High-dose external radiation and androgen deprivation are potent weapons for fighting prostate cancer, and both are supported by level 1 evidence. When men with locally advanced prostate cancer were randomized to external radiation with or without androgen deprivation, those with androgen deprivation experienced improved overall and disease-free survival.[1, 2] Randomized trials of high-dose (78 Gy) versus low-dose (70 Gy) radiation have shown improvement in biochemical recurrence, metastasis, and death from prostate cancer, without any change in overall survival.[3, 4]

Nevertheless, such improvements in cancer control must be balanced with the adverse effects of more aggressive treatment. Of the two randomized trials of external radiation with or without androgen deprivation one did not report on adverse effects,[1] while the other focused on genitourinary adverse effects, showing a difference only in the outcomes of gynecomastia and impotence.[2] Later, cohort studies using institutional or administrative data revealed a wide range of unintended consequences of androgen suppression therapy: bone fracture,[5] impaired glucose control,[6] cardiovascular disease, and sudden cardiac death.[6] Randomized trials of low-dose versus high-dose external radiation showed that there was additional late gastrointestinal morbidity with the higher dose.[3, 4] Intensity-modulated radiation therapy allows high-dose radiation delivery with rectal sparing.[7] Grade 3 or higher genitourinary adverse events were rare in all radiation series.

Common to all of these randomized trials was a lack of a reported protocol for assessing adverse effects of treatment. We in the prostate cancer field are not alone in this: a systematic review of 24 trials of chemoradiation for cervical cancer revealed that only 5 trials recorded late adverse effects in any detail.[8] We have a standardized method of grading adverse effects, but not for catching them.[9] For example, for how many months must a patient complain of slow urinary stream or dysuria (a grade 1 or 2 adverse effect) after radiation before that patient undergoes cystoscopy to look for a urethral stricture that is subsequently dilated (a grade 3 adverse effect)?

The cohort series presented by Nguyen et al[10] compared outcomes in high-risk prostate cancer treated with low-dose external radiation with or without androgen deprivation versus high-dose external radiation with or without androgen deprivation. The treatment groups were not randomized; therefore, any comparison of outcomes across groups suffers from biases such as treatment selection and differences in treatment era (the low-dose radiation therapy patients were treated in earlier years). The authors report rates of symptomatic local failure but do not report rates of adverse effects. They only report symptoms affecting quality of life among the subset of patients with a confirmed local recurrence.

It is essential that we approach the measurement of adverse effects of cancer therapy with the same vigor with which we measure cancer cure rates. We should not, as the authors do here, declare one treatment regimen superior to another without proper attention to adverse effects. Each patient's tolerance threshold for cancer recurrence and adverse effects will dictate an individualized approach to cancer management. The patient deserves to have the information needed to make an informed decision.


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No specific funding was disclosed.


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The authors made no disclosures.


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  • 1
    Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;360:103-106.
  • 2
    D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004;292:821-827.
  • 3
    Kuban DA, Levy LB, Cheung MR, et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys. 2011;79:1310-1317.
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    Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233-1239.
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    Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456.
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    Zelefsky MJ, Levin EJ, Hunt M, et al. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:1124-1129.
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    Green J, Kirwan J, Tierney J, et al. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix. Cochrane Database Syst Rev. 2005:CD002225.
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    Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341-1346.
  • 10
    Nguyen Q-N, Levy LB, Lee AK, et al. Long-term outcomes for men with high-risk prostate cancer treated definitively with external beam radiotherapy with or without androgen deprivation. Cancer. 2013;119:3265-3271.