What is the key factor determining effectiveness of radiotherapy for high-risk prostate cancer: a hidden message from RTOG 0521

The combination of radiotherapy and long-term androgen deprivation therapy (ADT) has been widely accepted as the standard treatment for high-risk prostate cancer by several randomized controlled trial (RCT) results (1,2). In this editorial comment, this author raises the two important factors influencing effectiveness of the combination therapy (radiation dose and recovery of testosterone) by quoting the result of RTOG 0521 (3).

Sartor et al. have reported a long-term outcome of the randomized RTOG 0521 trial: “ADT and external beam radiotherapy (EBRT) with or without docetaxel for localized high-risk prostate cancer” (3). Eligibility criteria for RTOG 0521 participation and early outcome were reported by Rosenthal et al. (4): “Patients within a high-risk prostate cancer of the conventional National Comprehensive Cancer Network were eligible, if they had either a Gleason score of 9 to 10, independent of prostate-specific antigen (PSA) or T stage; Gleason score of 7 to 8 and PSA of 20 ng/mL or greater, with any T stage; or Gleason score of 8 and PSA less than 20 ng/mL with T stage greater than or equal to T2.” (4); “Maximum allowed PSA was 150 ng/mL. Other criteria included no evidence of nodal or distant metastasis.” (4).

Treatment arms were as follows: “Arm 1 (ADT for 8 weeks followed by EBRT with 72.0 to 75.6 Gy followed by adjuvant ADT for a total of 24 months) or Arm 2 (ADT for 8 weeks followed by EBRT with concurrent ADT followed by adjuvant ADT for 24 months plus six cycles of docetaxel and prednisone administered concurrently with ADT beginning 28 days after completion of EBRT).” (4).

“Finally, 563 were eligible and included in the analysis. The median follow-up among survivors was 10.4 years.” (4).

Although “the initial publication reported a survival benefit of docetaxel after a median follow-up of 5.7 years” (4), “with the longer follow-up (a median follow-up of 10.4 years) in the present study, the data did not provide a benefit for the use of docetaxel in patients with high-risk clinically localized prostate cancer when combined with EBRT and ADT.” (3). Therefore, the authors of this report have concluded that “docetaxel should not be used in high-risk localized prostate cancer patients in combination with EBRT.” (3). On top of this conclusion, this author thinks that we should extract a hidden message from this long-term outcome of RTOG 0521. When we apply ADT as an adjuvant therapy of radiotherapy for prostate cancer, the true state of prostate cancer cure in each patient should be defined when we confirm low PSA values after confirming recovery of testosterone level to a normal range. This author has referred to the above-mentioned points previously in successful treatment of T4N1 prostate cancer (5) and very high-risk locally advanced prostate ductal adenocarcinoma, which is recognized as an aggressive phenotype of prostate cancer (6).

Long-term usage of ADT in combination with EBRT in a treatment protocol for prostate cancer patients such as those in RTOG 0521 (3,4) and STAMPEDE trials (7) contains a pitfall: if the PSA value is low even after long-term follow up, the true state of prostate cancer cure cannot be judged when the testosterone level of the patient is low. This is obvious because a low PSA value in conjunction with a low testosterone level just reveals a continuous effect of ADT. In the method section of the initial report on RTOG 0521, it is noted that testosterone was measured until normalization or initiation of salvage ADT (4). However, there is no mention of that point in the result section (3,4): obviously, measurement of testosterone by itself does not assure recovery of testosterone to the normal range. Therefore, the readers cannot know how many patients achieved recovery of testosterone to a normal range at their follow up. The authors have reported that “the PSA recurrence risk was 36.0% for ADT + EBRT and 36.3% for ADT + EBRT + docetaxel at 10 years of follow up” (3). Apart from discussing whether the PSA recurrence risk is acceptable, they should have incorporated the testosterone level in their follow-up in order to eliminate an effect of prolonged testosterone suppression.

This author and others proclaimed that dose escalation is a key factor in radiotherapy of prostate cancer (5,6,8-11): particularly in high-risk prostate cancer, a good local control by dose escalation is crucial for optimal outcome of radiotherapy (9-11). The use of prostate brachytherapy provides the advantage of safe delivery of a high biologically effective dose (BED) to the prostate (8-10,12). Also, this author has shown a quality low-dose-rate (LDR) method of high BED which can treat both inside and outside of the prostate with or without ADT (5,13-15).

The advantage of combination therapy with LDR brachytherapy and EBRT has been confirmed by the ASCENDE-RT (Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy) randomized trial (16).

In terms of radiation dose, Stone et al. have shown that patients with Gleason 8–10 disease receiving a BED ≥220 Gy (using α/β=2) by combination therapy with LDR brachytherapy and EBRT, obtained improvement in biochemical failure-free survival (BFFS) (9,17). In line with this concept, this author reported a good clinical outcome for high-risk and very-high-risk prostate cancer patients including those with pelvic lymph node metastasis by combination therapy with LDR brachytherapy and EBRT of BED ≥220 Gy (using α/β=2) (6,11). On the other hand, the BED (using α/β=2) of EBRT in this RTOG 0521 trial is only 135.8–143.6 Gy (calculated from an EBRT dose of 72–75.6 Gy by 1.8 Gy per fraction as described in Methods) (4). Furthermore, a recent RCT (TRIP/TRIGU0907) using combination therapy with LDR brachytherapy and EBRT for localized high-risk prostate cancer (average BED of 217 Gy) demonstrated similar good oncological outcome among the long-term ADT (30 M) arm and the short-term (6 M) arm (18).

This author admits that determinant role of BED and duration of ADT are not the aim of the RTOG 0521. However, this author believes that the aim of RCT in future should be carefully designed in these regards. Otherwise, the RCT will just result in a waste of time and resources.

In conclusion, this author recommends that physicians and researchers involved in radiation therapy of prostate cancer should change their mindset: The key factor determining the effectiveness of radiotherapy in high-risk prostate cancer patients is neither duration of ADT, nor addition of another drug, but radiation dose, namely BED.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

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