Abstract

This study explored which kinds of cancer are related to a higher incidence of subsequent myelodysplastic syndrome (MDS) after radiotherapy (RT) and chemotherapy (CT). We performed a nested case–control study by using data from the Taiwanese National Health Insurance (NHI) system. The case group included cancer patients who developed MDS. For the control group, 4 cancer patients without MDS were frequency-matched with each MDS case by age, sex, year of cancer diagnosis, and MDS index year. Overall, cancer patients who received RT or CT exhibited secondary MDS more frequently than did those who did not (RT: OR¼ 1.53; 95% CI¼ 1.33–1.77; CT: OR¼ 1.51; 95% CI¼ 1.25–1.82). Analysis by cancer site showed that RT increased the risk of MDS for patients with stomach, colorectal, liver, breast, endometrial, prostate, and kidney cancers. The major limitation of this study was the lack of certain essential data in the NHI Research Database, such as data regarding cancer stage and treatment dose details. This population-based nested case–control study determined that RT and CT predisposed patients in Taiwan to the development of MDS. This effect was more prominent when both modalities were used.

Keywords

Abbreviations: AML acute myeloid leukemia, CI = confidence interval, CT = chemotherapy, ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification, LHID = Longitudinal Health Insurance Database, MDS = myelodysplastic syndrome, NHIRD = National Health Insurance Research Database, NHRI = National Health Research Institute (NHRI), OR = odds ratio, RT = radiotherapy.

Introduction

---

Table 1. Baseline Characteristics Between Myelodysplastic Syndrome Group and Non-Myelodysplastic Syndrome Group.

 

 

 

 

 

 

 

 

 

---

DISCUSSION

The results from this population-based nested case– control study highlighted the fact that overall cancer treatment with either RT or CT can significantly increase the risk of subsequently developing MDS. Analysis by cancer site indicated that patients with stomach, colorectal, liver, breast, endometrial, prostate, and kidney cancers after RT had a significantly high risk of developing MDS. MDS is not uncommon. Approximately 20,000 cases of MDS were diagnosed in the United States in 2008, of which approximately 10% were therapy related.15 From our NHI database, 454 cases of MDS were diagnosed in Taiwan in 2008. The prognosis of MDS is relatively poor, Traditional cancer therapy operates by producing extensive DNA damage that in turn inhibits proliferation and activates cell-death pathways. People accidentally exposed to ionizing radiation, as well as cancer patients receiving RT, have been extensively linked to hematological malignancies.18–20 By contrast, alkylating agents, topoisomerase II inhibitors, and antimetabolites are frequently cited perpetrators of CT-induced MDS.13,15 Alkylating agents comprise a large group of anticancer drugs with clinical applications across almost all types of cancer. Our results showed that breast cancer survivors who received RT are more vulnerable to developing MDS compared with their counterparts, but not breast cancer survivors who received CT (Table 3). When we used breast cancer patients without RT and CT as the reference, neither the RT nor the CT group showed a significantly higher risk of MDS, but the group treated with both RT and CT did manifest a significantly higher risk of MDS (Table 5, OR ¼ 3.46; 95% CI ¼ 1.28–9.33). They suggested that using RT to treat breast cancer is associated with an increased risk of MDS/AML and affects an extremely small number of patients.27 It is reasonable that there have been more reports of MDS development among breast cancer survivors compared with other cancer survivors. Because of the relative success of cancer screening programs, early detection and timely and appropriate treatment have yielded more favorable prognoses for patients with breast cancer compared with patients with most other types of cancer. More survivors of prostate cancer can be expected compared with other cancers. RT is one of the major therapies for prostate cancer, but CT does not play a crucial role in the treatment of prostate cancerThe association between CT and MDS in prostate cancer was not that obvious because of the relatively small number of patients receiving CT (Table 3). Hematological malignancies were also studied to determine the association between cancer treatment and subsequent MDS.13,29,30 The present study failed to find any significant relationship between cancer treatment and MDS in these malignancies except for antimetabolites users among non-Hodgkin lymphoma with a higher MDS risk (Table 4 We subclassified CT into alkylating agent, topoisomerase II inhibitors, and antimetabolites to analyze because they are suggested to have increased risks of MDS.13 Tebbi et al found a novel association between topoisomerase inhibition and risk of secondary myeloid neoplasms in pediatric Hodgkin disease..35 Le Deley et al found that the risk of MDS is much higher with mitoxantrone-based CT than with anthracycline-based CT in breast cancer patients.20 Users of topoisomerase II inhibitors were found to have significantly higher risks for MDS among colorectal cancer and cervical cancer patients in our study. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been associated with MDS.9 Our data revealed that antimetabolite users had significantly higher risks of MDS among bladder cancer and non-Hodgkin lymphoma patients. A tendency of a positive joint effect of RT and CT was observed in our study. As shown in Table 5, a reference group of patients who did not receive RT or CT exhibited the joint effect of both treatments in lung, breast, endometrial, and cervical cancers. In these cancer sites, double-treatment groups, but not single-treatment groups, had significantly higher risks of MDS. When used single-treatment group as the reference, Table 5 also revealed consistent higher adjusted ORs of double-treatment group compared with single-treatment group (except for liver cancer), although P values seldom reached the significant level due to small case number. The positive interaction between RT and CT was observed in an early study conducted by Smith et al, who indicated that among patients receiving adjuvant CT for breast cancer, the risk of MDS increases with age, with the intensity of therapy, and with the use of breast RT.28 This implied that a synergistic effect of MDS may exist between RT and CT. Combining RT and CT (either concurrent or sequential) in cancer treatment has been proven to increase therapeutic results in several cancers.36–40 Treatment-related toxicity may be also additive.41–43 Therefore, combination therapy may confer a higher risk of MDS.  In conclusion, this population-based nested case–control study found that both RT and CT are related to the subsequent development of MDS. Some cancer sites are more susceptible to developing MDS after cancer treatment. which far outweigh the potential risk of MDS.

