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Chemoradiotherapy for anal cancer: are we as good as we think?

Radiochemotherapie für das Analkarzinom: Sind wir so gut, wie wir denken?

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Abstract

Definitive chemoradiotherapy (CRT) is the standard treatment for anal squamous cell carcinoma (ASCC). Data regarding treatment outcome according to TNM classification is scarce. Here, we review data of randomized trials and retrospective cohorts suggesting a poor 3‑year disease-free survival (DFS; or progression-free survival, PFS) of approximately 60%, or even lower, in patients with locally advanced T3–4 and/or N+ disease, while patients with T1–2N0 ASCC have 3‑year DFS/PFS rates exceeding 80%. These results are in line with our data in a cohort of 210 patients with ASCC treated with definitive 5‑fluorouracil/mitomycin C‑based CRT to a total dose of 50.4 Gy plus a boost of 3.6–10.8 Gy. The implications of these findings and the current trials testing radiotherapy dose escalation/de-escalation strategies are reported. Finally, we will discuss the strong rationale for testing immune checkpoint blockade (ICB) with CRT in clinical trials to improve results, especially in patients with advanced ASCC.

Zusammenfassung

Die Radiochemotherapie (RCT) ist die Standardbehandlung für das Analkarzinom, es gibt allerdings nur wenige publizierte Daten zu Behandlungsergebnissen aufgeschlüsselt nach TNM-Kategorien. Die hier zusammengefassten Daten aus randomisierten Studien und retrospektiven Auswertungen belegen ein schlechtes krankheitsfreies (DFS) oder progressionsfreies Überleben (PFS) von etwa nur 60% oder niedriger nach 3 Jahren für Patienten mit lokal fortgeschrittenen Analkarzinomen im Stadium T3–4 und/oder N+. Demgegenüber zeigen Patienten im Stadium T1–2N0 ein 3‑Jahres-DFS/-PFS von über 80%. Diese Daten korrespondieren mit den Ergebnissen aus unserer Klinik an 210 Patienten mit Analkarzinom, welche mit definitiver RCT mit 5‑Fluoruracil/Mitomycin C bis zu einer Gesamtdosis von 50,4 Gy plus Boost von 3,6–10,8 Gy behandelt wurden. Die Bedeutung dieser Daten im Kontext aktuell laufender Studien zu Eskalations- und Deeskalationsstrategien wird aufgezeigt. Schließlich diskutieren wir, warum die Hinzunahme von Immun-Checkpoint-Inhibitoren zur RCT eine deutliche Verbesserung der Behandlungsergebnisses insbesondere für lokal fortgeschrittene Analkarzinome bewirken könnte.

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References

  1. Shiels MS, Kreimer AR, Coghill AE et al (2015) Anal cancer incidence in the United States, 1977–2011: distinct patterns by histology and behavior. Cancer Epidemiol Biomarkers Prev 24:1548–1556. https://doi.org/10.1158/1055-9965.EPI-15-0044

    Article  PubMed  PubMed Central  Google Scholar 

  2. Nigro ND, Seydel HG, Considine B et al (1983) Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 51:1826–1829

    Article  CAS  PubMed  Google Scholar 

  3. Martin D, Balermpas P, Winkelmann R et al (2018) Anal squamous cell carcinoma—State of the art management and future perspectives. Cancer Treat Rev 65:11–21. https://doi.org/10.1016/j.ctrv.2018.02.001

    Article  PubMed  Google Scholar 

  4. James RD, Glynne-Jones R, Meadows HM et al (2013) Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 14:516–524. https://doi.org/10.1016/S1470-2045(13)70086-X

    Article  CAS  PubMed  Google Scholar 

  5. Peiffert D, Tournier-Rangeard L, Gérard J‑P et al (2012) Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 30:1941–1948. https://doi.org/10.1200/JCO.2011.35.4837

