Radiotherapy & Oncology
Volume 102, Issue 1 , Pages 10-13, January 2012

Preoperative treatment with capecitabine, bevacizumab and radiotherapy for primary locally advanced rectal cancer – A two stage phase II clinical trial☆

  • Gudrun Resch

      Affiliations

    • Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Austria
    • Corresponding Author InformationCorresponding author. Address: Klinikum Wels-Grieskirchen, Grieskirchnerstraße 42, A-4600 Wels, Austria.
    • ,
  • Alexander De Vries

      Affiliations

    • Department of Radiotherapy and Radio-Oncology, Feldkirch Hospital, Austria
    • ,
  • Dietmar Öfner

      Affiliations

    • Department of Surgery, Paracelsus Private Medical University Salzburg, Austria
    • ,
  • Wolfgang Eisterer

      Affiliations

    • Department of Internal Medicine I, Innsbruck Medical University, Austria
    • ,
  • Hans Rabl

      Affiliations

    • Department of Surgery, Leoben-Eisenerz Hospital, Austria
    • ,
  • Michael Jagoditsch

      Affiliations

    • Department of Surgery, St. Veit Hospital, Austria
    • ,
  • Michael Gnant

      Affiliations

    • Department of Surgery, Medical University of Vienna, Austria
    • ,
  • Josef Thaler

      Affiliations

    • Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Austria
    • ,
  • on behalf of the Austrian Breast and Colorectal Cancer Study Group

Received 20 October 2010; received in revised form 18 May 2011; accepted 5 June 2011. published online 11 July 2011.

Article Outline

Abstract 

Background and purpose

The aim of this single-arm multicenter phase II clinical trial was to assess the feasibility and tolerability of preoperative radiotherapy and simultaneous capecitabine and bevacizumab. Secondary endpoints were downstaging-rate and induction of complete pathological response.

Material and methods

Patients with cT3 rectal cancer were eligible. Capecitabine (825mg/sqm twice daily on radiotherapy-days weeks 1–4) and bevacizumab (5mg/kg on days 1, 15 and 29) were administered concurrently to pelvic radiotherapy (1.8Gy daily up to 45Gy in 5weeks). Surgery followed 6–8weeks later. A two-stage trial was designed with early termination at eight patients if more than three patients had experienced a common toxicity criteria ⩾grade 3 according to the NCI CTC guidelines.

Results

In the first stage eight patients were enrolled. Median age was 70years (range 55–76) and ECOG PS 0/1 (%) was 87.5/12.5. Major side effects were mostly intestinal bleeding (grade 3, 25%), diarrhea (grade 3, 25%), perianal and abdominal pain (grades 3 and 4, 25%) followed by anemia (grade 3, 12.5%). Tumor downstaging was observed in 37.5% of patients with complete pathological response in two patients (25%).

Conclusions

After interim analysis of feasibility and tolerability, accrual was terminated according to protocol due to ⩾grade 3 toxicities in 50% of patients. Complete pathological response was seen in 25% of patients but was accompanied by considerable toxicity. Further clinical trials are needed to clarify the role of bevacizumab in this setting.

Keywords: Rectal cancer, Chemoradiation, Capecitabine, Bevacizumab

 

Rectal cancer is a paradigm for multimodal management, as the combination of surgery, chemotherapy and radiotherapy (RT) is necessary to achieve the optimal outcome [1]. The incidence of rectal cancer in the European Union is approximately 35% of the total colorectal cancer incidence with 15–25/100.000 per year. The mortality is 4–10/100.000 per year with lower rates for females. [2].

Local recurrence and occurrence of metastases are serious problems in locally advanced, low rectal cancer (LARC). With conventional surgery alone the local recurrence rate was 20–45% and could be reduced to <10% by establishing the total mesorectal excision (TME) [3], [4]. Preoperative treatment in LARC is designed to improve survival, reduce local recurrence and increase sphincter-saving surgery [5], [6], [7], [8]. Efforts to improve such results have focused on preoperative combined radiochemotherapy (RCT) treatment regimens [9], [10], [11].

The addition of fluorouracil-based chemotherapy to preoperative RT demonstrated a significantly reduction in the rate of local recurrence in several trials versus RT alone but no trial showed any difference in OS [12], [13], [14], [15]. The alternative use of capecitabine plus RT showed similar efficacy in pathologic downstaging rate and complete pathologic response (pCR) rate in two retrospective studies comparing neoadjuvant 5-FU-based versus capecitabine-based RT [16], [17]. Sauer et al. [18] showed a significant reduction in local recurrence as well as a reduction in the acute and long-term toxicity by preoperative 5-FU based RCT versus postoperative RCT.

