Download - Lung Cancer
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Lung Cancer
Prof .G. Mantovani
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IL PROBLEMA DELLA TERAPIA MEDICA ADIUVANTE E NEOADIUVANTE DEL CA POLMONARE NSCLC
LA TERAPIA MEDICA ADIUVANTE DEL CA POLMONARE: STATO DELL’ARTE 2006Cagliari, 23 marzo 2006
Prof Giovanni Mantovani
Cattedra di Oncologia MedicaUniversità di Cagliari
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ASCO CLINICAL GUIDELINES NSCLC
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SUMMARY OF FINDINGSFollowing is a summary of the major clinical research advances and emerging cancer issues of 2005, as identified in this report:
Major Clinical Research Advances New Standards of Care for Early-Stage Breast, Lung, Colon Cancer.
While this report identifies important advances in nearly every type of cancer, several studies stand out as advances that will change the standard of care for some of the most common cancers in the United States. These studies identify three new adjuvant therapy strategies for treating early-stage breast, lung, and colon cancer.
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Chemotherapy Increases Survival After Lung Cancer SurgeryA large study has resolved the debate over the benefit of adjuvant chemotherapy in early-stage non-small cell lung cancer (NSCLC). The study showed that adjuvant chemotherapy reduced the risk of recurrence by 40%, and resulted in significantly higher five-year survival rates compared with surgery alone. This research is particularly important given the lack of effective treatment options and historically low survival rates among lung cancer patients.
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Lung cancer incidence and mortality have begun declining in recent years, due in large part to a decrease in smoking rates over the last several decades, particularly among men. However, the disease remains the leading cancer killer in the United States, with an estimated 163,510 deaths expected in 2005.
Because no reliable screening techniques exist for lung cancer, the disease is most often found at an advanced, incurable stage.
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Even lung cancer detected in its earliest stages has been difficult to treat, with just half of early-stage patients surviving five years after diagnosis.
However, two important studies published in 2005 have changed the outlook for lung cancer patients, showing that treatment with chemotherapy and newer, more targeted therapies can significantly extend survival for patients who have had—until now—a very poor prognosis.
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MAJOR ADVANCESDefinitive Study Demonstrates Effectiveness of Adjuvant Chemotherapy for Early-stage Lung Cancer Until now, questions have persisted about the benefit of adjuvant chemotherapy in the treatment of non-small cell lung cancer (NSCLC). The detailed results of a large randomized trial showed that giving chemotherapy after surgery to patients with early-stage NSCLC significantly extends survival. The study resolves a long-standing debate about the benefit of adjuvant chemotherapy, definitively demonstrating that such treatment has a beneficial role in the care of patients with operable NSCLC.
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Researchers with the National Cancer Institute of Canada Clinical Trials Group and the U.S. National Cancer Institute Intergroup Trial found that overall survival among patients with early-stage NSCLC who received the anticancer drugs vinorelbine and cisplatin after surgery was 94 months, compared with 73 months for patients who did not receive such adjuvant chemotherapy. Five-year survival was also higher in the chemotherapy group (69% versus 54%), and the risk of recurrence was 40% lower in the chemotherapy group.
These findings, along with those reported recently by the Adjuvant Navelbine International Trialist Association (ANITA) and the Cancer and Leukemia Group B (CALGB), confirm that adjuvant chemotherapy has a significant role in the treatment of patients with operable NSCLC who are in otherwise good health.
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La prognosi degli stadi iniziali del carcinoma polmonare non a piccole cellule dopo resezione chirurgica radicale, è da correlarsi con la stadiazione di malattia: le dimensioni del tumore ed il coinvolgimento dei linfonodi regionali ilari e mediastinici rappresentano le variabili prognostiche più significative, variando la probabilità di sopravvivenza a 5 anni dal 57% per i pazienti in stadio IB a meno del 30% per quelli in stadio II (Mountain CF – Regional Lymph node classification for lung Cancer staging. Chest 1997, 111: 1718-1723).
La diffusione metastatica a distanza rappresenta la principale causa di morte, mentre la probabilità di recidiva locale interessa circa 1/3 dei pazienti radicalmente operati.
AIOM GUIDELINES NSCLCTERAPIA ADIUVANTE POST-CHIRURGICA
(aggiornate ottobre 2005)
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Negli anni 80 la radioterapia post operatoria è stata a lungo utilizzata quale trattamento adiuvante pur in assenza di evidenze cliniche provenienti da studi clinici randomizzati.
