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Predictive Significance of Mucinous Histology on Pathologic Complete Response Rate Following Capecitabine-Based Neoadjuvant Chemoradiation in Rectal Cancer: a Comparative Study

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Abstract

Introduction

Currently, neoadjuvant fluoropyrimidine-based chemoradiation followed by surgery is considered the standard of care for locally advanced rectal cancer. The current study aimed to investigate the predictive significance of mucinous histology on the pathologic complete response rate following neoadjuvant chemoradiation in locally advanced rectal cancer and to propose potential new treatment protocol for this specific histology.

Material and Method

This retrospective study was conducted on 403 patients with locally advanced (clinically T3–4 and/or N1–2) rectal adenocarcinoma who had been treated at three tertiary academic hospitals between 2010 and 2015. Among those 403 patients, 46 (11%) had mucinous rectal cancer (MRC) and 358 (89%) had non-mucinous rectal cancer (NMRC). All patients underwent neoadjuvant chemoradiation with capecitabine followed by low anterior or abdominoperineal resection.

Results

There were 268 men and 135 women with a median age of 55 years (range, 26–82 years). Patients with MRC were younger (p = 0.002) and presented with a larger tumor size (p < 0.001) and a more advanced tumor stage (p = 0.033) compared to the ones with MNRC. In the univariate analysis, female gender (p = 0.009), distal tumor location (p = 0.035), higher tumor stage (p = 0.049), node positivity (p = 0.001), MRC histology (p = 0.017), and high pretreatment CEA level (p = 0.013) were observed to be predictive of a poor pathologic complete response. However, in the multivariate analysis, tumor stage was the single most predictive factor of response to neoadjuvant chemoradiation.

Conclusion

Mucinous adenocarcinoma is a significant predictive factor for poor pathologic complete response to neoadjuvant capecitabine-based chemoradiation in patients with locally advanced rectal cancer. New treatment modality based on biomarkers may be considered in future prospective studies because of MRC poor prognosis. Immunotherapy combined with chemotherapy and/or radiotherapy may be an attractive option because of the tumor microsatellite instability-high status.

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References

  1. Rule W, Meyer J. Current status of radiation therapy for the management of rectal cancer. Crit Rev Oncog. 2012;17(4):331–43.

    Article  PubMed  Google Scholar 

  2. Kaiser AM, Klaristenfeld D, Beart RW. Preoperative versus postoperative radiotherapy for rectal cancer in a decision analysis and outcome prediction model. Ann Surg Oncol. 2012;19(13):4150–60. https://doi.org/10.1245/s10434-012-2445-9.

    Article  PubMed  Google Scholar 

  3. Nelson VM, Benson AB 3rd. Pathological complete response after neoadjuvant therapy for rectal cancer and the role of adjuvant therapy. Curr Oncol Rep. 2013;15(2):152–61. https://doi.org/10.1007/s11912-013-0297-5.

    Article  CAS  PubMed  Google Scholar 

  4. Diaz-Gonzalez JA, Calvo FA, Cortes J, Garcia-Sabrido JL, Gomez-Espi M, Del Valle E, et al. Prognostic factors for disease-free survival in patients with T3-4 or N+ rectal cancer treated with preoperative chemoradiation therapy, surgery, and intraoperative irradiation. Int J Radiat Oncol Biol Phys. 2006;64(4):1122–8.

    Article  PubMed  Google Scholar 

  5. Martin ST, Heneghan HM, Winter DC. Systematic review of outcomes after intersphincteric resection for low rectal cancer. Br J Surg. 2012;99(5):603–12. https://doi.org/10.1002/bjs.8677.

