BERKELEY, CA (UroToday.com) - We have recently reported an increased risk of mesothelioma among prostate cancer patients treated with external beam radiotherapy (EBRT).[1]
The issue of second malignancies is of growing importance for prostate cancer. On the one hand, the widespread diffusion of prostate specific antigen testing determined a huge increase in the diagnosis of localized prostate cancer, a neoplasm characterized by a high rate of long-term survival.[2] On the other hand, there is yet no consensus concerning the appropriate treatment. The American Urological Association’s guideline for the management of clinically localized prostate cancer recommends that patients should be informed about the commonly accepted initial interventions including, at a minimum, active surveillance, radiotherapy (EBRT and interstitial), and radical prostatectomy.[3]
Parker and colleagues estimated that the 15-years cancer-related mortality for prostate cancer patients with a Gleason score of less than seven is almost null.[4] In this group of patients, the long-term carcinogenic effect of EBRT should be considered carefully. As all the therapeutic approaches proposed for localized prostate cancer have potential drawbacks,3 the treatment strategies should be discussed with the patient in order to make a conscious decision. All the available information on the personal history of the patient should be appraised to establish whether to use EBRT as a first-line approach. It has been suggested that other treatment modalities should be considered for patients who present multiple risk factors for secondary cancers.[5]
Our study, based on the U.S. Surveillance, Epidemiology and End Results (SEER) program data does have several limitations. The most relevant one is the absence of direct information on the exposure to asbestos. As asbestos exposure is the major cause of mesothelioma,[6] it might potentially represent a confounder of the association between EBRT and this cancer. We investigated the potential for confounding by performing additional analyses. Firstly, we assessed the effect of latency period (time since exposure to EBRT) and distance from the irradiated field (peritoneal or pleural mesothelioma). Secondly, we used the relative risk of mesothelioma in each case’s county of residence as a proxy for asbestos exposure. Thirdly, we conducted a target-adjustment sensitivity analysis to explore the difference in prevalence of occupational exposure to asbestos by EBRT status that would have been necessary to explain the observed association. Finally, we evaluated whether the estimates depended on the choice of the reference category (all non-irradiated patients or only surgically treated patients). We did not find any evidence supporting the hypothesis that the observed association between EBRT and mesothelioma was confounded by asbestos, yet the absence of information still represents a limitation of our study.
Indeed, we could not investigate the interaction between EBRT and former exposure to asbestos. Noteworthy, the latency periods that we observed for the incidence of mesothelioma after exposure to radiation were considerably shorter than those reported after exposure to asbestos.[6] The carcinogenesis is a multistage process;[7] recent biologically based models of carcinogen¬esis highlighted that ionizing radiation acts both as an initiator of premalignant clones and as a promoter of preexisting premalignant damage.[8] Considering that the available evidence strongly supports the role of asbestos in the initiation of mesothelioma,[9] we hypothesize that EBRT might increase, particularly, the risk of mesothelioma in those subjects presenting premalignant clones due to former exposure to asbestos. If that were the case, a multiplicative interaction between EBRT and former exposure to asbestos could exist. The implications of this interaction would be relevant for the management of prostate cancer patients; physicians should consider the history of exposure to asbestos when discussing treatment options with their patients. Future studies should try to assess the biological plausible interaction between asbestos and EBRT in determining the risk of mesothelioma.
Several studies have been conducted on the incidence of second malignancies after radiotherapy,[10] but their clinical relevance has been limited. EBRT is a valuable treatment option;[3] ending its use on the grounds of the possible risk of second malignancies could affect negatively the clinical management of prostate cancer patients. However, the identification of the sub-populations at high-risk of radiation-induced second malignancies could inform the best choice of the therapeutic strategy.
References:
- Farioli A, Violante FS, Mattioli S, Curti S, Kriebel D. Risk of mesothelioma following external beam radiotherapy for prostate cancer: a cohort analysis of SEER database. Cancer Causes Control. 2013;24:1535-45.
- Cooperberg MR, Lubeck DP, Mehta SS, et al. Time trends in clinical risk stratification for prostate cancer: Implications for outcomes (data from CaPSURE). J Urol. 2003;170:S21-S27.
- Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, Cookson MS, D'Amico AV, Dmochowski RR, Eton DT, Forman JD, Goldenberg SL, Hernandez J, Higano CS, Kraus SR, Moul JW, Tangen CM; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106-31.
- Parker C, Muston C, Mella J, et al. A model of the natural history of screen-detected prostate cancer, and the effect of radical treatment on overall survival. Br J Cancer. 2006;94:1361-1368.
- Bostrom PJ, Soloway MS. Secondary cancer after radiotherapy for prostate cancer: should we be more aware of the risk? Eur Urol. 2007;52:973-82.
- Moore AJ, Parker RJ, Wiggins J. Malignant mesothelioma. Orphanet J Rare Dis. 2008;3:34. doi: 10.1186/1750-1172-3-34.
- Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954r;8:1-12.
- Heidenreich WF, Cullings HM, Funamoto S, Paretzke HG. Promoting action of radiation in the atomic bomb survivor carcinogenesis data? Radiat Res. 2007;168:750–756.
- Mossman BT. Carcinogenesis and related cell and tissue responses to asbestos: a review. Ann Occup Hyg. 1994;38:617-24, 423.
- Berrington de Gonzalez A, Gilbert E, Curtis R, Inskip P, Kleinerman R, Morton L, Rajaraman P, Little MP. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-responserelationship. Int J Radiat Oncol Biol Phys. 2013;86:224-33.
Written by:
Francesco S. Violante, MD and Andrea Farioli, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Section of Occupational Medicine, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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