Cáncer de Pancreas Adyuvante

Transcripción

1 Dr. Albert Abad; Dr. José Luis Manzano. Servei Oncologia Mèdica Hospital Universitari Germans Trias i Pujol Institut Català d Oncologia. Badalona Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A, Wils J. OBJECTIVE The survival benefit of adjuvant radiotherapy and 5-fluorouracil versus observation alone after surgery was investigated in patients with pancreatic head and periampullary cancers. BACKGROUND DATA A previous study of adjuvant radiotherapy and chemotherapy in these cancers by the Gastrointestinal Tract Cancer Cooperative Group of EORTC has been followed by other studies with conflicting results. METHODS Eligible patients with T1-2N0-1aM0 pancreatic head or T1-3N0-1aM0 periampullary cancer and histologically proven adenocarcinoma were randomized after resection. RESULTS Between 1987 and 1995, 218 patients were randomized (108 patients in the observation group, 110 patients in the treatment group). Eleven patients were ineligible (five in the observation group and six in the treatment group). Baseline characteristics were comparable between the two groups. One hundred fourteen patients (55%) had pancreatic cancer (54 in the observation group and 60 in the treatment group). In the treatment arm, 21 patients (20%) received no treatment because of postoperative complications or patient refusal. In the treatment group, only minor toxicity was observed. The median duration of survival was 19.0 months for the observation group and 24.5 months in the treatment group (log-rank, p = 0.208). The 2-year survival estimates were 41% and 51 %, respectively. The results when stratifying for tumor location showed a 2- year survival rate of 26% in the observation group and 34% in the treatment group (log-rank, p = 0.099) in pancreatic head cancer; in periampullary cancer, the 2- year survival rate was 63% in the observation group and 67% in the treatment group (log-rank, p = 0.737). No reduction of locoregional recurrence rates was apparent in the groups CONCLUSIONS Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well tolerated. However, the benefit in this study was small; routine use of adjuvant chemoradiotherapy is not warranted as standard treatment in cancer of the head of the pancreas or periampullary region. 36 Noviembre-Diciembre 2007

2 Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Neoptolemos JP, Dunn JA, Stocken DD, Almond J, Link K, Beger H, Bassi C, Falconi M, Pederzoli P, Dervenis C, Fernandez-Cruz L, Lacaine F, Pap A, Spooner D, Kerr DJ, Friess H, Büchler MW; European Study Group for Pancreatic Cancer. Lancet Nov 10;358(9293): BACKGROUND The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. METHODS After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy).the primary endpoint was death, and all analyses were by intention to treat.findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI ], p=0.24).there was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [ ], p=0.0005).interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer. Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Stocken DD, Büchler MW, Dervenis C, Bassi C, Jeekel H, Klinkenbijl JH, Bakkevold KE, Takada T, Amano H, Neoptolemos JP; Pancreatic Cancer Meta-analysis Group. Br J Cancer Apr 25;92(8): BACKGROUND The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This metaanalysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (H = 0.75, 95% confidence interval (CI): 0.64, 0.90, P-values(strati- Noviembre-Diciembre

3 fied) (Pstrat) = 0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without.the 2- and 5- year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR = 1.09, 95% CI: 0.89, 1.32, Pstrat = 0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf I, Roll L, Doerken B, Riess H. JAMA Jan 17;297(3): CONTEXT The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists. OBJECTIVE To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more. DESIGN, SETTING, AND PATIENTS Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups. INTERVENTION Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175). MAIN OUTCOME MEASURES Primary end point was diseasefree survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat). RESULTS More than 80% of patients had R0 resection.the median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, ) and Noviembre-Diciembre 2007

4 months in the control group (95% confidence interval, ; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, ; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, ; estimated survival,20.5% at 3 years and 11.5% at 5 years; P =.06, log-rank). CONCLUSIONS Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas. Adjuvant therapy for pancreas cancer: advances and controversies. Mulcahy MF. Semin Oncol Aug;34(4): Although the benefit of adjuvant therapy for pancreas cancer is clear, the most effective therapy remains elusive. In the United States, combination therapy with chemotherapy and radiation remains the standard of care, while in other parts of the world the contribution of radiation is questioned. Clinical trials are reported evaluating the benefit of post-resection radiation and chemotherapy with 5-fluoruoracil (5FU), gemcitabine, and combination therapy; chemotherapy alone with either 5FU or gemcitabine; and pre-resection chemotherapy and radiation.attention to pancreas cancer staging, radiation techniques, and clinical trial design are paramount to interpreting the outcomes from adjuvant therapy. Therapeutic advances will be made with new approaches studied in carefully controlled trials. COMENTARIO El adenocarcinoma de páncreas exocrino constituye la 5 causa de muerte por cáncer en España. La supervivencia para este tumor es muy pobre no alcanzando el 20% a los 5 años para aquellos pacientes que han podido ser resecados y 8% si consideramos todos los pacientes. El factor más determinante de esta mala supervivencia es la precocidad que presenta en metastatizar de manera que el 50% de los casos presentan metástasis en el momento del diagnóstico estando las micrometástasis presentes en el 75% de los casos con tumores de 3 cm o más. Ante esta situación es claro que el tratamiento adyuvante a la cirugía es de gran importancia para cubrir este elevado porcentaje de pacientes con micrometástasis. Por otra parte se trata de un tumor poco sensible a los tratamientos. Existen pocos estudios randomizados de tratamiento adyuvante en esta neoplasia. En el estudio de la EORTC (Klinkenbijl 1999) comparando radioquimioterapia con observación ( no existe brazo de quimioterapia sola) que incluye 218 pacientes los autores concluyen que el beneficio obtenido con el tratamiento es marginal y no debe recomendarse la radioquimioterapia como un estándar en el tratamiento adyuvante. Es necesario resaltar que el estudio carecía de potencia estadística para demostrar si la tendencia a mejor de la rama de tratamiento era cierta lo que llevo a los autores a esta conclusión pero tampoco el estudio ESPAC-1 (European Study Group for Pancreatic Cancer) en Noviembre-Diciembre

