Survival Advantage With Adjuvant Chemotherapy for Locoregionally Advanced Rectal Cancer: A Veterans Health Administration Analysis

Authors:
Daphna Y. Spiegel Department of Radiation Oncology, Duke University, Durham, North Carolina;
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and

Search for other papers by Daphna Y. Spiegel in
Current site
Google Scholar
PubMed
Close
 MD
,
Matthew J. Boyer Department of Radiation Oncology, Duke University, Durham, North Carolina;

Search for other papers by Matthew J. Boyer in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Julian C. Hong Department of Radiation Oncology, Duke University, Durham, North Carolina;

Search for other papers by Julian C. Hong in
Current site
Google Scholar
PubMed
Close
 MD
,
Christina D. Williams Cooperative Studies Program Epidemiology Center-Durham, Durham Veterans Administration Medical Center,

Search for other papers by Christina D. Williams in
Current site
Google Scholar
PubMed
Close
 PhD
,
Michael J. Kelley Division of Medical Oncology, Department of Medicine, Duke University, and
Division of Hematology-Oncology, Medical Service, Durham Veterans Administration Medical Center, Durham, North Carolina.

Search for other papers by Michael J. Kelley in
Current site
Google Scholar
PubMed
Close
 MD
,
Joseph K. Salama Department of Radiation Oncology, Duke University, Durham, North Carolina;

Search for other papers by Joseph K. Salama in
Current site
Google Scholar
PubMed
Close
 MD
, and
Manisha Palta Department of Radiation Oncology, Duke University, Durham, North Carolina;

Search for other papers by Manisha Palta in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Background: Adjuvant chemotherapy (AC) after chemoradiation (CRT) and surgery for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States. This study examined the role, optimal regimen, and duration of AC using data from the largest integrated health system in the United States. Patients and Methods: Using the Veterans Affairs Central Cancer Registry, patients with stage II–III rectal cancer diagnosed in 2001 through 2011 who received neoadjuvant CRT and surgery with or without AC were identified. Kaplan-Meier analysis, log-rank tests, and propensity score (PS) adjustment analysis were used to assess survival. Results: A total of 866 patients were identified; 417 received AC and 449 did not (observation [OBS] group). Median follow-up was 109 months. Median disease-specific survival (DSS) was not reached. Six-year DSS was 73.7%; 79.5% for the AC group versus 68.0% for the OBS group. PS-matched analysis for DSS favored AC (P=.0002). Median overall survival (OS) was 90.8 months. Six-year OS was 56.7%; 64.3% for AC versus 49.6% for OBS. In PS-matched analysis, median OS was 117.4 months for AC and 74.3 months for OBS (P<.0001). A DSS advantage was seen when comparing ≥4 months with <4 months of AC (P=.023). No difference in DSS or OS was seen with single-agent versus multiagent AC. Conclusions: In this population of patients with LARC treated with neoadjuvant CRT and surgery, OS and DSS were improved among those treated with AC versus OBS. DSS benefits were seen with ≥4 months of AC. No additional benefit was observed with multiagent therapy. In the absence of phase III data, these findings support the use of AC for LARC.

Submitted March 4, 2019; accepted for publication June 11, 2019.

Previous presentation: Data was previously presented at the 2018 ASCO Gastrointestinal Cancers Symposium; January 18–20, 2018; San Francisco, California.

Author contributions: Study concept: Spiegel, Kelley, Salama, Palta. Data curation: Spiegel, Boyer, Hong, Williams. Formal analysis: Spiegel, Boyer, Hong, Salama, Palta. Investigation, validation, and visualization: Spiegel. Methodology: All authors. Supervision: Kelley, Salama, Palta. Project administration: Spiegel, Kelley, Salama, Palta. Resources and software: Spiegel, Kelley, Salama, Palta. Writing of original manuscript: Spiegel. Manuscript review and editing: All authors.

Disclosures: The authors have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Daphna Y. Spiegel, MD, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Email: dspiege1@bidmc.harvard.edu
  • Collapse
  • Expand
  • 1.

