With the successful completion of this trial, the RTOG has achieved several important landmarks. This is the first perspective multi-institutional study using a HDR prostate brachytherapy. This is the first brachytherapy trial based completely on three-dimensional electronic image data. By prescribing dose base on volume instead of points, this trial marks the arrival of image-guided brachytherapy for the treatment of prostate cancer. The application of HDR prostate brachytherapy in combination with external radiotherapy is well documented in the literature. Multiple single institutions data using a wide range of fractionations and implant schedules have been published in the literature. This study has been designed to study the safety of combining external beam radiotherapy with HDR brachytherapy. The technique and doses used in this study resulted acceptable level of toxicity.
Given the variety of different techniques of HDR brachytherapy, one of the initial challenges is to give a written description of the procedure that is acceptable by all potential participants, yet uniform enough to be scientific. It was reassuring that despite variation in techniques (number of catheters, catheter patterns, different templates), the acute toxicity from the treatment combination was low. The reported acute toxicity was mostly genitourinary. This is consistent with results from other studies using HDR boost. It is also consistent with the dosimetry. Quality assessment showed the most common structure that received dose above its constraint was the bladder. The organ at risk (OAR) with the highest dose constraint was the urethra. Both the dose to bladder and urethra may have contributed to the genitourinary toxicity, and these OARs may be the dose limiting structures. Avoiding injury and lower doses to the bladder and urethra may further reduce treatment toxicity.
So far, the late toxicity from this study shows a variety of single events without clustering. The most common category of adverse event is genitourinary. However, one patient has had multiple grade 3 AEs involved pain and bleeding from the rectum. It is reassuring the overall frequency and severity of the reported AE was low, and it are comparable to other prospective brachytherapy studies.(6
) This is also comparable to other prospective HDR brachytherapy studies. Borghede et al reported on the results of 50 patients treated with 50 Gy of external beam radiotherapy combined with 2 HDR brachytherapy implants delivering a total dose of 20 Gy (2 fractions). With a median follow-up time of 45 months, they reported 8% RTOG grade 3 urinary toxicity. There were no grade ≥ 3 gastrointestinal complications.(6
) Martinez et al reported results of a prospective dose escalation trial of HDR boost. Patients were treated with 46 Gy combined with 2-3 HDR implants delivering between 5.5 Gy × 3 to 11.5 Gy × 2. With 207 patients at a median follow-up time of 3.8 years, the 5 year RTOG GU grade 3 complication rates were 8%, 0.5% for GI grade 3, and 0.5% for GI grade 4 complications.(17
) Finally, from the only reported prospective randomized HDR trial, Hoskin et al reported on 109 patients randomized to external radiotherapy of 35.75 Gy/13 fractions and HDR boost of 17 Gy/2 fractions. At a median follow up of 30 months, the rate of grade 2 or worse bladder and bowel reactions were approximately 37% and 10% respectively. (24
The overall quality of implant dosimetry calculated based on submitted contours was very good. Ninety-eight percent of the V100PTV
were above 90%. However, the protocol treatment planning philosophy was not always followed. The goal of the protocol was to maximize the PTV coverage without sacrificing normal tissue sparing. Seven percent of V75Rectum
, and 15% of V75Bladder
received doses higher than the accepted values. Longer follow-up is needed to see if these and other dosimetry indices correlate with toxicity. Catheter migration between HDR fractions is another important quality issue that has been documented in the literature.(25
) If a “significant” catheter displacement occurs, the corrective actions including: adjusting the catheter and re-plan before delivering the second HDR fraction, or repeat the whole implant procedure. These options were written in the protocol, but no one chose this approach. Longer follow-up will tell if a more rigorous evaluation is needed. Finally, the dosimetry is only as accurate as the contours. Metallic markers, tubes, or even undiluted contrast can generate significant artifacts on CT and makes contouring and evaluation more challenging. The protocol forbids the use of metallic dummy markers. The use of other tubes or contrast should also be limited in future studies.
One limitation of this study is that it did not use a validated quality of life (QOL) instrument to study the effects of treatment on patients’ sexual function. Without QOL measurement taken before and after the treatment, it is difficult to make any conclusion about the effect of treatments on sexual function. The RTOG’s strategy is to include a quality of life measures in future phase III protocols. As expected the number of patients with grade 3 events, which is defined as decrease sexual function not helped by erectile aids, increased with longer follow-up.
This is a preliminary report of this study after it reached its primary end point. At the time of this report, the follow up time is too short to make any assessment on the efficacy of this treatment. Future updates of this study will include analysis efficacy and dosimetry.