However, within all the arguments he posed to support the routine use of brachytherapy alone for intermediate-risk disease, there are inconsistencies. Indeed, some of his perspectives actually represent cogent reasons to support our viewpoint for adding supplemental EBRT to brachytherapy in this patient population. So for this rebuttal, let’s carefully analyze Dr Stone’s arguments for the use of brachytherapy alone. The following key points will be critically LDK378 in vivo assessed: (1) benefit of further dose escalation to allow the delivery of a higher biologic effective dose (BED); (2) the efficacy for achieving the “trifecta” with brachytherapy alone, namely, low urinary

toxicity and maintained sexual function with durable tumor control; (3) secondary malignancy risk with EBRT; and (4) theoretical financial burden of more aggressive therapy using supplemental EBRT. Perhaps, unwittingly, Dr Stone is actually arguing in favor of supplemental EBRT by reinforcing the notion that further dose escalation improves tumor outcomes, and we could not agree more. As shown in our table 1 (2), when comparing series with ≥8-year outcomes, most implant alone reports have noted biochemical failure rates >20%, whereas combination therapy series have reported failure PI3K Inhibitor Library of approximately 10%. This is consistent with the data Dr Stone presented from Mount Sinai that reported that BED >200 Gy resulted in

improved biochemical control compared with lower doses (3). Dr Stone had also reported that doses >220 Gy were associated with further improvements in biochemical control (4). To achieve these kind of dose levels with an implant alone, one would require an I-125 D90 coverage of approximately 210 Gy … now that is a hot implant (hotter than any of the D90s even in his tables)! The addition of supplemental EBRT can readily achieve such high BEDs safely without resorting to excessive hot spots

within the target and still provide the necessary dose coverage for extraprostatic disease. A logical concern that Dr Stone brings forth is that the better tumor control with high BEDs may negate the ability to achieve the coveted Aldehyde dehydrogenase “trifecta” of brachytherapy and result in greater risks for long-term toxicity. However, the concern for toxicity with such high BEDs with combination therapy has been evaluated in three multi-institutional prospective Phase II trials that did not even use intensity-modulated radiotherapy (IMRT) (let alone image-guided radiotherapy [IGRT]) and had wide >1.5-cm margins on the prostate for the EBRT component. The CALGB reported 0.0% acute gastrointestinal (GI) Grade ≥3 toxicity and 0.0% late GI Grade ≥3 (5)! The Radiation Therapy Oncology Group (RTOG) reported only 2.9% late Grade ≥3 GI toxicity Reference 10 (Lawton et al) Dr Stone cited multiple retrospective single institution studies depicting the concern for increased toxicity with supplemental EBRT [6] and [7].