Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features

Authors: Ramon Salazar, Jaume Capdevila, Berta Laquente, Jose Luis Manzano, Carles Pericay, Mercedes Martínez Villacampa, Carlos López, Ferran Losa, Maria Jose Safont, Auxiliadora Gómez, Vicente Alonso, Pilar Escudero, Javier Gallego, Javier Sastre, Cristina Grávalos, Sebastiano Biondo, Amalia Palacios, Enrique Aranda

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Perioperatory chemoradiotherapy (CRT) improves local control and survival in patients with locally advanced rectal cancer (LARC). The objective of the current study was to evaluate the addition of bevacizumab (BEV) to preoperative capecitabine (CAP)-based CRT in LARC, and to explore biomarkers for downstaging.

Methods

Patients (pts) were randomized to receive 5 weeks of radiotherapy 45 Gy/25 fractions with concurrent CAP 825 mg/m2 twice daily 5 days per week and BEV 5 mg/kg once every 2 weeks (3 doses) (arm A), or the same schedule without BEV (arm B). The primary end point was pathologic complete response (ypCR: ypT0N0).

Results

Ninety pts were included in arm A (44) or arm B (46). Grade 3–4 treatment-related toxicity rates were 16% and 13%, respectively. All patients but one (arm A) proceeded to surgery. The ypCR rate was 16% in arm A and 11% in arm B (p =0.54). Fifty-nine percent vs 39% of pts achieved T-downstaging (arm A vs arm B; p =0.04). Serial samples for biomarker analyses were obtained for 50 out of 90 randomized pts (arm A/B: 22/28). Plasma angiopoietin-2 (Ang-2) levels decreased in arm A and increased in arm B (p <0.05 at all time points). Decrease in Ang-2 levels from baseline to day 57 was significantly associated with tumor downstaging (p =0.02).

Conclusions

The addition of BEV to CAP-based preoperative CRT has shown to be feasible in LARC. The association between decreasing Ang-2 levels and tumor downstaging should be further validated in customized studies.

