The Breast 23 (2014) 816e820
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer* Victor Pernin a, Lisa Belin b, Paul Cottu c, Patrick Bontemps d, Claire Lemanski e, Brigitte De La Lande f, Pierre Baumann g, Fernand Missohou h, Christelle Levy i, mi Dendale a, Karine Peignaux j, Pierre Bougnoux k, Fabrice Denis l, Marc Bollet a, Re m a a Nora Ady Vago , François Campana , Alain Fourquet , Youlia M. Kirova a, * a
Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France Institut Curie, Hospital, Biostatistic Department, 75005 Paris, France c Institut Curie, Hospital, Oncology Department, 75005 Paris, France d CHU Jean Minjoz, Radiotherapy Department, 25030 Besançon, France e Institut r egional du Cancer de Montpellier, Radiotherapy Department, 34298 Montpellier, France f Institut Curie, Hospital, Radiotherapy Department, 92210 Saint Cloud, France g Centre d'Oncologie de Gentilly, Radiotherapy Department, 54 100 Nancy, France h Centre Henri Becquerel, Radiotherapy Department, 76038 Rouen, France i Centre François Baclesse, Radiotherapy Department, 14000 Caen, France j Centre Georges-François Leclerc, D epartement de radioth erapie, 21000 Dijon, France k CHU Tours, Service de canc erologie, 37044 Tours, France l Centre Jean Bernard, D epartement de radioth erapie, 72000 Le Mans, France m Roche, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 May 2014 Received in revised form 20 August 2014 Accepted 25 August 2014 Available online 26 September 2014
The purpose of this multicenter prospective and descriptive study was to determine late toxicities and outcomes among patients with non-metastatic breast cancer receiving concurrent bevacizumab (BV) and radiation therapy (RT) in the clinical trials. Early and late toxicities were assessed and evaluation was available for 63 patients (pts) at 12 months. Acute radiation dermatitis was observed in 48 (76%): grade 1 for 27, grade 2 for 17 and grade 3 for 4 pts. Grade 2 acute oesophagitis was observed in one patient (2%). Little toxicity was described 1 year after the completion of RT: 7 pts (12%): grade 1e2 pain, 3 (5%) presented grade 1 fibrosis, and 2 pts (4%) e telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1e2 lymphoedema occurred. Only one patient experienced a LEVF value less than 50% one year after the end of RT. In conclusion, the concurrent BV with locoregional RT provides acceptable toxicities. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Radiotherapy Concurrent bevacizumab
Introduction Tumour angiogenesis plays a central role in the growth and survival of tumour tissue and is stimulated by numerous growth factors, particularly VEGF (Vascular Endothelial Growth Factor). Activation of VEGF in breast tumour tissues leads to the formation
*
The data collection was supported by Roche, France. * Corresponding author. Institut Curie, Department of Radiation Oncology, 75005 Paris, France. E-mail addresses: [email protected], [email protected] (Y.M. Kirova). http://dx.doi.org/10.1016/j.breast.2014.08.015 0960-9776/© 2014 Elsevier Ltd. All rights reserved.
of poorly functioning neovessels, contributing to decreased access of chemotherapy molecules to tumour cells and increased intratumour hypoxia. Bevacizumab (Avastin®, Genentech Pharmaceuticals, San Francisco, CA) is a humanised monoclonal antibody directed against VEGF. Combined therapy with bevacizumab and ionising radiation has been investigated in preclinical studies that revealed a radiosensitizing effect of bevacizumab [1]. The main mechanisms responsible for this effect have not been fully elucidated, but they appear to involve transient normalisation of the vasculature induced by bevacizumab, allowing increased tumour oxygenation thereby reinforcing the action of ionising radiation via radiolysis of water [2]. Due to the potential improvement of locoregional control and survival by means of the combination of
V. Pernin et al. / The Breast 23 (2014) 816e820
817
bevacizumab with standard treatment for non-metastatic breast cancer, clinical trials have been conducted in the adjuvant and neoadjuvant settings (BEVERLY I, BEVERLY II, BEATRICE and BETH). - The Beverly I trial (NCT00820547) is a phase 2 trial designed to determine the efficacy and safety of bevacizumab used in the neoadjuvant setting in combination with chemotherapy and in the adjuvant setting in combination with radiotherapy in patients with non-metastatic inflammatory breast cancer without Her2 overexpression. - The Beverly II trial (NCT00717405) is a phase 2 trial designed to determine the efficacy and safety of bevacizumab used in the neoadjuvant setting in combination with chemotherapy and trastuzumab and in the adjuvant setting in combination with radiotherapy in patients with non-metastatic inflammatory breast cancer with Her2 overexpression [3]. - The Beatrice trial (NCT00528567) is a phase 3 trial designed to evaluate the efficacy and safety of the addition of bevacizumab to chemotherapy in the adjuvant setting in patients with triplenegative breast cancer. - The pivotal BETH trial (NCT00625898) is a phase 3 clinical trial evaluating the advantages of the bevacizumab and trastuzumab combination together with adjuvant chemotherapy for the treatment of patients with early stage Her2-positive breast cancer.
Fig. 1. Presentation of clinical trials: bevacizumab with concurrent radiotherapy or description of the patient population.
radiation dermatitis, telangiectasia, and radiation fibrosis, lymphoedema of the arm, pneumonitis, plexitis, and LVEF rates as well as myocardial infarction. Toxicity was graded according to the Common Toxicity Criteria for Adverse Events version 3 or CTCAE v3. The cosmetic appearance of the conservatively treated breast was evaluated by the classification of cosmetic results described by Harris et al [4]. Statistical analysis
In these studies, bevacizumab was administered concurrently with locoregional radiotherapy of the breast. However, few data are available concerning the acute and late toxicity of concurrent bevacizumab and radiotherapy on healthy tissues included in irradiation fields. The only published study in the field of breast cancer reported acceptable acute toxicity of the concurrent combination [4], but no data concerning the late toxicity of the radiotherapy and bevacizumab combination in breast cancer are currently available. In order to address this issue, patients treated by adjuvant radiotherapy in trials evaluating bevacizumab in nonmetastatic breast cancer were enrolled in the TOLERAB study from October 2007 to August 2010.
