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Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study

Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer:... Background: Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC. Methods: Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/ m twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR). Results: 61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively. Conclusions: This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower. Keywords: capecitabine, chemoradiation, bevacizumab, locally advanced rectal cancer, LARC, phase II study Introduction sphincter preservation during surgery [1-4]. In LARC, Treatment of locally advanced rectal cancer (LARC) is the addition of 5-fluorouracil (5-FU) to preoperative RT multimodal and generally consists of surgery, radiation has been shown to improve pathological complete and chemotherapy. Preoperative radiotherapy (RT) has response rate, tumour downstaging [5] and locoregional control [6,7] compared with RT alone. Furthermore, been investigated as a neoadjuvant treatment for rectal cancer to improve local control and survival rates. The preoperative chemoradiotherapy improves locoregional potential advantages of preoperative RT include control with less toxicity compared with postoperative decreased tumour spread (local and distant), reduced chemoradiotherapy [4]. Thus, preoperative chemora- acute toxicity, increased sensitivity to RT and enhanced diotherapy with continuous infusional 5-FU has become a standard of care in rectal cancer, especially in tumours of the lower and middle rectum. * Correspondence: vvelenik@onko-i.si Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia Full list of author information is available at the end of the article © 2011 Velenik et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Velenik et al. Radiation Oncology 2011, 6:105 Page 2 of 8 http://www.ro-journal.com/content/6/1/105 The oral fluoropyrimidine capecitabine was designed to biochemistry, carcinoembryonic antigen, chest radiogra- mimic continuous 5-FU infusion and to generate 5-FU phy, ultrasonography and/or computed tomography preferentially in tumour tissue. Capecitabine has demon- (CT) scan of the whole abdomen. The extent of locore- strated efficacy comparable with intravenous 5-FU in gional disease was determined by magnetic resonance metastatic colorectal cancer as well as in the adjuvant set- imaging (MRI) of the pelvis of each patient. Eligible ting in colon cancers [8-14]. Furthermore, capecitabine patients had to have a histologically verified stage II or has been investigated in various protocols for rectal and III adenocarcinoma of the rectum, the disease had be other gastrointestinal cancers in combination with RT considered either resectable at the time of entry or [15]; indeed, equivalence of capecitabine plus RT and 5- thought likely to become resectable after preoperative FU plus RT as preoperative therapy in LARC was demon- chemoradiation with no evidence of distant metastases. strated in the systematic review by Saif and colleagues Other key inclusion criteria were: age 18-80 years; [16]. Recently, two phase III trials, the large National Sur- World Health Organization performance status of 0-2; gical Adjuvant Breast and Bowel Project (NSABP) R-04 adequate bone marrow, liver, renal and cardiac function Intergroup study [17] and a German trial [18], have con- (no history of clinically significant cardiovascular dis- firmed that capecitabine is non-inferior to 5-FU as compo- ease); no prior radiotherapy, chemotherapy or any tar- nent of neoadjuvant radiochemotherapy in rectal cancer, geting therapy for rectal cancer; ability to swallow oral and a retrospective analysis from a single centre found medications; and signed informed consent. Key exclu- preoperative capecitabine plus RT to have more favourable sion criteria included: other co-existing malignancy or results and higher downstaging rates that infusional 5-FU malignancy within the last 5 years prior the enrolment plus RT [19]. Preoperative capecitabine-based chemoradia- other than non-melanoma skin cancer or in situ carci- tion is now a standard treatment for LARC [4]. noma of the cervix; patients with severe concurrent Phase II studies evaluating preoperative doublet che- medical or psychiatric illness; a known hypersensitivity motherapy of oxaliplatin or irinotecan plus 5-FU or cape- to study drug; and pregnant or lactating patients. citabine combined with concurrent radiotherapy in LARC have reported either no change or an increase in Study design and treatment pathological complete response with the addition of oxa- The study design and treatment schedule are shown in liplatin or irinotecan, and this addition also frequently Figure 1. Three-dimensional CT-based treatment plan- resulted in increased acute toxicity [17,18,20-26]. ning was performed. The CT was taken on treatment The addition of bevacizumab, a humanized monoclo- position with 5 mm thick slices. The clinical target nal antibody to vascular endothelial growth factor volume was defined as covering the small pelvis from (VEGF), to chemotherapy has been shown to increase the L5-S1 interspace to 5 cm below the primary tumour. the efficacy of therapy in metastatic colorectal cancer The lateral borders were 5 mm outside the true bony [27].Itispostulatedthatcombiningbevacizumab with pelvis. The posterior margin covered the sacrum and chemoradiation may increase antitumour efficacy by the anterior margin encompassed the posterior one- maximizing inhibition of the VEGF pathway [28,29]. third to one-half of the bladder and/or vagina. An addi- That said, there are relatively limited data on the safety tional 1 cm in all directions was added to the clinical and efficacy of bevacizumab in combination with che- target volume to obtain the planning target volume. The motherapy and radiation in the neoadjuvant setting dose was prescribed to cover the planning target volume [30-34]. In this study we explored the safety and efficacy with a 95% reference isodose (95% of the International of neoadjuvant capecitabine, concurrent radiotherapy Commission on Radiation Unit point dose). and bevacizumab (CRAB) in LARC. RT was initiated on Day 1. Patients received a total irradiation dose of 45 Gy to the pelvis plus 5.4 Gy as a Patients and Methods boost to the primary tumour in 1.8 Gy daily fractions We undertook a prospective, open-label, single-arm over 5.5 weeks. Radiotherapy was delivered using 15 phase II study in patients with histologically proven ade- MV photon beams and four-field box technique, once nocarcinoma of the rectum (Clinicaltrials.gov registration daily, 5 days per week. All fields were treated daily. Mul- number: NCT00842686). The study was approved by the tileaf collimators were used to shape individual radiation relevant institutional review board, the National Ethics fields and for the protection of normal tissues. Patients Committee and the Ministry of Health. All patients gave were irradiated in a prone position with a full bladder written informed consent prior to any study procedure. and using a belly board to minimize exposure of the small bowel. Patients Chemotherapy was administered concomitantly with Patient pretreatment work-up comprised a complete RT and consisted of oral capecitabine at a daily dose of 1650 mg/m history, physical examination, full blood count, serum , divided into two equal doses given 12 Velenik et al. Radiation Oncology 2011, 6:105 Page 3 of 8 http://www.ro-journal.com/content/6/1/105 Histologically proven stage II/III rectal cancer Eligible for study Day -14 -8 1 8 15 22 29 35 38 Bevacizumab (5 mg/kg) Capecitabine (825 mg/m bd) Radiotherapy (1.8 Gy/day for 5 weeks + boost, total 50.4 Gy) Surgery 6-8 weeks later Capecitabine (1250 mg/m bd) 4-6 cycles Figure 1 Study design and treatment schedule. hours apart. One dose was taken 1 hour prior to RT. comprised capecitabine 1250 mg/m orally twice daily The chemotherapy started on the first day of RT (Day on Days 1-14 every 3 weeks; 4 (R0 resection) or 6 cycles 1), finished on the last day of RT (Day 38) and was con- (R1 resection) were recommended, beginning 6-8 weeks tinuous throughout the RT period (i.e. it included week- after surgery. ends). Bevacizumab was administered at a dose of 5 mg/ kg on treatment days: -14, 1, 15 and 29. The drug was Study assessments delivered as an intravenous infusion over a 30-90-min It has been shown that complete eradication of the pri- period. mary tumour observed in the histopathological speci- Resection was performed 6-8 weeks after the comple- men (pathological complete response [pCR]) correlates tion of chemoradiotherapy. A total mesorectal excision with afavourableoverall prognosis, so obtaining apCR was the recommended operation for mid and distal rec- might be beneficial [35]. Thus, the primary endpoint of tal tumours. Surgical management included a sphincter- pCR rate was selected for the current analysis. Second- preservation approach whenever possible. The option ary endpoints were: pathological response rate (plus for a temporary colostomy during surgery was left to tumour regression grade [TRG] according to Dworak the surgeon’s discretion. Complications after surgery scale); rate of sphincter-sparing surgical procedure; his- were recorded. topathological R0 resection rate; acute and late toxicity In patients achieving histopathological R0 or R1 resec- (SOMA/LENT scale); locoregional failure rate; disease- tion, adjuvant chemotherapy was recommended: this free survival; and overall survival. The effect of Velenik et al. Radiation Oncology 2011, 6:105 Page 4 of 8 http://www.ro-journal.com/content/6/1/105 preoperative chemoradiotherapy on tumour downstaging Table 1 Patients’ baseline and disease characteristics was assessed by comparing the pretreatment radiologi- Characteristics Patients (n = 61) cally determined TNM stage with the postoperative Median age, years (range) 60 (31-80) pathologic TNM stage. As an exploratory objective, the Gender, n (%): mutation status of KRAS in pre-therapeutic biopsies was Male 39 (64) established and correlation to pathological response was Female 22 (36) assessed. WHO performance status, n (%) During treatment, patients were evaluated weekly. 