Neoadjuvant Chemotherapy and Concomitant Boost Radiotherapy in the Treatment of Locally Advanced Rectal Cancer

Main Article Content

Mai AbdAllah Abdelazez
Soumaya Mohamed Eteba
Eman Hamza Elzahhaf
Sameh Roshdy Abdel Aziz
Rehab Omar
Eman Awad Abdallah

Abstract

Aims: This study aimed to examine the efficacy and toxicities of concomitant boost three-dimensional conformal radiotherapy along with multidrug chemotherapy (capecitabine and oxaliplatin) in neoadjuvant course for locally advanced rectal cancer (LARC).

Study Design: A phase II interventional nonrandomized study.

Place and Duration of Study: This Study was conducted at Clinical Oncology and nuclear medicine department of Mansoura University Hospitals (Egypt) between November 2016 and October 2019.

Methodology: Thirty patients (18 women, 12 men; age range 18-75 years) with (cT3-T4 and/or cN+) histologically confirmed rectal adenocarcinoma located within 12 cm of the anal verge were included in this study. Patients received three-dimensional conformal radiotherapy (3DCRT) to the pelvis of 45 Gy and a concomitant boost of 10 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). Radical surgery was scheduled six to eight weeks after chemoradiation. Acute toxicities were recorded according to Common Terminology Criteria for Adverse Event (CTCAE) v5.0. Potential prognostic factors were evaluated using a binomial logistic regression. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test.

Results: All patients received chemoradiation. Twenty-seven patients underwent surgical resection. Twenty-five patients underwent sphincter-sparing surgery (92.6%) and nine patients (33.3%) achieved pathological complete response (pCR). The incidences of grade III neutropenia, diarrhea, and radiation dermatitis were 6.7%, 6.7%, 3.3% respectively. The three-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS) rates were 7.4%, 63% and 74.1%, respectively. We found pre-surgical negative nodal status to be significantly associated with pCR (p=0.009). The pathological nodal stage was an independent prognostic factor to DFS.

Conclusion: The combination of oxaliplatin, capecitabine, and dose escalation using concomitant boost 3DCRT is safely administrated in patients with locally advanced rectal adenocarcinoma and it offers high pCR and sphincter preservation rate.

Keywords:
Rectal Cancer, three-dimensional conformal radiation therapy, concomitant boost, neoadjuvant chemoradiotherapy.

Article Details

How to Cite
Abdelazez, M. A., Eteba, S. M., Elzahhaf, E. H., Aziz, S. R. A., Omar, R., & Abdallah, E. A. (2021). Neoadjuvant Chemotherapy and Concomitant Boost Radiotherapy in the Treatment of Locally Advanced Rectal Cancer. Journal of Cancer and Tumor International, 11(1), 1-19. https://doi.org/10.9734/jcti/2021/v11i130140
Section
Original Research Article

References

Sauer R, Becker H, Hogenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med.2004;351:1731-1740.

Peters KC, van de Velde CJ, Leer JW, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients--a Dutch colorectal cancer group study. J Clin Oncol. 2005;23(25): 6199-6206.
DOI: 10.1200/JCO.2005.14.779

Capirci C, Valentini V, Cionini L, et al. Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys. 2008;72:99–107.

Martin ST, Heneghan HM, Winter DC. Systematic review and meta- analysis of outcomes following pathological complete response to neoadjuvant chemo-radiotherapy for rectal cancer. Br J Surg. 2012;99:918-28.

Gasent Blesa JM, Garde Noguera J, Laforga Canales JB, et al. Phase II trial of concomitant neoadjuvant chemotherapy with oxaliplatin and capecitabine and intensity-modulated radiotherapy (IMRT) in rectal cancer. J Gastrointest Cancer. 2012; 43(4):553–561.

Lee YC, Hsieh CC, Chuang JP. Prognostic significance of partial tumor regression after preoperative chemoradiotherapy for rectal cancer: A meta-analysis. Dis Colon Rectum. 2013;56:1093-1101.