Qualitative variables were described by frequencies and quantitative variables were described by their means and/or medians with variances and/or range. Chi-square test and Student's t-test were used for comparisons. When the conditions of application of these tests were not satisfied, nonparametric Fisher or Wilcoxon tests were preferred. CochraneArmitage test for trend was performed in order to compare ordinal qualitative variables between two groups. Analyses were performed with R version 2.13.2. software.
Materials and methods
Of the 63 patients who received concurrent bevacizumab and adjuvant radiotherapy for breast cancer, 59% were postmenopausal. The majority of patients were between the ages of 40 and 60 years. The right breast was affected in 38% of cases and the left breast was affected in 62% of cases. Clinical stages of breast cancer were distributed as follows: stage I: 30%, stage II: 33%, and stage IIIB: 35%. The most common histological type was invasive ductal carcinoma (89%), histological grade was generally high (grade III in 79% of cases), hormonal receptors were positive in 17% of patients, the Her2 receptor was overexpressed in 24% of cases and 70% patients presented triple-negative breast cancer (Table 1).
Patient screening The French multicentre non-interventional observational cohort TOLERAB study included, from October 2007 to August 2010, patients with non-metastatic breast cancer treated by local or locoregional radiotherapy and concurrent bevacizumab after either neoadjuvant or adjuvant chemotherapy in the trials BEVERLY 1, BEVERLY 2, BEATRICE or BETH (Fig. 1). Exclusion criteria were history of another cancer, medical conditions incompatible with administration of bevacizumab, impossibility to attend long-term follow-up, inability to provide informed consent and bilateral breast cancer. The patient's free written informed consent was obtained by the radiotherapist before inclusion in the study. Evaluation at 12 months was available for 63 patients. Evaluation tools The baseline evaluation comprised recording of medical history, WHO performance status, physical examination and a laboratory work-up. Patients were evaluated by the radiation oncologist once a week during radiotherapy, 4 weeks after completion of radiotherapy and then one year after completion of radiotherapy. Acute toxicity of treatment was assessed in terms of radiation dermatitis and oesophagitis and late toxicity was assessed in terms of pain,
Results Patient characteristics
Treatment characteristics Surgery Surgery was performed after neoadjuvant chemotherapy in 37% of patients, while primary surgery was performed in 63% of patients. Surgery consisted of total mastectomy for 44% of patients and breast-conserving surgery for 56% of patients. The sentinel lymph node technique was used in 21 patients (33%) and axillary lymph node dissection was performed in 83% of cases (Table 2). Chemotherapy Neoadjuvant chemotherapy was administered to 37% of patients according to a regimen comprising an anthracyclineetaxane combination. Of the 40 patients who received adjuvant chemotherapy
818
V. Pernin et al. / The Breast 23 (2014) 816e820
Table 1 Patient characteristics.
Table 3 Systemic treatments.
Patient characteristics
N (n ¼ 63)
%
Menopause Cardiovascular risk factors
37 13 10 6 2 1
59 21 16 10 3 2
11 39 13 0 39 24 56 4 3 2 24 14 0 22 0 1 32 24 4 2 0 1 19 17 4 0 22 1 2 11 50 11 50 2 15 48 44
17 2 21 0 62 38 89 6 5 3 38 22 0 35 0 2 51 38 6 3 0 2 30 27 6 0 35 2 3 18 79 17 79 3 24 76 70
Obesity (BMIa > 30) Hypertension Smoking Diabetes Deep arterial or venous thrombosis 70 years Left breast Right breast Invasive ductal Invasive lobular Others T0 T1 T2 T3 T4 Tx Missing data N0 N1 N2 N3 Nx Missing data Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Missing data I II III HRþ HRe Missing data Overexpression No overexpression
Age
Side Histology
Clinical T stage
Clinical N stage
UICC stage
Histological grade
Hormone receptor status
HER2 overexpression Triple-negative breast cancer a
BMI: body mass index.
(63% of all patients), 35 received an anthracyclineetaxane combination, 3 received taxane-based chemotherapy and 2 received anthracycline-based chemotherapy (Table 3). Trastuzumab Trastuzumab was administered in the neoadjuvant setting to 14 patients (22%) for a median duration of 12.17 months. Hormonal therapy was administered to 9 patients (14%). Bevacizumab was administered to all patients: 37% of patients received bevacizumab Table 2 Surgery characteristics. Surgery characteristics Treatment modality
Type of surgery
Axillary surgery
Neoadjuvant chemotherapy then surgery Surgery first Conservative surgery Mastectomy Conservative surgery then mastectomy No surgery Sentinel lymph node dissection Axillary dissection No axillary surgery
N (n ¼ 63)
%
23
37
40 35 28 0
63 44 56 0
0 21 52 1
0 33 83 2
Systemic treatment characteristics
N (n ¼ 63)
Neoadjuvant chemotherapy Neoadjuvant chemotherapy protocols Adjuvant chemotherapy Adjuvant chemotherapy protocols
23
37
23
37
40 2
63 3
3
5
35
55
14 7164 mg [3300e8670] 12.17 months [3.78e13.24] 9 5 4 63 23 40 15,000 mg [960e28,080] 11.5 months [2.07e13.31]
22
Neoadjuvant Trastuzumab
Sequential combination of taxanes and anthracyclines Anthracycline-based chemotherapy only Taxane-based chemotherapy only Sequential combination of taxanes and anthracyclines Median dose Median duration
Hormonal therapy Tamoxifen Aromatase inhibitor Bevacizumab Neoadjuvant Adjuvant Median dose Median duration
%
14 8 6 100 37 63
concurrently with neoadjuvant chemotherapy while 63% of patients received bevacizumab concurrently with adjuvant chemotherapy. The median duration of bevacizumab therapy was 11.5 months (Table 3). Radiotherapy Among the 63 patients who received concurrent bevacizumab and radiotherapy, 35 (56%) received radiotherapy to the whole breast alone at a median dose of 50 Gy with a boost to the tumour bed at a median dose of 16 Gy and 28 (44%) received chest wall radiotherapy at a median dose of 49 Gy. Radiotherapy of the draining lymph nodes was performed in 42 patients (67%); this radiotherapy concerned the supraclavicular nodes in 63% of cases and the internal mammary nodes in 40% of cases. The median duration of radiotherapy was 49 days for breast radiotherapy with a boost to the tumour bed ± lymph nodes and 35 days for radiotherapy of the chest wall ± lymph nodes. The median interval between surgery and radiotherapy was 41 days for patients receiving neoadjuvant chemotherapy and 183 days for patients receiving adjuvant chemotherapy (Table 4). Toxicities Acute toxicities 58 of 63 patients (92%) of our cohort were evaluated in the six months following radiotherapy. Among these patients, acute radiation dermatitis was observed in 48 patients (76%): grade 1 for 27 patients, grade 2 for 17 patients and grade 3 for 4 patients. All patients were evaluated for oesophagitis. Grade 2 acute oesophagitis was observed in one patient (2%) (Table 5). Cosmetic results Cosmetic assessment was performed in 25 patients (40%). Cosmetic results were grade 0 for 13 patients, grade 1 for 9 patients, grade 2 for 3 patients and no grade 3 results were observed (Table 6).