0 52 (85) Clinical examinations, complete blood count and serum chemistry analysis were performed. Adverse events were 1 9 (15) assessed according to National Cancer Institute Com- TN clinical stage, n (%) mon Toxicity Criteria (NCI-CTC) version 3.0. Re-eva- T3N0 12 (19.7) luation of the primary tumour with pelvic MRI was T2N1 1 (1.7) performed four weeks after the completion of preopera- T3N1 19 (31.1) tive treatment. T2N2 2 (3.3) Postoperative, pathological evaluation of the surgical T3N2 22 (36.1) specimen was performed. pCR was defined as the com- T4N2 5 (8.2) plete disappearance of all tumour cells. Histological Median clinical tumour size per MRI, cm (range) 6 (1-12) regression of the primary tumour was semi-quantita- Median tumour distance from anal verge, cm (range) 6 (0-11) tively determined according to a 5-point TRG scale: Type of surgery , n (%) TRG 0, no regression; TRG 1, minimal regression Low anterior resection 35 (57.4) Coloanal reconstruction 10 (16.4) (dominant tumour mass with obvious fibrosis and/or Abdominoperineal resection 14 (23.0) vasculopathy); TRG 2, moderate regression (predomi- Pelvic exenteration 2 (3.3) nantly fibrotic changes with few tumour cells or groups); TRG 3, good regression (very few tumour cells in fibro- As planned before the start of preoperative chemoradiotherapy. MRI, magnetic nuclear imaging; N, node; T, tumour; WHO, World Health tic tissue); TRG 4, total regression (no tumour cells, Organization. only fibrotic mass). Follow-up visits were scheduled at 3, 6, 12, 18, 24, 36, 48 and 60 months following the end of adjuvant chemotherapy. patients (4.9%) presented with stage T2 disease, 53 (86.9%) with stage T3, 5 (8.2%) with stage T4; lymph Statistical analysis node involvement was detected in 49 patients (80.3%). The primary endpoint of the study was pCR rate. In the ThemostfrequentMRI stagingwas uT3N+(67%).In medical literature, phase II studies of capecitabine and 28 patients (45.9%) the tumour invaded the mesorectal RT suggest a pCR rate in the range of 4-31%, while in fascia and in half of the patients (50%) the primary our published study the pCR rate was approximately 9%. tumour was sited ≤5 cm from the anal verge. We aimed to evaluate whether a 23% pCR rate could be All patients received neoadjuvant chemoradiotherapy achieved by adding bevacizumab to standard preopera- plus bevacizumab. Treatment was terminated in one tive treatment. Setting 10% as the lowest pCR rate of patient as a result of withdrawal of informed consent interest, and with alpha error of 5% and power of 80%, following four weeks of treatment. All other patients at least 50 evaluable patients were needed (calculated received 100% of the expected radiation treatment. using power sample calculation, for two samples, per- Treatment interruption was necessary for 7 patients centages, a =5%, 1-b = 20%). Assuming that ≥10% of (11.6%) because of grade 2 (n = 2) and grade 3 (n = 3) patients would not be evaluable, the estimated sample leucopenia, grade 3 diarrhoea (n = 1), and grade 3 (n = size required was at least 60 patients. 1) and grade 4 (n = 1) vascular toxicity. Other grade 3 Statistics were descriptive and all data were analysed toxicities included dermatitis (n = 6), proteinuria (n = 4) using the SPSS statistical software package, version 13 and hypertension (n = 1). There were no treatment- (SPSS Inc., Chicago, IL, USA). related deaths during the study. RT was interrupted for 2-7 days as a result of treat- Results ment (median interruption: 2 days), while 56 patients Patient characteristics and treatment rates (91%) received 95-100% of the designated chemotherapy Between February 2009 and March 2010, a total of 61 dose. Overall, 58 patients (95.1%) received all four infu- patients were recruited. Patients’ baseline and disease sions of bevacizumab while the remaining 3 patients characteristics are summarized in Table 1. Three received three infusions. Velenik et al. Radiation Oncology 2011, 6:105 Page 5 of 8 http://www.ro-journal.com/content/6/1/105 Treatment-related toxicities patients (15.0%). T-, N- and overall downstaging rates The frequency and grade of treatment-related acute were 46.7%, 65.0% and 75.0%, respectively. toxicities are summarised in Table 2. The most frequent KRAS mutations were found in 20 (33.9%) out of 59 adverse event reported with chemoradiotherapy was bioptic tumour samples obtained before preoperative grade 2 and 3 radiodermatitis. During treatment, 25 treatment. KRAS status was not associated with patholo- patients lost weight; the maximum body weight loss was gical response. 6.5% (median 3.3%). Of the remaining patients, 26 main- In total, 38 patients (62.3%) developed perioperative tained a constant weight and nine experienced a weight complications. The most frequent were delayed wound increase of up to 5% (median: 2.4%). healing (n = 18, 30.0%), infection/abscess (n = 12, 20.0%) and anastomotic leakage (n = 7, 11.7%). Six Surgery rates and outcomes patients required surgical re-intervention for anastomo- All patients underwent definitive surgery, although one tic leakage (n = 3), abdominal abscess (n = 2) and pneu- patient revealed distant metastases after completion of mothorax (n = 1). There were no perioperative deaths. chemoradiotherapy. Surgery was performed 25 to 79 A summary of perioperative toxicity is shown in Table days (median: 55 days) after the last day of chemora- 4. diotherapy. Exploratory surgery was performed in only 1 Postoperative chemotherapy was administered to 51 patient because of a large, unresectable T4 tumour with (83.6%) patients. Reasons for not administering adjuvant peritoneal carcinomatosis. The median hospital stay for chemotherapy were: progression of the disease (n = 2), surgery was 11 days (range: 7-32 days). misdiagnosis (n = 1); withdrawal from study (n = 1); > 8 Radical resection was achieved in 57 patients (95%) week interval between the operation and adjuvant ther- and 42 patients (70%) underwent sphincter-preserving apy (n = 1); and postoperative complications (n = 5). surgery. A temporary stoma was created in 41 patients. Postoperative chemotherapy comprised capecitabine In one patient pathohistological examination of the sur- 1250 mg/m on Days 1-14 every 3 weeks for 4 or 6 gical specimen revealed malignant melanoma; this cycles. A total of 42 patients received all planned cycles. patient was considered misdiagnosed and excluded from Two patients only received 3 cycles because of disease the efficacy analysis. progression (n = 1) and death because of pulmonary Pathological TNM stages in relation to preoperative thromboembolism (n = 1); 2 patients only received 2 TNM status are presented in Table 3. TRG 4 (pCR) was cycles because of diarrhoea and dehydration (n = 1) and recorded in 8/60 patients (13.3%) and TRG 3 in 9/60 nonspecific chest pain (n = 1); and 3 patients only received 1 cycle because of the development of presacral abscesses (n = 2) and nonspecific chest pain (n = 1). Table 2 Acute toxicities occurring during preoperative chemoradiotherapy Discussion Patients, n (%) This phase II study demonstrates the feasibility of preo- Toxicity Grade 1 Grade 2 Grade 3 Grade 4 perative chemoradiation with bevacizumab and capecita- Haematological: bine in patients with LARC. Indeed, a high R0 resection Leucocytopenia 12 (19.7) 5 (8.2) 3 (4.9) - rate was achieved despite tumour invasion of the mesor- Anaemia 5 (8.2) - - - ectal fascia in 46% of patients. A well-accepted approach Non-haematological: in the management of LARC is neoadjuvant fluoropyri- Diarrhoea 14 (22.9) 4 (6.5) 1 (1.6) - midine-based chemoradiation and a number of prospec- Fatigue 7 (11.5) 3 (4.9) - - tive and retrospective trials have suggested that Nausea 5 (8.2) - - - preoperative capecitabine is at least equivalent to infu- Anorexia 2 (3.3) - - - sional 5-fluorouracil when combined with RT [16-19], Dermatitis 3 (4.9) 14 (22.9) 6 (9.8) - and may improve tumour downstaging. In 2009, the US Hand-food syndrome 5 (8.2) 2 (3.3) - - National Comprehensive Cancer Network recommended Cystitis 3 (4.9) - - - capecitabine as an acceptable alternative to 