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Immune Checkpoint Blockade in Lower Gastrointestinal Cancers: A Systematic Review

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies. Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has demonstrated promising results in other tumour streams.x This review aims to assess the current use of immune checkpoint blockade in patients with lower gastrointestinal tumours.

Patients and Methods

Embase, Medline and Cochrane databases were searched for included studies. Clinical trials published in English and utilising immune checkpoint blockade for primary tumours situated in the lower gastrointestinal tract were included. Databases were searched for studies reporting on at least one of overall survival, progression-free survival or response to therapy.

Results

In total, 972 abstracts were screened, with 10 studies included in the final review. Eight trials (833 patients) assessed immune checkpoint blockade in the setting of colorectal cancers. These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab. A total of 20 patients across all studies achieved a complete response, and 111 patients achieved a partial response to treatment. Two trials (62 patients) assessed immune checkpoint blockade in anal cancer, utilising nivolumab and pembrolizumab. Two patients across both studies achieved a complete response, and 11 patients achieved a partial response.

Conclusions

A number of patients with advanced lower gastrointestinal tumours achieved a complete response to treatment for what would otherwise be considered palliative disease. Presented data have highlighted that particular patients may benefit from first-line or combination immunotherapy, and thus, further investigation is warranted to individualise treatment.

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References

  1. Tamas K, Walenkamp AM, de Vries EG, et al. Rectal and colon cancer: not just a different anatomic site. Cancer Treat Rev. 2015;41(8):671–9.

    Article  CAS  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145–64.

    Article  PubMed  Google Scholar 

  3. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–9.

    Article  CAS  PubMed  Google Scholar 

  4. Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20(6):849–61.

    Article  CAS  PubMed  Google Scholar 

  5. Garrett K, Kalady MF. Anal neoplasms. Surg Clin N Am. 2010;90(1):147–61.

    Article  PubMed  Google Scholar 

  6. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17(3):354–6.

    Article  CAS  PubMed  Google Scholar 

  7. Alamri Y, Buchwald P, Dixon L, et al. Salvage surgery in patients with recurrent or residual squamous cell carcinoma of the anus. Eur J Surg Oncol. 2016;42(11):1687–92.

    Article  CAS  PubMed  Google Scholar 

  8. Hur H, Jung KW, Kim BW, et al. Long-term oncologic outcome and its relevant factors in anal cancer in Korea: a nationwide data analysis. Ann Coloproctol. 2020;36(1):35–40.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fankhaenel B, Zimmer J, Bleyl D, et al. Long-term results achieved by guideline-based stage-dependent management of anal cancer in a non-HIV population. Int J Colorectal Dis. 2019;34(11):1895–905.

    Article  PubMed  Google Scholar 

  10. Jhawer M, Mani S, Lefkopoulou M, et al. Phase II study of mitomycin-C, adriamycin, cisplatin (MAP) and Bleomycin-CCNU in patients with advanced cancer of the anal canal: an eastern cooperative oncology group study E7282. Invest New Drugs. 2006;24(5):447–54.

    Article  CAS  PubMed  Google Scholar 

  11. Eng C, Chang GJ, You YN, et al. The role of systemic chemotherapy and multidisciplinary management in improving the overall survival of patients with metastatic squamous cell carcinoma of the anal canal. Oncotarget. 2014;5(22):11133–42.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Abbas A, Nehme E, Fakih M. Single-agent paclitaxel in advanced anal cancer after failure of cisplatin and 5-fluorouracil chemotherapy. Anticancer Res. 2011;31(12):4637–40.

    CAS  PubMed  Google Scholar 

  13. Rao S, Sclafani F, Eng C, et al. International rare cancers initiative multicenter randomized phase II trial of cisplatin and fluorouracil versus carboplatin and paclitaxel in advanced anal cancer: InterAAct. J Clin Oncol. 2020;38:2510–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Moon EK, Langer CJ, Albelda SM. The era of checkpoint blockade in lung cancer: taking the brakes off the immune system. Ann Am Thorac Soc. 2017;14(8):1248–60.

