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Variation in the Thoroughness of Pathologic Assessment and Response Rates of Locally Advanced Rectal Cancers After Chemoradiation

  • Oliver S. Chow
  • Sujata Patil
  • Metin Keskin
  • J. Joshua Smith
  • Maria Widmar
  • David D. Smith
  • Karin Avila
  • Jinru Shia
  • Peiguo Chu
  • Julio Garcia-AguilarEmail author
Article

Abstract

Background

Pathologic complete response (pCR) is associated with better prognosis and guides management for patients with advanced rectal cancer. Response rates vary between series for unclear reasons. We examine whether the thoroughness of pathologic assessment explains differences in pCR rates.

Methods

We retrospectively reviewed pathology reports from patients with stage II/III rectal cancer who underwent chemoradiation and resection in a prospective, multicenter trial. We utilized a novel measure for the thoroughness of pathologic assessment by dividing residual tumor size by the number of cassettes evaluated (tumor size to cassette ratio, TSCR), and evaluated whether TSCR is associated with pCR. We validated our findings using a separate cohort.

Results

From the trial cohort, 71 of 247 (29%) patients achieved pCR. The pCR rate ranged from 0 to 45% and mean TSCR ranged 0.29 to 0.87 across 12 institutions. Within each institution, a lower TSCR was associated with pCR, demonstrating a higher degree of thoroughness used for tumors that achieved pCR. Moreover, across all samples, low TSCR was independently associated with pCR on multivariable analysis. This finding was corroborated in a separate cohort of 201 tumors evaluated by five pathologists; each pathologist had a lower mean TSCR for pCR calls compared with non-pCR calls. However, the mean TSCR for an institution was not associated with its overall pCR rate.

Conclusions

Pathologists assess rectal cancers that have responded significantly to neoadjuvant therapy more thoroughly. Thoroughness does not appear to explain differences in pCR rates between institutions. Our results suggest pCR is not a sampling artifact.

Keywords

Rectal cancer Chemoradiotherapy RECIST Residual tumor Surgical pathology 

Notes

Statement of Author Contribution

Each of the authors included had a substantial contribution to the design, data acquisition, analysis, interpretation, and drafting and review of this manuscript and have agreed to the accuracy and the integrity of the work.

Funding

This study was supported by the National Institutes of Health (NIH) and National Cancer Institute (NCI) R01 Grant CA090559 (JGA) and Core Grant P30 CA008748 (JGA). No financial disclosures.