Targeted therapies have rapidly gained attraction in the treatment of advanced colorectal cancer and are under active investigation in adjuvant and neoadjuvant setting. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor (VEGF), demonstrated efficacy with significant improvement in progression free survival (PFS) and OS in patients with metastatic colorectal cancer [19], [20], [21].

The aim of this single-arm multicenter phase II clinical trial was to assess the feasibility and tolerability of preoperative RT with concomitant combination of bevacizumab and capecitabine in a homogenous group of patients with LARC. Secondary endpoints were downstaging-rate and induction of pCR.

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Patients and methods 

Study design 

This single-arm multicenter phase II clinical trial on behalf of the Austrian breast and colorectal cancer study group (ABCSG) evaluated the feasibility and safety of preoperative treatment with capecitabine, bevacizumab and RT in patients with LARC (Fig. 1). Secondary endpoints included downstaging and pathologic response. A two-stage trial was designed [22] with early termination at eight patients if more than three patients experienced a common toxicity criteria grade 3 or 4 according to the NCI CTC guidelines (version 3.0). Otherwise 25 patients were to be accrued. Clinical examination, computer tomography (CT) of the entire thorax and abdomen, pelvic magnetic resonance imaging (MRI) and standard laboratory work-up were undertaken within 28days of study entry. A urine pregnancy test was required for all women with childbearing potential, and contraceptive use was required of patients of childbearing age. The trial was approved by the medical ethics committees of all participating centers. Written informed consent was obtained from all patients before randomization.

Eligibility and exclusion criteria 

Patients with newly diagnosed clinical stage T3NxM0, locally advanced but potentially complete resectable (R0) adenocarcinoma of the rectum were eligible for this study. Other key eligibility criteria included: 18–80years, adequate metabolic, hematological, renal and hepatic functions, WHO performance status grades 0–2. Excluded were patients with prior malignancies (except non-melanoma skin carcinoma or in situ cervix cancer), prior pelvic irradiation or chemotherapy, clinically significant cardiovascular disease, uncontrolled hypertension (systolic >150mmHg, diastolic >100mmHg) or arrhythmia, major surgery within 28days before inclusion in this study, grade of common toxicity criteria more than 1 for peripheral neuropathy, active infection, history of significant neurological or psychiatric disorders. Pregnant or breastfeeding women were also excluded.

Radiotherapy 

Radiotherapy was performed using a linear accelerator for >4MeV photons. A computer plan was based on the CT scan in the same position. A three-field technique with lateral wedge filters was employed. Individualized blockings were used to protect lateral field corners, dorsal soft tissues (skin and rima ani), and, if necessary, cranial ventral parts of the small intestine. The upper field border was positioned at level L5–S1, depending on the location of the primary tumor. The ventral border depended on the location of the tumor and its degree of infiltration into the surrounding structures. Radiation therapy was delivered 5days a week for 5weeks with a fractionation of 1.8Gy to the reference point (isocenter). Total dose in the reference point was 45Gy. Radiation was discontinued if grade 4 toxicity according to the NCI CTC v3.0 guidelines occurred.

Chemotherapy 

Capecitabine was administered concurrently at 825mg/m2 bid on days of radiation during the first 4weeks (days 1–5, 8–12, 15–19 and 22–26). Toxicities were assessed and recorded at every visit and graded (grades 1–4) according to NCIC CTC v3.0. The capecitabine dose-modification scheme was applied if patients experienced grades 2–4 toxicities. Dose modification was not required for toxicities that were considered unlikely to become serious or life-threatening (e.g. alopecia or altered taste).The monoclonal antibody bevacizumab was administered by a 90-min intravenous infusion at 5mg/kg body weight on days 1, 15 and 29. If the first infusion was tolerated the second infusion was given in 60min and all subsequent infusions over 30min if 60min infusion was tolerated. Dose reduction for toxicity was not recommended but dosing with bevacizumab was hold or discontinued for defined adverse events.

Surgery and postoperative chemotherapy 

Surgery followed 6–8weeks after completion of chemoradiotherapy. The goal of surgery was complete removal of the primary tumor according to the principles of total mesorectal excision (TME) either by low anterior resection (LAR) or abdomino-perineal excision (APE). Adjuvant chemotherapy was not subject of this study and was performed at the discretion of the treating physician.

Assessment of response 

All patients were re-evaluated within 2weeks before surgery by pelvic MRI, thoracic-abdomino CT, clinical examination and laboratory evaluations, consisting of hematology and serum biochemistry. Histopathologic examination of the resected tumor followed the guidelines of the TNM system [23].