    Article  PubMed  Google Scholar 

  15. Ugurel S, Rohmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: the impact of MAP kinase pathway inhibition and immune checkpoint inhibition – update 2019. Eur J Cancer. 2020;130:126–38.

    Article  CAS  PubMed  Google Scholar 

  16. Forde PM, Chaft JE, Pardoll DM. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;379(9):e14.

    Article  PubMed  Google Scholar 

  17. Iafolla MAJ, Juergens RA. Update on programmed death-1 and programmed death-ligand 1 inhibition in the treatment of advanced or metastatic non-small cell lung cancer. Front Oncol. 2017;7:67.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cohen R, Rousseau B, Vidal J, Colle R, Diaz LA Jr, Andre T. Immune checkpoint inhibition in colorectal cancer: microsatellite instability and beyond. Target Oncol. 2020;15(1):11–24.

    Article  PubMed  Google Scholar 

  19. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62(10):1006–12.

    Article  Google Scholar 

  20. PEDro: Physiotherapy Evidence Database. 2020; https://www.pedro.org.au. Accessed 1 May 2020.

  21. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1–12.

    Article  CAS  PubMed  Google Scholar 

  22. Sterne JA, Hernan MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gauci ML, Lanoy E, Champiat S, et al. Long-Term survival in patients responding to anti-PD-1/PD-L1 therapy and disease outcome upon treatment discontinuation. Clin Cancer Res. 2019;25(3):946–56.

    Article  PubMed  Google Scholar 

  24. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Massarelli E, William W, Johnson F, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5(1):67–73.

    Article  PubMed  Google Scholar 

  27. Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(4):446–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138(6):2073–87.

    Article  CAS  PubMed  Google Scholar 

  31. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352(18):1851–60.

    Article  CAS  PubMed  Google Scholar 

  32. Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer. 2009;124(7):1626–36.

    Article  PubMed  CAS  Google Scholar 

  34. Hu WH, Miyai K, Cajas-Monson LC, Luo L, Liu L, Ramamoorthy SL. Tumor-infiltrating CD8(+) T lymphocytes associated with clinical outcome in anal squamous cell carcinoma. J Surg Oncol. 2015;112(4):421–6.

    Article  CAS  PubMed  Google Scholar 

  35. Salem ME, Puccini A, Grothey A, et al. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16(5):805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Richards L. Human papillomavirus—a powerful predictor of survival in patients with oropharyngeal cancer. Nat Rev Clin Oncol. 2010;7(9):481.

    Article  PubMed  Google Scholar 

  37. Grinnell M, Krishnan M, Ganti AK. HPV and the immune system in head and neck cancers: therapeutic considerations. Oncology. 2020;34(4):139–43.

    Google Scholar 

  38. Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer. 2018;119(2):153–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lenz H-J. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: clinical update. Gastrointestinal Cancers Symposium; 2020.

  40. Marabelle A, Cassier PA, Fakih M, et al. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: pooled results from the KEYNOTE-028 and KEYNOTE-158 studies. J Clin Oncol. 2020;38(15_suppl):4020.

    Article  Google Scholar 

  41. Diaz LA, Le DT, Kim TW, et al. Pembrolizumab monotherapy for patients with advanced MSI-H colorectal cancer: longer-term follow-up of the phase II, KEYNOTE-164 study. J Clin Oncol. 2020;38(15_suppl):4032.

    Article  Google Scholar 

  42. Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566–76.

    Article  CAS  PubMed  Google Scholar 

  43. Habr-Gama A, Sabbaga J, Gama-Rodrigues J, et al. Watch and wait approach following extended neoadjuvant chemoradiation for distal rectal cancer: are we getting closer to anal cancer management? Dis Colon Rectum. 2013;56(10):1109–17.

