Definitive Pelvic Radiotherapy and Survival of Patients With Newly Diagnosed Metastatic Anal Cancer

View More View Less
  • a Department of Radiation Oncology, West Cancer Center, and Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska; and Department of Hematology/Oncology, West Cancer Center, University of Tennessee Health Science Center, Memphis, Tennessee.
Restricted access

Background: Chemotherapy with or without pelvic radiotherapy (RT) is included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for metastatic anal cancer (MAC), despite limited clinical evidence for RT in this setting. In addition, increasing evidence shows that local therapies, including RT, may increase patient survival for some types of metastatic cancers. The purpose of this study was to evaluate the patterns of care and association between definitive pelvic RT and overall survival (OS) for patients with MAC. Methods: The National Cancer Database was analyzed to evaluate OS of patients with newly diagnosed MAC treated with chemotherapy with or without pelvic RT. Those who did not undergo treatment, treated with surgery, or without baseline variables were excluded. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score–matched analyses. Results: From 2004 through 2015, 437 patients received chemotherapy alone and 1,020 received pelvic chemoradiotherapy (CRT). At a median follow-up of 17.3 months, CRT was associated with improved OS on univariate (P<.001) and multivariate analysis (hazard ratio [HR], 0.70; 95% CI, 0.61–0.81; P<.001). Propensity score–matched analysis demonstrated superior median survival (21.3 vs 15.9 months) and 2-year OS rates (46% vs 34%) with CRT compared with chemotherapy alone (P<.001). Landmark analyses limited to long-term survivors of ≥1, ≥2, and ≥4 years showed improved OS with CRT in all subsets (all P<.05). CRT with therapeutic doses (≥45 Gy) was associated with longer median survival than palliative doses (<45 Gy) and chemotherapy alone (24.9 vs 10.9 vs 15.6 months, respectively; P<.001). The benefit of CRT was present among not only those with distant lymph node metastasis (HR, 0.63; P=.04) but also those with distant organ disease (HR, 0.74; P<.001). Conclusions: In this large hypothesis-generating analysis, patients with newly diagnosed MAC who received definitive pelvic RT with chemotherapy lived significantly longer than those who received chemotherapy alone. Prospective trials evaluating definitive local RT for MAC are warranted.

Author contributions: Study concept and design: All authors. Data acquisition: All authors. Data analysis and interpretation: All authors. Manuscript preparation: Y. Wang, VanderWalde. Critical revision: All authors. Statistical analysis: Y. Wang, Yu, Zhao, J. Wang, Lin, VanderWalde. Administrative, technical, or material support: All authors. Study supervision: VanderWalde.

Correspondence: Noam A. VanderWalde, MD, Department of Radiation Oncology, West Cancer Center, University of Tennessee Health Science Center, 7945 Wolf River Boulevard, Memphis, TN 38138. Email: nvanderw@westclinic.com

Supplementary Materials

    • Supplemental Data (PDF 453 KB)
  • 1.

    Shridhar R, Shibata D, Chan E. Anal cancer: current standards in care and recent changes in practice. CA Cancer J Clin 2015;65:139162.

  • 2.

    Ajani JA, Winter KA, Gunderson LL. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 2008;299:19141921.

    • Search Google Scholar
    • Export Citation
  • 3.

    James RD, Glynne-Jones R, Meadows HM. 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 x 2 factorial trial. Lancet Oncol 2013;14:516524.

    • Search Google Scholar
    • Export Citation
  • 4.

    Kachnic LA, Winter K, Myerson RJ. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:2733.

    • Search Google Scholar
    • Export Citation
  • 5.

    Holliday EB, Lester SC, Harmsen WS. Extended-field chemoradiation therapy for definitive treatment of anal canal squamous cell carcinoma involving the para-aortic lymph nodes. Int J Radiat Oncol Biol Phys 2018;102:102108.

    • Search Google Scholar
    • Export Citation
  • 6.

    Faivre C, Rougier P, Ducreux M. [5-fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer]. Bull Cancer 1999;86:861865 [in French].

    • Search Google Scholar
    • Export Citation
  • 7.

    Ghosn M, Kourie HR, Abdayem P. Anal cancer treatment: current status and future perspectives. World J Gastroenterol 2015;21:22942302.

  • 8.

    Benson AB III, Venook AP, Al-Hawary MM. Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018;16:852871.

    • Search Google Scholar
    • Export Citation
  • 9.

    Wang Y, Farmer M, Izaguirre E. Association of definitive pelvic radiotherapy and survival for patients with newly diagnosed metastatic cervical cancer. JAMA Oncol 2018;4:12881291.

    • Search Google Scholar
    • Export Citation
  • 10.

    Slotman BJ, van Tinteren H, Praag JO. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015;385:3642.

    • Search Google Scholar
    • Export Citation
  • 11.

    Mickisch GH, Garin A, van Poppel H. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358:966970.

    • Search Google Scholar
    • Export Citation
  • 12.

    Flanigan RC, Salmon SE, Blumenstein BA. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:16551659.

    • Search Google Scholar
    • Export Citation
  • 13.

    Rusthoven CG, Jones BL, Flaig TW. Improved survival with prostate radiation in addition to androgen deprivation therapy for men with newly diagnosed metastatic prostate cancer. J Clin Oncol 2016;34:28352842.