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Results 

In the first stage of this two-stage phase II clinical trial eight patients with LARC enrolled in four Austrian institutions. All patients included in this trial had a histologically proven adenocarcinoma of the rectum with a clinical stage T3NxM0 detected by MRI without evidence of distant metastases. Median age at time of initiating treatment was 70years (range 55–76). Of the patients, 4 (50%) were men and 4 (50%) were woman and ECOG performance status 0/1 (%) was 87.5/12.5. Four patients had hypertension as risk factor. One patient had additionally elevated liver enzyme grade 1. Baseline characteristics were listed in Table 1. RT with an amount of 45Gy in 25 fractions was planned (1.8Gy daily from Monday to Friday, days 1–33). Seven patients (87.5%) received the total dose of radiation. One patient missed 1day of RT. Capecitabine was taken orally twice daily, concurrently on RT-days during the first 4weeks (days 1–26, Monday to Friday). Seven patients (87.5%) received 100% of total planned dose of the oral prodrug capecitabine. Due to the occurrence of grade 3 diarrhea in week 3, one patient had a drug-interruption for 5days and capecitabine was restarted at 75% of the original dose according to the protocol. A further patient also experienced diarrhea grade 3 in week 3 which required an interruption for 2days without dose adjustment in the following cycle. Bevacizumab was administered on day 1, 15 and 29. Six of eight patients received all three infusions. Two patients discontinued treatment due to bleeding grade 3 in week 5. Surgery was performed 6–8weeks after completion of radiochemotherapy in seven patients. In one patient resection was not done due to peritoneal carcinomatosis at laparotomy. There were two perioperative complications, one postoperative ileus which required surgical intervention and one perineal wound dehiscence after abdomino-perineal resection.

Table 1. Baseline patients and tumor characteristics.
CharacteristicNo. of patients (%)
N8

Sex
Male4 (50%)
Female4 (50%)

Age (years)
Median70
Range55–76

ECOG performance status
07 (87.5%)
11 (12.5%)

Clinical TN stage
T38 (100%)
N01 (12.5%)
N14 (50%)
N21 (12.5%)
NX2 (25%)

Severe side effects (grades 3 and 4) were mostly perianal bleeding (grade 3, 25%), diarrhea (grade 3, 25%), perianal and abdominal pain (grades 3 and 4, 25%) followed by hematological complications (anemia grade 3, 12.5%) and postoperative ileus (grade 3, 12.5%) (listed in Table 2). There were no deaths related to radiochemotherapy or surgery. After the preplanned safety interim analysis, accrual was terminated due to the fact that four patients had a toxicity grade 3 or 4 following radiochemotherapy.

Table 2. Acute toxicities and perioperative complications grade 1–4 in patient 1–8; patient 3 and 6 had ypT0, patient 5 had ypT2.
Adverse eventPatient
12345678
Anemia2 3 2
Thrombocytopenia1 3 1
Leukopenia112 2 1
Neutropenia111 1 1
Diarrhea 32 3
Hand-food-syndrome11
Perianal bleeding3 3
Perianal pain1 4
Abdominal pain3 3
Nausea1 1
Dysuria 11
Anastomotic dehiscence 2
Postoperative ileus 3

Postoperative histology revealed a moderately differentiated tumor (grade 2) in 71.4% (5/7) and a poorly differentiated tumor (grade 3) in 28.6% (2/7). After radiochemotherapy for T3 rectal carcinomas, downstaging (defined as ypT0-2 lesions) occurred in 37.5% of patients (3/8). Two of them had ypT0 and one patient had ypT2. Three patients had N0 nodal status, 2 were N1 (1–3 lymph nodes) and 2 were N2 (>4 lymph nodes).

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Discussion 

5-FU based RCT and TME is considered a standard treatment for patients with stage II/III rectal cancer. Despite optimized local treatment with recurrence rates of 5–10%, distant metastases still occur in 25–30% [24], [25]. In order to enhance the effect of RCT the role of radiation sensitizing agents are studied now in several trials. Capecitabine, oxaliplatin, irinotecan as well as targeted therapies improved results for colorectal cancer patients when treated in the metastatic and/or adjuvant setting. Combining these agents with standard therapy treatment in patients with LARC had received an increasing interest. In recent years our study group designed clinical trials to improve the efficacy in terms of local recurrence and prevention of metastases in rectal cancer. In the R02 study [26] the addition of capecitabine and oxaliplatin to RT in LARC was evaluated. Tumor downstaging was observed in 53% of patients (31/59) and the only clinically relevant toxicity was diarrhea in 8%. In the following R03 study [27] the therapy included capecitabine, cetuximab and external beam radiotherapy. The main toxicity was also diarrhea in 11% and tumor downstaging occurred in 50%. In this phase II study (R04), we evaluated the feasibility and efficacy of capecitabine, bevacizumab and RT in patients with LARC. To our knowledge there are only two other phase I/II clinical trials investigating the feasibility of bevacizumab in combination with RCT in LARC.