    Article  PubMed  Google Scholar 

  44. Fernandez LM, Sao Juliao GP, Figueiredo NL, et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the International Watch & Wait Database: a retrospective, international, multicentre registry study. Lancet Oncol. 2021;22(1):43–50.

    Article  PubMed  Google Scholar 

  45. Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):278.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Sung WWY, Chow JCH, Cho WCS. Tumor mutational burden as a tissue-agnostic biomarker for cancer immunotherapy. Expert Rev Clin Pharmacol. 2021;14(2):141–3.

    Article  CAS  PubMed  Google Scholar 

  48. Fabrizio DA, George TJ Jr, Dunne RF, et al. Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition. J Gastrointest Oncol. 2018;9(4):610–7.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smeby J, Sveen A, Merok MA, et al. CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. Ann Oncol. 2018;29(5):1227–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405–14.

    Article  CAS  PubMed  Google Scholar 

  52. Tejpar S, Stintzing S, Ciardiello F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194–201.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Salem ME, Weinberg BA, Xiu J, et al. Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers. Oncotarget. 2017;8(49):86356–68.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yuki S, Bando H, Tsukada Y, et al. Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. J Clin Oncol. 2020;38(15_suppl):4100.

    Article  Google Scholar 

  55. Andre T, Shiu K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(18_suppl):LBA4.

    Article  Google Scholar 

  56. Shiu K-K, Andre T, Kim TW, et al. KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. J Clin Oncol. 2021;39(3_suppl):6.

    Article  Google Scholar 

  57. Chen EX, Jonker DJ, Loree JM, et al. Effect of combined immune checkpoint inhibition vs best supportive care alone in patients with advanced colorectal cancer: the Canadian Cancer Trials Group CO.26 study. JAMA Oncol. 2020;6(6):831–8.

    Article  PubMed  Google Scholar 

  58. Fumet JD, Isambert N, Hervieu A, et al. Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer. ESMO Open. 2018;3(4):e000375.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ghiringhelli F, Chibaudel B, Taieb J, et al. Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated, microsatellite-stable, previously untreated metastatic colorectal cancer (MCRC): results of the first intermediate analysis of the phase Ib/II MEDETREME trial. J Clin Oncol. 2020;38(15_suppl):3006.

    Article  Google Scholar 

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Acknowledgement

The authors acknowledge J. Berryman (liaison librarian at Brownless Biomedical Library, The University of Melbourne) for assisting with the systematic literature search.

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Authors and Affiliations

  1. Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    K. C. Wilson BSc (Hons), MBBS FRACS, M. P. Flood MRCS, R. G. Ramsay BSc (Hons), PhD & A. G. Heriot MB Bchir, MA, MD, FRACS, FRCS (Gen.), FRCSEd, MBA

  2. Differentiation and Transcription Laboratory, Sir Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    K. C. Wilson BSc (Hons), MBBS FRACS, M. P. Flood MRCS & R. G. Ramsay BSc (Hons), PhD

  3. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    M. Michael BSc (Hons), MBBS (Hons), DM, FRACP

  4. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia

    K. C. Wilson BSc (Hons), MBBS FRACS, M. P. Flood MRCS, D. Oh, N. Calvin, M. Michael BSc (Hons), MBBS (Hons), DM, FRACP & A. G. Heriot MB Bchir, MA, MD, FRACS, FRCS (Gen.), FRCSEd, MBA

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  1. K. C. Wilson BSc (Hons), MBBS FRACS
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Correspondence to K. C. Wilson BSc (Hons), MBBS FRACS.

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Wilson, K.C., Flood, M.P., Oh, D. et al. Immune Checkpoint Blockade in Lower Gastrointestinal Cancers: A Systematic Review. Ann Surg Oncol 28, 7463–7473 (2021). https://doi.org/10.1245/s10434-021-10192-x

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