V. Pernin et al. / The Breast 23 (2014) 816e820 Table 4 Radiotherapy characteristic.
Table 6 Cosmetic results.
Radiotherapy regimens
N (n ¼ 63)
%
Cosmetic results
Breast radiotherapy
35 50 [40e52]
56
Cosmetic evaluation
27 8
77 23
Cosmetics results
30 5
86 14
33 1 1 35 16 [10e18]
94 3 3 56
20 10 5 28 49 [40e54]
57 29 14 44
18 10
64 36
14 11 3 42 40 25
50 39 11 67 63 40
2
3
Median dose (Gy) Dose per fraction - 2 Gy - 2e5 Gy Irradiation technique - Dorsal decubitus - Lateral decubitus Type of radiation - Photon - Cobalt - Missing data Boost Median dose (Gy) Type of radiation - Photons - Electrons - Photons and electrons Chest wall radiotherapy Median dose (Gy) Dose per fraction - 2 Gy - >2 Gy Type of radiation - Photons -Electrons - Photons and electrons Lymph nodes (LN) RT Supraclavicular nodes Internal mammary nodes Axillary nodes Radiotherapy duration (days)
49 [29e63]
Breast radiotherapy and boost ± lymph node irradiation Missing data Chest wall radiotherapy ± lymph node irradiation Missing data
2 35 [20e50]
1
Median interval between surgery and radiotherapy (days) Neoadjuvant chemotherapy Adjuvant chemotherapy
41 [31e122] 183 [125e303]
Late toxicities 60 patients (95%) were evaluated at 1 year. Little toxicity were described at 1 year: 7 patients (12%) reported grade 1e2 pain, 3 patients (5%) presented grade 1 fibrosis, and 2 patients (4%) Table 5 Acute toxicities. N (n ¼ 63) Acute dermatitis Acute dermatitis evaluation Grade
Acute oesophagitis Acute oesophagitis evaluation Grade
819
Yes No Grade Grade Grade Grade Grade Yes No Grade Grade Grade Grade Grade
%
0 1 2 3 4
58 5 10 27 17 4 0
92 8 17 47 29 7 0
0 1 2 3 4
63 0 62 0 1 0 0
100 0 98 0 2 0 0
Yes No No evaluation (mastectomy) Grade 0 (no change) Grade 1 (minor changes) Grade 2 (operated breast deformed) Grade 3 (operated breast seriously deformed)
N (n ¼ 63)
%
25 23 15 13 9 3 0
40 40 22 21 14 5 0
presented telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1e2 lymphoedema occurred (Table 7). Cardiac toxicities one year after completion of radiotherapy With regard to left ventricular ejection fraction (LVEF), evaluation before the beginning of radiotherapy was available for 59 patients (94%) with a LVEF value more than 50% for all patients. One year after the completion of radiotherapy, LVEF evaluation was available for 57 patients (90%) and only one patient experienced a LEVF value less than 50% one year after the end of radiotherapy (Table 8). She was 49 years old with no cardiovascular risk factors and she received adjuvant chemotherapy then radiotherapy to the left breast plus a boost to the tumour bed. Discussion This observational study based on analysis of the toxicities observed in the main trials evaluating adjuvant or neoadjuvant bevacizumab therapy for non-metastatic breast cancer demonstrated the acceptable acute and late one year locoregional toxicity of concurrent bevacizumab and radiotherapy of the breast and/or lymph nodes. These are the largest published series in breast cancer patients in the literature after the paper of Goyal et al. [5]. These results concerning evaluation of acute toxicity are therefore comparable to those reported by Goyal et al., while also providing an analysis of oesophageal toxicity, cosmetic effects and late toxicity [6]. The effect of the concurrent combination of bevacizumab and radiotherapy on healthy tissues, particularly on the tumour vasculature, is therefore likely to increase the acute adverse effects of radiation and especially the late effects, such as cutaneous and subcutaneous toxicity (fibrosis, telangiectasia, lymphoedema of the arm), cardiac toxicity, pulmonary toxicity and gastrointestinal toxicity. The toxicity of concurrent bevacizumab and locoregional radiotherapy for breast cancer remains poorly defined. Most of the
Table 7 Late toxicities. Late toxicities Late toxicity evaluation
Yes No
N (n ¼ 63)
%
60 3
95 5
Late toxicities
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Pain Fibrosis Telangiectasia Arm lymphoedema Ulceration Myocardial infarction Pericarditis Dyspnoea Dysphagia Paresis
53 57 58 55 60 60 60 59 60 60
3 3 1 4 0 0 0 1 0 0
4 (7%) 0 1 (2%) 1 (2%) 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
0 _ _ 0 0 0 0 0 0 0
(88%) (95%) (96%) (92%) (100%) (100%) (100%) (98%) (100%) (100%)
(5%) (5%) (2%) (7%)
(2%)
820
V. Pernin et al. / The Breast 23 (2014) 816e820
Table 8 Cardiac toxicity. N (n ¼ 63)
%
Yes No Less than 50% More than 50% Yes No
59 4 0 59 57 6
94 6 0 100 90 10
Less than 50% More than 50% Missing data
1 55 1
2 96 2
Cardiac toxicity Cardiac toxicity evaluation before any treatment LVEF Cardiac toxicity evaluation one year after the radiotherapy LVEF
clinical data concerning the adverse effects of this combination are derived from clinical trials concerning pelvic sites [6e8]. These phase 1 or phase 2 trials appear to demonstrate an increased incidence of grade 3e4 acute toxicities, which was not observed in our study. The toxicities of the bevacizumab and radiotherapy combination in these trials varied according to tumour site, irradiation doses and the concomitant chemotherapy combinations. For example, the study by Crane et al. concerning the treatment of pancreatic cancer, published in 2006, reported grade III/IV cutaneous ulcerations with bleeding in irradiation fields (8%) and grade III gastrointestinal perforation (4%) [6]. Many studies of chemotherapy (5FU, capecitabine or FOLFOX) in combination with bevacizumab and radiotherapy for the treatment of cancer of the rectum have been conducted. Heterogeneous safety results have been reported by various studies [7e11]. It also appears difficult to deliver concurrent neoadjuvant radiotherapy and bevacizumab prior to surgical management of soft tissue sarcomas, as, in the study by Yoon et al., major postoperative complications were observed in 5 patients (25%), included 4 major surgical wound complications [12]. Consequently, concurrent bevacizumab and neoadjuvant radiotherapy may be particularly hazardous after gastrointestinal, pelvic