5-FU in this Hepatotoxicity 2 (3.3) 2 (3.3) - - setting [36]. Vascular - - 1 (1.6) 1 (1.6) The pCR rate of 13% observed with neoadjuvant cape- Proteinuria 10 (16.4) 2 (3.3) 4 (6.5) - citabine plus bevacizumab plus RT was similar to an Hypertension 2 (3.3) 2 (3.3) 1 (1.6) - earlier phase II study by our group examining neoadju- Infection 3 (4.9) 5 (8.2) - - vant single-agent capecitabine plus RT in LARC [37]. Pain 20 (32.8) 3 (4.9) - - This pCR rate, albeit relatively low, is within the range Bleeding 10 (16.4) - - - 0-31% reported across a number of phase II studies According to National Cancer Institute Common Toxicity Criteria (version 3) evaluating single-agent capecitabine plus RT [38-43]. In Velenik et al. Radiation Oncology 2011, 6:105 Page 6 of 8 http://www.ro-journal.com/content/6/1/105 Table 3 Distribution of postoperative pathological TMN stages compared with pretreatment clinical stages (n = 60) Before After surgery (pTNM) T0N0 T1N0 T2N0 T3N0 T2N1 T3N1 T4N1 T3N2 T3N0 34 3 2 T2N1 1 T3N1 53 4 4 1 1 T2N2 1 1 T3N2 1 2 13 1 1 4 T4N2 12 1 1 Total 8 (13.3%) 5 (8.3%) 14 (23.3%) 21 (35%) 1 (1.7%) 5 (8.3%) 1 (1.7%) 5 (8.3%) c - Clinical, p - pathological, T - Tumour, N - Node, M - Metastasis. one of the largest studies performed to date, the pCR outcome, a recently published pooled analysis of data rate was 12% [44], and in the recently presented from 3105 patients from 14 studies would suggest that NSABP-04 study the pCR ranged from 18 to 22% with patients with pCR after chemoradiation have better capecitabine and 5-FU achieving similar rates of long-term outcome than those without pCR [49]. improvement but no additional benefit being observed The adverse event profile observed during neoadjuvant with the addition of oxaliplatin to either of these agents capecitabine plus bevacizumab chemoradiotherapy was comparable with those reported in an earlier study [17]. A study by Ofner and co-workers [45] evaluating preoperative capecitabine and oxaliplatin reported a involving capecitabine plus bevacizumab with concur- pCR rate of 10% while studies investigating preoperative rent RT [31]. The most frequent preoperative adverse capecitabine, oxaliplatin and bevacizumab found rates of events were dermatitis, pain and leucopenia, and adverse 24-36% [32-34]. events related to bevacizumab therapy were relatively In the phase II trial by Crane and coworkers [31], 25 infrequent. Any postoperative adverse events were patients with LARC received neoadjuvant chemora- mainly related to delayed wound healing and infection/ diotherapy with bevacizumab (three doses of 5 mg/kg abscess. No treatment-related deaths were recorded. given every 2 weeks) and capecitabine (900 mg/m orally These results, together with those of Crane and co- twice daily on days of radiation therapy), followed by workers [31] suggest that the combination of neoadju- surgical resection a median of 7.3 weeks later. These vant capecitabine plus bevacizumab with concurrent RT authors reported a pCR rate of 32% (8 patients), which is feasible and well tolerated in the treatment of LARC. is considerably higher than that reported here. One pos- A high radical resection rate suggests its potential posi- sible explanation for the relatively low pCR rate tive effect on tumour downstaging. The observed observed in our study was that the patients in this study adverse events during neoadjuvant treatment in our had advanced tumours; indeed, most of the patients had study are comparable with those reported previously; regionally advanced disease and in almost half of the however, no clinically relevant increase in pathologic patients the tumour had invaded the mesorectal fascia. response rate was observed. Longer follow-up is needed However, caution is needed when comparing pCR rates to assess the impact on other efficacy endpoints. as the pCR rate itself is highly dependent on the quality Long-term follow-up data on survival and local con- of the pathological examination [46] and a longer inter- trol in patients with LARC having undergone neoadju- val between end of chemoradiotherapy and surgery (6-8 vant capecitabine plus bevacizumab chemoradiotherapy followed by surgery are eagerly awaited. It will also be weeks vs. 2 weeks) has been reported to increase pCR rate without reducing local recurrence rate or survival interesting to compare any long-term follow-up data [47,48]. While there has been much debate about with that which is currently available at the moment on whether pCR is associated with a favourable long-term single-agent capecitabine-based chemoradiotherapy [39,50] to help determine the benefits of adding bevaci- zumab to the regimen. Table 4 Perioperative adverse events (n = 60) Complication Patients, n (%) Conclusion Delayed healing of postoperative wound 18 (30.0) The results of this phase II study indicate that neoadju- Infection/abscess 12 (20.0) vant capecitabine chemoradiotherapy is an effective Pneumothorax 1 (1.7) treatment for patients with LARC and the incorporation Anastomotic leakage 7 (11.7) of bevacizumab into a standard capecitabine-based che- moradiotherapy regimen is feasible and well tolerated. Patients could have more than one adverse event. Velenik et al. Radiation Oncology 2011, 6:105 Page 7 of 8 http://www.ro-journal.com/content/6/1/105 11. Twelves C, Wong A, Nowacki MP, Abt M, Burris H, et al: Capecitabine as List of abbreviations adjuvant treatment for stage III colon cancer. N Engl J Med 2005, 5-FU: 5-fluorouracil; CT: computed tomography; LARC: locally advanced 352:2696-2704. rectal cancer; MRI: magnetic resonance imaging; pCR: pathological complete 12. Van Cutsem E, Findlay M, Osterwalder B, Kocha W, Dalley D, et al: response; RT: radiotherapy; TRG: tumour regression grade; VEGF: vascular Capecitabine, an oral fluoropyrimidine carbamate with substantial endothelial growth factor. activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 2000, 18:1337-1345. Acknowledgements 13. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, et al: Oral This was an investigator-initiated trial funded by Roche. capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III Author details 1 2 study. J Clin Oncol 2001, 19:4097-4106. Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia. University Medical Centre, Zaloska 7, 1000 Ljubljana, Slovenia. 14. Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated Authors’ contributions efficacy data and novel analyses from two large, randomized, phase III VV: contributions to conception and design, acquisition of data, analysis and trials. Br J Cancer 2004, 90:1190-1197. interpretation of data; involvement in drafting and reviewing the manuscript. 15. Glynne-Jones R, Dunst J, Sebag-Montefiore D: The integration of oral JO: contribution to acquisition of data, analysis and interpretation of data. capecitabine into chemoradiation regimens for locally advanced rectal MM: contribution to acquisition of data, analysis and interpretation of data. cancer: how successful have we been? Ann Oncol 2006, 17:361-371. MB: contribution to acquisition of data. FA: contribution to acquisition of 16. Saif MW, Hashmi S, Zelterman D, Almhanna K, Kim R: Capecitabine vs data, analysis and interpretation of data. IO: contribution to acquisition of continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A data. retrospective review. Int J Colorectal Dis 2008, 23:139-145. IE: contribution to acquisition of data, analysis and interpretation of data. EB: 17. Roh MS, Yothers GA, O’Connell MJ, Beart RW, Pitot HC, et al: The impact of contribution to acquisition of data, analysis and interpretation of data. MK: capecitabine and oxaliplatin in the preoperative multimodality contribution to acquisition of data. MO: contributions to acquisition of data, treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin analysis and interpretation of data; involvement in drafting and reviewing Oncol 2011, 29(suppl):Abst 3503.. the manuscript. All authors have read and approved the final version of the 18. Hofheinz R, Wenz FK, Post S, Matzdorff A, Laechelt S, et al: Capecitabine manuscript. (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Competing interests Long-term results of a randomized, phase III trial. J Clin Oncol 2011, 29(suppl):Abst 3504. This was an investigator-initiated trial supported by Roche. The authors 19. Kim DY, Jung KH, Kim TH, Kim DW, Chang HJ, et al: Comparison of 5- declare that they have no financial or non-financial competing interests. fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Received: 19 June 2011 Accepted: 31 August 2011 Biol Phys 2007, 67:378-384. Published: 31 August 2011 20. Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, et al: Comparison of two neoadjuvant chemoradiotherapy regimens for References locally advanced rectal cancer: results of the phase III trial ACCORD 12/ 1. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxì A, et al: Preoperative 0405-Prodige 2. J Clin Oncol 2010, 28:1638-1644. radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000, 21. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, et al: Primary tumor 284:1008-1015. response to preoperative chemoradiation with or without oxaliplatin in 2. Glimelius B, Isacsson U, Jung B, Pahlman L: Radiotherapy in addition to locally advanced rectal cancer: Pathologic results of the STAR-01 radical surgery in rectal cancer: evidence for a dose-response effect randomized phase III trial. J Clin Oncol 2011, 29:2773-2780. favoring preoperative treatment. Int J Radiat Oncol Biol Phys 1997, 22. Rödel C, Becker H, Fietkau R, Graeven U, Hohenberger W, et al: 37:281-287. Preoperative chemoradiotherapy and postoperative chemotherapy with 3. Pahlman L, Glimelius B: Pre- or postoperative radiotherapy in rectal and 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally rectosigmoid carcinoma. Report from a randomized multicentre trial. advanced rectal cancer: first results of the German CAO/ARO/AIO-04 Ann Surg 1990, 211:187-195. randomized phase III trial. J Clin Oncol 2011, 29(suppl):Abst LBA3505. 4. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, German Rectal 23. Mohiuddin M, Winter K, Mitchell E, Hanna N, Yuen A, et al: Randomized Cancer Study Group, et al: Preoperative versus postoperative phase II study of neoadjuvant combined-modality chemoradiotherapy chemoradiotherapy for rectal cancer. N Engl J Med 2004, 351:1731-1740. for distal rectal cancer: radiation therapy oncology group trial 0012. J 5. Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al: Enhanced Clin Oncol 2006, 24:650-655. tumorocidal effect of chemotherapy with preoperative radiotherapy for 24. Klautke G, Kuchenmeister U, Foitzik T, Ludwig K, Prall F, et al: Concurrent rectal cancer: preliminary results - EORTC 22921. J Clin Oncol 2005, chemoradiotherapy with capecitabine and weekly irinotecan as 23:5620-5627. preoperative treatment for rectal cancer: results from a phase I/II study. 6. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, EORTC Radiotherapy Br J Cancer 2006, 94:976-981. Group Trial 22921, et al: Chemotherapy with preoperative radiotherapy in 25. Navarro M, Dotor E, Rivera F, Sánchez-Rovira P, Vega-Villegas ME, et al: A rectal cancer. N Engl J Med 2006, 355:1114-1123. phase II study of preoperative radiotherapy and concomitant weekly 7. Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, et al: Preoperative irinotecan in combination with protracted venous infusion 5-fluorouracil, radiotherapy with or without concurrent fluorouracil and leucovorin in for resectable locally advanced rectal cancer. Int J Radiat Oncol Biol Phys T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006, 24:4620-4625. 2006, 66:201-205. 8. Bajetta E, Beretta E, Di Bartolomeo M, Mariani L, Valvo F, et al: Capecitabine 26. Willeke F, Horisberger K, Kraus-Tiefenbacher U, Wenz F, Leitner A, et al: A chemoradiation for rectal cancer after curative surgery. J Chemother phase II study of capecitabine and irinotecan in combination with 2006, 18:85-89. concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of 9. Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Capecitabine locally advanced rectal cancer. Br J Cancer 2007, 96:912-917. Colorectal Cancer Study Group, et al: First-line oral capecitabine therapy 27. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Eastern in metastatic colorectal cancer: a favorable safety profile compared with Cooperative Oncology Group Study E3200, et al: Bevacizumab in intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002, 13:566-575. combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for 10. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, et al: Comparison of oral previously treated metastatic colorectal cancer: results from the Eastern capecitabine versus intravenous fluorouracil plus leucovorin as first-line Cooperative Oncology Group Study E3200. J Clin Oncol 2007, treatment in 605 patients with metastatic colorectal cancer: results of a 25:1539-1544. randomised phase III study. J Clin Oncol 2001, 19:2282-2292. Velenik et al. Radiation Oncology 2011, 6:105 Page 8 of 8 http://www.ro-journal.com/content/6/1/105 28. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, et al: Direct 48. Glehen O, Chapet O, Adham M, Nemoz JC, Gerard JP: Long-term results of evidence that the VEGF-specific antibody bevacizumab has antivascular the Lyons R90-01 randomized trial of preoperative radiotherapy with effects in human rectal cancer. Nat Med 2004, 10:145-147. delayed surgery and its effect on sphincter-saving surgery in rectal 29. Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, et al: Surrogate cancer. Br J Surg 2003, 90:996-998. markers for antiangiogenic therapy and dose-limiting toxicities for 49. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, et al: Long-term bevacizumab with radiotherapy and chemotherapy: continued outcome in patients with a pathological complete response after experience of a phase I trial in rectal cancer patients. J Clin Oncol 2005, chemoradiation for rectal cancer: a pooled analysis of individual patient 23:8136-8139. data. Lancet Oncol 2010, 11:835-844. 30. Czito BG, Bendell JC, Willet CG, Morse MA, Blobe GC, et al: Bevacizumab, 50. Velenik V, Oblak I, Anderluh F: Long-term results from a randomized oxaliplatin, and capecitabine with radiation therapy in rectal cancer: phase II trial of neoadjuvant combined-modality therapy for locally Phase I trial results. Int J Radiat Oncol Biol Phys 2007, 68:472-478. advanced rectal cancer. Radiat Oncol 2010, 5:88. 31. Crane CH, Eng C, Feig BW, Das P, Skibber JM, et al: Phase II trial of doi:10.1186/1748-717X-6-105 neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally Cite this article as: Velenik et al.: Neoadjuvant capecitabine, advanced rectal cancer. Int J Radiat Oncol Biol Phys 2010, 76:824-830. radiotherapy, and bevacizumab (CRAB) in locally advanced rectal 32. Resch G, De Vries A, Ofner D, Eisterer W, Rabl H, et al: Preoperative cancer: results of an open-label phase II study. Radiation Oncology 2011 treatment with capecitabine, bevacizumab and radiotherapy for locally 6:105. advanced rectal cancer - A two stage phase II trial. Radiother Oncol 2011. 33. Kennecke H, Berry S, Wong R, Zhou C, Tankel K, et al: Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: A phase II trial. Eur J Cancer 34. Nogue M, Salud A, Vincente P, Arrivi A, Roca JM, et al: Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging- defined poor-prognosis locally advanced rectal cancer: the AVACROSS study. Oncologist 2011, 16:614-620. 35. Rodel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005, 23:8688-8696. 36. National Comprehensive Cancer Network: National Comprehensive Cancer Network clinical practice guidelines, Rectal cancer.[http://www.nccn.org/ professionals/physician_gls/f_guidelines.asp#site]. 37. Velenik V, Anderlih F, Oblak I, Strojan P, Zakotnik B: Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced respectable rectal cancer: prospective phase II trial. Croat Med J 2006, 47:693-700. 38. Craven I, Crellin A, Cooper R, Melcher A, Byrne P, et al: Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer. Br J Cancer 2007, 97:1333-1337. 39. Dunst J, Debus J, Rudat V, Wulf J, Budach W, et al: Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer. Strahlenther Onkol 2008, 184:450-456. 40. De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, et al: Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable rectal cancer: a multicentric phase II study. Ann Oncol 2006, 17:246-251. 41. Desai SP, El-Rayes BF, Ben-Josef E, Greenson JK, Knol JA, et al: A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer. Am J Clin Oncol 2007, 30:340-345. 42. Dupuis O, Vie B, Liedo G, Hennequin C, Noirclerc M, et al: Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR phase II study. Oncology 2007, 73:169-176. 43. Lay GC, Caraul B, Dessi M, Orrù S, Murtas R, et al: Phase II study of preoperative irradiation and chemotherapy with capecitabine in patients with locally advanced rectal carcinoma. J Exp Clin Cancer Res 2007, 26:61-70. 44. Kim JC, Kim TW, Kim JH, Yu CS, Kim HC, et al: Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in Submit your next manuscript to BioMed Central locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2005, and take full advantage of: 63:346-353. 45. Ofner D, De Vries AF, Schabert-Moser R, Greil R, Rabl H, et al: Preoperative • Convenient online submission oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT#NxM0, low rectal cancer: a • Thorough peer review phase II study. Strahlenther Onkol 2011, 187:100-107. • No space constraints or color figure charges 46. Chua YJ: Pathological complete response: still a relevant endpoint in • Immediate publication on acceptance rectal cancer? Lancet Oncol 2010, 11:807-808. 47. Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, et al: Influence of • Inclusion in PubMed, CAS, Scopus and Google Scholar the interval between preoperative radiation therapy and surgery on • Research which is freely available for redistribution downstaging and the rate of sphincter-saving surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999, 17:2396. 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Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study

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Springer Journals
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Copyright © 2011 by Velenik et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