    Wolmark N, Fisher B, Rockette H, et al.. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988;80:3036.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    André T, Boni C, Mounedji-Boudiaf L, et al.. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:23432351.

  • 3.

    André T, Boni C, Navarro M, 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 2009;27:31093116.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Fisher B, Wolmark N, Rockette H, et al.. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988;80:2129.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Bosset JF, Calais G, Mineur L, et al.. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results—EORTC 22921. J Clin Oncol 2005;23:56205627.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Bosset JF, Calais G, Mineur L, et al.. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol 2014;15:184190.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Bosset JF, Collette L, Calais G, et al.. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:11141123.

  • 8.

    Breugom AJ, Swets M, Bosset JF, 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 2015;16:200207.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Breugom AJ, van Gijn W, Muller EW, 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 2015;26:696701.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Cionini L, Sainato A, De Paoli A, et al.. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer [abstract]. Radiother Oncol 2010;96(Suppl):S113114.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Glynne-Jones R, Counsell N, Quirke P, et al.. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol 2014;25:13561362.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Benson AB III, Venook AP, Al-Hawary MM, et al.. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 1.2019. Accessed April 19, 2019. To view the most recent version, visit NCCN.org.

    • PubMed
    • Export Citation
  • 13.

    Dafni U. Landmark analysis at the 25-year landmark point. Circ Cardiovasc Qual Outcomes 2011;4:363371.

  • 14.

    Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol 2013;31:29632969.

  • 15.

    de Azambuja E, Holmes AP, Piccart-Gebhart M, et al.. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 2014;15:11371146.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Charlson ME, Pompei P, Ales KL, et al.. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373383.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Marventano S, Grosso G, Mistretta A, et al.. Evaluation of four comorbidity indices and Charlson comorbidity index adjustment for colorectal cancer patients. Int J Colorectal Dis 2014;29:11591169.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Landrum MB, Keating NL, Lamont EB, et al.. Survival of older patients with cancer in the Veterans Health Administration versus fee-for-service Medicare. J Clin Oncol 2012;30:10721079.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Petrelli F, Coinu A, Lonati V, et al.. A systematic review and meta-analysis of adjuvant chemotherapy after neoadjuvant treatment and surgery for rectal cancer. Int J Colorectal Dis 2015;30:447457.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Polanco PM, Mokdad AA, Zhu H, et al.. Association of adjuvant chemotherapy with overall survival in patients with rectal cancer and pathologic complete response following neoadjuvant chemotherapy and resection. JAMA Oncol 2018;4:938943.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Dossa F, Acuna SA, Rickles AS, 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 2018;4:930937.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Sainato A, Cernusco Luna Nunzia V, Valentini V, 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 2014;113:223229.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Hong YS, Nam BH, Kim KP, et al.. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol 2014;15:12451253.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Nilsson PJ, van Etten B, Hospers GA, et al.. Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer 2013;13:279.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Chau I, Brown G, Cunningham D, et al.. Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 2006;24:668674.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Fernández-Martos C, Pericay C, Aparicio J, et al.. Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo Cáncer de Recto 3 study. J Clin Oncol 2010;28:859865.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Calvo FA, Serrano FJ, Diaz-González JA, et al.. Improved incidence of pT0 downstaged surgical specimens in locally advanced rectal cancer (LARC) treated with induction oxaliplatin plus 5-fluorouracil and preoperative chemoradiation. Ann Oncol 2006;17:11031110.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Hajj C, Cercek A, Saltz L, et al.. Induction chemotherapy followed by chemoradiotherapy and total mesenteric excision for locally advanced rectal cancer with resectable metastases [abstract]. J Clin Oncol 2013;31(4 Suppl):Abstract 526.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    George TJ, Yothers G, Hong TS, et al.. NRG-GI002: a phase II clinical trial platform for total neoadjuvant therapy (TNT) in rectal cancer [abstract]. J Clin Oncol 2017;35(15 Suppl):Abstract TPS3629.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 6020 1696 185
PDF Downloads 2174 692 15
EPUB Downloads 0 0 0