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.

Zaključci autora: 

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.

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Dosadašnje spoznaje: 

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.

Ciljevi : 

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

Način pretraživanja: 

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.

Kriteriji odabira: 

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).

Prikupljanje i analiza podataka: 

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.

Ključni rezultati : 

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.

Bilješka o prijevodu: 

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

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