or soft tissue surgery, in contrast with breast surgery. Furthermore, the interval between surgery and radiotherapy was not increased for the 37 patients treated by neoadjuvant chemotherapy in our study. Although the benefit/risk balance of anti-angiogenic therapy in the metastatic setting appears to be favourable according to the data of the literature, the use of these agents in a curative situation can induce unacceptable long-term adverse effects. The improved response rates and progression-free intervals observed with bevacizumab in phase 3 trials in metastatic breast cancer were the basis for the transfer of anti-angiogenic therapy to non-metastatic breast cancer, although no improvement of overall survival was observed [13e15]. By analogy, in the context of colon cancer, for which bevacizumab allowed improvement of overall survival in the metastatic setting, the results of the phase 3 randomized NSABP c08 trial evaluating the addition of adjuvant bevacizumab to the treatment of patients with stage IIeIII colon cancer failed to demonstrate any improvement of disease-free survival. At the same time, the role of bevacizumab in metastatic breast cancer is limited. A potential application of our study would be concurrent bevacizumab and locoregional radiotherapy for the treatment of metastatic breast cancer. Concurrent bevacizumab and radiotherapy therefore appears to be particularly useful in patients with triple-negative metastatic breast cancer. Although bevacizumab administered concurrently with locoregional radiotherapy was well tolerated in our study, this combination cannot be recommended in clinical practice, as positive long-term results on the survival of patients included in trials evaluating neoadjuvant or adjuvant bevacizumab have yet to be
published and the acceptable locoregional toxicity of the combination must be confirmed with a follow-up of at least 3-years and 5-years. Conclusion Concurrent bevacizumab and locoregional radiotherapy for breast cancer did not induce any severe acute and late toxicities after one year of follow-up. However, this combination cannot be recommended in clinical practice until longer term survival data are available. Determination of late toxicity at 3-year and 5-year follow-up after completion of radiotherapy is currently underway. Conflict of interest statement None declared. References [1] Kozin SV, Winkler F, Garkavtsev I, Hicklin DJ, Jain RK, Boucher Y. Human tumor xenografts recurring after radiotherapy are more sensitive to antivascular endothelial growth factor receptor-2 treatment than treatmentnaive tumors. Cancer Res 1 Jun 2007;67(11):5076e82. [2] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 7 Jan 2005;307(5706):58e62. [3] Pierga JY, Petit T, Delozier T, Ferrero JM, Campone M, Gligorov J, et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Lancet Oncol Apr 2012;13(4):375e84. [4] Harris JR, Levene MB, Svensson G, Hellman S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys 1979 Feb;5(2):257e61. [5] Goyal S, Rao MS, Khan A, Huzzy L, Green C, Haffty BG. Evaluation of acute locoregional toxicity in patients with breast cancer treated with adjuvant radiotherapy in combination with bevacizumab. Int J Radiat Oncol Biol Phys 1 Feb 2011;79(2):408e13. [6] Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol Off J Am Soc Clin Oncol 1 Mar 2006;24(7):1145e51. [7] Velenik V, Ocvirk J, Music M, Bracko M, Anderluh F, Oblak I, et al. Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study. Radiat Oncol Lond Engl 2011;6:105. [8] Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol Off J Am Soc Clin Oncol 20 Jun 2009;27(18):3020e6. [9] Koukourakis MI, Giatromanolaki A, Tsoutsou P, Lyratzopoulos N, Pitiakoudis M, Kouklakis G, et al. Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a phase II study. Int J Radiat Oncol Biol Phys 1 Jun 2011;80(2):492e8. [10] Dipetrillo T, Pricolo V, Lagares-Garcia J, Vrees M, Klipfel A, Cataldo T, et al. Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer. Int J Radiat Oncol Biol Phys 1 Jan 2012;82(1):124e9. M, Salud A, Vicente P, Arriví A, Roca JM, Losa F, et al. Addition of [11] Nogue bevacizumab to XELOX induction therapy plus concomitant capecitabinebased chemoradiotherapy in magnetic resonance imaging-defined poorprognosis locally advanced rectal cancer: the AVACROSS study. Oncologist 2011;16(5):614e20. [12] Yoon SS, Duda DG, Karl DL, Kim TM, Kambadakone AR, Chen YL, et al. Phase II study of neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas. Int J Radiat Oncol Biol Phys 15 Nov 2011;81(4):1081e90. ras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. [13] Robert NJ, Die RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 1 Apr 2011;29(10): 1252e60. s J, Pivot X, Tomczak P, et al. Phase III study [14] Miles DW, Chan A, Dirix LY, Corte of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 10 Jul 2010;28(20):3239e47. [15] Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 27 Dec 2007;357(26):2666e76.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer* Victor Pernin a, Lisa Belin b, Paul Cottu c, Patrick Bontemps d, Claire Lemanski e, Brigitte De La Lande f, Pierre Baumann g, Fernand Missohou h, Christelle Levy i, mi Dendale a, Karine Peignaux j, Pierre Bougnoux k, Fabrice Denis l, Marc Bollet a, Re m a a Nora Ady Vago , François Campana , Alain Fourquet , Youlia M. Kirova a, * a
Institut Curie, Hospital, Radiotherapy Department, 75005 Paris, France Institut Curie, Hospital, Biostatistic Department, 75005 Paris, France c Institut Curie, Hospital, Oncology Department, 75005 Paris, France d CHU Jean Minjoz, Radiotherapy Department, 25030 Besançon, France e Institut r egional du Cancer de Montpellier, Radiotherapy Department, 34298 Montpellier, France f Institut Curie, Hospital, Radiotherapy Department, 92210 Saint Cloud, France g Centre d'Oncologie de Gentilly, Radiotherapy Department, 54 100 Nancy, France h Centre Henri Becquerel, Radiotherapy Department, 76038 Rouen, France i Centre François Baclesse, Radiotherapy Department, 14000 Caen, France j Centre Georges-François Leclerc, D epartement de radioth erapie, 21000 Dijon, France k CHU Tours, Service de canc erologie, 37044 Tours, France l Centre Jean Bernard, D epartement de radioth erapie, 72000 Le Mans, France m Roche, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 May 2014 Received in revised form 20 August 2014 Accepted 25 August 2014 Available online 26 September 2014
