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Tuesday, March 25, 2014

ONLINE FIRST: Reassurance from Large Study that Contrary to Earlier Thinking, Prostate Cancer Patients Receiving Radiation Do Not Have Increased Risk of MDS



Men who receive radiation treatment for prostate cancer are at no greater risk for developing myelodysplastic syndromes (MDS) than the general population, according to a study now available online ahead of print in the Journal of the National Cancer Institute.


Common thinking, passed down to oncologists and largely from review articles, has been that patients exposed to radiation or any type of chemotherapy who then develop MDS have therapy-related MDS, said Mikkael A. Sekeres, MD, MS, senior author of the study and Director of the Leukemia Program at Cleveland Clinic’s Taussig Cancer Institute.


He said that while he and his colleagues see numerous men in their 70s with a history of prostate cancer, as well as many men of this age with MDS, he was not convinced that it was truly a cause-and-effect relationship, and theorized that it was actually two separate diseases that happen to affect older men.


The study, a joint project of the Taussig Cancer Institute and the Glickman Urological & Kidney Institute – first author is Sudipto Mukherjee, MD, MPH -- evaluated data from 10,924 prostate cancer patients treated at Cleveland Clinic from 1986 to 2011 with either radical prostatectomy, external-beam radiation therapy (EBRT), or brachytherapy. The median age of patients was 69 for the EBRT group, 67 for the brachytherapy group, and 60 for the surgery group.


Overall, 47 percent of patients underwent radiation and 53 percent were treated with radical prostatectomy. Of the radiation patients, 43 percent had EBRT and 57 percent had brachytherapy. Individuals received one of three types of EBRT: four-field radiation (24%), three-dimensional conformal radiotherapy (21%), and intensity modulated radiation treatment (55%).


Thirty-one patients developed MDS: 16 in the EBRT group, nine in the brachytherapy group, and six in the radical prostatectomy group. The 10-year cumulative MDS incidence rates were 0.7, 1.8, and 0.2 percent, for EBRT, brachytherapy, and surgery patients, respectively.


The researchers noted that these MDS rates were similar to those seen in the Ohio Cancer Incidence Surveillance System (OCISS) and the Surveillance, Epidemiology, and End Results (SEER) database. In a univariate analysis, Cleveland Clinic patients with advanced age and those treated with radiation were found to be significantly more likely to develop MDS (hazard ratios [HR]: 1.14 and 3.44, respectively). The association was significant for both EBRT patients (HR = 2.82) and those undergoing brachytherapy (HR = 5.65).


However, multivariable analyses adjusting for age, radiation use, radiation modality, and body mass index revealed that only advanced age was significantly associated with MDS (HR = 1.13); there was also a slightly increased risk of MDS in brachytherapy patients, but that was not statistically significant.  


Asked for his opinion about the study, Christopher Rose, MD, Chief Technology Officer at Vantage Oncology in Manhattan Beach, Calif., said that while the median age of patients treated with external-beam radiation therapy was 69 in this study, the outcomes for younger men who would be expected to live another 20 to 25 years could be different.


Radiation Dose and Bone Marrow Volume

Also of note, he said, while IMRT was instituted at the Cleveland Clinic in 1998, over the course of the study, 24 percent of patients were treated with four-field therapy and 21 percent received three-dimensional conformal therapy, both of which result in a higher volume of bone marrow being exposed to a higher radiation dose.


In contrast, larger volumes of bone marrow are exposed to lower radiation doses with IMRT. “Lower dose might be more important than total volume of bone marrow being irradiated for the development of MDS, but we just do not know.”  He said that if the researchers were to repeat the study in five years to include only patients treated with IMRT, he suspects the results might be different because the total bone marrow compartment would be exposed to a different pattern of both radiation dose and volume.


Impact on Decision-making

A risk of MDS is certainly one of the factors that men with T1C prostate cancer will be considering when making challenging decisions about having their prostate removed or undergoing radiation therapy, said Sekeres, OT’s Clinical Advisory Editor for Hematology/Oncology. Often, patients are faced with so many potential outcomes that they may base their treatment decisions on what someone they trust did, he said, citing as an example the information discussed in Your Medical Mind by Jerome Groopman and Pamela Hartzbran, which he reviewed in OT’s 6/10/13 issue.


Eric M. Horwitz, MD, Chairman of Radiation Oncology at Fox Chase Cancer Center, said he considered the study to be well done -- “although there are clearly some limitations because it is conducted at a single institution.


“There are so many treatment choices for prostate cancer, and patients are better and better informed and are the ones who ultimately decide what to do. Our job is to provide the best information, but these long-term side effects including radiation exposure are a real issue of concern, and this study could help people understand what the risks are for MDS, adding one more piece to the puzzle.”


Also asked for his opinion, Chandan Guha, MB, PhD, Vice Chair of the Department of Radiation Oncology at Montefiore Medical Center in Bronx, NY, said that the paper shows that the most predominant risk factor for MDS in prostate cancer patients undergoing radiation is advancing age: Old stem cells have problems with DNA repair and don’t regenerate properly, contributing to MDS, he explained.


“Most of our patients don’t even talk about MDS because their doctors don’t talk about MDS with them, but patients do need to understand that MDS is essentially an aging of the stem cells of the blood. With this process, there is a greater tendency to get leukemia, especially acute myeloid leukemia.”


The general bias with prostate cancer patients is that older men usually undergo radiation while younger men get surgery, he noted. Because advanced age is the biggest risk factor for MDS, individuals getting radiation, who tend to be older anyway, are more likely to already have defective stem cells.


Additional Study

Sekeres said further research needs to include longer follow-up of men who undergo brachytherapy -- “It’s a relatively new technology in the grand scheme of treatment for prostate cancer, and there is a concern that circulating stem cells could still put a man at risk of DNA damage when stem cells circulate near implanted seeds.”


Guha agreed: The theory of stem cells circulating near brachytherapy seeds implanted by the prostate is interesting --“the seed implant story is far from over.”