Zhu J, Liu F, Gu W, et al. Concomitant boost IMRT-based neoadjuvant chemo-radiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study. Radiat Oncol. 2014;9:70.

Appelt AL, Ploen J, Vogelius IR, Bentzen SM, Jakobsen A. Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2013;85: 74-80.

Burbach JP, den Harder AM, Intven M, et al. Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: A systematic review and meta-analysis. Radiother Oncol. 2014;113:1-9.

Burbach JP, Verkooijen HM, Intven M, et al. Randomized controlled trial for pre-operative dose-escalation BOOST in locally advanced rectal cancer (RECTAL BOOST study): Study protocol for a randomized controlled trial. Trials. 2015; 16:58.

Gasent Blesa JM, Garde Noguera J, Laforga Canales JB, et al. Phase II trial of concomitant neoadjuvant chemotherapy with oxaliplatin and capecitabine and intensity-modulated radiotherapy (IMRT) in rectal cancer. J Gastrointest Cancer. 2012; 43(4):553–561.

Bajetta E, Celio L, Ferrario E, et al. Capecitabine plus oxaliplatin and irinotecan regimen every other week: a phase I/II study in first-line treatment of metastatic colorectal cancer. Ann Oncol. 2007;18:1810–6.

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.

Allegra CJ, Yothers G, O’Connell MJ, et al. Neoadjuvant 5-FU or capecitabine plus radiation with or without oxaliplatin in rectal cancer patients: a phase III randomized clinical trial. J Natl Cancer Inst. 2015; 107(11).

Haddad P, Miraie M, Farhan F, et al. Addition of oxaliplatin to neoadjuvant radiochemotherapy in MRI-defined T3, T4 or Nþ rectal cancer: a randomized clinical trial. Asia Pac J Clin Oncol. 2017;13(6): 416–422.

Schmoll HJ, Haustermans K, Price TJ, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine +/- oxaliplatin in locally advanced rectal cancer: final results of PETACC-6. J Clin Oncol. 2018;36(15): 3500.

Hüttner FJ, Probst P, Kalkum E, et al. Addition of Platinum Derivatives to Fluoropyrimidine-Based Neoadjuvant Chemoradiotherapy for Stage II/III Rectal Cancer: Systematic Review and Meta-Analysis. J Natl Cancer Inst. 2019;111: 887.

Chen W, Wang W, Li Y, et al. Prospective clinical study of capecitabine plus oxaliplatin concurrent chemoradiotherapy after radical resection of rectal cancer. Chen et al. Cancer Cell Int. 2018;18:123.

Neoadjuvant-intensified treatment for rectal cancer: time to change?

Musio D, De Felice F, Bulzonetti N, Guarnaccia R. J Gastroenterol. 2013; 19(20):3052-61.
DOI:10.3748/wjg.v19.i20.3052.PMID: 23716984. Free PMC article.

Wang, J, Guan Y, Gu W. et al. Radiat Oncol Long-course neoadjuvant chemo-radiotherapy with versus without a concomitant boost in locally advanced rectal cancer: A randomized, multicenter, phase II trial (FDRT-002). 2019;14:215.
Available:https://doi.org/10.1186/s13014-019-1420-z

Couwenberg AM, Burbach JPM, Berbee M, Lacle MM, et al. Efficacy of dose-escalated chemoradiation on complete tumor response in patients with locally advanced rectal cancer (RECTAL-BOOST): A phase 2 randomized controlled trial. Int J Radiat Oncol Biol Phys. 2020; 108(4):1008-1018.
DOI: 10.1016/j.ijrobp.2020.06.013.

Epub 2020 Jun 19.
PMID: 32565319 Free article

Hearn, D Atwell, K Cahill, J Elks, D Vignarajah. Neoadjuvant radiotherapy dose escalation in locally advanced rectal cancer: A systematic review and meta-analysis of modern treatment approaches and outcomes. Clinical Oncology. 2021‏; 33(1):1-14.
Available:https://doi.org/10.1016/j.clon.2020.06.008

Willett C, Ryan D. Neoadjuvant chemo-radiotherapy, radiotherapy, and chemotherapy for rectal adenocarcinoma; 2020.
Available:www.uptodate.com.