References

  1. 1.
    Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens J-H, Liersch T, Schmidberger H, Raab R. Preoperative versus postoperative chemoradiotherapy for rectal cancer. The New England journal of medicine 2004; 351: 1731–40.Google Scholar
  2. 2.
    Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011; 29: 2773–80.Google Scholar
  3. 3.
    Gérard J-P, Azria D, Gourgou-Bourgade S, Martel-Lafay I, Hennequin C, Etienne P-L, Vendrely V, François E, de La Roche G, Bouché O, Mirabel X, Denis B, Mineur L, Berdah J-F, Mahé M-A, Bécouarn Y, Dupuis O, Lledo G, Seitz J-F et al. Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012; 30: 4558–65.Google Scholar
  4. 4.
    Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab H-R, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F 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. The Lancet. Oncology 2012; 13: 679–87.Google Scholar
  5. 5.
    O’Connell MJ, Colangelo LH, Beart RW, Petrelli NJ, Allegra CJ, Sharif S, Pitot HC, Shields AF, Landry JC, Ryan DP, Parda DS, Mohiuddin M, Arora A, Evans LS, Bahary N, Soori GS, Eakle J, Robertson JM, Moore DF et al. Capecitabine and oxaliplatin in the preoperative multimodality treatment of rectal cancer: surgical end points from National Surgical Adjuvant Breast and Bowel Project trial R-04. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014; 32: 1927–34.Google Scholar
  6. 6.
    Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo L-J, Calvo FA, García-Aguilar J, Glynne-Jones R, Haustermans K, Mohiuddin M, Pucciarelli S, Small W, Suárez J, Theodoropoulos G, Biondo S, Beets-Tan RGH, Beets GL. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. The Lancet. Oncology 2010; 11: 835–44.Google Scholar
  7. 7.
    de Campos-Lobato LF, Stocchi L, da Luz Moreira A, Geisler D, Dietz DW, Lavery IC, Fazio VW, Kalady MF. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Annals of surgical oncology 2011; 18: 1590–8.Google Scholar
  8. 8.
    Duldulao MP, Lee W, Nelson RA, Li W, Chen Z, Kim J, Garcia-Aguilar J. Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma. Annals of surgical oncology 2013; 20: 2166–71.Google Scholar
  9. 9.
    Gaedcke J, Grade M, Jung K, Schirmer M, Jo P, Obermeyer C, Wolff HA, Herrmann MK, Beissbarth T, Becker H, Ried T, Ghadimi M. KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 2010; 94: 76–81.Google Scholar
  10. 10.
    Chow OS, Kuk D, Keskin M, Smith JJ, Camacho N, Pelossof R, Chen C-T, Chen Z, Avila K, Weiser MR, Berger MF, Patil S, Bergsland E, Garcia-Aguilar J. KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy. Annals of Surgical Oncology 2016; 23: 2548–55.Google Scholar
  11. 11.
    Lopes-Ramos C, Koyama FC, Habr-Gama A, Salim ACM, Bettoni F, Asprino PF, França GS, Gama-Rodrigues J, Parmigiani RB, Perez RO, Galante PAF, Camargo AA. Comprehensive evaluation of the effectiveness of gene expression signatures to predict complete response to neoadjuvant chemoradiotherapy and guide surgical intervention in rectal cancer. Cancer Genetics 2015; 208: 319–26.Google Scholar
  12. 12.
    Schou J V, Larsen FO, Rasch L, Linnemann D, Langhoff J, Høgdall E, Nielsen DL, Vistisen K, Fromm A, Jensen B V. Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before total mesorectal excision in patients with locally advanced rectal cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2012; 23: 2627–33.Google Scholar
  13. 13.
    Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, Tait D, Massey A, Tebbutt NC, Chau I. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial. The Lancet. Oncology 2010; 11: 241–8.Google Scholar
  14. 14.
    Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, Tait D, Brown G, Wotherspoon A, Gonzalez de Castro D, Chua YJ, Wong R, Barbachano Y, Oates J, Chau I. Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012; 30: 1620–7.Google Scholar
  15. 15.
    Cercek A, Goodman KA, Hajj C, Weisberger E, Segal NH, Reidy-Lagunes DL, Stadler ZK, Wu AJ, Weiser MR, Paty PB, Guillem JG, Nash GM, Temple LK, Garcia-Aguilar J, Saltz LB. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. Journal of the National Comprehensive Cancer Network : JNCCN 2014; 12: 513–9.Google Scholar
  16. 16.
    Lorimer PD, Motz BM, Kirks RC, Boselli DM, Walsh KK, Prabhu RS, Hill JS, Salo JC. Pathologic Complete Response Rates After Neoadjuvant Treatment in Rectal Cancer: An Analysis of the National Cancer Database. Annals of Surgical Oncology 2017; 24: 2095–103.Google Scholar
  17. 17.
    Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, Stamos MJ, Ternent CA, Herzig DO, Fichera A, Polite BN, Dietz DW, Patil S, Avila K. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. The Lancet Oncology 2015; 16: 957–66.Google Scholar
  18. 18.
    Jass JR, O’Brien MJ, Riddell RH, Snover DC. Recommendations for the reporting of surgically resected specimens of colorectal carcinoma. Human pathology 2007; 38: 537–45.Google Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2019

Authors and Affiliations

  1. 1.Department of SurgeryBeth Israel Deaconess Medical CenterBostonUSA
  2. 2.Department of SurgeryMemorial Sloan Kettering Cancer CenterNew YorkUSA
  3. 3.Division of BiostatisticsCity of HopeDuarteUSA
  4. 4.Department of PathologyCity of HopeDuarteUSA

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