    Article  CAS  PubMed  Google Scholar 

  6. Maas M, Lambregts DMJ, Nelemans PJ, Heijnen LA, Martens MH, Leijtens JWA, et al. Assessment of clinical complete response after chemoradiation for rectal cancer with digital rectal examination, endoscopy, and MRI: selection for organ-saving treatment. Ann Surg Oncol. 2015;22(12):3873–80. https://doi.org/10.1245/s10434-015-4687-9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lambregts DM, Vandecaveye V, Barbaro B, Bakers FC, Lambrecht M, Maas M, et al. Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study. Ann Surg Oncol. 2011;18(8):2224–31. https://doi.org/10.1245/s10434-011-1607-5.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hur H, Kim NK, Min BS, Baik SH, Lee KY, Koom WS, et al. Can a biomarker-based scoring system predict pathologic complete response after preoperative chemoradiotherapy for rectal cancer? Dis Colon Rectum. 2014;57(5):592–601. https://doi.org/10.1097/dcr.0000000000000109.

    Article  PubMed  Google Scholar 

  9. Debunne H, Ceelen W. Mucinous differentiation in colorectal cancer: molecular, histological and clinical aspects. Acta Chir Belg. 2013;113(6):385–90.

    Article  CAS  PubMed  Google Scholar 

  10. Grillo-Ruggieri F, Mantello G, Berardi R, Cardinali M, Fenu F, Iovini G, et al. Mucinous rectal adenocarcinoma can be associated to tumor downstaging after preoperative chemoradiotherapy. Dis Colon Rectum. 2007;50(10):1594–603. https://doi.org/10.1007/s10350-007-9026-1.

    Article  PubMed  Google Scholar 

  11. Catalano V, Loupakis F, Graziano F, Torresi U, Bisonni R, Mari D, et al. Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy. Br J Cancer. 2009;100(6):881–7. https://doi.org/10.1038/sj.bjc.6604955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Benson AB, Venook AP, Cederquist L, Chan E, Chen YJ, Cooper HS, et al. Colon cancer, version 1.2017: clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15(3):370–98.

    Article  CAS  Google Scholar 

  13. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4. https://doi.org/10.1245/s10434-010-0985-4.

    Article  PubMed  Google Scholar 

  14. Hosseini S, Bananzadeh AM, Salek R, Zare-Bandamiri M, Kermani AT, Mohammadianpanah M. Prognostic significance of mucinous histologic subtype on oncologic outcomes in patients with colorectal cancer. Ann Coloproctol. 2017;33(2):57–63. https://doi.org/10.3393/ac.2017.33.2.57.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann Surg Oncol. 2012;19(9):2814–21. https://doi.org/10.1245/s10434-012-2321-7.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chew MH, Yeo SAE, Ng ZP, Lim KH, Koh PK, Ng KH, et al. Critical analysis of mucin and signet ring cell as prognostic factors in an Asian population of 2,764 sporadic colorectal cancers. Int J Color Dis. 2010;25(10):1221–9. https://doi.org/10.1007/s00384-010-1033-3.

    Article  Google Scholar 

  17. Gosens MJEM, Klaassen RA, Tan-Go I, Rutten HJT, Martijn H, Van Den Brule AJC, et al. Circumferential margin involvement is the crucial prognostic factor after multimodality treatment in patients with locally advanced rectal carcinoma. Clin Cancer Res. 2007;13(22):6617–23. https://doi.org/10.1158/1078-0432.CCR-07-1197.

    Article  CAS  PubMed  Google Scholar 

  18. Mawdsley S, Glynne-Jones R, Grainger J, Richman P, Makris A, Harrison M, et al. Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival? Int J Radiat Oncol Biol Phys. 2005;63(3):745–52. https://doi.org/10.1016/j.ijrobp.2005.03.003.

    Article  PubMed  Google Scholar 

  19. Numata M, Shiozawa M, Watanabe T, Tamagawa H, Yamamoto N, Morinaga S, et al. The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease. World J Surg Oncol. 2012;10:109. https://doi.org/10.1186/1477-7819-10-109.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Oberholzer K, Menig M, Kreft A, Schneider A, Junginger T, Heintz A, et al. Rectal cancer: mucinous carcinoma on magnetic resonance imaging indicates poor response to neoadjuvant chemoradiation. Int J Radiat Oncol Biol Phys. 2012;82(2):842–8. https://doi.org/10.1016/j.ijrobp.2010.08.057.