DOI
10.1186/1748-717X-6-105
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21880132
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Abstract

Background: Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC. Methods: Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/ m twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR). Results: 61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively. Conclusions: This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower. Keywords: capecitabine, chemoradiation, bevacizumab, locally advanced rectal cancer, LARC, phase II study Introduction sphincter preservation during surgery [1-4]. In LARC, Treatment of locally advanced rectal cancer (LARC) is the addition of 5-fluorouracil (5-FU) to preoperative RT multimodal and generally consists of surgery, radiation has been shown to improve pathological complete and chemotherapy. Preoperative radiotherapy (RT) has response rate, tumour downstaging [5] and locoregional control [6,7] compared with RT alone. Furthermore, been investigated as a neoadjuvant treatment for rectal cancer to improve local control and survival rates. The preoperative chemoradiotherapy improves locoregional potential advantages of preoperative RT include control with less toxicity compared with postoperative decreased tumour spread (local and distant), reduced chemoradiotherapy [4]. Thus, preoperative chemora- acute toxicity, increased sensitivity to RT and enhanced diotherapy with continuous infusional 5-FU has become a standard of care in rectal cancer, especially in tumours of the lower and middle rectum. * Correspondence: vvelenik@onko-i.si Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia Full list of author information is available at the end of the article © 2011 Velenik et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Velenik et al. Radiation Oncology 2011, 6:105 Page 2 of 8 http://www.ro-journal.com/content/6/1/105 The oral fluoropyrimidine capecitabine was designed to biochemistry, carcinoembryonic antigen, chest radiogra- mimic continuous 5-FU infusion and to generate 5-FU phy, ultrasonography and/or computed tomography preferentially in tumour tissue. Capecitabine has demon- (CT) scan of the whole abdomen. The extent of locore- strated efficacy comparable with intravenous 5-FU in gional disease was determined by magnetic resonance metastatic colorectal cancer as well as in the adjuvant set- imaging (MRI) of the pelvis of each patient. Eligible ting in colon cancers [8-14]. Furthermore, capecitabine patients had to have a histologically verified stage II or has been investigated in various protocols for rectal and III adenocarcinoma of the rectum, the disease had be other gastrointestinal cancers in combination with RT considered either resectable at the time of entry or [15]; indeed, equivalence of capecitabine plus RT and 5- thought likely to become resectable after preoperative FU plus RT as preoperative therapy in LARC was demon- chemoradiation with no evidence of distant metastases. strated in the systematic review by Saif and colleagues Other key inclusion criteria were: age 18-80 years; [16]. Recently, two phase III trials, the large National Sur- World Health Organization performance status of 0-2; gical Adjuvant Breast and Bowel Project (NSABP) R-04 adequate bone marrow, liver, renal and cardiac function Intergroup study [17] and a German trial [18], have con- (no history of clinically significant cardiovascular dis- firmed that capecitabine is non-inferior to 5-FU as compo- ease); no prior radiotherapy, chemotherapy or any tar- nent of neoadjuvant radiochemotherapy in rectal cancer, geting therapy for rectal cancer; ability to swallow oral and a retrospective analysis from a single centre found medications; and signed informed consent. Key exclu- preoperative capecitabine plus RT to have more favourable sion criteria included: other co-existing malignancy or results and higher downstaging rates that infusional 5-FU malignancy within the last 5 years prior the enrolment plus RT [19]. Preoperative capecitabine-based chemoradia- other than non-melanoma skin cancer or in situ carci- tion is now a standard treatment for LARC [4]. noma of the cervix; patients with severe concurrent Phase II studies evaluating preoperative doublet che- medical or psychiatric illness; a known hypersensitivity motherapy of oxaliplatin or irinotecan plus 5-FU or cape- to study drug; and pregnant or lactating patients. citabine combined with concurrent radiotherapy in LARC have reported either no change or an increase in Study design and treatment pathological complete response with the addition of oxa- The study design and treatment schedule are shown in liplatin or irinotecan, and this addition also frequently Figure 1. Three-dimensional CT-based treatment plan- resulted in increased acute toxicity [17,18,20-26]. ning was performed. The CT was taken on treatment The addition of bevacizumab, a humanized monoclo- position with 5 mm thick slices. The clinical target nal antibody to vascular endothelial growth factor volume was defined as covering the small pelvis from (VEGF), to chemotherapy has been shown to increase the L5-S1 interspace to 5 cm below the primary tumour. the efficacy of therapy in metastatic colorectal cancer The lateral borders were 5 mm outside the true bony [27].Itispostulatedthatcombiningbevacizumab with pelvis. The posterior margin covered the sacrum and chemoradiation may increase antitumour efficacy by the anterior margin encompassed the posterior one- maximizing inhibition of the VEGF pathway [28,29]. third to one-half of the bladder and/or vagina. An addi- That said, there are relatively limited data on the safety tional 1 cm in all directions was added to the clinical and efficacy of bevacizumab in combination with che- target volume to obtain the planning target volume. The motherapy and radiation in the neoadjuvant setting dose was prescribed to cover the planning target volume [30-34]. In this study we explored the safety and efficacy with a 95% reference isodose (95% of the International of neoadjuvant capecitabine, concurrent radiotherapy Commission on Radiation Unit point dose). and bevacizumab (CRAB) in LARC. RT was initiated on Day 1. Patients received a total irradiation dose of 45 Gy to the pelvis plus 5.4 Gy as a Patients and Methods boost to the primary tumour in 1.8 Gy daily fractions We undertook a prospective, open-label, single-arm over 5.5 weeks. Radiotherapy was delivered using 15 phase II study in patients with histologically proven ade- MV photon beams and four-field box technique, once nocarcinoma of the rectum (Clinicaltrials.gov registration daily, 5 days per week. All fields were treated daily. Mul- number: NCT00842686). The study was approved by the tileaf collimators were used to shape individual radiation relevant institutional review board, the National Ethics fields and for the protection of normal tissues. Patients Committee and the Ministry of Health. All patients gave were irradiated in a prone position with a full bladder written informed consent prior to any study procedure. and using a belly board to minimize exposure of the small bowel. Patients Chemotherapy was administered concomitantly with Patient pretreatment work-up comprised a complete RT and consisted of oral capecitabine at a daily dose of 1650 mg/m history, physical examination, full blood count, serum , divided into two equal doses given 12 Velenik et al. Radiation Oncology 2011, 6:105 Page 3 of 8 http://www.ro-journal.com/content/6/1/105 Histologically proven stage II/III rectal cancer Eligible for study Day -14 -8 1 8 15 22 29 35 38 Bevacizumab (5 mg/kg) Capecitabine (825 mg/m bd) Radiotherapy (1.8 Gy/day for 5 weeks + boost, total 50.4 Gy) Surgery 6-8 weeks later Capecitabine (1250 mg/m bd) 4-6 cycles Figure 1 Study design and treatment schedule. hours apart. One dose was taken 1 hour prior to RT. comprised capecitabine 1250 mg/m orally twice daily The chemotherapy started on the first day of RT (Day on Days 1-14 every 3 weeks; 4 (R0 resection) or 6 cycles 1), finished on the last day of RT (Day 38) and was con- (R1 resection) were recommended, beginning 6-8 weeks tinuous throughout the RT period (i.e. it included week- after surgery. ends). Bevacizumab was administered at a dose of 5 mg/ kg on treatment days: -14, 1, 15 and 29. The drug was Study assessments delivered as an intravenous infusion over a 30-90-min It has been shown that complete eradication of the pri- period. mary tumour observed in the histopathological speci- Resection was performed 6-8 weeks after the comple- men (pathological complete response [pCR]) correlates tion of chemoradiotherapy. A total mesorectal excision with afavourableoverall prognosis, so obtaining apCR was the recommended operation for mid and distal rec- might be beneficial [35]. Thus, the primary endpoint of tal tumours. Surgical management included a sphincter- pCR rate was selected for the current analysis. Second- preservation approach whenever possible. The option ary endpoints were: pathological response rate (plus for a temporary colostomy during surgery was left to tumour regression grade [TRG] according to Dworak the surgeon’s discretion. Complications after surgery scale); rate of sphincter-sparing surgical procedure; his- were recorded. topathological R0 resection rate; acute and late toxicity In patients achieving histopathological R0 or R1 resec- (SOMA/LENT scale); locoregional failure rate; disease- tion, adjuvant chemotherapy was recommended: this free survival; and overall survival. The effect of Velenik et al. Radiation Oncology 2011, 6:105 Page 4 of 8 http://www.ro-journal.com/content/6/1/105 preoperative chemoradiotherapy on tumour downstaging Table 1 Patients’ baseline and disease characteristics was assessed by comparing the pretreatment radiologi- Characteristics Patients (n = 61) cally determined TNM stage with the postoperative Median age, years (range) 60 (31-80) pathologic TNM stage. As an exploratory objective, the Gender, n (%): mutation status of KRAS in pre-therapeutic biopsies was Male 39 (64) established and correlation to pathological response was Female 22 (36) assessed. WHO performance status, n (%) During treatment, patients were evaluated weekly. 