Reconsidering the Case for Brachytherapy Plus EBRT in High-Risk Prostate Cancer

In the article entitled "Interstitial Brachytherapy Should Be Standard of Care for Treatment of High-Risk Prostate Cancer," Merrick, Wallner, and Butler once again make the case for interstitial brachytherapy as a primary treatment for prostate cancer (see their earlier article, "Permanent Prostate Brachytherapy: Is Supplemental External-Beam Radiation Therapy Necessary?" in ONCOLOGY, April 2006).[1] This time Nathan Bittner has joined as the lead author.

The group makes many of the same points that they did 2 years ago-that extracapsular extension can be adequately treated with brachytherapy, likewise most seminal vesicle invasion that is usually proximal, and that previous brachytherapy studies reporting poor outcomes for patients in intermediate- and high-risk categories are explained by poor technique, which has been corrected over the past several years. Furthermore, they "attempt to dispel some common misconceptions about prostate brachytherapy" and "in doing so, … hope to convince the reader that brachytherapy is the best available local therapy and should be standard of care in the treatment of high-risk prostate cancer."

Finally, the authors seem to imply that brachytherapy should be the standard of care for high-risk disease, as they feel that modern data suggest that brachytherapy with supplemental external-beam radiation therapy (EBRT) produces a better cancer-free outcome compared to external-beam irradiation alone (or prostatectomy). So it seems that-at least in this instance-it is advantageous to embrace supplemental external-beam radiation, which the authors largely deemed unnecessary previously, since much of the supporting data for high-risk disease includes EBRT and sometimes hormone therapy as well. The current article is written with such conviction that it does cause one to consider the authors' proposal. Let us then more carefully examine some of the issues.

Extracapsular Extension and Seminal Vesicle Involvement

With regard to extracapsular extension, it seems reasonable to assume that adequate coverage generally may be possible with the combination of EBRT and brachytherapy if 3- to 6-mm 100% dose margins are consistently attainable with an implant, as the authors suggest. However, according to the prostatectomy-based model of Schwartz et al,[2] depending on predictive factors within the high-risk group, some patients may have tumor extension outside the 6-mm implantable limit more than half the time. An additional worry concerns the prostate base and beyond, where it is well known that dose may often be compromised with implant, and where patients with high-risk disease may have extension to the bladder neck or into and around the seminal vesicles (SV).

Although the authors report that implanting the SV is possible, they also admit that the dose distribution is "variable" and even a "formidable challenge" when it comes to the more distal SV. What consistently accurate method do we have to help us decide which patients can get by with just 45 Gy, and to exactly how much of the SV? Although Stock and colleagues show an 8-year biochemical disease-free survival (BDFS) of 83% for all high-risk patients (Table 1 of the Bittner et al article), they also report a 7-year BDFS of 67% for biopsy-confirmed SV involvement with their implant technique.[3,4] Moreover, SV involvement typically heralds a more advanced disease state that often cannot be cured by local treatment. This, of course, is the reason for applying systemic therapy, either hormonal or cytotoxic, as in the current adjuvant prostatectomy clinical trials.[5]

Although local control is an important goal, and we should aim to adequately treat the entire volume at risk, we should not lose site of what so many studies have taught us: that for locally advanced and biologically aggressive prostate cancer, combination with systemic therapy is mandatory. It has been noted recently that the high-risk category is changing in that more patients have high Gleason scores as compared to advanced-stage, bulky lesions.[6] Perhaps there is a subset of patients within the high-risk category for whom brachytherapy with supplemental EBRT may be more suitable. This subset may have already been selected out in the brachytherapy series.

Interpretive Bias?

It is always interesting to see how the interpretation of the same data can so greatly differ depending on one's bias. On referencing Table 1, the authors say that "most modern data would suggest that a regimen of brachytherapy combined with supplemental EBRT offers a therapeutic advantage over EBRT alone." I have a different take on the compiled list of outcomes. In view of the differences in risk-group definition, amount of hormone therapy, radiation dose, failure definitions, and follow-up, outcomes largely seem to fall into the same ballpark. This is always the problem in comparing retrospective data as compared to randomized studies.

