Pelvic nodal irradiation, delivered with various schedules of androgen deprivation therapy, has been the historic standard for locally advanced prostate cancer (13
). The two minimum requirements for clinical benefit from pelvic radiotherapy are the selection of patients at sufficiently high risk for nodal metastatic involvement and the safe delivery of radiation doses sufficiently high to sterilize nodal metastases.
There are a number of models that estimate the risk of pelvic nodal involvement (17
many of which may underestimate such risk, given their reliance on nodal pathology from limited rather than extended lymph node dissections. Extended pelvic lymph node dissections have revealed that nodal involvement is often not contiguous (22
), whereas limited lymphadenectomy usually results in sampling of only obturator and external iliac lymph nodes. Higher rates of nodal positivity have been reported with extended lymph node dissections compared to historical standard node dissections (23
), leading some to recommend extended dissection including internal iliac, external iliac, obturator, and presacral regions in patients with clinical parameters that place them at higher risk (22
). While one randomized trial failed to demonstrate increased nodal positivity when comparing extended to standard dissection, the study included largely low risk patients, and only 6.5% of all patients were found to have pathologically involved nodes (27
Conversely, there is evidence for model overestimation as well. An analysis of the Surveillance, Epidemiology, and End Results Registry (SEER) 2004 database suggested that the Roach formula overestimates pelvic lymph node risk by a factor of 16 for patients with Roach score ≤ 10%, 7 for Roach score 10–20%, and 2.5 for Roach score > 20%. This analysis, however, was based on a population of almost exclusively cT1/2 patients who had a median of only 5 nodes surgically removed, and the overall rate of involved nodes was only 3.29% (28
Thus, failure of randomized trials to demonstrate long-term efficacy of nodal irradiation (2
) could relate, in some part, to the inability to select and study patients at sufficiently high risk of harboring nodal metastases. Lymphotropic nanoparticle enhanced MRI is one approach that may offer potential to better select patients at risk for nodal metastases. MRI with lymphotropic superparamagnetic nanoparticles has in one study demonstrated an overall sensitivity of 90.5% and specificity of 90.4% on a node-by-node basis for detection of nodal metastases (29
). This diagnostic tool, should it ever become widely available, could, in addition to facilitating a decision regarding pelvic radiation, also help to identify patients better treated with pelvic nodal and prostate irradiation rather than prostatectomy. Specifically, Heesakkers et al.
reported that 41% of patients with histologically confirmed nodes detected by MR lymphography had nodal metastases in areas outside of the region of routine pelvic lymph node dissection; additionally, 41% of patients had positive nodes both inside and outside the routine dissection area (30
Toxicity related dose limitations may also have decreased the ability to demonstrate a clinical benefit from pelvic radiation therapy. Pelvic nodal doses of 45–46.8 Gy have not demonstrated consistent benefit in randomized trials compared with treatment to only the prostate (2
). In most other malignant diseases, a dose of 45 Gy would be considered suboptimal to sterilize microscopic disease in the absence of chemotherapy. Head and neck squamous cell carcinomas are typically regarded as radiocurable, and the draining neck lymphatics are often treated to 54 Gy using conventional fractionation, with or without chemotherapy (31
). Furthermore, there is evidence for dose response in prostate cancer not only in the definitive setting but also for presumptive microscopic disease in the post-prostatectomy setting. King et al.
reported 5-year biochemical control of 25% for a prostate bed dose of 60 Gy compared to 58% for a dose of 70 Gy (p<0.0001) (6
). A subsequent analysis of salvage trials reported a gain in tumor control probability per additional gray within the steep portion of the probability curve of 3.8%/Gy (5
). By this measure, the increase in dose in our study from the 45–50.4 Gy range to 56 Gy could result in significantly increased rates of sterilization of microscopic nodal disease. Unknown at this point is the potential dose modifying effect that concurrent androgen deprivation therapy might have on dose response.
The escalation of nodal dose to 56 Gy in our series does not appear to increase either acute or late GU or GI toxicity when compared to preliminary toxicity reporting from a series from the University of Colorado delivering 50.4 Gy to the nodal basin concurrently with 70 Gy to the prostate in 28 fractions (33
). Interestingly, the median volume of small bowel receiving ≥ 45 Gy in our study was only 116.9 cc, below the recommended limit of 195 cc from the recent QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) series when the entire peritoneal potential space of bowel is included (34
). Thirteen patients in our series marginally exceed the 195 cc limit (maximum 549cc), but only 2 of these 13 developed grade 2 acute GI toxicities, neither of whom subsequently experienced scorable late GI toxicity. As indicated earlier, none of the dose-volume descriptors correlated with early GU toxicity, and only the volume of bowel receiving ≥ 30 Gy correlated with early GI toxicity (p=0.029).
Potential differences in patient characteristics and the preliminary nature of the biochemical control estimates of our study preclude detailed comparisons between these results and those of other studies that involved high risk patients treated with androgen deprivation and pelvic radiotherapy. However, with a median of 12 months of androgen deprivation therapy, this study’s estimated 3 year biochemical disease free survival of 81.2% ± 6.6%, does appear consistent with the RTOG 9413 reported 4-year biochemical control rate of 70% with 4 months of neoadjuvant/concurrent androgen deprivation (2
). and with the RTOG 9202 reported 5-year biochemical control rate of 66.6% with 28 months total androgen deprivation (38
The hypofractionated regimen of 70 Gy in 28 fractions of 2.5 Gy delivered to the prostate in this present trial is familiar and potentially attractive. This is both because prostate hypofractionated radiotherapy has been hypothesized to enjoy a radiobiological advantage over conventional fractionation (8
), and because it is the fractionation regimen used both by Cleveland Clinic’s well tolerated and effective study of prostate only radiotherapy in 770 patients (39
) and by the experimental arm of ongoing RTOG trial 0415.