REFERENCES

1. Cancer Statistics Annual Report: Taiwan Cancer Registry. Available from http://tcr.cph.ntu.edu.tw/main.php?Page=N2. Accessed September 25, 2014.
2.  Pollack LA, Rowland JH, Crammer C, et al. Introduction: charting the landscape of cancer survivors’ health-related outcomes and care. Cancer. 2009;115:4265–4269.
3.  Choi M, Craft B, Geraci SA. Surveillance and monitoring of adult cancer survivors. Am J Med. 2011;124:598–601. 
4. Cazzola M, Malcovati L. Myelodysplastic syndromes – coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536–538.
5.  Besa EC. Myelodysplastic syndromes (refractory anemia). A perspective of the biologic, clinical, and therapeutic issues. Med Clin North Am. 1992;76:599–617.
6.  Germing U, Kobbe G, Haas R, et al. Myelodysplastic syndromes: diagnosis, prognosis, and treatment. Dtsch Arztebl Int. 2013;110:783–790.
7. Cole M, Strair R. Acute myelogenous leukemia and myelodysplasia secondary to breast cancer treatment: case studies and literature review. Am J Med Sci. 2010;339:36–40.
8.  Leone G, Pagano L, Ben-Yehuda D, et al. Therapy-related leukemia and myelodysplasia: susceptibility and incidence. Haematologica. 2007;92:1389–1398.
9.  Bonin SR, Lanciano RM, Smith MR, et al. Treatment-related myelodysplastic syndrome following abdominopelvic radiotherapy for endometrial cancer. Gynecol Oncol. 1995;57:430–432.
10.  Mukherjee S, Reddy CA, Ciezki JP, et al. Risk for developing myelodysplastic syndromes in prostate cancer patients definitively treated with radiation. J Natl Cancer Inst. 2014;106:djt462.
11.  Sugiyama K, Kurisu K, Arita K, et al. Myelodyeplastic syndrome following therapy for brain tumor – two case reports. Neurol Med Chir (Tokyo). 2002;42:170–174.
12.  Sill H, Olipitz W, Zebisch A, et al. Therapy-related myeloid neoplasms: pathobiology and clinical characteristics. Br J Pharmacol. 2011;162:792–805.
13. Graubert T. Therapy-related myelodysplastic syndrome: models and genetics. Biol Blood Marrow Transplant. 2010;16:S45–S47.
14. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–199.
15.  Grossi A, Liumbruno GM. New drugs in the treatment of myelodysplastic syndromes: are they changing the role of transfusion support? Blood Transfus. 2008;6:191–198.
16.  Ojha RP, Fischbach LA, Zhou Y, et al. Acute myeloid leukemia incidence following radiation therapy for localized or locally advanced prostate adenocarcinoma. Cancer Epidemiol. 2010;34:274– 278.
17. Warlick ED, Smith BD. Myelodysplastic syndromes: review of pathophysiology and current novel treatment approaches. Curr Cancer Drug Targets. 2007;7:541–558Review.
18. Rund D, Ben Yehuda D. Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment. Hematology. 2004;9:179–187.
19. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, et al. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood. 2002;99:1909–1912.
20. Moloney WC. Radiogenic leukemia revisited. Blood. 1987;70:905– 908.
21. Leleu X, Soumerai J, Roccaro A, et al. Increased incidence of transformation and myelodysplasia/acute leukemia in patients with Waldenstrom macroglobulinemia treated with nucleoside analogs. J Clin Oncol. 2009;27:250–255.