This report, over 20 years after initiation of S8794, demonstrates that adjuvant radiotherapy at the relatively modest dose used in the late 1980's significantly reduces the risk of metastases in a man with pathologic evidence of extraprostatic disease after radical prostatectomy. This significant reduction was realized despite the application of salvage radiotherapy, perhaps the most commonly-used approach to these patients today, in a third of the patients in the observation group. Additionally, this reduction in metastases and improvement in survival was despite an almost doubled use of hormonal therapy in the observation group. It is important to place this outcome in perspective. The median 1.7 year survival benefit may apply to over 30,000 men per year in the US.10,11
In the realm of advanced prostate cancer, the only treatment proven to improve survival - docetaxel - improves survival by only 1.9 – 2.3 months.12,13
In addition to the most important outcomes of prostate cancer (metastases and survival), all other measures of disease recurrence were improved with adjuvant radiotherapy. For those men with an undetectable PSA postoperatively, the median delay in time to PSA recurrence was substantial: over 7 years.7
Despite significant reductions in adverse outcomes related to prostate cancer progression with adjuvant radiotherapy, we have previously reported on side effects and quality of life in the two groups in this study. We conducted a companion quality of life study in 217 men randomized to S8794 with assessments at baseline, 6 weeks, 6 months, and annually for five years.8
A strength of this analysis was the inclusion of a 6-week assessment, designed to capture the side effects of radiotherapy at their peak. Tenderness and urgency of bowel movements were significantly more common at the 6 week time point (47% versus 5%) in the radiotherapy group but by two years, there was little difference between the groups. Urinary frequency was more commonly seen in the radiation group but there was no difference in the rate of erectile dysfunction (common in both groups) between groups. Global assessment of quality of life, while initially worse in the adjuvant radiotherapy group became similar by year 2 and was increasingly superior in the radiotherapy group over the following 3 years. This gradual switch toward a superior quality of life with the adjuvant radiotherapy group should be examined in the context of the increased rates of PSA recurrence, salvage radiotherapy, and hormonal therapy in the observation group and which all have negative impacts on quality of life.14,15
A limitation of this study is the incomplete central pathologic review with only 311/425 (73%) having complete central pathology review; nevertheless, of those with full review, there was a 95% concordance between central and institutional pathology reviews. This was also a limitation of the EORTC 22911 adjuvant radiotherapy trial in which central review was only conducted in high volume institutions and for 566 of 1005 patients. Similar to our study, 552/566 were deemed eligible after review. A review of the EORTC trial, however, found that with central review, only positive margin patients benefitted from adjuvant radiation.16
Additionally, it must be acknowledged that Gleason grades assigned during this trial are probably lower than would be assigned with a contemporary review; such would be the case for any study with 20-year outcomes.17
It is also important to acknowledge that the extent of disease in patients from the late 1980’s and early 1990’s may have been of a greater volume than contemporary patients, potentially increasing the differences in outcomes between treatment arms. Balancing against this bias may be the radiation dose used. Higher contemporary doses of radiotherapy may have increased differences in outcomes.
For many if not most clinicians who face the patient with evidence of extraprostatic disease and in whom the postoperative PSA is undetectable, a common strategy is simply to follow the PSA and initiate radiotherapy at the time PSA becomes detectable or prior to the achievement of some PSA threshold (e.g., 1.5 ng/mL).18,19
These data argue that the salvage radiotherapy approach may place the patient at a higher risk of metastasis and death. The first evidence of this comes from the study group crossovers in this trial: about one third of subjects assigned to observation ultimately received radiotherapy at the time of a PSA or local relapse. The study thus compared immediate (adjuvant) radiotherapy to treatment at the time of disease recurrence (salvage radiotherapy). The second observation is that, although there is a significant benefit of radiotherapy for the subset of patients with detectable PSA post-prostatectomy (see ), that group’s metastasis-free survival is inferior to those who received radiotherapy when the PSA was still undetectable (). Although these two observations are based on observations from subsets of the data, they do argue that the practice of waiting until PSA is detectable, while associated with a superior initial quality of life and fewer patients receiving radiotherapy, risks later decrements in health-related quality of life due to increased burden of therapies as well as an increased risk of metastasis and death.
This study points out two challenges for the academic and clinical trials community. The first is that important therapeutic advances in the management of localized prostate cancer require large numbers of patients and just as importantly prolonged follow-up. The hundreds of publications involving case series of patients treated with and without radiotherapy could not accurately compare outcomes of treatment due to inherent selection biases and unmeasured disease and patient-related variables. In the absence of initiating and completing these randomized studies, optimal patient care cannot be attained. To that end, the second challenge will be to build upon the observations of this study. One suggestion would be to randomize patients with T3N0M0 prostate cancer to either adjuvant radiotherapy or to salvage radiotherapy as soon as an ultrasensitive PSA is positive.20
We have examined possible study designs such as this and have found that to test whether delayed radiotherapy is not inferior to immediate radiotherapy (defined as a metastasis-free survival hazard ratio of delayed/immediate of ≤ 1.10) and using rates of failure as seen in this study, a two-sided alpha of 0.05 and a power of 90%, and an accrual over 8 years with 9 additional years of follow-up would require a sample size of 8300. With the poor track record of accrual of patients with localized prostate cancer to clinical trials in the US, unless there is a fundamental change in the structure of clinical trials, it is unlikely that such a trial will be started or completed.
We look forward to updates of the EORTC randomized trial as well as the German ARO 96-02/AUO AP 09/95 study that randomized 385 patients after prostatectomy to radiotherapy with 60 Gy or observation alone. Ultimately, because of very similar designs across the studies, we anticipate that meta-analyses will be conducted.