We initiated a two stage phase II trial. After eight patients an interim analysis was performed. Accrual was terminated according to protocol due to ⩾grade 3 toxicities in half of patients. A tumor downstaging was achieved in 38% with pCR of 25%. Major side effects were mostly intestinal bleeding (grade 3, 25%), diarrhea (grade 3, 25%), perianal and abdominal pain (grades 3 and 4, 25%). However, both patients with pCR experienced grade 3 toxicities.

Study design and treatment schedule in our trial are comparable with the other two trials using bevacizumab and RCT in LARC. Willet et al. [28], [29] investigated the safety and efficacy of neoadjuvant bevacizumab (5 or 10mg/kg) on day one of each cycle, fluorouracil infusion (225mg/m2/24h) during cycles 2–4 and RT (50.4Gy in two fractions over 5.5weeks) in a phase I/II study in 32 patients with LARC. In phase I six patients received 5mg/kg of bevacizumab without dose-limiting toxicity (DLT) and five patients received 10mg/kg bevacizumab, whereas in two of them gastrointestinal DLT occurred. Therefore 21 patients received the lower dose of bevacizumab in the following phase II study. T-downstaging was achieved in 50% of patients with pCR of 16% with acceptable toxicities [28], [29]. Most adverse events were mild, only some patients experienced grade 3 toxicities: diarrhea in 22%, hypertension in 9%, radiation dermatitis in 6% and most of postoperative complications were wound infection (3/32), ileus (2/32), delayed healing of perineal incision (2/32) and pulmonary embolus, anastomotic leak, presacral abscess each in one patient. Crane et al. [30] evaluated the efficacy and safety of bevacizumab (5mg/kg every 2weeks), capecitabine (900mg/m2 twice daily on days of radiation) and RT (50.4Gy in 28 fractions over 5.5weeks) in 25 patients with cT3 rectal cancer. T-downstaging was achieved in 64% of patients with pCR of 32% without grade 3 hand-food syndrome, gastrointestinal toxicities or significant hematologic toxicities [30]. Perianal desquamation in 6/25 patients was the only grade 3 acute toxicity. Perioperative major complications included perianal wound dehiscence (2/25) and anastomotic dehiscence (1/25).

Response rates and toxicities including diarrhea are comparable to our study with the exception of hemorrhage. None of these studies reported bleeding complications whereas in our trial 2/8 patients had perianal bleeding complications requiring blood transfusions. The reason for the difference of this bleeding complication in our trial is not known. Phases I and II studies identified hypertension, hemorrhage, thrombembolism and proteinuria as possible bevacizumab-associated adverse reactions [31], [32]. Overall the incidence of grade ⩾3 hemorrhagic events among patients receiving bevacizumab is indicated with 3.5% [33]. From the point of view our criteria for early termination might have been too restrictive because diarrhea is a common side effect of chemoradiotherapy and postoperative ileus is independent of RCT.

Concerning the efficacy of bevacizumab combined with RCT in early stage rectal cancer there are only results from three phase I/II clinical trials including 65 patients. Complete pathological response rates occurred in 16–32% of patients. Although these response rates are encouraging, increased toxicities seems to preclude the intensification of the standard RCT schedule. In the next protocol of our group we will incorporate bevacizumab into an induction chemotherapy followed by standard RCT and surgery to further improve the results.

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Funding 

The study was sponsored by Roche Pharma AG.