    • Search Google Scholar
    • Export Citation
  • 14.

    Hanna N, Sun M, Meyer CP. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Data Base study. J Clin Oncol 2016;34:32673275.

    • Search Google Scholar
    • Export Citation
  • 15.

    Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:10581066.

    • Search Google Scholar
    • Export Citation
  • 16.

    Seisen T, Sun M, Leow JJ. Efficacy of high-intensity local treatment for metastatic urothelial carcinoma of the bladder: a propensity score-weighted analysis from the National Cancer Data Base. J Clin Oncol 2016;34:35293536.

    • Search Google Scholar
    • Export Citation
  • 17.

    Ost P, Reynders D, Decaestecker K. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol 2018;36:446453.

    • Search Google Scholar
    • Export Citation
  • 18.

    Gomez DR, Blumenschein GR Jr, Lee JJ. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol 2016;17:16721682.

    • Search Google Scholar
    • Export Citation
  • 19.

    O'Shaughnessy MJ, McBride SM, Vargas HA. A pilot study of a multimodal treatment paradigm to accelerate drug evaluations in early-stage metastatic prostate cancer. Urology 2017;102:164172.

    • Search Google Scholar
    • Export Citation
  • 20.

    Boffa DJ, Rosen JE, Mallin K. Using the National Cancer Database for outcomes research: a review. JAMA Oncol 2017;3:17221728.

  • 21.

    Guo SY, Fraser MW. Propensity Score Analysis: Statistical Methods and Applications. Los Angeles, CA: SAGE Publications; 2014.

  • 22.

    Anderson JR, Cain KC, Gelber RD. Analysis of survival by tumor response. J Clin Oncol 1983;1:710719.

  • 23.

    Repka MC, Aghdam N, Karlin AW. Social determinants of stage IV anal cancer and the impact of pelvic radiotherapy in the metastatic setting. Cancer Med 2017;6:24972506.

    • Search Google Scholar
    • Export Citation
  • 24.

    Eng C, Chang GJ, You YN. 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;5:1113311142.

    • Search Google Scholar
    • Export Citation
  • 25.

    Comen E, Norton L, Massague J. Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 2011;8:369377.

  • 26.

    Hiratsuka S, Watanabe A, Aburatani H. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat Cell Biol 2006;8:13691375.

    • Search Google Scholar
    • Export Citation
  • 27.

    Danna EA, Sinha P, Gilbert M. Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 2004;64:22052211.

    • Search Google Scholar
    • Export Citation
  • 28.

    Leung CT, Brugge JS. Tumor self-seeding: bidirectional flow of tumor cells. Cell 2009;139:12261228.

  • 29.

    Newton PK, Mason J, Bethel K. Spreaders and sponges define metastasis in lung cancer: a Markov chain Monte Carlo mathematical model. Cancer Res 2013;73:27602769.

    • Search Google Scholar
    • Export Citation
  • 30.

    Demaria S, Ng B, Devitt ML. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004;58:862870.

    • Search Google Scholar
    • Export Citation
  • 31.

    Vanpouille-Box C, Pilones KA, Wennerberg E. In situ vaccination by radiotherapy to improve responses to anti-CTLA-4 treatment. Vaccine 2015;33:74157422.

    • Search Google Scholar
    • Export Citation
  • 32.

    Golden EB, Chhabra A, Chachoua A. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 2015;16:795803.

    • Search Google Scholar
    • Export Citation
  • 33.

    Shi F, Wang X, Teng F. Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy. Cancer Biol Ther 2017;18:137141.

    • Search Google Scholar
    • Export Citation
  • 34.

    Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin 2017;67:6585.

    • Search Google Scholar
    • Export Citation
  • 35.

    Aboudaram A, Modesto A, Chaltiel L. Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination. Melanoma Res 2017;27:485491.

    • Search Google Scholar
    • Export Citation
  • 36.

    Golden EB, Demaria S, Schiff PB. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 2013;1:365372.

    • Search Google Scholar
    • Export Citation
  • 37.

    Shaverdian N, Lisberg AE, Bornazyan K. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol 2017;18:895903.

    • Search Google Scholar
    • Export Citation
  • 38.

    Ott PA, Piha-Paul SA, Munster P. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 2017;28:10361041.

    • Search Google Scholar
    • Export Citation
  • 39.

    Morris VK, Salem ME, Nimeiri H. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017;18:446453.

    • Search Google Scholar
    • Export Citation
  • 40.

    Iyengar P, Wardak Z, Gerber DE. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol 2018;4:e173501.

    • Search Google Scholar
    • Export Citation
  • 41.

    Morris VK, Rashid A, Rodriguez-Bigas M. Clinicopathologic features associated with human papillomavirus/p16 in patients with metastatic squamous cell carcinoma of the anal canal. Oncologist 2015;20:12471252.

    • Search Google Scholar
    • Export Citation
  • 42.

    Alfa-Wali M, Allen-Mersh T, Antoniou A. Chemoradiotherapy for anal cancer in HIV patients causes prolonged CD4 cell count suppression. Ann Oncol 2012;23:141147.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 951 267 46
PDF Downloads 294 143 8
EPUB Downloads 0 0 0