0 52 (85) Clinical examinations, complete blood count and serum chemistry analysis were performed. Adverse events were 1 9 (15) assessed according to National Cancer Institute Com- TN clinical stage, n (%) mon Toxicity Criteria (NCI-CTC) version 3.0. Re-eva- T3N0 12 (19.7) luation of the primary tumour with pelvic MRI was T2N1 1 (1.7) performed four weeks after the completion of preopera- T3N1 19 (31.1) tive treatment. T2N2 2 (3.3) Postoperative, pathological evaluation of the surgical T3N2 22 (36.1) specimen was performed. pCR was defined as the com- T4N2 5 (8.2) plete disappearance of all tumour cells. Histological Median clinical tumour size per MRI, cm (range) 6 (1-12) regression of the primary tumour was semi-quantita- Median tumour distance from anal verge, cm (range) 6 (0-11) tively determined according to a 5-point TRG scale: Type of surgery , n (%) TRG 0, no regression; TRG 1, minimal regression Low anterior resection 35 (57.4) Coloanal reconstruction 10 (16.4) (dominant tumour mass with obvious fibrosis and/or Abdominoperineal resection 14 (23.0) vasculopathy); TRG 2, moderate regression (predomi- Pelvic exenteration 2 (3.3) nantly fibrotic changes with few tumour cells or groups); TRG 3, good regression (very few tumour cells in fibro- As planned before the start of preoperative chemoradiotherapy. MRI, magnetic nuclear imaging; N, node; T, tumour; WHO, World Health tic tissue); TRG 4, total regression (no tumour cells, Organization. only fibrotic mass). Follow-up visits were scheduled at 3, 6, 12, 18, 24, 36, 48 and 60 months following the end of adjuvant chemotherapy. patients (4.9%) presented with stage T2 disease, 53 (86.9%) with stage T3, 5 (8.2%) with stage T4; lymph Statistical analysis node involvement was detected in 49 patients (80.3%). The primary endpoint of the study was pCR rate. In the ThemostfrequentMRI stagingwas uT3N+(67%).In medical literature, phase II studies of capecitabine and 28 patients (45.9%) the tumour invaded the mesorectal RT suggest a pCR rate in the range of 4-31%, while in fascia and in half of the patients (50%) the primary our published study the pCR rate was approximately 9%. tumour was sited ≤5 cm from the anal verge. We aimed to evaluate whether a 23% pCR rate could be All patients received neoadjuvant chemoradiotherapy achieved by adding bevacizumab to standard preopera- plus bevacizumab. Treatment was terminated in one tive treatment. Setting 10% as the lowest pCR rate of patient as a result of withdrawal of informed consent interest, and with alpha error of 5% and power of 80%, following four weeks of treatment. All other patients at least 50 evaluable patients were needed (calculated received 100% of the expected radiation treatment. using power sample calculation, for two samples, per- Treatment interruption was necessary for 7 patients centages, a =5%, 1-b = 20%). Assuming that ≥10% of (11.6%) because of grade 2 (n = 2) and grade 3 (n = 3) patients would not be evaluable, the estimated sample leucopenia, grade 3 diarrhoea (n = 1), and grade 3 (n = size required was at least 60 patients. 1) and grade 4 (n = 1) vascular toxicity. Other grade 3 Statistics were descriptive and all data were analysed toxicities included dermatitis (n = 6), proteinuria (n = 4) using the SPSS statistical software package, version 13 and hypertension (n = 1). There were no treatment- (SPSS Inc., Chicago, IL, USA). related deaths during the study. RT was interrupted for 2-7 days as a result of treat- Results ment (median interruption: 2 days), while 56 patients Patient characteristics and treatment rates (91%) received 95-100% of the designated chemotherapy Between February 2009 and March 2010, a total of 61 dose. Overall, 58 patients (95.1%) received all four infu- patients were recruited. Patients’ baseline and disease sions of bevacizumab while the remaining 3 patients characteristics are summarized in Table 1. Three received three infusions. Velenik et al. Radiation Oncology 2011, 6:105 Page 5 of 8 http://www.ro-journal.com/content/6/1/105 Treatment-related toxicities patients (15.0%). T-, N- and overall downstaging rates The frequency and grade of treatment-related acute were 46.7%, 65.0% and 75.0%, respectively. toxicities are summarised in Table 2. The most frequent KRAS mutations were found in 20 (33.9%) out of 59 adverse event reported with chemoradiotherapy was bioptic tumour samples obtained before preoperative grade 2 and 3 radiodermatitis. During treatment, 25 treatment. KRAS status was not associated with patholo- patients lost weight; the maximum body weight loss was gical response. 6.5% (median 3.3%). Of the remaining patients, 26 main- In total, 38 patients (62.3%) developed perioperative tained a constant weight and nine experienced a weight complications. The most frequent were delayed wound increase of up to 5% (median: 2.4%). healing (n = 18, 30.0%), infection/abscess (n = 12, 20.0%) and anastomotic leakage (n = 7, 11.7%). Six Surgery rates and outcomes patients required surgical re-intervention for anastomo- All patients underwent definitive surgery, although one tic leakage (n = 3), abdominal abscess (n = 2) and pneu- patient revealed distant metastases after completion of mothorax (n = 1). There were no perioperative deaths. chemoradiotherapy. Surgery was performed 25 to 79 A summary of perioperative toxicity is shown in Table days (median: 55 days) after the last day of chemora- 4. diotherapy. Exploratory surgery was performed in only 1 Postoperative chemotherapy was administered to 51 patient because of a large, unresectable T4 tumour with (83.6%) patients. Reasons for not administering adjuvant peritoneal carcinomatosis. The median hospital stay for chemotherapy were: progression of the disease (n = 2), surgery was 11 days (range: 7-32 days). misdiagnosis (n = 1); withdrawal from study (n = 1); > 8 Radical resection was achieved in 57 patients (95%) week interval between the operation and adjuvant ther- and 42 patients (70%) underwent sphincter-preserving apy (n = 1); and postoperative complications (n = 5). surgery. A temporary stoma was created in 41 patients. Postoperative chemotherapy comprised capecitabine In one patient pathohistological examination of the sur- 1250 mg/m on Days 1-14 every 3 weeks for 4 or 6 gical specimen revealed malignant melanoma; this cycles. A total of 42 patients received all planned cycles. patient was considered misdiagnosed and excluded from Two patients only received 3 cycles because of disease the efficacy analysis. progression (n = 1) and death because of pulmonary Pathological TNM stages in relation to preoperative thromboembolism (n = 1); 2 patients only received 2 TNM status are presented in Table 3. TRG 4 (pCR) was cycles because of diarrhoea and dehydration (n = 1) and recorded in 8/60 patients (13.3%) and TRG 3 in 9/60 nonspecific chest pain (n = 1); and 3 patients only received 1 cycle because of the development of presacral abscesses (n = 2) and nonspecific chest pain (n = 1). Table 2 Acute toxicities occurring during preoperative chemoradiotherapy Discussion Patients, n (%) This phase II study demonstrates the feasibility of preo- Toxicity Grade 1 Grade 2 Grade 3 Grade 4 perative chemoradiation with bevacizumab and capecita- Haematological: bine in patients with LARC. Indeed, a high R0 resection Leucocytopenia 12 (19.7) 5 (8.2) 3 (4.9) - rate was achieved despite tumour invasion of the mesor- Anaemia 5 (8.2) - - - ectal fascia in 46% of patients. A well-accepted approach Non-haematological: in the management of LARC is neoadjuvant fluoropyri- Diarrhoea 14 (22.9) 4 (6.5) 1 (1.6) - midine-based chemoradiation and a number of prospec- Fatigue 7 (11.5) 3 (4.9) - - tive and retrospective trials have suggested that Nausea 5 (8.2) - - - preoperative capecitabine is at least equivalent to infu- Anorexia 2 (3.3) - - - sional 5-fluorouracil when combined with RT [16-19], Dermatitis 3 (4.9) 14 (22.9) 6 (9.8) - and may improve tumour downstaging. In 2009, the US Hand-food syndrome 5 (8.2) 2 (3.3) - - National Comprehensive Cancer Network recommended Cystitis 3 (4.9) - - - capecitabine as an