne (adjuvantne) terapije nakon operacije kako bi se smanjio rizik od smrti u osoba s visoko-rizičnim melanomom, koji su imali agresivniji tumor prema patološkim osobinama kao što su debljina primarnog tumora i zahvaćenost regionalnih limfnih čvorova (stupanj bolesti).

Jedini spoj koji je pokazao određeni pozitivni terapijski učinak u ovoj skupini pacijenata je interferon alfa, protein koji proizvode ljudski makrofazi (jedna vrsta bijelih krvnih stanica) i koji je poznat po svojoj protuvirusnoj i protutumorskoj aktivnosti.

U ovom Cochrane sustavnom pregledu analizirani su podatci iz 18 randomiziranih kontroliranih ispitivanja, u koje je uključeno više od 10.000 ispitanika, i u kojima je ispitana hipoteza da liječenje interferonom može poboljšati preživljenje osoba oboljelih od melanoma koji imaju visok rizik od širenja nakon kirurškog uklanjanja tumora.

Iako sve analizirane studije nisu pokazale korist u smislu preživljenja za pacijente liječene interferonom, kombinacija svih dostupnih dokaza je pokazala da liječenje interferonom nakon operacije poboljšava preživljenje osoba s visoko-rizičnim melanomom. U prosjeku je toksičnost povezana s primjenom interferona (nuspojave kao što su vrućica i umor) bila ograničena, i nuspojave bi nestale završetkom liječenja. Budući je interferon alfa jedini odobreni lijek za uporabu nakon kirurgije visoko-rizičnih melanoma, nužno je uložiti napore kako bi se prepoznali pacijenti kojima bi terapija interferonom alfa mogla najviše koristiti, kako bi se izbjegao nepotrebni razvoj nuspojava u osoba kojima takvo liječenje ne bi bilo korisno. Trenutno se provode istraživanja u kojima se ispituje učinak kombinacije interferona s drugim novim lijekovima na produljenje očekivanog trajanja života u osoba s visoko-rizičnim melanomom.

Bilješke prijevoda

Cochrane Hrvatska
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Интерферон для лечения пациентов с меланомой после хирургического удаления опухоли

Меланома кожи является одним из самых смертоносных видов рака кожи, и заболеваемость ею растет во всех западных странах. Более того, меланома является одной из солидных опухолей, наиболее устойчивых к лечению химиотерапией, это означает, что перспективы для людей, у которых рак распространился в организме (отдаленные метастазы) мрачные, и из этих больных только 10% выживают более 5 лет.

После хирургического удаления первичной опухоли и при отсутствии отдаленных метастазов заболевания, люди с меланомой имеют вариабельный прогноз: на самом деле, от 40% до 90% этих пациентов живы через 5 лет. Поэтому адъювантная (т.е. послеоперационная) терапия была предложена, чтобы снизить риск смерти у пациентов с меланомой высокого риска, имеющих более агрессивные опухоли, которые идентифицируются в соответствии с патологическими особенностями, например, первичной толщиной опухоли и состоянием регионарных лимфатических узлов (стадия болезни).

Единственное соединение, которое показало положительные терапевтические эффекты в этой группе пациентов – это интерферон-альфа, который является белком, вырабатываемым в макрофагах человека (один из типов белых кровяных клеток) и известен своей противовирусной и противоопухолевой активностью.

В этом обзоре мы собрали доказательства из 18 рандомизированных контролируемых испытаний, включивших более 10000 участников, для проверки гипотезы, что лечение интерфероном может улучшить выживание людей с меланомой с высоким риском распространения после хирургического удаления опухоли.

В то время как не все исследования показали увеличение выживаемости пациентов, получавших интерферон, объединив имеющиеся доказательства, мы обнаружили, что послеоперационное применение интерферона улучшает выживаемость пациентов с меланомой высокого риска. В среднем, токсичность, ассоциированная с применением интерферона (такая, как лихорадка и усталость) ограничена; кроме того, она является обратимой, когда терапия прекращается. Поскольку интерферон-альфа является единственным препаратом, одобренным к применению после операции у пациентов с меланомой высокого риска, усилия по выявлению тех, кто может извлечь наибольшую пользу из этого лечения очень важны для того, чтобы избежать ненужную токсичность у тех, кто не получит пользу от лечения интерфероном-альфа. Сочетание интерферона с новыми лекарственными средствами является другой сферой продолжающихся исследований для увеличения продолжительности жизни людей с меланомой высокого риска.

Заметки по переводу

Перевод: Титаренко Альбина Фаритовна. Редактирование: Хазиахметова Вероника Николаевна, Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет. По вопросам, связанным с этим переводом, пожалуйста, свяжитесь с нами по адресу: lezign@gmail.com

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