Trial registry

Clinicaltrials.gov identifier NCT01043484. Trial registration date: 12/30/2009.
Literature
1.
Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, et al. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26:3687–94.CrossRef
2.
Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–40.CrossRefPubMed
3.
Twelves C, Gollins S, Grieve R, Samuel L. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer. Ann Oncol Off J Eur Soc Med Oncol ESMO. 2006;17:239–45.CrossRef
4.
Kocakova I, Svoboda M, Kubosova K, Chrenko V, Roubalova E, Krejci E, et al. Preoperative radiotherapy and concomitant capecitabine treatment induce thymidylate synthase and thymidine phosphorylase mRNAs in rectal carcinoma. Neoplasma. 2007;54:447–53.PubMed
5.
Hofheinz R-D, Wenz F, Post S, Matzdorff A, Laechelt S, Hartmann JT, et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012;13:579–88.CrossRefPubMed
6.
Crane CH, Eng C, Feig BW, Das P, Skibber JM, Chang GJ, et al. Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2010;76:824–30.CrossRefPubMed
7.
Kennecke H, Berry S, Wong R, Zhou C, Tankel K, Easaw J, 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 Oxf Engl 1990. 2012;48:37–45.
8.
Nogué M, Salud A, Vicente P, Arriví A, Roca JM, Losa F, 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. The oncologist. 2011;16:614–20.CrossRefPubMedPubMedCentral
9.
Spigel DR, Bendell JC, McCleod M, Shipley DL, Arrowsmith E, Barnes EK, et al. Phase II study of bevacizumab and chemoradiation in the preoperative or adjuvant treatment of patients with stage II/III rectal cancer. Clin Colorectal Cancer. 2012;11:45–52.CrossRefPubMed
10.
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.CrossRef
11.
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. 2009;27:3020–6.CrossRef
12.
García M, Martinez-Villacampa M, Santos C, Navarro V, Teule A, Losa F, et al. Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally-advanced rectal cancer. Companion Pap: In press.
13.
Batchelor TT, Sorensen AG, di Tomaso E, Zhang W-T, Duda DG, Cohen KS, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95.CrossRefPubMedPubMedCentral
14.
Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer. 2010;103:1407–14.CrossRefPubMedPubMedCentral
15.
Kaseb AO, Garrett-Mayer E, Morris JS, Xiao L, Lin E, Onicescu G, et al. Efficacy of bevacizumab plus erlotinib for advanced hepatocellular carcinoma and predictors of outcome: final results of a phase II trial. Oncology. 2012;82:67–74.CrossRefPubMed
16.
Loupakis F, Falcone A, Masi G, Fioravanti A, Kerbel RS, Del Tacca M, et al. Vascular endothelial growth factor levels in immunodepleted plasma of cancer patients as a possible pharmacodynamic marker for bevacizumab activity. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25:1816–8.CrossRef
17.
Lu J-F, Bruno R, Eppler S, Novotny W, Lum B, Gaudreault J. Clinical pharmacokinetics of bevacizumab in patients with solid tumors. Cancer Chemother Pharmacol. 2008;62:779–86.CrossRefPubMed
18.
Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23:8136–9.CrossRef
19.
Zahiragic L, Schliemann C, Bieker R, Thoennissen NH, Burow K, Kramer C, et al. Bevacizumab reduces VEGF expression in patients with relapsed and refractory acute myeloid leukemia without clinical antileukemic activity. Leukemia. 2007;21:1310–2.CrossRefPubMed
20.
Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27:3027–35.CrossRef
21.
Harmey JH, Bouchier-Hayes D. Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. BioEssays News Rev Mol Cell Dev Biol. 2002;24:280–3.CrossRef
22.
Saclarides TJ, Speziale NJ, Drab E, Szeluga DJ, Rubin DB. Tumor angiogenesis and rectal carcinoma. Dis Colon Rectum. 1994;37:921–6.CrossRefPubMed
23.
Takebayashi Y, Aklyama S, Yamada K, Akiba S, Aikou T. Angiogenesis as an unfavorable prognostic factor in human colorectal carcinoma. Cancer. 1996;78:226–31.CrossRefPubMed
24.
Tanigawa N, Amaya H, Matsumura M, Lu C, Kitaoka A, Matsuyama K, et al. Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res. 1997;57:1043–6.PubMed
25.
Tomisaki S, Ohno S, Ichiyoshi Y, Kuwano H, Maehara Y, Sugimachi K. Microvessel quantification and its possible relation with liver metastasis in colorectal cancer. Cancer. 1996;77(8 Suppl):1722–8.CrossRefPubMed
26.
Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations Cancer. 1994;73:2680–6.PubMed
27.
Weidner N. Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat. 1995;36:169–80.CrossRefPubMed
28.
Bazarbashi S, El-Bassiouni M, Abdelsalam M, Soudy H, Sanea NA, Jabbar AA, et al. A modern regimen of pre-operative concurrent chemo-radiation therapy in locally advanced rectal cancer. J Surg Oncol. 2008;98:167–74.CrossRefPubMed
29.
Chan AK, Wong AO, Jenken DA. Preoperative capecitabine and pelvic radiation in locally advanced rectal cancer–is it equivalent to 5-FU infusion plus leucovorin and radiotherapy? Int J Radiat Oncol Biol Phys. 2010;76:1413–9.CrossRefPubMed
30.
Craven I, Crellin A, Cooper R, Melcher A, Byrne P, Sebag-Montefiore D. Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer. Br J Cancer. 2007;97:1333–7.CrossRefPubMedPubMedCentral
31.
De Bruin AFJ, Nuyttens JJ, Ferenschild FTJ, Planting AST, Verhoef C, de Wilt JHW. Preoperative chemoradiation with capecitabine in locally advanced rectal cancer. Neth J Med. 2008;66:71–6.PubMed
32.
Dupuis O, Vie B, Lledo G, Hennequin C, Noirclerc M, Bennamoun M, et al. Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR Phase II Study. Oncology. 2007;73:169–76.CrossRefPubMed
33.
Kim J-S, Kim J-S, Cho M-J, Song K-S, Yoon W-H. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2002;54:403–8.CrossRefPubMed
34.
Korkolis DP, Boskos CS, Plataniotis GD, Gontikakis E, Karaitianos IJ, Avgerinos K, et al. Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer. Anticancer Res. 2007;27:541–5.PubMed
35.
Marsh RW, George TJ, Siddiqui T, Mendenhall WM, Zlotecki RA, Grobmyer S, et al. A phase II trial of neoadjuvant capecitabine combined with hyperfractionated accelerated radiation therapy in locally advanced rectal cancer. Am J Clin Oncol. 2010;33:251–6.
36.
Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep. 1985;69:1375–81.PubMed
37.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting Recommendations for Tumor Marker Prognostic Studies. J Clin Oncol. 2005;23:9067–72.CrossRefPubMed
38.
Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29:2773–80.CrossRef
39.
Gérard J-P, Azria D, Gourgou-Bourgade S, Martel-Laffay I, Hennequin C, Etienne P-L, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28:1638–44.CrossRef
40.
Chua YJ. Pathological complete response: still a relevant endpoint in rectal cancer? Lancet Oncol. 2010;11:807–8.CrossRefPubMed
41.
Jubb AM, Harris AL. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol. 2010;11:1172–83.CrossRefPubMed
42.
Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10:165–77.CrossRefPubMed
43.
44.
Imanishi Y, Hu B, Jarzynka MJ, Guo P, Elishaev E, Bar-Joseph I, et al. Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res. 2007;67:4254–63.CrossRefPubMedPubMedCentral
45.
Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, et al. Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2006;24:217–27.CrossRef
Metadata
Title
A randomized phase II study of capecitabine-based chemoradiation with or without bevacizumab in resectable locally advanced rectal cancer: clinical and biological features
Authors
Ramon Salazar
Jaume Capdevila
Berta Laquente
Jose Luis Manzano
Carles Pericay
Mercedes Martínez Villacampa
Carlos López
Ferran Losa
Maria Jose Safont
Auxiliadora Gómez
Vicente Alonso
Pilar Escudero
Javier Gallego
Javier Sastre
Cristina Grávalos
Sebastiano Biondo
Amalia Palacios
Enrique Aranda
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1053-z

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Impact of comorbidities and use of common medications on cancer and non-cancer specific survival in esophageal carcinoma

Research article

Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study

Research article

Socioeconomic disparities in breast cancer incidence and survival among parous women: findings from a population-based cohort, 1964–2008

Research article

Postoperative complications affect early recurrence of hepatocellular carcinoma after curative resection

Case report

Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) associated with B-cell lymphoma: report of a rare case

Research article

International trends in primary liver cancer incidence from 1973 to 2007
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits