Brachytherapy for prostate cancer: feasible but oncological equivalence unproven Debasish Sundi and Misop Han Johns Hopkins Medical Institutions, James Buchanan Brady Urological Institute, Baltimore, MD, USA

We read with interest the accompanying review by Chao et al. [1] on the indications for and comparative effectiveness of brachytherapy, a treatment method for clinically localised prostate cancer (PCa). To foster a balanced discussion and to understand the role of brachytherapy from a broader perspective, in the present editorial, we will highlight several opposing views. The review by Chao et al. begins with the central tenet that ‘contemporary treatment options for PCa are considered to have comparable efficacy’. There are several reasons to challenge this statement. First, there are no randomised trials comparing oncological efficacy between surgery (radical prostatectomy [RP]) and external beam radiation therapy (EBRT), between RP and brachytherapy or between EBRT and brachytherapy. Second, the single key study cited by Chao et al. was actually a meta-analysis of retrospective studies that suggested brachytherapy was similar to other treatments for PCa [2]; however, the main outcome in that meta-analysis was biochemical relapse-free survival. In addition to the major problem of using different definitions of biochemical relapse between treatment methods, we argue that the endpoints that truly matter after PCa treatment are metastasis-free survival, cancer-specific survival and overall survival. Unfortunately, the meta-analysis was also limited by significant methodological concerns and potential biases [3]; therefore, it is entirely unproven that brachytherapy is oncologically similar to EBRT or RP. Third, where Chao et al. presented oncological outcomes of brachytherapy (references 31 and 32 in the accompanying article) other than biochemical relapse-free survival, overall or cancer-specific survival after brachytherapy was not directly compared with survival after other treatments [2,4]. Finally, not only has brachytherapy not been proven to be superior or equivalent to EBRT, but several large observational studies strongly suggest that RP may provide more durable cancer control than EBRT, especially for intermediate- and high-risk disease [5–9]. Nevertheless, we suggest that among major PCa treatment options, whether brachytherapy is similar to RP and/or EBRT can only be properly assessed in a randomised © 2014 The Authors BJU International © 2014 BJU International | doi:10.1111/bju.12837 Published by John Wiley & Sons Ltd. www.bjui.org

prospective clinical trial. Comparing treatments as different as brachytherapy and RP in prospective randomised fashion has proven to be difficult [10], but remains crucial to assess treatment non-inferiority. In terms of health-related quality-of-life outcomes, the large multicentre study comparisons of multiple PCa treatments (references 40 and 53 in Chao et al. [1]) have shown that patients who undergo brachytherapy may actually have significant side effects, which, with some measures (bowel function and irritative and obstructive urinary symptoms), may even be more severe than after surgery [11,12]. Of importance to patients and referring physicians, a procedural learning curve is at play here as well: brachytherapy side effects appear to be higher when performed at centres with less experience [13,14]. Furthermore, although a single brachytherapy treatment appears to be better tolerated that other treatments, combining brachytherapy with EBRT and/or androgen deprivation therapy can suddenly submit a patient to a prolonged PCa treatment and accompanying adverse side effects [12]. How often is a secondary treatment co-administered with brachytherapy? In a large series including over 40% of patients with low-risk disease performed at a centre with a high level of experience, the answer is in over half of cases [15]. Despite these opposing viewpoints, we agree that brachytherapy may be underused as a primary PCa treatment. Unfortunately, at this point, there is simply no way to know the comparative oncological effectiveness of brachytherapy with respect to RP and/or EBRT. Further confusing matters, newer radiation techniques such as CyberKnife and proton beam radiotherapy have been reported to be similar to brachytherapy in terms of dosimetry and short-term results, but patients and physicians are again left to make uninformed decisions because of the lack of long-term oncological and toxicity outcomes among these treatment methods [15–17]. Cryotherapy is an increasingly utilized alternative to brachytherapy; both use similar techniques, performed in an outpatient setting. Studies suggest favourable side effect

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Comment

profiles for both (more bowel toxicity but better sexual function for brachytherapy compared with cryotherapy), but again long-term comparative oncological data are lacking [18,19]. A significant proportion of brachytherapy recipients are low-risk [2,4,20] and in such patients it is especially important to pause and ask if any treatment is warranted at all. In other words, what is the comparative oncological efficacy of surveillance or observation in low-risk PCa? Excellent observational evidence shows that cancer-specific mortality rates among well-selected men on surveillance are very low (≤1%) [21], and the PIVOT trial [22] is an example of level one evidence that shows no survival difference between men with low-risk disease who undergo radical treatment vs those who are observed; thus, the relevant clinical question should sometimes be observation/ surveillance vs treatment, not treatment via brachytherapy vs treatment by RP/EBRT. In our opinion, younger and healthier men with more aggressive cancers have the most to lose by choosing brachytherapy. For the older patient with comorbidities that may preclude more aggressive therapies, however, brachytherapy may be an option, given its overall favourable side effect profile (in the absence of systemic androgen deprivation). In addition, brachytherapy is probably not associated with a greater risk of secondary malignancies [23,24]; therefore, the dilemmas going forward in the absence of randomised prospective evidence are, firstly, proper patient selection, in step with individual patient attitudes toward treatment tolerability and oncological risk and, secondly, how to properly assess comparative oncological outcomes of brachytherapy given patient and treatment selection biases.

Conflict of Interest

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References 1

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Chao M, Grimm P, Yaxley J, Jagavkar R, Ng M, Lawrentschuk N. Brachytherapy: state of the art radiotherapy in prostate cancer. BJU Int 2015; accepted Sylvester JE, Grimm PD, Wong J, Galbreath RW, Merrick G, Blasko JC. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following I(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011; 81: 376–81 Sooriakumaran P, Spahn M, Wiklund P. Apples and oranges: comparison of treatment methods for prostate cancer using biochemical recurrence as an endpoint. BJU Int 2012; 110: 477–8 Potters L, Morgenstern C, Calugaru E et al. 12-Year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol 2005; 173: 1562–6

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D’Amico AV, Whittington R, Malkowicz SB et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969–74 Zelefsky MJ, Eastham JA, Cronin AM et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol 2010; 28: 1508–13 Abdollah F, Sun M, Thuret R et al. A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988–2006. Eur Urol; 2011 59: 88–95 Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010; 116: 5226–34 Sooriakumaran P, Nyberg T, Akre O et al. Comparative effectiveness of radical prostatectomy and radiotherapy in prostate cancer?: observational study of mortality outcomes. BMJ 2014; 348: 1–13 Ahmed HU, Berge V, Bottomley D et al. Can we deliver randomized trials of focal therapy in prostate cancer? Nat Rev Clin Oncol 2014; 22: 1–10 Buron C, Le Vu B, Cosset J-M et al. Brachytherapy versus prostatectomy in localized prostate cancer: results of a French multicenter prospective medico-economic study. Int J Radiat Oncol Biol Phys 2007; 67: 812–22 Sanda MG, Dunn RL, Michalski J et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 358: 1250–61 Chan EK, Keyes M, Pickles T et al. Decline in acute urinary toxicity: a long-term study in 2011 patients with prostate brachytherapy within a provincial institution. Brachytherapy 2014 13: 46–52 Bockholt N, DeRoo E, Nepple K et al. First 100 cases at a low volume prostate brachytherapy institution: learning curve and the importance of continuous quality improvement. Can J Urol 2013; 20: 6907–12 Jabbari S, Weinberg VK, Shinohara K et al. Equivalent biochemical control and improved prostate-specific antigen nadir after permanent prostate seed implant brachytherapy versus high-dose three-dimensional conformal radiotherapy and high-dose conformal proton beam radiotherapy boost. Int J Radiat Oncol Biol Phys 2010; 76: 36–42 Fuller DB, Naitoh J, Lee C, Hardy S, Jin H. Virtual HDR CyberKnife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations. Int J Radiat Oncol Biol Phys 2008; 70: 1588–97 Ju AW, Wang H, Oermann EK et al. Hypofractionated stereotactic body radiation therapy as monotherapy for intermediate-risk prostate cancer. Radiat Oncol 2013 8: 1–10 Malcolm JB, Fabrizio MD, Barone BB et al. Quality of life after open or robotic prostatectomy, cryoablation or brachytherapy for localized prostate cancer. J Urol 2010 183: 1822–8 Williams SB, Lei Y, Nguyen PL et al. Comparative effectiveness of cryotherapy vs brachytherapy for localised prostate cancer. BJU Int 2012; 110 (2 Pt 2): E92–8 Grimm P, Billiet I, Bostwick D et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012; 110: E431–2; author reply E432 Dall’era MA, Albertsen PC, Bangma C et al. Active surveillance for prostate cancer: a systematic review of the Literature. Eur Urol 2012 7: 1–8

Comment

22 Wilt TJ, Brawer MK, Jones KM et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203–13 23 Hinnen KA, Schaapveld M, van Vulpen M et al. Prostate brachytherapy and second primary cancer risk: a competitive risk analysis. J Clin Oncol 2011; 29: 4510–5 24 Musunuru H, Mason M, Murray L et al. Second primary cancers occurring after I-125 brachytherapy as monotherapy for early prostate cancer. Clin Oncol (R Coll Radiol) 2014 26: 210–5

Correspondence: Misop Han, 600 North Wolfe Street, Marburg 1, Baltimore, MD 21287, USA. e-mail: [email protected] Abbreviations: PCa, prostate cancer; RP, radical prostatectomy; EBRT, external beam radiation therapy.

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