Strahlenther Onkol (2015) 191:17–25 DOI 10.1007/s00066-014-0759-1

O r i g i n a l a rt i c l e

Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients with resected pancreatic adenocarcinoma Claudio V. Sole · Felipe A. Calvo · Freddy Atahualpa · Alejandro Berlin · Rafael Herranz · Luis Gonzalez-Bayon · Jose Luis García-Sabrido

Received: 6 June 2014 / Accepted: 6 September 2014 / Published online: 8 October 2014 © Springer-Verlag Berlin Heidelberg 2014

Abstract Background  To analyze prognostic factors associated with long-term outcomes in patients with resected pancreatic cancer treated with chemotherapy (CT) and surgery with or without external beam radiotherapy (EBRT).

C. V. Sole, M.D., Ph.D.c () Department of Radiation Oncology, Instituto de Radiomedicina (IRAM), Ave. Americo Vespucio Norte 1314, 7630370 Santiago, Chile e-mail: [email protected] C. V. Sole, M.D., Ph.D.c · F. A. Calvo, M.D., Ph.D. · F. Atahualpa, M.D., Ph.D. · L. Gonzalez-Bayon, M.D., Ph.D. · J. L. García-Sabrido, M.D., Ph.D. School of Medicine, Complutense University, Madrid, Spain F. A. Calvo, M.D., Ph.D. Department of Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain F. Atahualpa, M.D., Ph.D. · L. Gonzalez-Bayon, M.D., Ph.D. · J. L. García-Sabrido, M.D., Ph.D. General Surgery Service III, Hospital General Universitario Gregorio Marañón, Madrid, Spain A. Berlin, M.D. Department of Radiation Oncology, Clinica Alemana de Santiago, Santiago, Chile R. Herranz, M.D. Department of Radiation Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain

Patients and methods From January 1995 to December 2012, 95 patients with adenocarcinoma of the pancreas and locoregional disease [clinical stage IB-IIA (n = 45; 47 %), IIB-IIIC (n = 50; 53 %)] were treated with curative resection [R0 (n = 52; 55 %), R1 (n = 43, 45 %)] and CT with (n = 60; 63 %) or without (n = 35; 37 %) EBRT (45–50.4 Gy). Additionally, 29 patients (48 %) also received a pre-anastomosis IOERT boost (applicator diameter size, 7–10 cm; dose, 10– 15 Gy; beam energy, 9–18 MeV). Results  With a median follow-up of 17.2 months (range, 1–182), 2-year overall survival (OS), disease-free survival (DFS), and locoregional control were 28, 20, and 53 %, respectively. Univariate analyses showed that IIB-IIIC stage (HR, 2.23; p = 0.04), R1 margin resection status (HR, 2.09; p = 0.04), no vascular resection (HR, 0.42; p = 0.02), and not receiving external beam radiotherapy (HR, 2.70; p = 0.004) were associated with locoregional recurrence. In the multivariate analysis, only R1 margin resection status (HR, 2.63; p = 0.009) and not receiving EBRT (HR, 2.91; p = 0.002) retained significance with regard to locoregional recurrence. We observed no difference in toxicity between patients treated with or without EBRT (p = 0.44). Overall treatment mortality was 3 %. No long-term treatment–related death occurred. Conclusions  Although adjuvant CT is still the standard of care for resected pancreatic tumors, OS remains modest owing to the high risk of distant metastases. Locoregional treatment needs to be tested in the context of more efficient systemic therapy. Keywords  Radiotherapy · Resected pancreatic cancer · Locoregional recurrence · Chemotherapy · External beam radiotherapy

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Die Bedeutung der Radiotherapie als Teil eines multidisziplinären Behandlungskonzepts von Patienten mit reseziertem Pankreasadenokarzinom und erfolgter Chemotherapie Zusammenfassung Ziel  Zur Evaluierung von Prognosefaktoren im Rahmen von Langzeitresultaten bei Patienten mit reseziertem Pankreaskarzinom und verabreichter Chemotherapie (CT) mit oder ohne zusätzlicher externer Radiotherapie (EBRT). Material und Methoden Von Januar 1995 bis Dezember 2012 wurde bei 95 Patienten nach Diagnose eines Adenokarzinoms des Pankreas im lokoregionären Erkrankungsstadium (klinisches Stadium IB–IIA [n = 45, 47 %], IIB–IIIC [n = 50, 53 %]) eine kurative Resektion (R0 [n = 52, 55 %], R1 [n = 43, 45 %]) vorgenommen, welcher eine Chemotherapie (n = 60, 63 %) mit (n = 60, 63 %) oder ohne (n = 35, 37 %) EBRT (45–50,4 Gy) folgte. 29 Patienten (48 %) erhielten einen zusätzlichen intraoperativen Tumorbett-Boost mit Elektronen (IOERT) im Anastomosenbereich (Tubusdurchmesser: 7–10 cm; Dosis: 10–15 Gy; Elektronenenergie: 9–18 MeV). Ergebnisse  Nach einer medianen Beobachtungszeit von 17,2 Monaten (Spanne 1–182 Monate) betrugen die 5-Jahresraten des Gesamtüberlebens (OS), krankheitsfreien Überlebens (DFS) und der lokoregionären Kontrolle entsprechend 28, 20, und 53 %. Univariate Analysen zeigten, dass das klinische Tumorstadium IIB–IIIC (HR 2,23; p = 0,04), ein R1-Resektionsstatus (HR 2,09; p = 0,04), fehlende Gefäßresektion (HR 0,42; p = 0,02) sowie der Verzicht auf eine EBRT (HR 2,95; p = 0,004) mit vermehrten lokoregionären Rezidivereignissen verbunden waren, während in den multivariaten Untersuchungen nur der R1-Resektionsstatus (HR 2,63; p = 0,009) und das Fehlen einer zusätzlichen EBRT (HR 2,91; p = 0,002) statistische Signifikanz behielten. In Abhängigkeit davon, ob bei Patienten eine EBRT durchgeführt wurde oder nicht, konnte dabei im direkten Vergleich kein Unterschied hinsichtlich akuter (p = 0,44) oder chronischer (p = 0,52) Toxizität festgestellt werden. Insgesamt lag die therapieassoziierte Mortalität bei 3 %, wobei nach Langzeitbeobachtung kein Todesfall als direkte Folge der Behandlung auftrat. Schlussfolgerung  Obwohl die lokale Tumorkontrolle durch eine zusätzliche EBRT verbessert wird, bleibt das OS wegen einem höheren Risiko zur Fernmetastasierung weiterhin mäßig. Der Erfolg einer lokoregionären Behandlung sollte in Verbindung mit effizienteren Systemtherapien geprüft werden. Schlüsselwörter  Radiotherapie · Reseziertes Pankreaskarzinom · Lokoregionäres Rezidiv · Chemotherapie · Externe kurative Strahlentherapie

