Association of Chemotherapy for Solid Tumors With Development of Therapy-Related Myelodysplastic Syndrome or Acute Myeloid Leukemia in the Modern Era | Hematology | JAMA Oncology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Howlader  N, Noone  A, Krapcho  M,  et al. SEER Cancer statistics review, 1975-2014, National Cancer Institute. Updated April 2, 2018. Accessed May 25, 2018.
McNerney  ME, Godley  LA, Le Beau  MM.  Therapy-related myeloid neoplasms: when genetics and environment collide.  Nat Rev Cancer. 2017;17(9):513-527. doi:10.1038/nrc.2017.60PubMedGoogle ScholarCrossref
Travis  LB, Holowaty  EJ, Bergfeldt  K,  et al.  Risk of leukemia after platinum-based chemotherapy for ovarian cancer.  N Engl J Med. 1999;340(5):351-357. doi:10.1056/NEJM199902043400504PubMedGoogle ScholarCrossref
Greene  MH, Harris  EL, Gershenson  DM,  et al.  Melphalan may be a more potent leukemogen than cyclophosphamide.  Ann Intern Med. 1986;105(3):360-367. doi:10.7326/0003-4819-105-3-360PubMedGoogle ScholarCrossref
Radivoyevitch  T, Sachs  RK, Gale  RP,  et al.  Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation.  Leukemia. 2016;30(2):285-294. doi:10.1038/leu.2015.258PubMedGoogle ScholarCrossref
Curtis  RE, Ries  LAG. Methods. In: Curtis RE, Freedman DM, Ron E, et al, eds. New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973-2000. Bethesda, MD: National Cancer Institute; 2006. NIH publication No. 05-5302.
Swerdlow  SH, Campo  E, Harris  NL,  et al.  World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.
Swerdlow  SH, Campo  E, Pileri  SA,  et al.  The 2016 revision of the World Health Organization classification of lymphoid neoplasms.  Blood. 2016;127(20):2375-2390. doi:10.1182/blood-2016-01-643569PubMedGoogle ScholarCrossref
Warren  JL, Klabunde  CN, Schrag  D, Bach  PB, Riley  GF.  Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population.  Med Care. 2002;40(8)(suppl):IV-3-IV-18. doi:10.1097/01.MLR.0000020942.47004.03PubMedGoogle Scholar
Sahai  H, Khurshid  A.  Confidence intervals for the mean of a Poisson distribution: a review.  Biometrical J. 1993;35:857-867. doi:10.1002/bimj.4710350716Google ScholarCrossref
Sahai  H, Khurshid  A.  Statistics in Epidemiology: Methods, Techniques, and Applications. Boca Raton, FL: CRC Press, Inc; 1996.
Preston  D, Lubin  J, Pierce  D, McConney  M, Shilnikova  N.  Epicure Risk Regression and Person-Year Computation Software: Command Summary and User Guide. Ottawa, Ontario: Risk Sciences International; 2015.
Yasui  Y, Liu  Y, Neglia  JP,  et al.  A methodological issue in the analysis of second-primary cancer incidence in long-term survivors of childhood cancers.  Am J Epidemiol. 2003;158(11):1108-1113. doi:10.1093/aje/kwg278PubMedGoogle ScholarCrossref
Coviello  V, Boggess  M.  Cumulative incidence estimation in the presence of competing risks.  Stata J. 2004;4:103-112.Google ScholarCrossref
Siegel  RL, Miller  KD, Jemal  A.  Cancer statistics, 2018.  CA Cancer J Clin. 2018;68(1):7-30. doi:10.3322/caac.21442PubMedGoogle ScholarCrossref
Linet  MS, Morton  LM, Devesa  SS, Dores  GM. Leukemias. In: Thun  M, Linet  MS, Cerhan  JR, Haiman  CA, Schottenfeld  D, eds.  Schottenfeld & Fraumeni: Cancer Epidemiology & Prevention. 4th ed. New York: Oxford University Press; 2017:715-744.
Morton  LM, Dores  GM, Tucker  MA,  et al.  Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008.  Blood. 2013;121(15):2996-3004. doi:10.1182/blood-2012-08-448068PubMedGoogle ScholarCrossref
Adelstein  DJ, Li  Y, Adams  GL,  et al.  An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer.  J Clin Oncol. 2003;21(1):92-98. doi:10.1200/JCO.2003.01.008PubMedGoogle ScholarCrossref
Van Cutsem  E, Moiseyenko  VM, Tjulandin  S,  et al; V325 Study Group.  Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group.  J Clin Oncol. 2006;24(31):4991-4997. doi:10.1200/JCO.2006.06.8429PubMedGoogle ScholarCrossref
André  T, Boni  C, Mounedji-Boudiaf  L,  et al; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators.  Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.  N Engl J Med. 2004;350(23):2343-2351. doi:10.1056/NEJMoa032709PubMedGoogle ScholarCrossref
Pointreau  Y, Garaud  P, Chapet  S,  et al.  Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation.  J Natl Cancer Inst. 2009;101(7):498-506. doi:10.1093/jnci/djp007PubMedGoogle ScholarCrossref
Moore  DH, Thomas  GM, Montana  GS, Saxer  A, Gallup  DG, Olt  G.  Preoperative chemoradiation for advanced vulvar cancer: a phase II study of the Gynecologic Oncology Group.  Int J Radiat Oncol Biol Phys. 1998;42(1):79-85. doi:10.1016/S0360-3016(98)00193-XPubMedGoogle ScholarCrossref
Khushalani  NI, Leichman  CG, Proulx  G,  et al.  Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: report of a clinical trial for patients with esophageal cancer.  J Clin Oncol. 2002;20(12):2844-2850. doi:10.1200/JCO.2002.12.032PubMedGoogle ScholarCrossref
