ORIGINAL PAPER
Neoadjuvant Conformal Chemoradiation with Induction Chemotherapy for Rectal Adenocarcinoma. A Prospective Observational Study Zsolt Fekete1, 2, Alina-Simona Muntean2, Ştefan Hica2, Alin Rancea1, 2, Liliana Resiga2, Csaba Csutak1, 3, Nicolae Todor2, Viorica Magdalena Nagy1, 2
1) University of Medicine and Pharmacy Iuliu Haţieganu 2) Institute of Oncology Prof. Dr. Ion Chiricuţă 3) Scandia Imagistica Cluj-Napoca, Romania
Address for correspondence: Zsolt Fekete University of Medicine and Pharmacy Iuliu Haţieganu Victor Babeş Str. 8 400012 Cluj-Napoca, Romania
[email protected]
Received: 05.12.2013 Accepted: 31.03.2014
ABSTRACT Background & Aims: The purpose of this prospective observational study was to evaluate the rate and the prognostic factors for down-staging and complete response for rectal adenocarcinoma after induction chemotherapy and neoadjuvant chemoradiation followed by surgery, and to analyze the rate of sphinctersaving surgery. Methods: We included from March 2011 to October 2013 a number of 88 patients hospitalized with locally advanced rectal adenocarcinoma in the Prof. Dr. Ion Chiricuta Institute of Oncology, Cluj. The treatment schedule included 2-4 cycles of Oxaliplatin plus a fluoropyrimidine followed by concomitant chemoradiation with a dose of 50 Gy in 25 fractions combined with a fluoropyrimidine monotherapy. Results:The rate of T down-staging was 49.4% (40/81 evaluable patients). Independent prognostic factors for T down-staging were: age >57 years (p 80 U/ml, versus only 10.5% of G1/2 tumors (p=0.03).
Table IV. Studied prognostic factors for T down-staging Prognostic factor
Down-staged number
Not down-staged number
p
female male
13 (52%) 29 (65.9%)
12 (48%) 15 (34.09%)
0.26
≤57 years >57 years
9 (30%) 31 (60.8%)
21 (70%) 20 (39.2%)
5
15 (37.5%) 25 (61%)
25 (62.5%) 16 (39%)
0.03
Involvement of the sigmoid Yes No
8 (53.3%) 32 (48.5%)
7 (46.7%) 34 (51.5%)
0.73
Invasion of the perirectal fascia Yes No
11 (44%) 18 (46.2%)
14 (56%) 21 (53.8%)
0.87
21 (60%) 4 (30.8%)
14 (40%) 19 (69.2%)
Number of chemotherapy cycles with Oxaliplatin ≤3 >3
12 (37.5%) 18 (60%)
20 (62.5%) 12 (40%)
p=0.08 PROC =0.05
Duration of radiotherapy (days) ≤35 >35
12 (33.3%) 28 (62.2%)
24 (66.7%) 17 (37.8%)
5 ng/ml [20] CA 19-9 is becoming an important marker in colorectal cancer, although it is not included yet in standard protocols. It has been shown since the nineties that it is an independent prognostic factor [21] and is useful in metastatic disease [22]; recently its value has been demonstrated for follow-up [23]. Increased CA 19-9 has been correlated with high CEA, lymph node metastasis, right colon tumors, large tumor size and peritoneal seeding [24]. We have shown that CA 19-9 is more frequently increased in G3 tumors, independently of the (clinically established) stage. The limits of our study are the relatively small number of patients, a certain degree of heterogeneity of the patient groups and the fact that it was only an observational study and not a randomized clinical trial.
CONCLUSIONS Neoadjuvant chemoradiation with induction chemotherapy containing Oxaliplatin produces important down-staging in rectal adenocarcinoma and results in a high rate of sphincter preserving surgery. There are several prognostic factors for T down-staging and complete response. Based on our results, we consider that a randomized clinical trial in LARC with Oxaliplatin induction chemotherapy in one arm to compare the down-staging, complete response, local relapse and metastasis rate should be performed. Conflicts of interest. None to declare. Acknowledgements. The authors thank the staff of the Prof. Dr. Ion Chiricuţă Institute of Oncology for making available the infrastructure of the Institute for the purpose of the study, and for delivering treatment and assisting in gathering information. This study was
177 accomplished with the sponsorship of the European Social Fund through POSDRU project no. 107/1.5/S/78702.
REFERENCES 1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444-1450. 2. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740. 3. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol 2011;29:4633-4640. 4. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results. Ann Surg 2004;240:711-717. 5. Aschele C, Cionini L, Lonardi S, 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 2011;29:2773-2780. 6. Park IJ, You YN, Agarwal A, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012;30:1770-1776. 7. Schiffmann L, Klautke G, Wedermann N, et al. Prognosis of rectal cancer patients improves with downstaging by intensified neoadjuvant radiochemotherapy - a matched pair analysis. BMC Cancer 2013;13:388. 8. Sun Myint A, Grieve RJ, McDonald AC, et al. Combined modality treatment of early rectal cancer: the UK experience. Clin Oncol (R Coll Radiol) 2007;19:674-681. 9. Sun Myint A, Fekete Z, Whitmarsh K, et al. A multimodality personalized treatment for elderly patients with early low rectal cancer. Paper presented at: 9th NCRI Cancer Conference; 2013 November 3-6; Liverpool, UK. 10. Colon and Rectum. In: Edge SB, Byrd DR, Compton CC, et al. (Eds): AJCC Cancer Staging Manual (7th Edn). Springer Verlag, New York, 2009:143-164. 11. Fernandez-Martos C, Pericay C, Salud A, et al. Three-year outcomes of GCR-3: a phase II randomized trial comparing conventional preoperative chemoradiation (CRT) followed by surgery and postoperative adjuvant chemotherapy (CT) with induction CT followed by CRT and surgery in locally advanced rectal cancer [abstract]. J Clin Oncol 2011;29 (15 Suppl):3552. 12. Ricardi U, Racca P, Franco P, et al. Prospective phase II trial of neoadjuvant chemo-radiotherapy with Oxaliplatin and Capecitabine in locally advanced rectal cancer (XELOXART). Med Oncol 2013;30:581. 13. Zorcolo L, Rosman AS, Restivo A, et al. Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis. Ann Surg Oncol 2012;19:2822-2832. 14. National Comprehensive Cancer Network. Rectal cancer. NCCN Guidelines for Treatment of Cancer by Site. Available from: http://www. nccn.org/professionals/physician_gls/f_guidelines.asp 15. Gérard JP, Azria D, Gourgou-Bourgade S, 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 2010;28:1638-1644. 16. Roh MS, Yothers GA, O‘Connell MJ, et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients
J Gastrointestin Liver Dis, June 2014 Vol. 23 No 2: 171-178
178 with carcinoma of the rectum: NSABP R-04. ASCO Meeting Abstracts, Jun 9, 2011:3503. 17. Rödel C, Liersch T, Becker H, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 2012;13:679-687. 18. Calvo F, Serrano F, Gomez-Espi M, et al. Induction Oxaliplatin + 5-FU improves further the incidence of pT0 downstaged surgical specimens in ≥cT3 rectal cancer treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 2003;57 (2 Suppl):S178-S179. 19. Foster JD, Jones EL, Falk S, Cooper EJ, Francis NK. Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature. Dis Colon Rectum 2013;56:921-930.
J Gastrointestin Liver Dis, June 2014 Vol. 23 No 2: 171-178
Fekete et al 20. Yeo SG, Kim DY, Chang HJ, et al. Reappraisal of pretreatment carcinoembryonic antigen in patients with rectal cancer receiving preoperative chemoradiotherapy. Tumori 2013;99:93-99. 21. Filella X, Molina R, Grau JJ, et al. Prognostic value of CA 19.9 levels in colorectal cancer. Ann Surg 1992;216:55–59. 22. Wang WS, Lin JK, Chiou TJ, et al. CA19-9 as the most significant prognostic indicator of metastatic colorectal cancer. Hepatogastroenterology 2002;49:160-164. 23. Yang SH, Jiang JK, Chang SC, Juang CJ, Lin JK. Clinical significance of CA19-9 in the follow-up of colorectal cancer patients with elevated preoperative serum CA19-9. Hepatogastroenterology 2013;60:1021-1027. 24. Yu H, Son GM, Joh YG. The clinical significance of preoperative serum levels of carbohydrate antigen 19-9 in colorectal cancer. J Korean Surg Soc 2013;84:231–237.