acceptable alternative to 5-FU in this Hepatotoxicity 2 (3.3) 2 (3.3) - - setting [36]. Vascular - - 1 (1.6) 1 (1.6) The pCR rate of 13% observed with neoadjuvant cape- Proteinuria 10 (16.4) 2 (3.3) 4 (6.5) - citabine plus bevacizumab plus RT was similar to an Hypertension 2 (3.3) 2 (3.3) 1 (1.6) - earlier phase II study by our group examining neoadju- Infection 3 (4.9) 5 (8.2) - - vant single-agent capecitabine plus RT in LARC [37]. Pain 20 (32.8) 3 (4.9) - - This pCR rate, albeit relatively low, is within the range Bleeding 10 (16.4) - - - 0-31% reported across a number of phase II studies According to National Cancer Institute Common Toxicity Criteria (version 3) evaluating single-agent capecitabine plus RT [38-43]. In Velenik et al. Radiation Oncology 2011, 6:105 Page 6 of 8 http://www.ro-journal.com/content/6/1/105 Table 3 Distribution of postoperative pathological TMN stages compared with pretreatment clinical stages (n = 60) Before After surgery (pTNM) T0N0 T1N0 T2N0 T3N0 T2N1 T3N1 T4N1 T3N2 T3N0 34 3 2 T2N1 1 T3N1 53 4 4 1 1 T2N2 1 1 T3N2 1 2 13 1 1 4 T4N2 12 1 1 Total 8 (13.3%) 5 (8.3%) 14 (23.3%) 21 (35%) 1 (1.7%) 5 (8.3%) 1 (1.7%) 5 (8.3%) c - Clinical, p - pathological, T - Tumour, N - Node, M - Metastasis. one of the largest studies performed to date, the pCR outcome, a recently published pooled analysis of data rate was 12% [44], and in the recently presented from 3105 patients from 14 studies would suggest that NSABP-04 study the pCR ranged from 18 to 22% with patients with pCR after chemoradiation have better capecitabine and 5-FU achieving similar rates of long-term outcome than those without pCR [49]. improvement but no additional benefit being observed The adverse event profile observed during neoadjuvant with the addition of oxaliplatin to either of these agents capecitabine plus bevacizumab chemoradiotherapy was comparable with those reported in an earlier study [17]. A study by Ofner and co-workers [45] evaluating preoperative capecitabine and oxaliplatin reported a involving capecitabine plus bevacizumab with concur- pCR rate of 10% while studies investigating preoperative rent RT [31]. The most frequent preoperative adverse capecitabine, oxaliplatin and bevacizumab found rates of events were dermatitis, pain and leucopenia, and adverse 24-36% [32-34]. events related to bevacizumab therapy were relatively In the phase II trial by Crane and coworkers [31], 25 infrequent. Any postoperative adverse events were patients with LARC received neoadjuvant chemora- mainly related to delayed wound healing and infection/ diotherapy with bevacizumab (three doses of 5 mg/kg abscess. No treatment-related deaths were recorded. given every 2 weeks) and capecitabine (900 mg/m orally These results, together with those of Crane and co- twice daily on days of radiation therapy), followed by workers [31] suggest that the combination of neoadju- surgical resection a median of 7.3 weeks later. These vant capecitabine plus bevacizumab with concurrent RT authors reported a pCR rate of 32% (8 patients), which is feasible and well tolerated in the treatment of LARC. is considerably higher than that reported here. One pos- A high radical resection rate suggests its potential posi- sible explanation for the relatively low pCR rate tive effect on tumour downstaging. The observed observed in our study was that the patients in this study adverse events during neoadjuvant treatment in our had advanced tumours; indeed, most of the patients had study are comparable with those reported previously; regionally advanced disease and in almost half of the however, no clinically relevant increase in pathologic patients the tumour had invaded the mesorectal fascia. response rate was observed. Longer follow-up is needed However, caution is needed when comparing pCR rates to assess the impact on other efficacy endpoints. as the pCR rate itself is highly dependent on the quality Long-term follow-up data on survival and local con- of the pathological examination [46] and a longer inter- trol in patients with LARC having undergone neoadju- val between end of chemoradiotherapy and surgery (6-8 vant capecitabine plus bevacizumab chemoradiotherapy followed by surgery are eagerly awaited. It will also be weeks vs. 2 weeks) has been reported to increase pCR rate without reducing local recurrence rate or survival interesting to compare any long-term follow-up data [47,48]. While there has been much debate about with that which is currently available at the moment on whether pCR is associated with a favourable long-term single-agent capecitabine-based chemoradiotherapy [39,50] to help determine the benefits of adding bevaci- zumab to the regimen. Table 4 Perioperative adverse events (n = 60) Complication Patients, n (%) Conclusion Delayed healing of postoperative wound 18 (30.0) The results of this phase II study indicate that neoadju- Infection/abscess 12 (20.0) vant capecitabine chemoradiotherapy is an effective Pneumothorax 1 (1.7) treatment for patients with LARC and the incorporation Anastomotic leakage 7 (11.7) of bevacizumab into a standard capecitabine-based che- moradiotherapy regimen is feasible and well tolerated. Patients could have more than one adverse event. Velenik et al. Radiation Oncology 2011, 6:105 Page 7 of 8 http://www.ro-journal.com/content/6/1/105 11. Twelves C, Wong A, Nowacki MP, Abt M, Burris H, et al: Capecitabine as List of abbreviations adjuvant treatment for stage III colon cancer. N Engl J Med 2005, 5-FU: 5-fluorouracil; CT: computed tomography; LARC: locally advanced 352:2696-2704. rectal cancer; MRI: magnetic resonance imaging; pCR: pathological complete 12. Van Cutsem E, Findlay M, Osterwalder B, Kocha W, Dalley D, et al: response; RT: radiotherapy; TRG: tumour regression grade; VEGF: vascular Capecitabine, an oral fluoropyrimidine carbamate with substantial endothelial growth factor. activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 2000, 18:1337-1345. Acknowledgements 13. Van Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, et al: Oral This was an investigator-initiated trial funded by Roche. capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III Author details 1 2 study. J Clin Oncol 2001, 19:4097-4106. Institute of Oncology, Zaloska 2, 1000 Ljubljana, Slovenia. University Medical Centre, Zaloska 7, 1000 Ljubljana, Slovenia. 14. Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated Authors’ contributions efficacy data and novel analyses from two large, randomized, phase III VV: contributions to conception and design, acquisition of data, analysis and trials. Br J Cancer 2004, 90:1190-1197. interpretation of data; involvement in drafting and reviewing the manuscript. 15. Glynne-Jones R, Dunst J, Sebag-Montefiore D: The integration of oral JO: contribution to acquisition of data, analysis and interpretation of data. capecitabine into chemoradiation regimens for locally advanced rectal MM: contribution to acquisition of data, analysis and interpretation of data. cancer: how successful have we been? Ann Oncol 2006, 17:361-371. MB: contribution to acquisition of data. FA: contribution to acquisition of 16. Saif MW, Hashmi S, Zelterman D, Almhanna K, Kim R: Capecitabine vs data, analysis and interpretation of data. IO: contribution to acquisition of continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A data. retrospective review. Int J Colorectal Dis 2008, 23:139-145. IE: contribution to acquisition of data, analysis and interpretation of data. EB: 17. Roh MS, Yothers GA, O’Connell MJ, Beart RW, Pitot HC, et al: The impact of contribution to acquisition of data, analysis and interpretation of data. MK: capecitabine and oxaliplatin in the preoperative multimodality contribution to acquisition of data. MO: contributions to acquisition of data, treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin analysis and interpretation of data; involvement in drafting and reviewing Oncol 2011, 29(suppl):Abst 3503.. the manuscript. All authors have read and approved the final version of the 18. Hofheinz R, Wenz FK, Post S, Matzdorff A, Laechelt S, et al: Capecitabine manuscript. (Cape) versus 5-fluorouracil (5-FU)-based (neo)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Competing interests Long-term results of a randomized, phase III trial. J Clin Oncol 2011, 29(suppl):Abst 3504. This was an investigator-initiated trial supported by Roche. The authors 19. Kim DY, Jung KH, Kim TH, Kim DW, Chang HJ, et al: Comparison of 5- declare that they have no financial or non-financial competing interests. fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Received: 19 June 2011 Accepted: 31 August 2011 Biol Phys 2007, 67:378-384. Published: 31 August 2011 20. Gérard JP, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, et al: Comparison of two neoadjuvant chemoradiotherapy regimens for References locally advanced rectal cancer: results of the phase III trial ACCORD 12/ 1. Camma C, Giunta M, Fiorica F, Pagliaro L, Craxì A, et al: Preoperative 0405-Prodige 2. J Clin Oncol 2010, 28:1638-1644. radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000, 21. Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, et al: Primary tumor 284:1008-1015. response to preoperative chemoradiation with or without oxaliplatin in 2. Glimelius B, Isacsson U, Jung B, Pahlman L: Radiotherapy in addition to locally advanced rectal cancer: Pathologic results of the STAR-01 radical surgery in rectal cancer: evidence for a dose-response effect randomized phase III trial. J Clin Oncol 2011, 29:2773-2780. favoring preoperative treatment. Int J Radiat Oncol Biol Phys 1997, 22. Rödel C, Becker H, Fietkau R, Graeven U, Hohenberger W, et al: 37:281-287. Preoperative chemoradiotherapy and postoperative chemotherapy with 3. Pahlman L, Glimelius B: Pre- or postoperative radiotherapy in rectal and 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally rectosigmoid carcinoma. Report from a randomized multicentre trial. advanced rectal cancer: first results of the German CAO/ARO/AIO-04 Ann Surg 1990, 211:187-195. randomized phase III trial. J Clin Oncol 2011, 29(suppl):Abst LBA3505. 4. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, German Rectal 23. Mohiuddin M, Winter K, Mitchell E, Hanna N, Yuen A, et al: Randomized Cancer Study Group, et al: Preoperative versus postoperative phase II study of neoadjuvant combined-modality chemoradiotherapy chemoradiotherapy for rectal cancer. N Engl J Med 2004, 351:1731-1740. for distal rectal cancer: radiation therapy oncology group trial 0012. J 5. Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al: Enhanced Clin Oncol 2006, 24:650-655. tumorocidal effect of chemotherapy with preoperative radiotherapy for 24. Klautke G, Kuchenmeister U, Foitzik T, Ludwig K, Prall F, et al: Concurrent rectal cancer: preliminary results - EORTC 22921. J Clin Oncol 2005, chemoradiotherapy with capecitabine and weekly irinotecan as 23:5620-5627. preoperative treatment for rectal cancer: results from a phase I/II study. 6. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, EORTC Radiotherapy Br J Cancer 2006, 94:976-981. Group Trial 22921, et al: Chemotherapy with preoperative radiotherapy in 25. Navarro M, Dotor E, Rivera F, Sánchez-Rovira P, Vega-Villegas ME, et al: A rectal cancer. N Engl J Med 2006, 355:1114-1123. phase II study of preoperative radiotherapy and concomitant weekly 7. Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, et al: Preoperative irinotecan in combination with protracted venous infusion 5-fluorouracil, radiotherapy with or without concurrent fluorouracil and leucovorin in for resectable locally advanced rectal cancer. Int J Radiat Oncol Biol Phys T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006, 24:4620-4625. 2006, 66:201-205. 8. Bajetta E, Beretta E, Di Bartolomeo M, Mariani L, Valvo F, et al: Capecitabine 26. Willeke F, Horisberger K, Kraus-Tiefenbacher U, Wenz F, Leitner A, et al: A chemoradiation for rectal cancer after curative surgery. J Chemother phase II study of capecitabine and irinotecan in combination with 2006, 18:85-89. concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of 9. Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Capecitabine locally advanced rectal cancer. Br J Cancer 2007, 96:912-917. Colorectal Cancer Study Group, et al: First-line oral capecitabine therapy 27. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Eastern in metastatic colorectal cancer: a favorable safety profile compared with Cooperative Oncology Group Study E3200, et al: Bevacizumab in intravenous 5-fluorouracil/leucovorin. Ann Oncol 2002, 13:566-575. combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for 10. Hoff PM, Ansari R, Batist G, Cox J, Kocha W, et al: Comparison of oral previously treated metastatic colorectal cancer: results from the Eastern capecitabine versus intravenous fluorouracil plus leucovorin as first-line Cooperative Oncology Group Study E3200. J Clin Oncol 2007, treatment in 605 patients with metastatic colorectal cancer: results of a 25:1539-1544. randomised phase III study. J Clin Oncol 2001, 19:2282-2292. Velenik et al. Radiation Oncology 2011, 6:105 Page 8 of 8 http://www.ro-journal.com/content/6/1/105 28. Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, et al: Direct 48. Glehen O, Chapet O, Adham M, Nemoz JC, Gerard JP: Long-term results of evidence that the VEGF-specific antibody bevacizumab has antivascular the Lyons R90-01 randomized trial of preoperative radiotherapy with effects in human rectal cancer. Nat Med 2004, 10:145-147. delayed surgery and its effect on sphincter-saving surgery in rectal 29. Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, et al: Surrogate cancer. Br J Surg 2003, 90:996-998. markers for antiangiogenic therapy and dose-limiting toxicities for 49. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, et al: Long-term bevacizumab with radiotherapy and chemotherapy: continued outcome in patients with a pathological complete response after experience of a phase I trial in rectal cancer patients. J Clin Oncol 2005, chemoradiation for rectal cancer: a pooled analysis of individual patient 23:8136-8139. data. Lancet Oncol 2010, 11:835-844. 30. Czito BG, Bendell JC, Willet CG, Morse MA, Blobe GC, et al: Bevacizumab, 50. Velenik V, Oblak I, Anderluh F: Long-term results from a randomized oxaliplatin, and capecitabine with radiation therapy in rectal cancer: phase II trial of neoadjuvant combined-modality therapy for locally Phase I trial results. Int J Radiat Oncol Biol Phys 2007, 68:472-478. advanced rectal cancer. Radiat Oncol 2010, 5:88. 31. Crane CH, Eng C, Feig BW, Das P, Skibber JM, et al: Phase II trial of doi:10.1186/1748-717X-6-105 neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally Cite this article as: Velenik et al.: Neoadjuvant capecitabine, advanced rectal cancer. Int J Radiat Oncol Biol Phys 2010, 76:824-830. radiotherapy, and bevacizumab (CRAB) in locally advanced rectal 32. Resch G, De Vries A, Ofner D, Eisterer W, Rabl H, et al: Preoperative cancer: results of an open-label phase II study. Radiation Oncology 2011 treatment with capecitabine, bevacizumab and radiotherapy for locally 6:105. advanced rectal cancer - A two stage phase II trial. Radiother Oncol 2011. 33. Kennecke H, Berry S, Wong R, Zhou C, Tankel K, et al: Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: A phase II trial. Eur J Cancer 34. Nogue M, Salud A, Vincente P, Arrivi A, Roca JM, et al: Addition of bevacizumab to XELOX induction therapy plus concomitant capecitabine-based chemoradiotherapy in magnetic resonance imaging- defined poor-prognosis locally advanced rectal cancer: the AVACROSS study. Oncologist 2011, 16:614-620. 35. Rodel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005, 23:8688-8696. 36. National Comprehensive Cancer Network: National Comprehensive Cancer Network clinical practice guidelines, Rectal cancer.[http://www.nccn.org/ professionals/physician_gls/f_guidelines.asp#site]. 37. Velenik V, Anderlih F, Oblak I, Strojan P, Zakotnik B: Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced respectable rectal cancer: prospective phase II trial. Croat Med J 2006, 47:693-700. 38. Craven I, Crellin A, Cooper R, Melcher A, Byrne P, et al: Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer. Br J Cancer 2007, 97:1333-1337. 39. Dunst J, Debus J, Rudat V, Wulf J, Budach W, et al: Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer. Strahlenther Onkol 2008, 184:450-456. 40. De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, et al: Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable rectal cancer: a multicentric phase II study. Ann Oncol 2006, 17:246-251. 41. Desai SP, El-Rayes BF, Ben-Josef E, Greenson JK, Knol JA, et al: A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer. Am J Clin Oncol 2007, 30:340-345. 42. Dupuis O, Vie B, Liedo G, Hennequin C, Noirclerc M, et al: Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR phase II study. Oncology 2007, 73:169-176. 43. Lay GC, Caraul B, Dessi M, Orrù S, Murtas R, et al: Phase II study of preoperative irradiation and chemotherapy with capecitabine in patients with locally advanced rectal carcinoma. J Exp Clin Cancer Res 2007, 26:61-70. 44. Kim JC, Kim TW, Kim JH, Yu CS, Kim HC, et al: Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in Submit your next manuscript to BioMed Central locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2005, and take full advantage of: 63:346-353. 45. Ofner D, De Vries AF, Schabert-Moser R, Greil R, Rabl H, et al: Preoperative • Convenient online submission oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT#NxM0, low rectal cancer: a • Thorough peer review phase II study. Strahlenther Onkol 2011, 187:100-107. • No space constraints or color figure charges 46. Chua YJ: Pathological complete response: still a relevant endpoint in • Immediate publication on acceptance rectal cancer? Lancet Oncol 2010, 11:807-808. 47. Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean JP, et al: Influence of • Inclusion in PubMed, CAS, Scopus and Google Scholar the interval between preoperative radiation therapy and surgery on • Research which is freely available for redistribution downstaging and the rate of sphincter-saving surgery for rectal cancer: the Lyon R90-01 randomized trial. J Clin Oncol 1999, 17:2396. Submit your manuscript at www.biomedcentral.com/submit

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