Tepper  J, Krasna  MJ, Niedzwiecki  D,  et al.  Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781.  J Clin Oncol. 2008;26(7):1086-1092. doi:10.1200/JCO.2007.12.9593PubMedGoogle ScholarCrossref
van Hagen  P, Hulshof  MC, van Lanschot  JJ,  et al; CROSS Group.  Preoperative chemoradiotherapy for esophageal or junctional cancer.  N Engl J Med. 2012;366(22):2074-2084. doi:10.1056/NEJMoa1112088PubMedGoogle ScholarCrossref
Bramwell  VH, Burgers  M, Sneath  R,  et al.  A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup.  J Clin Oncol. 1992;10(10):1579-1591. doi:10.1200/JCO.1992.10.10.1579PubMedGoogle ScholarCrossref
Keys  HM, Bundy  BN, Stehman  FB,  et al.  Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma.  N Engl J Med. 1999;340(15):1154-1161. doi:10.1056/NEJM199904153401503PubMedGoogle ScholarCrossref
Humber  CE, Tierney  JF, Symonds  RP,  et al.  Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration.  Ann Oncol. 2007;18(3):409-420. doi:10.1093/annonc/mdl417PubMedGoogle ScholarCrossref
Travis  LB, Andersson  M, Gospodarowicz  M,  et al.  Treatment-associated leukemia following testicular cancer.  J Natl Cancer Inst. 2000;92(14):1165-1171. doi:10.1093/jnci/92.14.1165PubMedGoogle ScholarCrossref
Griffiths  RW, Zee  YK, Evans  S,  et al.  Outcomes after multiple lines of chemotherapy for platinum-resistant epithelial cancers of the ovary, peritoneum, and fallopian tube.  Int J Gynecol Cancer. 2011;21(1):58-65. doi:10.1097/IGC.0b013e3182049273PubMedGoogle ScholarCrossref
Deans  AJ, West  SC.  DNA interstrand crosslink repair and cancer.  Nat Rev Cancer. 2011;11(7):467-480. doi:10.1038/nrc3088PubMedGoogle ScholarCrossref
Kelland  L.  The resurgence of platinum-based cancer chemotherapy.  Nat Rev Cancer. 2007;7(8):573-584. doi:10.1038/nrc2167PubMedGoogle ScholarCrossref
Mehmood  RK.  Review of cisplatin and oxaliplatin in current immunogenic and monoclonal antibody treatments.  Oncol Rev. 2014;8(2):256. doi:10.4081/oncol.2014.256PubMedGoogle ScholarCrossref
Hartmann  JT, Lipp  HP.  Toxicity of platinum compounds.  Expert Opin Pharmacother. 2003;4(6):889-901. doi:10.1517/14656566.4.6.889PubMedGoogle ScholarCrossref
Yin  M, Joshi  M, Meijer  RP,  et al.  Neoadjuvant chemotherapy for muscle-invasive bladder cancer: a systematic review and two-step meta-analysis.  Oncologist. 2016;21(6):708-715. doi:10.1634/theoncologist.2015-0440PubMedGoogle ScholarCrossref
Advanced Bladder Cancer (ABC) Meta-analysis Collaboration.  Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data.  Eur Urol. 2005;48(2):202-205. doi:10.1016/j.eururo.2005.04.006PubMedGoogle ScholarCrossref
Advanced Bladder Cancer Meta-analysis Collaboration.  Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis.  Lancet. 2003;361(9373):1927-1934. doi:10.1016/S0140-6736(03)13580-5PubMedGoogle ScholarCrossref
Northover  J, Glynne-Jones  R, Sebag-Montefiore  D,  et al.  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. 2010;102(7):1123-1128. doi:10.1038/sj.bjc.6605605PubMedGoogle ScholarCrossref
James  RD, Glynne-Jones  R, Meadows  HM,  et al.  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. 2013;14(6):516-524. doi:10.1016/S1470-2045(13)70086-XPubMedGoogle ScholarCrossref
Faivre  C, Rougier  P, Ducreux  M,  et al.  5-Fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer [in French].  Bull Cancer. 1999;86(10):861-865.PubMedGoogle Scholar
Malagari  K, Kiakidis  T, Pomoni  M,  et al.  Pharmacokinetics, safety, and efficacy of chemoembolization with doxorubicin-loaded tightly calibrated small microspheres in patients with hepatocellular carcinoma.  Cardiovasc Intervent Radiol. 2016;39(10):1379-1391. doi:10.1007/s00270-016-1382-6PubMedGoogle ScholarCrossref
Conroy  T, Desseigne  F, Ychou  M,  et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup.  FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.  N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923PubMedGoogle ScholarCrossref
Bhatia  S.  Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors.  Cancer. 2015;121(5):648-663. doi:10.1002/cncr.29096PubMedGoogle ScholarCrossref
Liang  F, Zhang  S, Xue  H, Chen  Q.  Risk of second primary cancers in cancer patients treated with cisplatin: a systematic review and meta-analysis of randomized studies.  BMC Cancer. 2017;17(1):871. doi:10.1186/s12885-017-3902-4PubMedGoogle ScholarCrossref
Lund  JL, Stürmer  T, Harlan  LC,  et al.  Identifying specific chemotherapeutic agents in Medicare data: a validation study.  Med Care. 2013;51(5):e27-e34. doi:10.1097/MLR.0b013e31823ab60fPubMedGoogle ScholarCrossref
Baudino  TA.  Targeted cancer therapy: the next generation of cancer treatment.  Curr Drug Discov Technol. 2015;12(1):3-20. doi:10.2174/1570163812666150602144310PubMedGoogle ScholarCrossref
Original Investigation
December 20, 2018