5 un estudio 2x2 de elevada complejidad estadística que es el más amplio realizado hasta el momento (Neoptolemos 2004) alcanza a demostrar ningún beneficio para la radioterapia sino al contrario, en él, la radioterapia produce un efecto deletéreo siendo los pacientes que obtienen beneficio los pacientes en la rama de quimioterapia sola. Hay que señalar que el citostático utilizado es 5- fluorouracilo, fármaco que no ha demostrado actividad evidente en la enfermedad avanzada. Consideramos de gran valor el meta-análisis del mismo grupo de Neoptolemos (Stocken 2005) en el que se incluyen los dos estudios anteriores más los resultados de ESPAC de 2001 (1) junto con estudios más antiguos Kalser et al 1985 (2) del GITSG 1987 (3), Bakkevold et al 1993 (4) y Tacada et al (2002) (5). Este meta-análisis incluye también los datos de 261 pacientes no publicados previamente. El estudio demuestra el efecto beneficioso de la quimioeterapia adyuvante, insistimos con 5-fluorouracilo, mientras que la radioquimioterapia mantiene su efecto deletéreo respecto a no BIBLIOGRAFÍA tratamiento empeorando la supervivencia en 5%. Es de destacar no obstante el posible beneficio de la radioterapia en el subgrupo de pacientes con márgenes invadidos (R1). Los resultados del meta-análisis muestran que la quimioterapia es efectiva en el tratamiento adyuvante del cáncer de páncreas y plantea la necesidad de estudios específicos de radioquimioterapia en el subgrupo de pacientes con cirugía R1. Naturalmente el establecimiento de gemcitabina como estándar en el tratamiento del adenocarcinoma de páncreas avanzado y metastático ha llevado a testar este citostático tambien en el regimen de adyuvancia. La comparación de gemcitabina con observación (Oettle 2007) en un estudio aleatorizado que incluye 368 pacientes con cirugía R0 o R1. Los resultados si bien son favorables no nos parecen definitivos. Existe diferencia significativa en el intervalo libre de enfermedad (ILE), 13,4 meses vs 6,9 meses (p<.001) que es igual para los pacientes con R0 y R1, pero no existen diferencias en supervivencia. El objetivo principal del estudio fue el ILE y en este sentido el estudio es positivo concluyendo los autores que los resultados apoyan el uso de gemcitabina como tratamiento adyuvante del cáncer de páncreas. De acuerdo, pero qué pasa con 5-fluorouracilo?, 2 importantes estudios y un meta-análisis demuestran mejoría significativa cuando se utiliza en tratamiento adyuvante. El estudio ESPAC-3 (v2) ( ex.htm) cuyos resultados no conocemos todavía, compara 5- fluorouracilo con gemcitabina y nos habrá de proporcionar información importante al respecto. Teniendo en cuenta el efecto radiopotenciador de gemcitabina, también son necesarios estudios de radioquimioterapia con este agente citostático. A tener en cuenta el posible papel de los agentes antidiana, tal como erlotinib, aprobado ya para el tratamiento del adenocarcinoma de páncreas metastático. Finalmente citar una reciente revisión (Mulcahy 2007) en la que se analizan todos estos aspectos. 1. Neoptolemos JP, Dunn JA, Stocken DD et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: A randomized controlled trial. Lancet 2001, 358: Kalser MH, Ellenberg SS. Pancreatic cancer.adjuvant combined radiation and chemotherapy following curative resection.ann Surg 1985, 120: Gastrointestinal Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987, 59: Bakkevold KE,Arnesjo B, Dahl O Kambestad B.Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater. Results of a controlled, prospective, randomized multicentre study. Eur J Cancer 1993, 29: Takada T, Amano H,Yasuda H et al. Is postoperative adjuvant chemotherapy useful for gall-bladder carcinoma? Cancer 2002, 95: Noviembre-Diciembre 2007