Long-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer

Vaneja Velenik, Irena Oblak, Franc Anderluh, Vaneja Velenik, Irena Oblak, Franc Anderluh

Abstract

Background: This study evaluated the effectiveness and safety of preoperative chemoradiotherapy with capecitabine in patients with locally advanced resectable rectal cancer. This report summarizes the results of the phase II study together with long-term (5-year) follow-up.

Methods: Between June 2004 and January 2005, 57 patients with operable, clinical stage II-III adenocarcinoma of the rectum entered the study. Radiation dose was 45 Gy delivered as 25 fractions of 1.8 Gy. Concurrent chemotherapy with oral capecitabine 825 mg/m² twice daily was administered during radiotherapy and at weekends. Surgery was scheduled 6 weeks after the completion of the chemoradiotherapy. Patients received four cycles of postoperative chemotherapy comprising either capecitabine 1250 mg/m² bid days 1-14 every 3 weeks or bolus i.v. 5-fluorouracil 425 mg/m²/day and leucovorin 20 mg/m²/day days 1-5 every 4 weeks (choice was at the oncologist's discretion). Study endpoints included complete pathological remission, proportion of R0 resections and sphincter-sparing procedures, toxicity, survival parameters and long-term (5-year) rectal and urogenital morbidity assessment.

Results: One patient died after receiving 27 Gy because of a pulmonary embolism. Fifty-six patients completed radiochemotherapy and had surgery. Median follow-up time was 62 months. No patients were lost to follow-up. R0 resection was achieved in 55 patients. A complete pathological response was observed in 5 patients (9.1%); T-, N- and overall downstaging rates were 40%, 52.9% and 49.1%, respectively. The 5-year overall survival rate, recurrence-free survival, and local control was 61.4% (95% CI: 48.9-73.9%), 52.4% (95% CI: 39.3-65.5%), and 87.4% (95% CI: 75.0-99.8%), respectively. In 5 patients local relapse has occurred; dissemination was observed in 19 patients and secondary malignancies have occurred in 2 patients. The most frequent side-effect of the preoperative combined therapy was dermatitis (grade 3 in 19 patients). The proportion of patients with severe late (SOMA grade 3 and 4) rectal, bladder and sexual toxicity was 40%, 19.2% and 51.7%, respectively.

Conclusions: This study confirms data from other non-randomised studies that capecitabine-based preoperative chemoradiation is a feasible treatment option for locally advanced rectal cancer, with positive 5-year overall survival, recurrence-free survival, and local control rates.

Figures

Figure 1
Figure 1
Distribution of patients through the trial.
Figure 2
Figure 2
Local recurrence-free survival (n = 56).
Figure 3
Figure 3
Recurrence-free survival (n = 57).
Figure 4
Figure 4
Overall survival (n = 57).