Association of Chemotherapy for Solid Tumors With Development of Therapy-Related Myelodysplastic Syndrome or Acute Myeloid Leukemia in the Modern Era

Author Affiliations
  • 1Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • 2Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • 3Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
JAMA Oncol. 2019;5(3):318-325. doi:10.1001/jamaoncol.2018.5625
Key Points

Question  What is the association of therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) with chemotherapy for solid cancer in the modern treatment era?

Findings  In this population-based study of 700 612 adults in a US cancer data registry, based on 1619 tMDS/AML cases, the risk of tMDS/AML was significantly increased 1.5-fold to more than 10-fold after chemotherapy for 22 of 23 solid cancer types investigated (all except colon cancer).

Meaning  Although tMDS/AML is rare, gains in solid cancer survival from modern treatment approaches should be balanced against tMDS/AML risks and other chemotherapy-related adverse effects; continued efforts to develop effective agents and cancer treatment approaches with fewer late sequelae are needed.


Importance  Therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) is a rare, usually fatal complication of chemotherapy, including certain alkylating agents, topoisomerase II inhibitors, and platinum compounds. With the introduction of new chemotherapeutic agents, expanded indications for established agents, and increased neoadjuvant and adjuvant chemotherapy, tMDS/AML risks in the modern age are poorly understood.

Objectives  To quantify tMDS/AML risk after chemotherapy for solid cancer among United States adults since 2000 and correlate tMDS/AML risk patterns with chemotherapy treatment practices.

Design, Setting, and Participants  A population-based cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims. Risk analyses included 1619 tMDS/AML cases among 700 612 adults (age, 20-84 years) who were diagnosed with first primary solid cancer during 2000 to 2013 (followed up through 2014), received initial chemotherapy, and survived 1 year or longer, as reported to SEER. Descriptive analyses were conducted of SEER records linked with Medicare claims for chemotherapy in 165 820 older adults (age, 66-84 years) receiving initial chemotherapy for a first primary solid cancer in 2000-2013. Data analysis was conducted from October 2017 to April 2018.

Exposures  Receipt of initial chemotherapy for solid cancer.

Main Outcomes and Measures  Second primary tMDS/AML.

Results  Based on 1619 tMDS/AML cases in the SEER database (mean [SD] age, 64.3 [12.2] years; 1148 [70.9%] female), tMDS/AML risks were statistically significantly elevated after chemotherapy for 22 of 23 solid cancers (all except colon). Relative risks ranged from 1.5 to greater than 10 and excess absolute risks from 1.4 to greater than 15 cases per 10 000 person-years compared with the general population. Overall survival following tMDS/AML diagnosis was poor (1270 of 1619 patients [78.4%] died; median overall survival, 7 months). For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy. In the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, in initial chemotherapy increased substantially since 2000, most notably for gastrointestinal tract cancers (esophagus, stomach, colon, and rectum; 10% in 2000-2001 to 81% during 2012-2013).

Conclusions and Relevance  Large-scale, United States population-based data demonstrate excess tMDS/AML risks following chemotherapy for nearly all solid tumor types, consistent with expanded use of known leukemogenic agents in the 21st century. Continued efforts to reduce treatment-related adverse events, particularly for solid cancer patients with favorable prognosis, are needed.