    Article  PubMed  Google Scholar 

  21. Russell MC, You YN, Hu CY, Cormier JN, Feig BW, Skibber JM, et al. A novel risk-adjusted nomogram for rectal cancer surgery outcomes. JAMA Surg. 2013;148(8):769–77. https://doi.org/10.1001/jamasurg.2013.2136.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sengul N, Wexner SD, Woodhouse S, Arrigain S, Xu M, Larach JA, et al. Effects of radiotherapy on different histopathological types of rectal carcinoma. Color Dis. 2006;8(4):283–8. https://doi.org/10.1111/j.1463-1318.2005.00934.x.

    Article  CAS  Google Scholar 

  23. Shin US, Yu CS, Kim JH, Kim TW, Lim SB, Yoon SN, et al. Mucinous rectal cancer: effectiveness of preoperative chemoradiotherapy and prognosis. Ann Surg Oncol. 2011;18(8):2232–9. https://doi.org/10.1245/s10434-011-1612-8.

    Article  PubMed  Google Scholar 

  24. Hötker AM, Garcia-Aguilar J, Gollub MJ. Multiparametric MRI of rectal cancer in the assessment of response to therapy: a systematic review. Dis Colon Rectum. 2014;57(6):790–9. https://doi.org/10.1097/DCR.0000000000000127.

    Article  PubMed  Google Scholar 

  25. Hugen N, van de Velde CJ, Bosch SL, Fütterer JJ, Elferink MA, Marijnen CA, et al. Modern treatment of rectal cancer closes the gap between common adenocarcinoma and mucinous carcinoma. Ann Surg Oncol. 2015;22(8):2669–76. https://doi.org/10.1245/s10434-014-4339-5.

    Article  PubMed  Google Scholar 

  26. McCawley N, Clancy C, O'Neill BDP, Deasy J, McNamara DA, Burke JP. Mucinous rectal adenocarcinoma is associated with a poor response to neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. Dis Colon Rectum. 2016;59(12):1200–8. https://doi.org/10.1097/DCR.0000000000000635.

    Article  PubMed  Google Scholar 

  27. Patel SV, Roxburgh CS, Vakiani E, Shia J, Smith JJ, Temple LK, et al. Distance to the anal verge is associated with pathologic complete response to neoadjuvant therapy in locally advanced rectal cancer. J Surg Oncol. 2016;114(5):637–41. https://doi.org/10.1002/jso.24358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Probst CP, Becerra AZ, Aquina CT, Tejani MA, Wexner SD, Garcia-Aguilar J, et al. Extended intervals after neoadjuvant therapy in locally advanced rectal cancer: the key to improved tumor response and potential organ preservation. J Am Coll Surg. 2015;221(2):430–40. https://doi.org/10.1016/j.jamcollsurg.2015.04.010.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yu SKT, Chand M, Tait DM, Brown G. Magnetic resonance imaging defined mucinous rectal carcinoma is an independent imaging biomarker for poor prognosis and poor response to preoperative chemoradiotherapy. Eur J Cancer. 2014;50(5):920–7. https://doi.org/10.1016/j.ejca.2013.12.007.

    Article  PubMed  Google Scholar 

  30. Moureau-Zabotto L, Farnault B, De Chaisemartin C, Esterni B, Lelong B, Viret F, et al. Predictive factors of tumor response after neoadjuvant chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2011;80(2):483–91. https://doi.org/10.1016/j.ijrobp.2010.02.025.

    Article  PubMed  Google Scholar 

  31. Negri FV, Wotherspoon A, Cunningham D, Norman AR, Chong G, Ross PJ. Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer. Ann Oncol. 2005;16(8):1305–10. https://doi.org/10.1093/annonc/mdi244.

    Article  CAS  PubMed  Google Scholar 

  32. Bonetti LR, Lionti S, Domati F, Barresi V. Do pathological variables have prognostic significance in rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy and surgery? World J Gastroenterol. 2017;23(8):1412–23. https://doi.org/10.3748/wjg.v23.i8.1412.

