Clinical Study

Association between adjuvant chemotherapy and survival in patients with rectal cancer and pathological complete response after neoadjuvant chemoradiotherapy and resection

Abstract

Background

For patients with locally advanced rectal cancer (LARC), it is unclear whether neoadjuvant chemoradiotherapy-induced pathologic complete response (pCR) individuals would further benefit from adjuvant chemotherapy (ACT).

Methods

The pCR individuals who received different ACT cycles were paired by propensity score matching. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan–Meier and log-rank test.

Results

In total, 1041 pCR individuals were identified from 5567 LARC cases. Specifically, 303 pCR cases had no ACT treatment, and 738 pCR patients received fluoropyrimidine-based ACT (median, 4 cycles) treatment. After 1:3 propensity score matching, 297 cases without ACT treatment were matched to 712 cases who received ACT treatment. Kaplan–Meier analysis showed that pCR individuals treated with or without ACT had the similar 3-year outcome (OS, DFS, LRFS and DMFS) (all P > 0.05). Moreover, the pCR patients received different ACT cycle(s) (0 vs. 1–4 cycles, 0 vs. ≥5 cycles) had comparable 3-year OS, DFS, LRFS and DMFS (all P > 0.05). In stratified analysis, ACT treatment did not improve 3-year survival (OS, DFS, LRFS and DMFS) for the baseline high-risk (cT3–4/cN1–2) subgroup patients (all P > 0.05).

Conclusion

ACT, which did not improve survival, is unnecessary to neoadjuvant treatment-induced pCR LARC patients.

Trial registration

2019ZSLYEC-136 (24-6-2019).

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    NCCN. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer (version 2.2019). https://doi.org/10.6004/jnccn.2009.0057.

  2. 2.

    Sauer, R., Becker, H., Hohenberger, W., Rodel, C., Wittekind, C., Fietkau, R. et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N. Engl. J. Med. 351, 1731–1740 (2004).

    CAS  Article  Google Scholar 

  3. 3.

    Sebag-Montefiore, D., Stephens, R. J., Steele, R., Monson, J., Grieve, R., Khanna, S. et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373, 811–820 (2009).

    Article  Google Scholar 

  4. 4.

    Collette, L., Bosset, J. F., den Dulk, M., Nguyen, F., Mineur, L., Maingon, P. et al. Patients with curative resection of cT3–4 rectal cancer after preoperative radiotherapy or radiochemotherapy: does anybody benefit from adjuvant fluorouracil-based chemotherapy? A trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group. J. Clin. Oncol. 25, 4379–4386 (2007).

    CAS  Article  Google Scholar 

  5. 5.

    Maas, M., Nelemans, P. J., Valentini, V., Das, P., Rodel, C., Kuo, L. J. et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 11, 835–844 (2010).

    Article  Google Scholar 

  6. 6.

    Park, I. J., You, Y. N., Agarwal, A., Skibber, J. M., Rodriguez-Bigas, M. A., Eng, C. et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J. Clin. Oncol. 30, 1770–1776 (2012).

    CAS  Article  Google Scholar 

  7. 7.

    Garcia-Aguilar, J., Chow, O. S., Smith, D. D., Marcet, J. E., Cataldo, P. A., Varma, M. G. et al. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 16, 957–966 (2015).

    CAS  Article  Google Scholar 

  8. 8.

    Cercek, A., Roxburgh, C. S. D., Strombom, P., Smith, J. J., Temple, L. K. F., Nash, G. M. et al. Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer. JAMA Oncol. 4, e180071 (2018).

    Article  Google Scholar 

  9. 9.

    Zhang, J. W., Cai, Y., Xie, X. Y., Hu, H. B., Ling, J. Y., Wu, Z. H., et al. Nomogram for predicting pathological complete response and tumor downstaging in patients with locally advanced rectal cancer on the basis of a randomized clinical trial. Gastroenterol. Rep. (Oxf.) 8, 234–241 (2020).

    CAS  Article  Google Scholar 

  10. 10.