The purpose of this multicenter prospective and descriptive study was to determine late toxicities and outcomes among patients with non-metastatic breast cancer receiving concurrent bevacizumab (BV) and radiation therapy (RT) in the clinical trials. Early and late toxicities were assessed and evaluation was available for 63 patients (pts) at 12 months. Acute radiation dermatitis was observed in 48 (76%): grade 1 for 27, grade 2 for 17 and grade 3 for 4 pts. Grade 2 acute oesophagitis was observed in one patient (2%). Little toxicity was described 1 year after the completion of RT: 7 pts (12%): grade 1e2 pain, 3 (5%) presented grade 1 fibrosis, and 2 pts (4%) e telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1e2 lymphoedema occurred. Only one patient experienced a LEVF value less than 50% one year after the end of RT. In conclusion, the concurrent BV with locoregional RT provides acceptable toxicities. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Radiotherapy Concurrent bevacizumab
Introduction Tumour angiogenesis plays a central role in the growth and survival of tumour tissue and is stimulated by numerous growth factors, particularly VEGF (Vascular Endothelial Growth Factor). Activation of VEGF in breast tumour tissues leads to the formation
*
The data collection was supported by Roche, France. * Corresponding author. Institut Curie, Department of Radiation Oncology, 75005 Paris, France. E-mail addresses: [email protected], [email protected] (Y.M. Kirova). http://dx.doi.org/10.1016/j.breast.2014.08.015 0960-9776/© 2014 Elsevier Ltd. All rights reserved.
of poorly functioning neovessels, contributing to decreased access of chemotherapy molecules to tumour cells and increased intratumour hypoxia. Bevacizumab (Avastin®, Genentech Pharmaceuticals, San Francisco, CA) is a humanised monoclonal antibody directed against VEGF. Combined therapy with bevacizumab and ionising radiation has been investigated in preclinical studies that revealed a radiosensitizing effect of bevacizumab [1]. The main mechanisms responsible for this effect have not been fully elucidated, but they appear to involve transient normalisation of the vasculature induced by bevacizumab, allowing increased tumour oxygenation thereby reinforcing the action of ionising radiation via radiolysis of water [2]. Due to the potential improvement of locoregional control and survival by means of the combination of
V. Pernin et al. / The Breast 23 (2014) 816e820
817
bevacizumab with standard treatment for non-metastatic breast cancer, clinical trials have been conducted in the adjuvant and neoadjuvant settings (BEVERLY I, BEVERLY II, BEATRICE and BETH). - The Beverly I trial (NCT00820547) is a phase 2 trial designed to determine the efficacy and safety of bevacizumab used in the neoadjuvant setting in combination with chemotherapy and in the adjuvant setting in combination with radiotherapy in patients with non-metastatic inflammatory breast cancer without Her2 overexpression. - The Beverly II trial (NCT00717405) is a phase 2 trial designed to determine the efficacy and safety of bevacizumab used in the neoadjuvant setting in combination with chemotherapy and trastuzumab and in the adjuvant setting in combination with radiotherapy in patients with non-metastatic inflammatory breast cancer with Her2 overexpression [3]. - The Beatrice trial (NCT00528567) is a phase 3 trial designed to evaluate the efficacy and safety of the addition of bevacizumab to chemotherapy in the adjuvant setting in patients with triplenegative breast cancer. - The pivotal BETH trial (NCT00625898) is a phase 3 clinical trial evaluating the advantages of the bevacizumab and trastuzumab combination together with adjuvant chemotherapy for the treatment of patients with early stage Her2-positive breast cancer.
Fig. 1. Presentation of clinical trials: bevacizumab with concurrent radiotherapy or description of the patient population.
radiation dermatitis, telangiectasia, and radiation fibrosis, lymphoedema of the arm, pneumonitis, plexitis, and LVEF rates as well as myocardial infarction. Toxicity was graded according to the Common Toxicity Criteria for Adverse Events version 3 or CTCAE v3. The cosmetic appearance of the conservatively treated breast was evaluated by the classification of cosmetic results described by Harris et al [4]. Statistical analysis
In these studies, bevacizumab was administered concurrently with locoregional radiotherapy of the breast. However, few data are available concerning the acute and late toxicity of concurrent bevacizumab and radiotherapy on healthy tissues included in irradiation fields. The only published study in the field of breast cancer reported acceptable acute toxicity of the concurrent combination [4], but no data concerning the late toxicity of the radiotherapy and bevacizumab combination in breast cancer are currently available. In order to address this issue, patients treated by adjuvant radiotherapy in trials evaluating bevacizumab in nonmetastatic breast cancer were enrolled in the TOLERAB study from October 2007 to August 2010.
Qualitative variables were described by frequencies and quantitative variables were described by their means and/or medians with variances and/or range. Chi-square test and Student's t-test were used for comparisons. When the conditions of application of these tests were not satisfied, nonparametric Fisher or Wilcoxon tests were preferred. CochraneArmitage test for trend was performed in order to compare ordinal qualitative variables between two groups. Analyses were performed with R version 2.13.2. software.