Una meta-analisi degli studi di radioterapia adiuvante nei pazienti radicalmente resecati (Post-Operative Radio Therapy meta-analysis) ha dimostrato un effetto negativo sulla sopravvivenza, con il 21% di incremento relativo del rischio di morte equivalente ad un aumento del rischio di morte assoluto del 7% a due anni ed una riduzione della sopravvivenza dal 55% al 48%.
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L’effetto avverso è risultato essere maggiore nei pazienti in stadio I/II mentre l’evidenza è risultata essere minore per quelli in stadio III. Se da un lato sono formulabili giustificate critiche a come tale meta analisi è stata condotta l’inclusione di studi con differenti dosi totali e modalità di erogazione delle frazioni radioterapiche, in un periodo di tempo troppo lungo e utilizzando apparecchiature spesso non moderne) dall’altro lato, allo stato attuale delle conoscenze non esiste evidenza scientifica a favore di un trattamento radioterapico adiuvante standard.
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Molti studi di chemioterapia sono stati completati negli anni ’80 e nell’ambito di una metaanalisi sul ruolo della chemioterapia nel carcinoma polmonare non a piccole cellule sono stati considerati 8 studi randomizzati di chemioterapia adiuvante contenente cisplatino confrontati con il solo trattamento chirurgico. Complessivamente si è dimostrato un modesto miglioramento, non statisticamente significativo della sopravvivenza a 5 anni pari al 5% mentre altre combinazioni non contenenti cisplatino o agenti alchilanti non hanno dimostrato efficacia alcuna o si sono dimostrati dannosi per la sopravvivenza.
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Tali dati hanno costituito la base razionale per una serie di studi prospettici di chemioterapia adiuvante completati verso la fine del secolo scorso. Complessivamente questi studi presentato disegni statistici più appropriati rispetto agli studi condotti in precedenza, hanno impiegato combinazioni chemioterapiche più recenti, alcuni (BR10, CALGB) sono stati condotti esclusivamente in stadi iniziali di malattia mentre in altri (IALT, ALPI) è stato consentito l’uso sequenziale della radioterapia adiuvante.Sfortunatamente alcuni di questi studi sono stati interrotti prima del raggiungimento della numerosità di pazienti richiesta dal disegno statistico a causa del limitato arruolamento.
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Due di questi studi (ALPI e IALT) hanno arruolato un numero di pazienti superiore a 1.000 per ciascuno dei 2 studi al contrario di tutti gli altri studi ove il campione di pazienti è risultato essere inferiore.
Il primo di questi, lo studio ALPI non ha dimostrato un vantaggio significativo in sopravvivenza mediana e a lungo termine per i pazienti trattati con tre cicli di cisplatino, vindesina e mitomicina-C, pur evidenziando un miglioramento sia del tempo alla progressione di malattia che alla sopravvivenza globale (Scagliotti).Successivamente quattro di questi studi randomizzati hanno dimostrato un vantaggio statisticamente significativo della sopravvivenza mediana e di quella a 5 anni per regimi di chemioterapia contenenti cisplatino.
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Nello studio IALT, 1867 pazienti con carcinoma polmonare non a piccole cellule in stadio chirurgico I- IIIA sono stati randomizzati al trattamento con tre cicli di cisplatino ed etoposide o alcaloidi della vinca oppure al solo follow up post-operatorio, ed è stato riportato un miglioramento statisticamente significativo della sopravvivenza a 5 anni del 4.1% per il gruppo ricevente chemioterapia adiuvante (44.5% vs 40.4%) (NEJM). Occorre sottolineare come la parte preponderante del vantaggio sia stato osservata nello stadio III e negli individui con età inferiore a 65 anni. Inoltre lo studio ha arruolato meno del 60% dell’originale numero di pazienti previsto aumentando così le possibilità dell’errore statistico di tipo I.
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Successivamente lo studio NCIC-BR10 in 482 pazienti con carcinoma polmonare non a piccole cellule in stadio IB e II ha confermato un significativo prolungamento della sopravvivenza per il gruppo trattato con cisplatino e vinorelbina rispetto al gruppo sottoposto a sola osservazione (69% vs 54% di sopravvivenza a 5 anni, P=0.03); tuttavia il vantaggio di sopravvivenza è risultato essere limitato allo stadio II. Da notare come in questo studio sia stata documentata neutropenia di grado III-IV nell’88% dei casi e di neutropenia febbrile nel 7%.