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C. V. Sole et al.

Introduction Pancreatic cancer remains one of the most lethal oncologic malignancies. Even in the twenty-first century, successful treatment of pancreatic adenocarcinoma remains challenging. As the majority of patients present with advanced disease, only 10–20 % of patients present with disease amenable to resection [1]. Most of those patients who undergo resection will eventually die as a result of their disease, given the high rate of distant metastases and local recurrence (LR) (50–90 %) [1]. Surgery alone is an option that can be improved, since it cures no more than 15 % of cases [1]. Using histopathology, LR is detected more frequently than that estimated when using imaging. Autopsy findings for patients who had undergone potentially curative pancreatectomy revealed the incidence of LR to be 75 % [2]. Attempts to promote local control and survival by performing extended lymphatic resection have met with conflicting results [3] and have been associated with unacceptable morbidity and mortality in some centers [4]. Collaborative groups have focused their research efforts on adjuvant chemotherapy (CT), due to the significant perioperative morbidity and disappointing results obtained with external beam radiotherapy (EBRT) [5, 6] and chemoradiation (CRT) [7, 8]. Nonetheless, all these trials had major limitations and attracted wide criticism. Moreover, adjuvant CT alone appears to be insufficient for inducing favorable local control [8]. We hypothesized that improvement of local control induced by radiotherapy may affect survival. In this difficult clinical scenario we evaluated a practical chemoradiation procedure before or after surgical resection with curative intent, and discuss the clinical potential of combined therapy. The purpose of this study was to investigate whether EBRT is effective in promoting local control with acceptable tolerance. Patients and methods Patient characteristics and staging From January 1995 to March 2012, patients with pathologically confirmed adenocarcinoma of the pancreas (n = 95) were treated using a multimodal approach in a single institution. The pretreatment evaluation consisted of a complete history and physical examination, complete blood count, renal and liver function tests, chest X-ray, and computed tomography (CT) scan of the abdomen and pelvis. Positron emission tomography (PET) was available from 2009. Patients who had distant metastatic disease, stage T1-T2 disease without lymphadenopathy (patients with T2 with lymphadenopathy were included), noncurative resections (R2), or poor performance status (Eastern Cooperative Oncology Group > 2)

Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients

were excluded from this analysis. Consideration for surgical approach, EBRT, and adjuvant chemotherapy (CT) was discussed onan individual basis. The Tumor Board considered for multimodal recommendation: initial treatment characteristics, location, tumor resectability, and clinical status of patients. The two treatment strategies used were as follows: A protocol that consisted of pre- or postoperative concurrent CRT, surgery, with or without IOERT [60 patients (63 %), EBRT group]; and a protocol, with surgical resection and adjuvant CT [35 patients (37 %), CT group]. Both protocols were approved by the local institutional review board and met governmental agency guidelines. All patients treated with EBRT (n = 60) were invited to participate in the institutional intraoperative radiation therapy (IORT) program, but 31 (52 %) refused. Data were prospectively collected and retrospectively analyzed at the scheduled time points during follow-up. Patients were reclassified for the analysis according to the staging system of the 7th American Joint Committee on Cancer/Union Internationale Contre le Cancer. Tumors were considered borderline resectable if they exhibited any of the following: involvement of the superior mesenteric vein/portal vein with tumor abutment, impingement and narrowing of the vessel lumen, encasement of the superior mesenteric vein/portal vein without encasement of the nearby arteries, short segment occlusion by thrombus or encasement of suitable proximal and distal vessels allowing safe resection and reconstruction, gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or abutment of the hepatic artery without celiac trunk involvement, and abutment of

Role of radiotherapy in the chemotherapy-containing multidisciplinary management of patients with resected pancreatic adenocarcinoma.

To analyze prognostic factors associated with long-term outcomes in patients with resected pancreatic cancer treated with chemotherapy (CT) and surger...
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