The optimization of management of post-prostatectomy patients at higher risk of biochemical progression is an area of ongoing investigation. Prospective randomized trials 5–7
of adjuvant therapy for patients at risk of local recurrence have provided definitive evidence of the clinical benefit of post-prostatectomy radiotherapy in terms of biochemical control 11, 12, 23
, metastasis-free survival and cause-specific and overall survival, but have arguably left unresolved the issue of optimal timing of the radiation. The fact that a number of non-randomized salvage trials have demonstrated the importance of early intervention, a practice not routinely followed in the observation arms of the randomized adjuvant trials, leaves incompletely answered the question of whether patients are best managed by an adjuvant versus an early salvage approach 24
Our institutional practice has been one of early salvage therapy 13
. This present report includes 108 patients and demonstrates that a hypofractionated schedule of 65 Gy in 26 fractions of 2.5 Gy each is well tolerated and yields excellent 4-year biochemical control (67.0 +/− 5.3%), with only an infrequent use of concurrent, short-term androgen deprivation. Multivariate analysis demonstrated higher Gleason score (p=0.057) and lack of positive margins (p=0.088) to be the only factors to maintain association with biochemical progression following salvage RT.
Several studies of radiation therapy alone for prostate cancer have suggested that delivering larger daily radiation fraction sizes may be radiobiologically advantageous. Such a hypofractionated approach is now being extensively investigated in the nonsurgical setting 25, 26
. While it is less clear whether such a radiobiological advantage applies in the post-prostatectomy setting where microscopic rather than macroscopic cancer would be expected, a hypofractionated approach to salvage therapy still clearly offers advantages in terms of cost and of coveniences to the patient.
Based upon a reasonable range of standard radiobiological modeling parameters, the fractionation regimen used in this study (65 Gy in 2.5 Gy fractions) would be expected to be equivalent to a dose in 2 Gy fractions (EQD2
) of between 68 and 74.4 Gy, a dose range found to be more effective than lower doses in other studies 27–29
. Retrospective studies have demonstrated salvage RT after biochemical recurrence using standard 1.8–2 Gy fractions to total doses of 60–70 Gy to be variably effective, with 5-year biochemical recurrence-free rates ranging from 10–66% at 5 years (as summarized in 23
). The largest, multi-institutional reports have come from Stephenson et al
, who have reported actuarial biochemical control rates of 45% at 4-years 10
and 32% at 6 years 9
. Furthermore, that group highlighted the importance of pre-salvage PSA as a prognostic marker for control after salvage radiotherapy, with the lowest-risk patients (pre-salvage PSA ≤0.5) achieving biochemical control of 48% at 6-years. We demonstrate actuarial biochemical control at 4 years (67.0%, +/− 5.3%) and 5 years (67.0% +/− 7%) in a patient cohort with a median pre-salvage PSA of 0.44 (range 0.05–9.50).
On the other hand, the fraction size response of the pertinent surrounding normal organs such as rectum and bladder is arguably somewhat better defined. The fraction size and dose we used would be equivalent, in terms of normal tissue toxicity, to about 71.5 Gy delivered instead in 2 Gy fractions, a total dose within the upper range used in most retrospective salvage studies. Our regimen, as reported here, has been very well tolerated. While possible differences in volumes of bladder and rectum included in the clinical target volumes in this present and other studies cannot easily be accounted for, the low late toxicities observed here compare favorably with a recent salvage series of 68 patients who received 74 Gy in 2 Gy fractions, in which late grade ≥2 GU side effects were reported in 31% (with 6% strictures), and late grade ≥2 GI toxicities were noted in 13% 30
. Similar low late toxicity rates were noted in a prospective evaluation of toxicities in patients receiving 60–66 Gy salvage RT in standard fractions 31
. Of note, no late grade 3 or 4 toxicities were seen in this present study, and late grade 2 side effects were usually easily treated or resolved spontaneously, with only a 3% and 1% prevalence of late grade 2 GU and GI toxicities, respectively, at last follow-up.
Limitations of our study stem from its retrospective nature, and from the heterogeneity that exists with regard to treatment parameters and pathologic factors in this patient cohort. While the utility of concurrent hormone ablation has not been prospectively evaluated in the salvage setting, 8 patients in our series (7.4%) received concurrent hormone ablation, and this may have augmented the biochemical control rates presented. Furthermore, 14 patients (13%) received radiation to high doses (52–56 Gy) to the pelvic lymph nodes, with unknown impact on overall biochemical control for this patient cohort. Additionally, while most patients (73%) had pT2 tumors with a relatively low pre-salvage PSA (median 0.44), a few patients were included with very high-risk disease, including 2 patients with node positivity, patients with bulky recurrence, and 2 patients with markedly high PSAs (8.95 & 9.50 ng/ml). These heterogeneous pretreatment and treatment factors, in addition to the inability to completely account for the differences in clinical and pathologic variables between studies, preclude definitive comparison of biochemical outcomes. Nonetheless, our outcomes utilizing a hypofractionated approach appear at least comparable to, if not more favorable than those from series using standard fractionation.
The prospective randomized trials investigating adjuvant radiotherapy after radical prostatectomy have demonstrated that 36–54% of patients in their observation arms do not develop biochemically recurrent disease in the timeframe of the studies’ followup 5–7
, indicating, as with any adjuvant treatment, that some patients do not derive benefit. Additionally, analysis of these three trials demonstrated ultimate biochemical progressions in the adjuvant arms of 26–35%, suggesting that the use of adjuvant RT doses of 60–64 Gy to the prostatic fossa ultimately prevents recurrence in less than half of the patients destined to have biochemical progression, numbers not too dissimilar to the biochemical control rates seen in many studies of salvage radiotherapy. Thus, while the clinical benefits of postprostatectomy radiation therapy in high risk patients have been clearly established in randomized trials, the optimal timing of such treatment remains an investigational question, one that is currently being re-explored in three large randomized trials: GETUG-17 (ClinicalTrials.gov identi er NCT00667069), RAVES (Radiotherapy Adjuvant Versus Early Salvage; ClinicalTrials.gov identi er NCT00860652), and RADICALS (Radiotherapy and Androgen Deprivation In Combination After Local Surgery) 32
. These trials will ultimately determine whether close postoperative observation of patients with positive margins, extracapsular extension, or seminal vesicle invasion and early initiation of salvage RT after biochemical progression will provide an effective, perhaps optimal postoperative management approach. With an overall goal of maximizing benefit versus risk and cost, there certainly is likely to also exist a middle ground, where patients deemed to be at very high risk for local failure are offered adjuvant therapy, whereas others at lower but still significant risk are followed closely and, if necessary, salvaged early.
In summary, hypofractionated radiotherapy (65 Gy in 2.5 Gy fractions in 5+ weeks) is a convenient, resource efficient and safe approach for salvage after radical prostatectomy. It reduces the length of treatment by from 1–1/2 to 3 weeks relative to other treatment schedules commonly employed. Biochemical control rates at 4 – 5 years are encouraging and await further confirmation with longer followup. The low toxicities and early favorable biochemical control outcomes found, if confirmed, may warrant future testing of similarly expedited courses of radiation therapy in an adjuvant setting as well.