Questions of timing of hormone therapy as well as radiation field size in patients with adenocarcinoma of the prostate with a risk of lymph node involvement of > 15% were the primary goals of this study. Progression Free Survival as can be seen in shows that there was no difference in progression free survival by timing of hormones. show that there was no difference in progression free survival by radiation field size. Unfortunately the lack of benefit of whole pelvis vs. prostate only radiation or adjuvant vs. neoadjuvant hormonal manipulation in this group of patients was not likely to be found because in the design of the study it was assumed that there would be no interaction between field size and timing of hormone therapy. Clearly this exists, and therefore, the analysis of this study becomes more complex.
What is clear is that the study was not powered to compare the four treatment arms one against the other. Yet when one looks at the WPRT + NHT arms compared to the PORT + NHT arm there is a trend towards statistical significance in the endpoints of PFS (p=0.023), biochemical failure per protocol definition (p=0.013) and biochemical failure nadir + 2 ng/ml definition (p=0.009). This suggests that if one selects to use NHT for this population of prostate cancer patients there appears to be a benefit to WPRT over PORT. To expand on the concept of NHT based on the data presented here, shows the PFS curves for WPRT + NHT vs. the other 3 arms of this trial. This analysis is not statistically valid based on the design of the trial, but seemed reasonable to evaluate as one tries to understand the interactions between timing of hormone therapy and field size. From one certainly could make an additional argument in favor of WPRT + NHTthat would correspond to the results of RTOG 92-02 and 86-10. This result is further supported by a subset analysis of arms 1 & 2 of 94-13 by Roach et al.(18
) This analysis shows a clear benefit in both biochemical control and PFS in favor of the WPRT.(18
) Given the results of RTOG protocol 92-02 as well as 86-10(2
) it seems reasonable that for this population one would select to use neoadjuvant hormonal manipulation.
Progression Free Survival (protocol definition of biochemical failure) Arm 1 vs. Arm 2–4
Another clear observation is that WPRT + AHT is the least desirable option with regards to overall survival. reveals that WPRT and AHT trends towards worse survival compared to the other three arms, p=0.019 vs. WPRT + NHT, p=0.019 vs. PORT+NHT p=0.01 vs. PORT+AHT. This can be graphically seen in . The observation that WPRT+AHT would offer a worse outcome is somewhat surprising given the results of WPRT + NHT. Yet when one evaluates the published randomized data suggesting the use of hormone therapy in this group of patients, none of the data to date has looked at short course adjuvant hormone therapy.(1
) So the result although unexpected was not incongruous with prior data because the prior data for adjuvant therapy utilized only long term adjuvant therapy, (i.e., 2–3 years).
So why would WPRT appear to be beneficial when hormone therapy is given neoadjuvantly and concurrently as in Arm 1, yet detrimental to survival when hormones are given adjuvantly? And why don’t we see that interaction in the PORT arms (Arms 2 & 4)?
One possible explanation for the benefit of WPRT + NHT over WPRT + AHT may lie in the immune modulation of anti-androgen therapy. Mercader et al(19
) have shown that anti-androgen ablation therapy results in T-cell infiltration of the prostate which increases apoptosis. This peaks at about 3–4 weeks into treatment with hormone therapy. It may be possible that T-cell infiltration occurs within the involved lymph nodes, such that there is an increase in apoptosis preradiation therapy and during radiation therapy which may make the radiation therapy more effective at the doses used to treat the lymph nodes. Since we do not see a statistical difference in PORT + NHT vs. PORT + AHT the above phenomena may be dose dependent, such that the doses of 70 Gy are high enough that we cannot see the effects. Other authors have noted a beneficial effect of intratumoral T-cells in other malignancies such as ovarian carcinoma.(20
Given that there is no question that there is an interaction between timing of hormone therapy and radiation therapy field size in this patient population, one is left with the question of how best to treat these patients. Based on this analysis and the randomized trials to date(1
) which show a benefit to radiation therapy and hormone therapy in this patient population, it is clear that NHT+WPRT remains the standard of care. Further follow up will help elucidate this stance with regards to cause specific and overall survival.