    Article  Google Scholar 

  33. Kazama Y, Watanabe T, Kanazawa T, Tada T, Tanaka J, Nagawa H. Mucinous carcinomas of the colon and rectum show higher rates of microsatellite instability and lower rates of chromosomal instability: a study matched for T classification and tumor location. Cancer. 2005;103(10):2023–9. https://doi.org/10.1002/cncr.21022.

    Article  CAS  PubMed  Google Scholar 

  34. Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterol. 1999;117(1):123–31. https://doi.org/10.1016/S0016-5085(99)70558-5.

    Article  CAS  Google Scholar 

  35. Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut. 2006;55(6):848–55. https://doi.org/10.1136/gut.2005.073015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57. https://doi.org/10.1056/NEJMoa022289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158(2):527–35. https://doi.org/10.1016/S0002-9440(10)63994-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. 1999;154(6):1805–13. https://doi.org/10.1016/S0002-9440(10)65436-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43–51. https://doi.org/10.1158/2159-8290.CD-14-0863.

    Article  CAS  PubMed  Google Scholar 

  40. Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomark Prev. 2014;23(12):2965–70. https://doi.org/10.1158/1055-9965.EPI-14-0654.

    Article  CAS  Google Scholar 

  41. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20. https://doi.org/10.1056/NEJMoa1500596.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gunther JR, Chadha AS, Shin US, Park IJ, Kattepogu KV, Grant JD, et al. Preoperative radiation dose escalation for rectal cancer using a concomitant boost strategy improves tumor downstaging without increasing toxicity: a matched-pair analysis. Adv Radiat Oncol. 2017;2(3):455–64. https://doi.org/10.1016/j.adro.2017.04.001.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Omidvari S, Zohourinia S, Ansari M, Ghahramani L, Zare-Bandamiri M, Mosalaei A, et al. Efficacy and safety of low-dose-rate endorectal brachytherapy as a boost to neoadjuvant chemoradiation in the treatment of locally advanced distal rectal cancer: a phase-II clinical trial. Ann Coloproctol. 2015;31(4):123–30. https://doi.org/10.3393/ac.2015.31.4.123.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. https://doi.org/10.1200/jco.2017.76.2229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang ZX, Cao JX, Liu ZP, Cui YX, Li CY, Li D, et al. Combination of chemotherapy and immunotherapy for colon cancer in China: a meta-analysis. World J Gastroenterol. 2014;20(4):1095–106. https://doi.org/10.3748/wjg.v20.i4.1095.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank Dayleen De Riggs for the editing of this manuscript.

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Authors and Affiliations

  1. Cancer Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Sare Hosseini

  2. Department of Radiation Oncology, Howard University Hospital, 2401 Georgia Avenue, NW, Room 2055, Washington, DC, 20060, USA

    NamPhong Nguyen

  3. Colorectal Research Center, Department of Radiation Oncology, Shiraz University of Medical Sciences, Shiraz, 71936, Iran

    Mohammad Mohammadianpanah

  4. Department of Radiation Oncology, Shiraz University of Medical Sciences, Shiraz, Iran

    Sepideh Mirzaei

  5. Colorectal Research Center, Department of Colorectal Surgery, Shiraz University of Medical Sciences, Shiraz, Iran

    Ali Mohammad Bananzadeh

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  1. Sare Hosseini
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Corresponding author

Correspondence to Mohammad Mohammadianpanah.

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This retrospective study was conducted at the radiation oncology departments of three tertiary academic Iranian hospitals following approval by their respective institutional review boards (IRB) in accordance with Helsinki’s code of ethics guidelines.

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The authors declare that they have no conflict of interest.

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Hosseini, S., Nguyen, N., Mohammadianpanah, M. et al. Predictive Significance of Mucinous Histology on Pathologic Complete Response Rate Following Capecitabine-Based Neoadjuvant Chemoradiation in Rectal Cancer: a Comparative Study. J Gastrointest Canc 50, 716–722 (2019). https://doi.org/10.1007/s12029-018-0136-x

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