Materials and methods
Of the 63 patients who received concurrent bevacizumab and adjuvant radiotherapy for breast cancer, 59% were postmenopausal. The majority of patients were between the ages of 40 and 60 years. The right breast was affected in 38% of cases and the left breast was affected in 62% of cases. Clinical stages of breast cancer were distributed as follows: stage I: 30%, stage II: 33%, and stage IIIB: 35%. The most common histological type was invasive ductal carcinoma (89%), histological grade was generally high (grade III in 79% of cases), hormonal receptors were positive in 17% of patients, the Her2 receptor was overexpressed in 24% of cases and 70% patients presented triple-negative breast cancer (Table 1).
Patient screening The French multicentre non-interventional observational cohort TOLERAB study included, from October 2007 to August 2010, patients with non-metastatic breast cancer treated by local or locoregional radiotherapy and concurrent bevacizumab after either neoadjuvant or adjuvant chemotherapy in the trials BEVERLY 1, BEVERLY 2, BEATRICE or BETH (Fig. 1). Exclusion criteria were history of another cancer, medical conditions incompatible with administration of bevacizumab, impossibility to attend long-term follow-up, inability to provide informed consent and bilateral breast cancer. The patient's free written informed consent was obtained by the radiotherapist before inclusion in the study. Evaluation at 12 months was available for 63 patients. Evaluation tools The baseline evaluation comprised recording of medical history, WHO performance status, physical examination and a laboratory work-up. Patients were evaluated by the radiation oncologist once a week during radiotherapy, 4 weeks after completion of radiotherapy and then one year after completion of radiotherapy. Acute toxicity of treatment was assessed in terms of radiation dermatitis and oesophagitis and late toxicity was assessed in terms of pain,
Results Patient characteristics
Treatment characteristics Surgery Surgery was performed after neoadjuvant chemotherapy in 37% of patients, while primary surgery was performed in 63% of patients. Surgery consisted of total mastectomy for 44% of patients and breast-conserving surgery for 56% of patients. The sentinel lymph node technique was used in 21 patients (33%) and axillary lymph node dissection was performed in 83% of cases (Table 2). Chemotherapy Neoadjuvant chemotherapy was administered to 37% of patients according to a regimen comprising an anthracyclineetaxane combination. Of the 40 patients who received adjuvant chemotherapy
818
V. Pernin et al. / The Breast 23 (2014) 816e820
Table 1 Patient characteristics.
Table 3 Systemic treatments.
Patient characteristics
N (n ¼ 63)
%
Menopause Cardiovascular risk factors
37 13 10 6 2 1
59 21 16 10 3 2
11 39 13 0 39 24 56 4 3 2 24 14 0 22 0 1 32 24 4 2 0 1 19 17 4 0 22 1 2 11 50 11 50 2 15 48 44
17 2 21 0 62 38 89 6 5 3 38 22 0 35 0 2 51 38 6 3 0 2 30 27 6 0 35 2 3 18 79 17 79 3 24 76 70
Obesity (BMIa > 30) Hypertension Smoking Diabetes Deep arterial or venous thrombosis 70 years Left breast Right breast Invasive ductal Invasive lobular Others T0 T1 T2 T3 T4 Tx Missing data N0 N1 N2 N3 Nx Missing data Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Missing data I II III HRþ HRe Missing data Overexpression No overexpression
Age
Side Histology
Clinical T stage
Clinical N stage
UICC stage
Histological grade
Hormone receptor status
HER2 overexpression Triple-negative breast cancer a
BMI: body mass index.
(63% of all patients), 35 received an anthracyclineetaxane combination, 3 received taxane-based chemotherapy and 2 received anthracycline-based chemotherapy (Table 3). Trastuzumab Trastuzumab was administered in the neoadjuvant setting to 14 patients (22%) for a median duration of 12.17 months. Hormonal therapy was administered to 9 patients (14%). Bevacizumab was administered to all patients: 37% of patients received bevacizumab Table 2 Surgery characteristics. Surgery characteristics Treatment modality
Type of surgery
Axillary surgery
Neoadjuvant chemotherapy then surgery Surgery first Conservative surgery Mastectomy Conservative surgery then mastectomy No surgery Sentinel lymph node dissection Axillary dissection No axillary surgery
N (n ¼ 63)
%
23
37
40 35 28 0
63 44 56 0
0 21 52 1
0 33 83 2
Systemic treatment characteristics
N (n ¼ 63)
Neoadjuvant chemotherapy Neoadjuvant chemotherapy protocols Adjuvant chemotherapy Adjuvant chemotherapy protocols
23
37
23
37
40 2
63 3
3
5
35
55
14 7164 mg [3300e8670] 12.17 months [3.78e13.24] 9 5 4 63 23 40 15,000 mg [960e28,080] 11.5 months [2.07e13.31]
22
Neoadjuvant Trastuzumab
Sequential combination of taxanes and anthracyclines Anthracycline-based chemotherapy only Taxane-based chemotherapy only Sequential combination of taxanes and anthracyclines Median dose Median duration
Hormonal therapy Tamoxifen Aromatase inhibitor Bevacizumab Neoadjuvant Adjuvant Median dose Median duration
%
14 8 6 100 37 63
concurrently with neoadjuvant chemotherapy while 63% of patients received bevacizumab concurrently with adjuvant chemotherapy. The median duration of bevacizumab therapy was 11.5 months (Table 3). Radiotherapy Among the 63 patients who received concurrent bevacizumab and radiotherapy, 35 (56%) received radiotherapy to the whole breast alone at a median dose of 50 Gy with a boost to the tumour bed at a median dose of 16 Gy and 28 (44%) received chest wall radiotherapy at a median dose of 49 Gy. Radiotherapy of the draining lymph nodes was performed in 42 patients (67%); this radiotherapy concerned the supraclavicular nodes in 63% of cases and the internal mammary nodes in 40% of cases. The median duration of radiotherapy was 49 days for breast radiotherapy with a boost to the tumour bed ± lymph nodes and 35 days for radiotherapy of the chest wall ± lymph nodes. The median interval between surgery and radiotherapy was 41 days for patients receiving neoadjuvant chemotherapy and 183 days for patients receiving adjuvant chemotherapy (Table 4). Toxicities Acute toxicities 58 of 63 patients (92%) of our cohort were evaluated in the six months following radiotherapy. Among these patients, acute radiation dermatitis was observed in 48 patients (76%): grade 1 for 27 patients, grade 2 for 17 patients and grade 3 for 4 patients. All patients were evaluated for oesophagitis. Grade 2 acute oesophagitis was observed in one patient (2%) (Table 5). Cosmetic results Cosmetic assessment was performed in 25 patients (40%). Cosmetic results were grade 0 for 13 patients, grade 1 for 9 patients, grade 2 for 3 patients and no grade 3 results were observed (Table 6).