    Fokas, E., Strobel, P., Fietkau, R., Ghadimi, M., Liersch, T., Grabenbauer, G. G. et al. Tumor regression grading after preoperative chemoradiotherapy as a prognostic factor and individual-level surrogate for disease-free survival in rectal cancer. J. Natl Cancer Inst. 109, 12 (2017).

    Article  Google Scholar 

  11. 11.

    Moertel, C. G., Fleming, T. R., Macdonald, J. S., Haller, D. G., Laurie, J. A., Goodman, P. J. et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N. Engl. J. Med. 322, 352–358 (1990).

    CAS  Article  Google Scholar 

  12. 12.

    Twelves, C., Wong, A., Nowacki, M. P., Abt, M., Burris, H. 3rd, Carrato, A. et al. Capecitabine as adjuvant treatment for stage III colon cancer. N. Engl. J. Med. 352, 2696–2704 (2005).

    CAS  Article  Google Scholar 

  13. 13.

    Andre, T., Boni, C., Navarro, M., Tabernero, J., Hickish, T., Topham, C. et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J. Clin. Oncol. 27, 3109–3116 (2009).

    CAS  Article  Google Scholar 

  14. 14.

    Quasar Collaborative, G., Gray, R., Barnwell, J., McConkey, C., Hills, R. K., Williams, N. S. et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370, 2020–2029 (2007).

    Article  Google Scholar 

  15. 15.

    Bosset, J. F., Calais, G., Mineur, L., Maingon, P., Stojanovic-Rundic, S., Bensadoun, R. J. et al. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 15, 184–190 (2014).

    CAS  Article  Google Scholar 

  16. 16.

    Sainato, A., Cernusco Luna Nunzia, V., Valentini, V., De Paoli, A., Maurizi, E. R., Lupattelli, M. et al. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): long term results of a randomized trial (I-CNR-RT). Radiother. Oncol. 113, 223–229 (2014).

    Article  Google Scholar 

  17. 17.

    Breugom, A. J., van Gijn, W., Muller, E. W., Berglund, A., van den Broek, C. B., Fokstuen, T. et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann. Oncol. 26, 696–701 (2015).

    CAS  Article  Google Scholar 

  18. 18.

    Carvalho, C. & Glynne-Jones, R. Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer. Lancet Oncol. 18, e354–e363 (2017).

    Article  Google Scholar 

  19. 19.

    Bujko, K., Glynne-Jones, R. & Bujko, M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann. Oncol. 21, 1743–1750 (2010).

    CAS  Article  Google Scholar 

  20. 20.

    Shahab, D., Gabriel, E., Attwood, K., Ma, W. W., Francescutti, V., Nurkin, S. et al. Adjuvant chemotherapy is associated with improved overall survival in locally advanced rectal cancer after achievement of a pathologic complete response to chemoradiation. Clin. Colorectal Cancer 16, 300–307 (2017).

    Article  Google Scholar 

  21. 21.

    Xu, Z., Mohile, S. G., Tejani, M. A., Becerra, A. Z., Probst, C. P., Aquina, C. T. et al. Poor compliance with adjuvant chemotherapy use associated with poorer survival in patients with rectal cancer: an NCDB analysis. Cancer 123, 52–61 (2017).

    CAS  Article  Google Scholar 

  22. 22.

    Turner, M. C., Keenan, J. E., Rushing, C. N., Gulack, B. C., Nussbaum, D. P., Benrashid, E. et al. Adjuvant chemotherapy improves survival following resection of locally advanced rectal cancer with pathologic complete response. J. Gastrointest. Surg. 23, 1614–1622 (2019).

    Article  Google Scholar 

  23. 23.

    Dossa, F., Acuna, S. A., Rickles, A. S., Berho, M., Wexner, S. D., Quereshy, F. A. et al. Association between adjuvant chemotherapy and overall survival in patients with rectal cancer and pathological complete response after neoadjuvant chemotherapy and resection. JAMA Oncol. 4, 930–937 (2018).

    Article  Google Scholar 

  24. 24.

    Tomasello, G., Ghidini, M. & Petrelli, F. Adjuvant chemotherapy in patients with rectal cancer achieving pathologic complete response after neoadjuvant chemoradiation and surgery. Eur. J. Cancer 108, 97–99 (2019).