    Article  CAS  PubMed  Google Scholar 

  6. Gunderson LL, Winter KA, Ajani JA et al (2012) Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 30:4344–4351. https://doi.org/10.1200/JCO.2012.43.8085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oblak I, Petric P, Anderluh F et al (2012) Long term outcome after combined modality treatment for anal cancer. Radiol Oncol. https://doi.org/10.2478/v10019-012-0022-2

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tomaszewski JM, Link E, Leong T et al (2012) Twenty-five-year experience with radical chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys 83:552–558. https://doi.org/10.1016/j.ijrobp.2011.07.007

    Article  PubMed  Google Scholar 

  9. Leon O, Guren M, Hagberg O et al (2014) Anal carcinoma—Survival and recurrence in a large cohort of patients treated according to Nordic guidelines. Radiother Oncol 113:352–358. https://doi.org/10.1016/j.radonc.2014.10.002

    Article  PubMed  Google Scholar 

  10. Nilsson PJ, Svensson C, Goldman S, Glimelius B (2002) Salvage abdominoperineal resection in anal epidermoid cancer. Br J Surg 89:1425–1429. https://doi.org/10.1046/j.1365-2168.2002.02231.x

    Article  CAS  PubMed  Google Scholar 

  11. UKCCCR Anal Cancer Trial Working Party (1996) Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5‑fluorouracil, and mitomycin. Lancet 348:1049–1054

    Article  Google Scholar 

  12. Northover J, Glynne-Jones R, Sebag-Montefiore D et al (2010) Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer 102:1123–1128. https://doi.org/10.1038/sj.bjc.6605605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Glynne-Jones R, Sebag-Montefiore D, Adams R et al (2013) Prognostic factors for recurrence and survival in anal cancer: generating hypotheses from the mature outcomes of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I). Cancer 119:748–755. https://doi.org/10.1002/cncr.27825

    Article  CAS  PubMed  Google Scholar 

  14. Ajani JA, Winter KA, Gunderson LL et al (2008) Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 299:1914–1921. https://doi.org/10.1001/jama.299.16.1914

    Article  CAS  PubMed  Google Scholar 

  15. Ajani JA, Winter KA, Gunderson LL et al (2010) Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the intergroup trial (RTOG 98-11). Cancer 116:4007–4013. https://doi.org/10.1002/cncr.25188

    Article  PubMed  Google Scholar 

  16. Martin D, Balermpas P, Fokas E et al (2017) Are there HIV-specific differences for anal cancer patients treated with standard chemoradiotherapy in the era of combined antiretroviral therapy? Clin Oncol 29:248–255. https://doi.org/10.1016/j.clon.2016.12.010

    Article  CAS  Google Scholar 

  17. Gryc T, Ott O, Putz F et al (2016) Interstitial brachytherapy as a boost to patients with anal carcinoma and poor response to chemoradiation: single-institution long-term results. Brachytherapy 15:865–872. https://doi.org/10.1016/j.brachy.2016.08.003

    Article  PubMed  Google Scholar 

  18. Pan YB, Maeda Y, Wilson A et al (2018) Late gastrointestinal toxicity after radiotherapy for anal cancer: a systematic literature review. Acta Oncol. https://doi.org/10.1080/0284186X.2018.1503713

    Article  PubMed  Google Scholar 

  19. Martin V, Zanellato E, Franzetti-Pellanda A et al (2014) EGFR, KRAS, BRAF, and PIK3CA characterization in squamous cell anal cancer. Histol Histopathol 29:513–521. https://doi.org/10.14670/HH-29.10.513

    Article  CAS  PubMed  Google Scholar 

  20. Serup-Hansen E, Linnemann D, Høgdall E et al (2015) KRAS and BRAF mutations in anal carcinoma. APMIS 123:53–59. https://doi.org/10.1111/apm.12306