V. Pernin et al. / The Breast 23 (2014) 816e820 Table 4 Radiotherapy characteristic.
Table 6 Cosmetic results.
Radiotherapy regimens
N (n ¼ 63)
%
Cosmetic results
Breast radiotherapy
35 50 [40e52]
56
Cosmetic evaluation
27 8
77 23
Cosmetics results
30 5
86 14
33 1 1 35 16 [10e18]
94 3 3 56
20 10 5 28 49 [40e54]
57 29 14 44
18 10
64 36
14 11 3 42 40 25
50 39 11 67 63 40
2
3
Median dose (Gy) Dose per fraction - 2 Gy - 2e5 Gy Irradiation technique - Dorsal decubitus - Lateral decubitus Type of radiation - Photon - Cobalt - Missing data Boost Median dose (Gy) Type of radiation - Photons - Electrons - Photons and electrons Chest wall radiotherapy Median dose (Gy) Dose per fraction - 2 Gy - >2 Gy Type of radiation - Photons -Electrons - Photons and electrons Lymph nodes (LN) RT Supraclavicular nodes Internal mammary nodes Axillary nodes Radiotherapy duration (days)
49 [29e63]
Breast radiotherapy and boost ± lymph node irradiation Missing data Chest wall radiotherapy ± lymph node irradiation Missing data
2 35 [20e50]
1
Median interval between surgery and radiotherapy (days) Neoadjuvant chemotherapy Adjuvant chemotherapy
41 [31e122] 183 [125e303]
Late toxicities 60 patients (95%) were evaluated at 1 year. Little toxicity were described at 1 year: 7 patients (12%) reported grade 1e2 pain, 3 patients (5%) presented grade 1 fibrosis, and 2 patients (4%) Table 5 Acute toxicities. N (n ¼ 63) Acute dermatitis Acute dermatitis evaluation Grade
Acute oesophagitis Acute oesophagitis evaluation Grade
819
Yes No Grade Grade Grade Grade Grade Yes No Grade Grade Grade Grade Grade
%
0 1 2 3 4
58 5 10 27 17 4 0
92 8 17 47 29 7 0
0 1 2 3 4
63 0 62 0 1 0 0
100 0 98 0 2 0 0
Yes No No evaluation (mastectomy) Grade 0 (no change) Grade 1 (minor changes) Grade 2 (operated breast deformed) Grade 3 (operated breast seriously deformed)
N (n ¼ 63)
%
25 23 15 13 9 3 0
40 40 22 21 14 5 0
presented telangiectasia. One patient (2%) experienced grade 1 dyspnoea. Five grade 1e2 lymphoedema occurred (Table 7). Cardiac toxicities one year after completion of radiotherapy With regard to left ventricular ejection fraction (LVEF), evaluation before the beginning of radiotherapy was available for 59 patients (94%) with a LVEF value more than 50% for all patients. One year after the completion of radiotherapy, LVEF evaluation was available for 57 patients (90%) and only one patient experienced a LEVF value less than 50% one year after the end of radiotherapy (Table 8). She was 49 years old with no cardiovascular risk factors and she received adjuvant chemotherapy then radiotherapy to the left breast plus a boost to the tumour bed. Discussion This observational study based on analysis of the toxicities observed in the main trials evaluating adjuvant or neoadjuvant bevacizumab therapy for non-metastatic breast cancer demonstrated the acceptable acute and late one year locoregional toxicity of concurrent bevacizumab and radiotherapy of the breast and/or lymph nodes. These are the largest published series in breast cancer patients in the literature after the paper of Goyal et al. [5]. These results concerning evaluation of acute toxicity are therefore comparable to those reported by Goyal et al., while also providing an analysis of oesophageal toxicity, cosmetic effects and late toxicity [6]. The effect of the concurrent combination of bevacizumab and radiotherapy on healthy tissues, particularly on the tumour vasculature, is therefore likely to increase the acute adverse effects of radiation and especially the late effects, such as cutaneous and subcutaneous toxicity (fibrosis, telangiectasia, lymphoedema of the arm), cardiac toxicity, pulmonary toxicity and gastrointestinal toxicity. The toxicity of concurrent bevacizumab and locoregional radiotherapy for breast cancer remains poorly defined. Most of the
Table 7 Late toxicities. Late toxicities Late toxicity evaluation
Yes No
N (n ¼ 63)
%
60 3
95 5
Late toxicities
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Pain Fibrosis Telangiectasia Arm lymphoedema Ulceration Myocardial infarction Pericarditis Dyspnoea Dysphagia Paresis
53 57 58 55 60 60 60 59 60 60
3 3 1 4 0 0 0 1 0 0
4 (7%) 0 1 (2%) 1 (2%) 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0
0 _ _ 0 0 0 0 0 0 0
(88%) (95%) (96%) (92%) (100%) (100%) (100%) (98%) (100%) (100%)
(5%) (5%) (2%) (7%)
(2%)
820
V. Pernin et al. / The Breast 23 (2014) 816e820
Table 8 Cardiac toxicity. N (n ¼ 63)
%
Yes No Less than 50% More than 50% Yes No
59 4 0 59 57 6
94 6 0 100 90 10
Less than 50% More than 50% Missing data
1 55 1
2 96 2
Cardiac toxicity Cardiac toxicity evaluation before any treatment LVEF Cardiac toxicity evaluation one year after the radiotherapy LVEF
clinical data concerning the adverse effects of this combination are derived from clinical trials concerning pelvic sites [6e8]. These phase 1 or phase 2 trials appear to demonstrate an increased incidence of grade 3e4 acute toxicities, which was not observed in our study. The toxicities of the bevacizumab and radiotherapy combination in these trials varied according to tumour site, irradiation doses and the concomitant chemotherapy combinations. For example, the study by Crane et al. concerning the treatment of pancreatic cancer, published in 2006, reported grade III/IV cutaneous ulcerations with bleeding in irradiation fields (8%) and grade III gastrointestinal perforation (4%) [6]. Many studies of chemotherapy (5FU, capecitabine or FOLFOX) in combination with bevacizumab and radiotherapy for the treatment of cancer of the rectum have been conducted. Heterogeneous safety results have been reported by various