Myelodysplastic Syndromes and Acute Myeloid Leukemia in Prostate Cancer Patients after Radiotherapy, a Population-Based Study

Background:  Radiation is a known risk factor for myeloid malignancies.  Approximately 1.4% of prostate cancer patients who undergo radiotherapy and survive >10 years will develop a secondary cancer.  However, the impact of radiotherapy on the development of second myeloid malignancies among prostate cancer patients is unclear.

Methods: We performed a retrospective cohort study of elderly prostate cancer patients (diagnosed with clinical stages T1-T3 at the age of 66-99 years during 1999-2009) using the linked Surveillance, Epidemiology and End Results (SEER) – Medicare database.  Patients who received chemotherapy after prostate cancer diagnosis or had radiotherapy for prostate cancer recurrence were excluded.  We searched Medicare claims and SEER records to identify incident myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) diagnoses after prostate cancer diagnosis.  Patients were followed from the diagnosis of prostate cancer through the diagnosis of a second malignancy, death or end of study (12/31/2010 for prostate cancer patients diagnosed in 1999-2003, and 12/31/2012 for those diagnosed in 2004-2011), whichever came first.  Competing risk analysis was conducted to assess the impact of radiotherapy on the development of second MDS/AML, compared with surgery.  Death and developing a second malignancy other than MDS/AML were considered competing events.  Competing risks regression models were performed using the Fine and Gray method to provide estimates of hazard ratios (HRs).  Age at prostate diagnosis, race, Elixhauser comorbidity score excluding anemia, history of anemia, disability function score (in quartiles), stage of prostate cancer, and year of prostate cancer diagnosis were adjusted for in the multivariate model. 

Results:  A total of 32,212 prostate cancer patients were included, with a median follow-up of 4.91 years.  Patients who received surgery (n = 17,503) were younger than those who underwent radiotherapy (n = 14,709).  Intensity-modulated radiotherapy (IMRT) was the most common type of radiotherapy received (n = 8,813, 59.9%; median follow-up: 3.91 years), followed by brachytherapy (n = 3,201, 21.8%; median follow-up: 5.67 years) and external beam radiotherapy (EBRT, n = 2,695, 18.3%; median follow-up: 7.84 years). 

We observed 158 incident cases of MDS/AML (123 MDS cases and 35 AML cases) after the diagnosis of prostate cancer. The median time to develop MDS/AML was 3.30 (range: 0.20-9.77) years.  In the multivariate model, compared with prostate cancer patients who received surgery only, patients who underwent radiotherapy had a significantly increased risk of developing second MDS/AML (HR = 1.54, 95% confidence interval [CI]: 1.09-2.11).  When the analysis was stratified by specific radiation modality, increased risk of second MDS/AML was observed in each group, but the increase only reached statistical significance in the IMRT group (HR = 1.66, 95% CI: 1.09-2.52) (Table). 

We also conducted a separate analysis of the 123 patients who developed MDS.  In the unadjusted model, compared with prostate cancer patients who received surgery only, patients who underwent any type of radiotherapy, EBRT, or IMRT had significantly increased risk of MDS.  However, after adjusting for other factors, the magnitude of the effect diminished, and the effect was no longer statistically significant (Table).  

CONCLUSIONS: Our findings suggest that radiotherapy for prostate cancer increases the risk of MDS/AML, and the impact may differ by radiation modality.  Additional studies with longer follow-up are needed to further clarify the role of radiotherapy in the development of subsequent myeloid malignancies.

Table. Risk of Second MDS/AML after Radiotherapy among Prostate Cancer Patients

		Second cancer of interest		Unadjusted			Adjusted
		n (%)		HR (95% CI)	p		HR (95% CI)	p
MDS/AML (n=158)
Surgery		60 (0.34)		1.00			1.00
Radiotherapy		98 (0.67)		1.94 (1.41-2.68)	<.01		1.54 (1.09-2.17)	0.01
	Brachytherapy	19 (0.59)		1.58 (0.94-2.64)	0.08		1.35 (0.80-2.27)	0.26
	EBRT	29 (1.08)		2.13 (1.36-3.34)	<.01		1.51 (0.91-2.50)	0.11
	IMRT	50 (0.57)		2.02 (1.39-2.93)	<.01		1.66 (1.09-2.52)	0.02
MDS (n=123)
Surgery		49 (0.28)		1.00			1.00
Radiotherapy		74 (0.50)		1.80 (1.25-2.58)	<.01		1.43 (0.97-2.12)	0.07
	Brachytherapy	15 (0.47)		1.53 (0.86-2.73)	0.20		1.32 (0.74-2.35)	0.35
	EBRT	24 (0.89)		2.17 (1.33-3.54)	<.01		1.53 (0.87-2.70)	0.14
	IMRT	35 (0.40)		1.72 (1.11-2.65)	0.01		1.43 (0.88-2.33)	0.15