Role of Androgen Deprivation Therapy in Early Salvage Radiation Among Patients With Prostate-Specific Antigen Level of 0.5 or Less

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}

In this study, we examined the outcomes of salvage radiation plus or minus ADT in patients followed with ultrasensitive PSA and salvaged early at a PSA of ≤ 0.5. We focused on this population because they are most representative of the patients currently seen in practice, in whom early salvage therapy is often favored.

We found that ADT use among men with negative margins was associated with a significant reduction in the risk of second failure ( Table 2 ), and there was a 31% absolute increase in 4-year failure-free survival with the use of hormones in this subgroup. This association was not observed among men with positive margins.

The clinical implication of this study is that among those men who are followed with ultrasensitive PSA and salvaged early (PSA ≤ 0.5), it is possible that those with positive margins receiving salvage radiation may be safely spared from the morbidity of ADT.

The observed association between ADT and failure-free survival is a plausible one in patients with negative margins. ADT is a systemic therapy that has the ability to reach any distant micro-metastases that are not treated with local radiation. It is more likely that those with negative margins who recur do so because of residual micro-metastatic disease outside of the regional pelvic field covered by radiation, and it is thus reasonable that systemic therapy would benefit these patients, supporting the findings of the RTOG 96-01. Likewise, patients with positive margins are more likely to have had a local recurrence, and it is likely that with a PSA ≤ 0.5, radiotherapy to doses > 60 Gy is enough to eliminate microscopic disease in the prostate bed, and the addition of ADT does not seem to be necessary.^{10 and 11}

These results also support the work by Cheung et al, ¹² in which both a favorable group and an unfavorable group were identified for response to salvage radiation alone versus radiation plus ADT. Those patients with positive margins and pre-radiotherapy PSA ≤ 0.5 ng/mL comprised the favorable group who fared well with salvage radiotherapy alone and did not appear to require ADT. Patients with pre-salvage PSA > 0.5 or negative margins were thought to need ADT, which is consistent with the findings of the current study.

Our results do not directly address what to do for patients who have persistently detectable PSA after surgery. Extrapolating from these results, one might hypothesize that as long as the persistent PSA is ≤ 0.5, those with negative margins should receive adjuvant radiation plus ADT and those with positive margins may receive adjuvant radiation alone, but this will need to be tested in a cohort exclusively of men with persistently detectable postoperative PSA.

There are certain points that deserve additional consideration. As in most other studies on this topic, we conducted a retrospective study, and the data presented are not from a prospective randomized trial. Second, only 24 patients experienced a distant metastasis, and when this was used as the endpoint for analysis, there were no significant results; thus, our study focuses on the endpoint of biochemical failure. In the RTOG 96.01, a 17% difference in biochemical failure-free survival translated to a 5% difference in distant metastases, and it is reasonable to expect that with further follow-up of our cohort the results observed with biochemical failure could lead to a reduction in metastases. It would be ideal with further follow-up to also know the impact of ADT on freedom from distant metastases, prostate cancer–specific mortality, and overall survival. ² Another point to consider is that in this study, 41% of the patients had a PSA of 0.3 to 0.5 by the time they received salvage radiation, and with the growing evidence that earlier initiation of salvage radiation at lower PSA levels is better, more patients will likely be receiving salvage radiation at even lower PSA levels (ie, < 0.3). Whether ADT is still useful for patients with negative margins and PSA < 0.3 will need to be specifically tested in a larger series, but given the presumed distant component of recurrence in patients with negative margins, it is likely that ADT will still have a benefit in these patients.

Finally, it should be noted that although we did not observe a significant benefit to the use of ADT in men with positive margins and a PSA ≤ 0.5, those with local-only disease may have a protracted disease course, and so it remains possible that with further follow-up and larger cohorts it would be possible to detect a significant benefit to ADT in men with positive margins. In our study, the nonsignificant HR for the impact of ADT with positive margins was 0.78, which is less profound than the significant HR of 0.27 due to ADT for men with negative margins. However, even if the 0.78 HR for men with positive margins was significant, clinicians would still need to decide whether this relatively small risk reduction would be worth the additional side effects of ADT, and for many patients with slowly growing disease, this trade-off may not be worthwhile. Clearly, though, further follow-up is needed to completely rule out a benefit in this positive margin group.

Among patients who undergo radical prostatectomy (RP) as definitive treatment for localized prostate cancer, approximately 20% to 40% may experience a prostate-specific antigen (PSA) recurrence.^{1, 2, and 3}Salvage radiotherapy in this setting has been associated with reductions in prostate-cancer specific and overall mortality in select patients. ⁴ The Radiation Therapy Oncology Group (RTOG) 96-01 randomized trial of salvage radiotherapy with or without 2 years of bicalutamide (Casodex; AstraZeneca Pharmaceuticals LP, London, UK) has suggested that androgen deprivation therapy (ADT) can improve biochemical recurrence-free survival and metastasis-free survival in this patient population. ⁵ However, the RTOG 96-01 trial was not conducted in the era of ultrasensitive PSA and may have included patients with higher pre-salvage PSA (85% had PSA < 1.6, and 15% had PSA 1.6-4.0) than typically seen today in the salvage setting. Therefore, it remains unknown whether patients followed closely with ultrasensitive PSA and salvaged early at a PSA ≤ 0.5 have the same benefit from ADT. In this study, we examine patients salvaged at a low PSA (≤ 0.5) after RP to determine whether they benefit from the addition of ADT or whether these men may be spared the additional side effects of ADT.^{6 and 7}