studies [7e11]. It also appears difficult to deliver concurrent neoadjuvant radiotherapy and bevacizumab prior to surgical management of soft tissue sarcomas, as, in the study by Yoon et al., major postoperative complications were observed in 5 patients (25%), included 4 major surgical wound complications [12]. Consequently, concurrent bevacizumab and neoadjuvant radiotherapy may be particularly hazardous after gastrointestinal, pelvic or soft tissue surgery, in contrast with breast surgery. Furthermore, the interval between surgery and radiotherapy was not increased for the 37 patients treated by neoadjuvant chemotherapy in our study. Although the benefit/risk balance of anti-angiogenic therapy in the metastatic setting appears to be favourable according to the data of the literature, the use of these agents in a curative situation can induce unacceptable long-term adverse effects. The improved response rates and progression-free intervals observed with bevacizumab in phase 3 trials in metastatic breast cancer were the basis for the transfer of anti-angiogenic therapy to non-metastatic breast cancer, although no improvement of overall survival was observed [13e15]. By analogy, in the context of colon cancer, for which bevacizumab allowed improvement of overall survival in the metastatic setting, the results of the phase 3 randomized NSABP c08 trial evaluating the addition of adjuvant bevacizumab to the treatment of patients with stage IIeIII colon cancer failed to demonstrate any improvement of disease-free survival. At the same time, the role of bevacizumab in metastatic breast cancer is limited. A potential application of our study would be concurrent bevacizumab and locoregional radiotherapy for the treatment of metastatic breast cancer. Concurrent bevacizumab and radiotherapy therefore appears to be particularly useful in patients with triple-negative metastatic breast cancer. Although bevacizumab administered concurrently with locoregional radiotherapy was well tolerated in our study, this combination cannot be recommended in clinical practice, as positive long-term results on the survival of patients included in trials evaluating neoadjuvant or adjuvant bevacizumab have yet to be
published and the acceptable locoregional toxicity of the combination must be confirmed with a follow-up of at least 3-years and 5-years. Conclusion Concurrent bevacizumab and locoregional radiotherapy for breast cancer did not induce any severe acute and late toxicities after one year of follow-up. However, this combination cannot be recommended in clinical practice until longer term survival data are available. Determination of late toxicity at 3-year and 5-year follow-up after completion of radiotherapy is currently underway. Conflict of interest statement None declared. References [1] Kozin SV, Winkler F, Garkavtsev I, Hicklin DJ, Jain RK, Boucher Y. Human tumor xenografts recurring after radiotherapy are more sensitive to antivascular endothelial growth factor receptor-2 treatment than treatmentnaive tumors. Cancer Res 1 Jun 2007;67(11):5076e82. [2] Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 7 Jan 2005;307(5706):58e62. [3] Pierga JY, Petit T, Delozier T, Ferrero JM, Campone M, Gligorov J, et al. Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study. Lancet Oncol Apr 2012;13(4):375e84. [4] Harris JR, Levene MB, Svensson G, Hellman S. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys 1979 Feb;5(2):257e61. [5] Goyal S, Rao MS, Khan A, Huzzy L, Green C, Haffty BG. Evaluation of acute locoregional toxicity in patients with breast cancer treated with adjuvant radiotherapy in combination with bevacizumab. Int J Radiat Oncol Biol Phys 1 Feb 2011;79(2):408e13. [6] Crane CH, Ellis LM, Abbruzzese JL, Amos C, Xiong HQ, Ho L, et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol Off J Am Soc Clin Oncol 1 Mar 2006;24(7):1145e51. [7] Velenik V, Ocvirk J, Music M, Bracko M, Anderluh F, Oblak I, et al. Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study. Radiat Oncol Lond Engl 2011;6:105. [8] Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol Off J Am Soc Clin Oncol 20 Jun 2009;27(18):3020e6. [9] Koukourakis MI, Giatromanolaki A, Tsoutsou P, Lyratzopoulos N, Pitiakoudis M, Kouklakis G, et al. Bevacizumab, capecitabine, amifostine, and preoperative hypofractionated accelerated radiotherapy (HypoArc) for rectal cancer: a phase II study. Int J Radiat Oncol Biol Phys 1 Jun 2011;80(2):492e8. [10] Dipetrillo T, Pricolo V, Lagares-Garcia J, Vrees M, Klipfel A, Cataldo T, et al. Neoadjuvant bevacizumab, oxaliplatin, 5-fluorouracil, and radiation for rectal cancer. Int J Radiat Oncol Biol Phys 1 Jan 2012;82(1):124e9. M, Salud A, Vicente P, Arriví A, Roca JM, Losa F, et al. Addition of [11] Nogue bevacizumab to XELOX induction therapy plus concomitant capecitabinebased chemoradiotherapy in magnetic resonance imaging-defined poorprognosis locally advanced rectal cancer: the AVACROSS study. Oncologist 2011;16(5):614e20. [12] Yoon SS, Duda DG, Karl DL, Kim TM, Kambadakone AR, Chen YL, et al. Phase II study of neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas. Int J Radiat Oncol Biol Phys 15 Nov 2011;81(4):1081e90. ras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. [13] Robert NJ, Die RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 1 Apr 2011;29(10): 1252e60. s J, Pivot X, Tomczak P, et al. Phase III study [14] Miles DW, Chan A, Dirix LY, Corte of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 10 Jul 2010;28(20):3239e47. [15] Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 27 Dec 2007;357(26):2666e76.