References

    1. Cammà C, Giunta M, Fiorica F, Pagliaro L, Craxì A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA. 2000;284:1008–1015. doi: 10.1001/jama.284.8.1008.
    1. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet. 2001;358:1291–1304. doi: 10.1016/S0140-6736(01)06409-1.
    1. Gagel B, Piroth M, Pinkawa M, Pinkawa M, Reinartz P, Zimny M, Fischedik K, Stanzel S, Breuer C, Skobel E, Asadpour B, Schmachtenberg A, Buell U, Eble MJ. Gemcitabine concurrent with thoracic radiotherapy after induction chemotherapy with gemcitabine/vinorelbine in locally advanced non-small cell lung cancer. A phase I study. Strahlenther Onkol. 2006;182:263–269. doi: 10.1007/s00066-006-1485-0.
    1. Kortmann B, Reimer T, Gerber B, Klautke G, Fietkau R. Concurrent radiochemotherapy of locally recurrent or advanced sarcomas of the uterus. Strahlenther Onkol. 2006;182:318–324. doi: 10.1007/s00066-006-1491-2.
    1. Rades D, Schulte R, Yekebas EF, Homann N, Schild SE, Dunst J. Radio(chemo)therapy plus resection versus radio(chemo)therapy alone for the treatment of stage III esophageal cancer. Strahlenther Onkol. 2007;183:10–16. doi: 10.1007/s00066-007-1583-7.
    1. Semrau S, Gerber B, Reimer T, Klautke G, Fietkau R. Concurrent radiotherapy and taxane chemotherapy in patients with locoregional recurrence of breast cancer. Strahlenther Onkol. 2006;182:596–603. doi: 10.1007/s00066-006-1549-1.
    1. Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Briffaux A, Collette L. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results - EORTC 22921. J Clin Oncol. 2005;23:5620–5627. doi: 10.1200/JCO.2005.02.113.
    1. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC. EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355:1114–1123. doi: 10.1056/NEJMoa060829.
    1. Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol. 2006;24:4620–4625. doi: 10.1200/JCO.2006.06.7629.
    1. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R. German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731–1740. doi: 10.1056/NEJMoa040694.
    1. Bajetta E, Beretta E, Di Bartolomeo M, Mariani L, Valvo F, Ferrario E, Mancin M, Dognini G, Buzzoni R. Capecitabine chemoradiation for rectal cancer after curative surgery. J Chemother. 2006;18:85–89.
    1. Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Boyer M, Bugat R, Burger U, Garin A, Graeven U, McKendric J, Maroun J, Marshall J, Osterwalder B, Pérez-Manga G, Rosso R, Rougier P, Schilsky RL. Capecitabine Colorectal Cancer Study Group. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol. 2002;13:566–575. doi: 10.1093/annonc/mdf089.
    1. Twelves C, Wong A, Nowacki MP, Abt M, Burris H, Carrato A, Cassidy J, Cervantes A, Fagerberg J, Georgoulias V, Husseini F, Jodrell D, Koralewski P, Kröning H, Maroun J, Marschner N, McKendrick J, Pawlicki M, Rosso R, Schüller J, Seitz JF, Stabuc B, Tujakowski J, Van Hazel G, Zaluski J, Scheithauer W. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696–2704. doi: 10.1056/NEJMoa043116.
    1. Van Cutsem E, Findlay M, Osterwalder B, Kocha W, Dalley D, Pazdur R, Cassidy J, Dirix L, Twelves C, Allman D, Seitz JF, Schölmerich J, Burger HU, Verweij J. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol. 2000;18:1337–1345.
    1. Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, Graeven U, Lokich J, Madajewicz S, Maroun JA, Marshall JL, Mitchell EP, Perez-Manga G, Rougier P, Schmiegel W, Schoelmerich J, Sobrero A, Schilsky RL. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomized, phase III trials. Br J Cancer. 2004;90:1190–1197. doi: 10.1038/sj.bjc.6601676.
    1. Glynne-Jones R, Dunst J, Sebag-Montefiore D. The integration of oral capecitabine into chemoradiation regimens for locally advanced rectal cancer: how successful have we been? Ann Oncol. 2006;17:361–371. doi: 10.1093/annonc/mdj052.
    1. Saif MW, Hashmi S, Zelterman D, Almhanna K, Kim R. Capecitabine vs continuous infusion 5-FU in neoadjuvant treatment of rectal cancer. A retrospective review. Int J Colorectal Dis. 2008;23:139–145. doi: 10.1007/s00384-007-0382-z.
    1. Kim DY, Jung KH, Kim TH, Kim DW, Chang HJ, Jeong JY, Kim YH, Son SH, Yun T, Hong CW, Sohn DK, Lim SB, Choi HS, Jeong SY, Park JG. Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007;67:378–384.
    1. 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.
    1. National Comprehensive Cancer Network. National Comprehensive Cancer Network clinical practice guidelines, Rectal cancer.
    1. LENT SOMA tables. Radiother Oncol. 1995. pp. 17–60.