    Article  Google Scholar 

  25. 25.

    Ma, B., Ren, Y., Chen, Y., Lian, B., Jiang, P., Li, Y. et al. Is adjuvant chemotherapy necessary for locally advanced rectal cancer patients with pathological complete response after neoadjuvant chemoradiotherapy and radical surgery? A systematic review and meta-analysis. Int. J. Colorectal Dis. 34, 113–121 (2019).

    Article  Google Scholar 

  26. 26.

    Breugom, A. J., Swets, M., Bosset, J. F., Collette, L., Sainato, A., Cionini, L. et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 16, 200–207 (2015).

    CAS  Article  Google Scholar 

  27. 27.

    Capirci, C., Valentini, V., Cionini, L., De Paoli, A., Rodel, C., Glynne-Jones, R. 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. 72, 99–107 (2008).

    Article  Google Scholar 

  28. 28.

    Beets, G. L. & Glimelius, B. L. Adjuvant chemotherapy for rectal cancer still controversial. Lancet Oncol. 15, 130–131 (2014).

    Article  Google Scholar 

  29. 29.

    Polanco, P. M., Mokdad, A. A., Zhu, H., Choti, M. A. & Huerta, S. Association of adjuvant chemotherapy with overall survival in patients with rectal cancer and pathologic complete response following neoadjuvant chemotherapy and resection. JAMA Oncol. 4, 938–943 (2018).

    Article  Google Scholar 

  30. 30.

    Chang, G. J. Is there validity in propensity score-matched estimates of adjuvant chemotherapy effects for patients with rectal cancer? JAMA Oncol. 4, 921–923 (2018).

    Article  Google Scholar 

  31. 31.

    Fokas, E., Liersch, T., Fietkau, R., Hohenberger, W., Beissbarth, T., Hess, C. et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J. Clin. Oncol. 32, 1554–1562 (2014).

    Article  Google Scholar 

  32. 32.

    Rodel, C., Martus, P., Papadoupolos, T., Fuzesi, L., Klimpfinger, M., Fietkau, R. et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J. Clin. Oncol. 23, 8688–8696 (2005).

    Article  Google Scholar 

  33. 33.

    Glynne-Jones, R., Wyrwicz, L., Tiret, E., Brown, G., Rodel, C., Cervantes, A. et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29(Suppl. 4), iv263 (2018).

    CAS  Article  Google Scholar 

  34. 34.

    Rödel, C., Graeven, U., Fietkau, R., Hohenberger, W., Hothorn, T., Arnold, D. 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. 16, 979–989 (2015).

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Author information

Affiliations

Authors

Contributions

X.-B.W. and J.A.A. was the principal investigator and designed the study. F.H. performed contouring, treatment planning, and statistical analysis. H.-Q.J., Y.D., Z.J., Z.L., B.H., X.W., Y.Z., Y.L., B.Q., J.Z., Z.Z., Q.P., J.W. and W.L. provided patient data. F.H., H.C., X.P., and S.L. reviewed the data. All authors discussed the data. X.-B.W. and F.H. wrote the original manuscript and subsequent revisions, which were reviewed by all other authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jaffer A. Ajani or Xiang-Bo Wan.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the central ethics committee of the Sixth Affiliated Hospital, Sun Yat-sen University in accordance with the Declaration of Helsinki (No. 2019ZSLYEC-136). The written consent of patients was waived by the ethical committee of the Sixth Affiliated Hospital, Sun Yat-sen University.

Consent to publish

Not applicable.

Data availability

The datasets used during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

This study was supported by International Centre for Genetic Engineering and Biotechnology Research Grant (No. CRP/CHN16-04_EC) and Natural Science Foundation of China (Nos. 81872188 and 81703080).

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

He, F., Ju, H., Ding, Y. et al. Association between adjuvant chemotherapy and survival in patients with rectal cancer and pathological complete response after neoadjuvant chemoradiotherapy and resection. Br J Cancer 123, 1244–1252 (2020). https://doi.org/10.1038/s41416-020-0989-1

Download citation

Search