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References 

  1. Sebag-Montefiore D, Bujko K, Valentini V, et al. Rectal cancer multidisciplinary management: evidences and future landscape. Radiother Oncol. 2009;92:145–147
  2. Glimelius B, Oliveira J. Rectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20:54–56
  3. Dahlberg M, Glimelius B, Pahlman L. Changing strategy for rectal cancer is associated with improved outcome. Br J Surg. 1999;86:379–384
  4. McFarlane JK, Ryall RP, Heald RJ. Mesorectal excision for rectal cancer. Lancet. 1993;341:457–460
  5. Kapiteijn E, Marijnen C, Nagtegaal I, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638–646
  6. Swedish rectal cancer trial: improved survival with preoperative radiotherapy in respectable rectal cancer. N Engl J Med 1997;336:980–7.
  7. Folkesson J, Birgisson H, Pahlman L, et al. Swedish rectal cancer trail: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol. 2005;23:5644–5650
  8. Gerard JP. Radiotherapy in the conservative treatment of rectal cancer. Evidence-based medicine and opinion. Radiother Oncol. 2005;74:227–233
  9. Giralt J, Tabernero J, Navalpotro B, et al. Pre-operative chemotherapy with UFT and leucovorin in patients with advanced rectal cancer: a phase II study. Radiother Oncol. 2009;89:263–269
  10. Klautke G, Küchenmeister U, Foitzik T, et al. Intensified irinotecan-based neoadjuvant chemoradiotherapy in rectal cancer: four consecutive designed studies to minimize acute toxicity and optimize efficacy measured by pathologic complete response. Radiother Oncol. 2007;85:379–384
  11. Debucquoy A, Roels S, Goethals L, et al. Double blind randomized phase II study with radiation + 5-fluorouracil ± celecoxib for resectable rectal cancer. Radiother Oncol. 2009;93:273–278
  12. Crane CH, Skibber JM, Birnbaum EH, et al. The addition of continuos infusion 5-FU to preoperative radiation therapy increases tumor response, leading to increased sphincter preservation in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2003;57:84–89
  13. Wiltshire KL, Ward IG, Swallow C, et al. Preoperative radiation with concurrent chemotherapy for resectable rectal cancer: effect of dose escalation on pathologic complete response, local recurrence-free survival, disease-free survival, and overall survival. Int J Radiat Oncol Biol Phys. 2006;64:709–716
  14. Bosset J, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123
  15. Gerard J, Bonnetain F, Conroy T, et al. Preoperative radiotherapy + 5 FU/folinic acid in T3–4 rectal cancer: results of the FFCD 9203 randomized trial. J Clin Oncol. 2006;24:4620–4625
  16. Kim DY, Jung KH, Kim TH, et al. Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007;67:378–384
  17. Das P, Lin EH, Bhatia S, et al. Preoperative chemoradiotherapy with capecitabine vs protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys. 2006;66:1378–1383
  18. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiatiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740
  19. Kabbinavar F, Hurwitz H, Fehrenbacher L, et al. Phase II randomized trial comparing bevacizumab plus fluorouracil/leucovorin with FU/LV in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–65
  20. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, flurouracil and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342
  21. Saltz L, Diaz-Rubio E, Scheithauer W, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–2019
  22. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled Clin Trials. 1989;10:1–10
  23. Hermanek P, Wittekind C. The pathologist and the residual tumor (R) classification. Pathol Res Pract. 1994;190:115–123
  24. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123
  25. Gerad J, Bonnetain R, Conroy T, et al. Preoperative concurrent chemoradiotherapy (CT-RT) improves local control in T3-T4 rectal cancers. Results of the FFCD 9203 randomized trial. Eur J Cancer. 2005;3:170
  26. Öfner D, DeVries A, Schaberl-Moser R, et al. Preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with newly diagnosed, primary operable, cT3NxM0, low rectal cancer: a phase II study. Strahlenther Onkol. 2011;187:100–107
  27. Eisterer W, DeVries A, Öfner D, et al. Neoadjuvant chemoradiation therapy with capecitabine (X) plus cetuximab (C), and external beam radiotherapy (RT) in locally advanced rectal cancer (LARC): ABCSG trial R03. J Clin Oncol. 2009;27:[Abstract #4109]
  28. Willett C, Duda DG, di Tomaso E, et al. Efficacy, safety and biomarkers of neoadjuvant bevacizumab, radiation therapy and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27:3020–3026
  29. Willett C, Boucher Y, Duda DG, et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in recal cancer patients. J Clin Oncol. 2005;23:8136–8139
  30. Crane CH, Eng C, Feig BW, et al. Phase II trial of neoadjuvant bevacizumab, capecitabine and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2010;76:824–830
  31. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001;19:843–850
  32. Kabbinavar F, Hurwitz H, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–65
  33. Hapani S, Sher A, Chu D, Wu S. Increases risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38

☆ Previous presentation: Abstract published at ASCO GI 2010, # 496.

PII: S0167-8140(11)00319-7

doi:10.1016/j.radonc.2011.06.008

Radiotherapy & Oncology
Volume 102, Issue 1 , Pages 10-13, January 2012

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