    Article  CAS  PubMed  Google Scholar 

  21. Casadei Gardini A, Capelli L, Ulivi P et al (2014) KRAS, BRAF and PIK3CA status in squamous cell anal carcinoma (SCAC). PLoS ONE 9:e92071. https://doi.org/10.1371/journal.pone.0092071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garg MK, Zhao F, Sparano JA et al (2017) Cetuximab plus chemoradiotherapy in Immunocompetent patients with anal carcinoma: a phase II eastern cooperative oncology group–American College of Radiology Imaging Network Cancer Research Group Trial (E3205). J Clin Oncol 35:718–726. https://doi.org/10.1200/JCO.2016.69.1667

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sparano JA, Lee JY, Palefsky J et al (2016) Cetuximab plus chemoradiotherapy for HIV-associated anal carcinoma: a phase II AIDS malignancy consortium trial. J Clin Oncol 35:727–733. https://doi.org/10.1200/JCO.2016.69.1642

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ott OJ, Schmidt M, Semrau S et al (2018) Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus. Strahlenther Onkol. https://doi.org/10.1007/s00066-018-1396-x

    Article  PubMed  Google Scholar 

  25. Ouhoummane N, Steben M, Coutlée F et al (2013) Squamous anal cancer: patient characteristics and HPV type distribution. Cancer Epidemiol 37:807–812. https://doi.org/10.1016/j.canep.2013.09.015

    Article  CAS  PubMed  Google Scholar 

  26. Balermpas P, Martin D, Wieland U et al (2017) Human papilloma virus load and PD-1/PD-L1, CD8+ and FOXP3 in anal cancer patients treated with chemoradiotherapy: rationale for immunotherapy. Oncoimmunology 6:e1288331. https://doi.org/10.1080/2162402X.2017.1288331

    Article  PubMed  PubMed Central  Google Scholar 

  27. Govindarajan R, Gujja S, Siegel ER et al (2016) Programmed cell death-ligand 1 (PD-L1) expression in anal cancer. Am J Clin Oncol. https://doi.org/10.1097/COC.0000000000000343

    Article  Google Scholar 

  28. Zhao Y‑J, Sun W‑P, Peng J‑H et al (2018) Programmed death-ligand 1 expression correlates with diminished CD8+ T cell infiltration and predicts poor prognosis in anal squamous cell carcinoma patients. Cancer Manag Res 10:1–11. https://doi.org/10.2147/CMAR.S153965

    Article  PubMed  Google Scholar 

  29. Ott PA, Piha-Paul SA, Munster P et al (2017) Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 28:1036–1041. https://doi.org/10.1093/annonc/mdx029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Morris VK, Salem ME, Nimeiri H et al (2017) Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol 18:446–453. https://doi.org/10.1016/S1470-2045(17)30104-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461. https://doi.org/10.1016/j.ccell.2015.03.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Antonia SJ, Villegas A, Daniel D et al (2017) Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 377:1919–1929. https://doi.org/10.1056/NEJMoa1709937

    Article  CAS  PubMed  Google Scholar 

  33. Antonia SJ, Villegas A, Daniel D et al (2018) Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. https://doi.org/10.1056/NEJMoa1809697

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Radiotherapy and Oncology, Goethe-University Frankfurt am Main, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    D. Martin M.D., C. Rödel & E. Fokas

  2. German Cancer Research Center (DKFZ), Heidelberg, Germany

    C. Rödel & E. Fokas

  3. partner site: Frankfurt a. M., German Cancer Consortium (DKTK), Frankfurt a. M., Germany

    C. Rödel & E. Fokas

Authors
  1. D. Martin M.D.
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Correspondence to D. Martin M.D..

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D. Martin, C. Rödel and E. Fokas declare that they have no competing interests.

Ethical standards

All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Martin, D., Rödel, C. & Fokas, E. Chemoradiotherapy for anal cancer: are we as good as we think?. Strahlenther Onkol 195, 369–373 (2019). https://doi.org/10.1007/s00066-019-01444-7

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  • DOI: https://doi.org/10.1007/s00066-019-01444-7

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