    1. Velenik V, Anderluh F, Oblak I, Strojan P, Segedin B, Zakotnik B. Science and multidisciplinary management of GI malignancies: Proceedings book. Alexandria, VA: American Society of Clinical Oncology; 2008. Preoperative capecitabine and concomitant radiotherapy in operable rectal cancer: a phase II study with 2 years follow-up; p. 325.
    1. Dunst J, Debus J, Rudat V, Wulf J, Budach W, Hoelscher T, Reese T, Mose S, Roedel C, Zuehlke H, Hinke A. Neoadjuvant capecitabine combined with standard radiotherapy in patients with locally advanced rectal cancer. Strahlenther Onkol. 2008;184:450–456. doi: 10.1007/s00066-008-1751-4.
    1. 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;97:1333–1337. doi: 10.1038/sj.bjc.6604042.
    1. Chau I, Brown G, Cunningham D, Tait D, Wotherspoon A, Norman AR, Tebbutt N, Hill M, Ross PJ, Massey A, Oates J. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor risk rectal cancer. J Clin Oncol. 2006;24:668–674. doi: 10.1200/JCO.2005.04.4875.
    1. De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, Pasetto L, Santantonio M, Sarti E, Mantello G, Innocente R, Frustaci S, Corvò R, Rosso R. Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable rectal cancer: a multicentric phase II study. Ann Oncol. 2006;17:246–251. doi: 10.1093/annonc/mdj041.
    1. Desai SP, El-Rayes BF, Ben-Josef E, Greenson JK, Knol JA, Huang EH, Griffith KA, Philip PA, McGinn CJ, Zalupski MM. A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer. Am J Clin Oncol. 2007;30:340–345. doi: 10.1097/COC.0b013e318033ed63.
    1. Dunst J, Reese T, Sutter T, Zühlke H, Hinke A, Kölling-Schlebusch K, Frings S. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol. 2002;20:3983–3991. doi: 10.1200/JCO.2002.02.049.
    1. Dupuis O, Vie B, Liedo G, Hennequin C, Noirclerc M, Bennamoun M, Jacob JH. Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR phase II study. Oncology. 2007;73:169–176. doi: 10.1159/000127383.
    1. Freedman GM, Meropol NJ, Sigurdson ER, Hoffman J, Callahan E, Price R, Cheng J, Cohen S, Lewis N, Watkins-Bruner D, Rogatko A, Konski A. Phase I trial of preoperative hypofractionated intensity-modulated radiotherapy with incorporated boost and oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2007;67:1389–1393.
    1. Kim JS, Kim JS, Cho MJ, Song KS, Yoon WH. Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2002;54:403–408.
    1. Kocakova I, Svoboda M, Klocova K, Chrenko V, Roubalova E, Krejci E, Sefr R, Slampa P, Frgala T, Zaloudik J. Combined therapy of locally advanced rectal adenocarcinoma with capecitabine and concurrent radiotherapy. Proc Am Soc Clin Oncol. 2004;23:299 abstract 3720.
    1. Korkolis DP, Boskos CS, Plataniotis GD, Gontikakis E, Karaitianos IJ, Avgerinos K, Katopodi A, Xinopoulos D, Dimitroulopoulos D, Beroukas K, Vassilopoulos PP. Pre-operative chemoradiotherapy with oral capecitabine in locally advanced, resectable rectal cancer. Anticancer Res. 2007;27:541–545.
    1. Lay GC, Caraul B, Dessi M, Orrù S, Murtas R, Deidda MA, Farigu R, Farci D, Maxia L, Casula G, Amichetti M. 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.
    1. Lin EH, Skibber J, Delcos M. A phase II study of capecitabine and concomitant boost radiotherapy (XRT) in patients with locally advanced rectal cancer. J Clin Oncol. 2005;23(Suppl 16):269s. abstract 3593.
    1. Ngan SY, Michael M, Mackay J, McKendrick J, Leong T, Lim Joon D, Zalcberg JR. A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br J Cancer. 2004;91:1019–1024.
    1. Shen W, Liu Y, Ma X. Capecitabine combined with radiotherapy in Chinese patients with advanced or relapsed rectal carcinoma. Proc Am Soc Clin Oncol. 2004;23:287 abstract 3671.
    1. Veerasarn V, Phromratanapongse P, Lorvidhava V, Lertsanguansinchai P, Lertbutsayanukul C, Panichevaluk A, Boonnuch W, Chinswangwatanakul V, Lohsiriwat D, Rojanasakul A, Thavichaigarn P, Jivapaisarnpong P. Preoperative capacitabine with pelvic radiotherapy for locally advanced rectal cancer (phase I trial) J Med Assoc Thai. 2006;89:1874–1884.
    1. Wong SJ, Sadasiwan C, Erickson B. A phase I trial of preoperative capecitabine and concurrent radiation for locally advanced rectal cancer. Proc Am Soc Clin Oncol. 2004;23:312 abstract 3771.
    1. Kim JC, Kim TW, Kim JH, Yu CS, Kim HC, Chang HM. Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2005;63:346–353. doi: 10.1016/j.ijrobp.2005.05.005.
    1. Das P, Lin EH, Bhatia S, Skibber JM, Rodriguez-Bigas MA, Feig BW, Chang GJ, Hoff PM, Eng C, Wolff RA, Delclos ME, Krishnan S, Janjan NA, Crane CH. Preoperative chemoradiation with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis. Int J Radiat Oncol Biol Phys. 2006;66:1378–1383.

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