Bahadoer RR, Dijkstra EA, Etten BV, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): A randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):29-42.

Martin ST, Heneghan HM, Winter DC. Systematic review and meta- analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg. 2012;99:918-28.

Aschele C. Final results of STAR-01: A randomized phase III trial comparing preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer. J Clin Oncol. 2016;34(15): 3521.

Rödel C, Graeven U, Fietkau R, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): Final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;168: 979–989.

Schmoll HJ, Haustermans K, Price TJ, et al. Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine +/- oxaliplatin in locally advanced rectal cancer: final results of PETACC-6. J Clin Oncol. 2018;36(15): 3500.

Simson DK, Mitra S, Ahlawat P, et al. Prospective study of neoadjuvant chemoradiotherapy using intensity-modulated radiotherapy and 5 fluorouracil for locally advanced rectal cancer – toxicities and response assessment. Cancer Management and Research. 2018: 10;519–526.

Armstrong D, Raissouni S, Price HJ, et al. Predictors of pathologic complete response after neoadjuvant treatment for rectal cancer: A multicenter study. Clin Colorectal Cancer. 2015; 14:291-5.

Yu SK, Tait D, Chau I, Brown G. MRI predictive factors for tumor response in rectal cancer following neoadjuvant chemoradiation therapy--implications for induction chemotherapy? Int J Radiat Oncol Biol Phys. 2013;87:505-11.

Garland ML, Vather R, Bunkley N, et al. Clinical tumour size and nodal status predict pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer. Int J Colorectal Dis. 2014;29:30.

Zhang C, Feng Ye F, Liu Y, et al. Morphologic predictors of pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Oncotarget, 2018;9(4): 4862-4874.

Letaief F, Nasri M, Ayadi M, et al. Potential predictive factors for pathologic complete response after the neoadjuvant treatment of rectal adenocarcinoma: A single center experience. Cancer Biol Med. 2017;14(3).

Engel R, Oliva K, Koulis c, et al. Predictive factors of complete pathological response in patients with locally advanced rectal cancer. International Journal of Colorectal Disease. 2020;35:1759–1767.

Park JS, Baek JH, Lee WS, et al. Long-term oncologic outcomes in pathologic tumor response after neoadjuvant chemoradiation for locally advanced rectal cancer. Korean Journal of Clinical Oncology. 2018;14:37-42.

Kim DW, Kim DY, Kim TH, et al. Is T classification still correlated with lymph node status after preoperative chemoradiotherapy for rectal cancer? Cancer. 2006;106:1694–1700.

Mirbagheri N, Kumar B, Deb S, et al. Lymph node status as a prognostic indicator after preoperative neoadjuvant chemoradiotherapy of rectal cancer. Colorectal Dis. 2014;16:O339–O346.

Langrand-Escure J, Diao P, Garcia MA, Wang G, et al. Outcome and prognostic factors in 593 non-metastatic rectal cancer patients: A mono-institutional survey. Scientific Reports. 2018;8: 10708.
DOI: 10.1038/s41598-018-29040-2.

Fokas E, Liersch T, Fietkau R, et al. Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: The reverse of the Will Rogers phenomenon? Cancer. 2015;121:1724-7.

Gunther JR, Chadha AS, Sup Shin US, et al. Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: A matched-pair analysis. Advances in Radiation Oncology. 2017;2:455-464.

Jiao D, Zhang R, Gong Z, et al. Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study. Chin J Cancer Res. 2015;27(6):588–596.

Yang TJ, Oh JH, Son CH, et al. Predictors of acute gastrointestinal toxicity during pelvic chemoradiotherapy in patients with rectal cancer. Gastrointest Cancer Res. 2013;6(5–6):129–136.

Deng Y, Chi P, Lan P, et al. Modified FOLFOX6 with or without radiation in neoadjuvant treatment of locally advanced rectal cancer: final results of the Chinese FOWARC multicenter randomized trial. J Clin Oncol. 2018;3 6(15):3502.