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Il CALGB (Cancer and Leukemia Group B) ha effettuato uno studio di chemioterapia adiuvante con carboplatino e paclitaxel arruolando unicamente pazienti in stadio IB: benché anche in questo studio sia stato osservato un significativo vantaggio di sopravvivenza a favore della chemioterapia adiuvante va sottolineato come, a differenza degli altri studi, il periodo di follow up sia ancora molto limitato (36 mesi) e come sia stato deciso di interrompere prematuramente lo studio sulla base di una presupposta superiorità nel braccio sperimentale.
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L’efficacia del trattamento adiuvante è stata ribadita da un altro studio prospettico (ANITA) nel quale 840 pazienti in stadio IB, II e IIIA sono stati randomizzati dopo chirurgia radicale al trattamento con cisplatino e vinorelbina, oppure alla semplice osservazione clinica. La sopravvivenza a 5 e 7 anni è stata del 51% e 45% nel gruppo chemiotrattato rispetto al 43% e 37% in quello di controllo. Il vantaggio di sopravvivenza è risultato evidente in pazienti in stadio II e IIIA, ma non in quelli in stadio IB, ed ha confermato una percentuale di neutropenia dell’86% e di neutropenia febbrile del 8.5%, analogamente a quanto in precedenza osservato nello studio canadese sopra riportato.
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Negli ultimi venti anni i ricercatori giapponesi hanno completato una serie di studi di chemioterapia adiuvante, impiegando una fluoropirimidina orale, combinazione del tegafur ed uracile per periodi prolungati da 6 mesi a due anni. In una meta-analisi pubblicata nel corso del 2005, comprendente 2003 pazienti randomizzati al trattamento con UFT oppure al semplice controllo, in grande maggioranza in stadio I (96%), gli autori giapponesi segnalano un vantaggio in termini di sopravvivenza significativo a 5 e 7 anni per i pazienti trattati. Va segnalato come l’UFT sia un farmaco completamente inattivo nella malattia avanzata e come in tutti questi studi impieganti UFT non sia mai stato segnalato un miglioramento del tempo alla progressione nel gruppo di pazienti trattati con UFT.
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I risultati complessivi di tutti gli studi di adiuvante eseguiti dopo la meta-analisi del 1995 hanno aperto un importante dibattito scientifico sul ruolo della chemioterapia adiuvante nel carcinoma polmonare non a piccole cellule radicalmente operato.Dall’analisi complessiva di tutti gli studi emerge un beneficio per i regimi contenenti platino che pare modificare favorevolmente la storia naturale della malattia. Tuttavia la tossicità associata alla chemioterapia con cisplatino, le comorbidità vascolari e metaboliche frequentemente associate al NSCLC, l’età spesso oltre i 70 di questi pazienti ed il modesto beneficio assoluto in sopravvivenza degli studi più numerosi, impongono cautela nel definire la chemioterapia precauzionale, nuovo standard di trattamento post chirurgico degli stadi iniziali del NSCLC.
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Data la natura di questi studi resta non quantificato il possibile ruolo di confondimento di alcuni fattori quali la percentuale di individui che hanno smesso di fumare dopo chirurgia radicale tra pazienti sottoposti a chemioterapia verso i controlli ed il ruolo della dissezione linfonodale mediastinica verso il semplice sampling linfonodale.Le linee guida internazionali convergono nel suggerire che una chemioterapia contenente platino per 4 cicli di trattamento debba essere proposta a pazienti in buone condizioni generali, con il PS di 0-1, senza significative comorbidità che abbiano avuto una buona risposta dopo l’intervento chirurgico.
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RECENT ADJUVANT THERAPY TRIALSAuthor # Pts Treatment 5 year
Survival %
HR P-value
Arriagada IALT 2004
1867 Cisplatin + VP16 Vinorelbine Vinblastine VindesineOBS
44.5
40.40.86 0.003
WintonNC.IC-BR102004
482 CDDP + Vinorelbine
OBS
69
540.69 0.003
StraussCALGB 2004
344 CBDCA + Paclitaxel
OBS
71
590.002
DouillardANITA 2005
840 CDDP + Vinorelbine
OBS
51
430.001
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Studio Clinico
Stage IA Stage IB Stage II Stage IIIA
ALPI Negative Negative Negative Negative
IALT Negative Negative Negative Positive
NCIC-BR10 Not tested Negative Positive Not tested
CALGB Not tested Positive Not tested Not tested
ANITA Not tested Negative Positive Positive
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