Longer follow-up isn't necessarily a big advantage in high-risk disease since the majority of prostate-specific antigen (PSA) failures, at least with modern doses, tend to occur early (by 5 to 6 years).[7] If one compares the outcome at 8 years after treatment with 81 Gy (67% BDFS[8]) and with 78 Gy (63% BDFS[9]) to the 61% to 72% BDFS of four of the brachytherapy/EBRT studies in Table 1, there would seem to be little difference. The 83% BDFS reported by Mount Sinai[3] included 9 months of hormone therapy. Although the Schiffler Cancer Center study reported a BDFS of 87% at 10 years,[10] it would seem unjustified to support a significant change in treatment philosophy based on one retrospective, single-institution trial of 204 patients. While it may appear that outcome is similar across treatment modalities for the entire group of high-risk patients, one must consider each patient's individual circumstances and the points already made regarding tumor bulk and extension.

Toxicity Issues

Even if we allow that cancer-free outcome may be similar for both treatment modalities (at least for some high-risk patients), we must also consider toxicity. In the ONCOLOGY 2006 article, three of the current authors report that "there is increasing evidence that supplemental XRT increases brachytherapy-related urinary, rectal, and sexual morbidity."[1] In the current article, the authors now feel that "interstitial implant should improve the tolerance of supplemental EBRT to the pelvis by reducing cumulative doses to organs at risk such as the rectum, bowel, and bladder."

Information from a recently reported phase II Radiation Therapy Oncology Group (RTOG) study, conducted for the express purpose of evaluating the toxicity of brachytherapy combined with EBRT, supports the authors' 2006 premise. In this study, the incidence of late grade 3 gastrointestinal/genitourinary toxicity was 8% at 18 months and was estimated to be 15% at 48 months.[11] This can be compared to the RTOG studies with brachytherapy alone and high-dose EBRT alone, which report late grade 3 complication rates that are at least one-half those reported for brachytherapy combined with EBRT-2% and 4%, respectively-at 24 months posttreatment.[12,13] Although single-institution studies may report lower complication rates, it is important to note that the RTOG results represent what is realistic across institutions for treatment (brachytherapy with supplemental EBRT), which has been proposed as standard of care.

On a practical note, once the 5-week, 25-treatment, supplemental EBRT component is complete, why not just continue for another 2.5 to 3 weeks and complete an entire course of EBRT instead of stopping, waiting a few weeks, and gearing up for another therapeutic modality, with its preoperative evaluation, anesthesia, and the stress and side effects of an invasive procedure? Furthermore, given the hypofractionation studies that are underway, the entire EBRT-alone treatment course may soon be 25 treatments or less.

Final Considerations

I do agree with Bittner and colleagues on two points: (1) dose escalation is necessary in high-risk disease both for local control and for the impact of local control on distant disease, and (2) outcome with prostatectomy for high-risk disease has been disappointing, and to date, there has been no apparent advantage to this treatment approach. Thus, protocols are exploring new combined approaches similar to those that have proven effective in other malignancies.

In summary, high-risk adenocarcinoma of the prostate, in general, is a disease category that lends itself best to an integrated multidisciplinary approach. In view of the heterogeneity of tumor characteristics and biology within this category, there is the opportunity to refine treatment to an individualized, evidence-based approach through appropriate studies. Just how brachytherapy combined with external-beam irradiation might fit into this schema remains uncertain. To date, the enthusiasm for this particular modality has been underwhelming for the reasons noted.

-Deborah A. Kuban, MD FACR, FASTRO

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

The main article can be found here:
Interstitial Brachytherapy Should Be Standard of Care for High-Risk Prostate Cancer

References:

References
1. Merrick GS, Wallner KE, Butler WM, et al: Permanent prostate brachytherapy: Is supplemental external-beam radiation therapy necessary? Oncology (Williston Park) 20:514-521, 2006.
2. Schwartz D, Sengupta S, Hillman D, et al: Prediction of radial distance of extraprostatic extension from pretherapy factors. Int J Radiat Oncol Biol Phys 69:411-418, 2007.
3. Stock R, Ho A, Cesaretti J, et al: Changing the patterns of failure for high-risk prostate cancer patients by optimizing local control. Int J Radiat Oncol Biol Phys 66:389-394, 2006.
4. Stock R, Lo Y, Gaildon M, et al: Does prostate brachytherapy treat the seminal vesicles? A dose-volume histogram analysis of seminal vesicles in patients undergoing combined Pd-103 prostate implantation and external beam irradiation. Int J Radiat Oncol Biol Phys 45:385-389, 1999.
5. Eastham J, Kelly W, Grossfeld G, et al: Cancer and Leukemia Group B (CALGB) 90203: A randomized phase 3 study of radical prostatectomy for patients with high-risk localized disease. Urology 62:55-62, 2003.
6. Krane CJ, Presti JC Jr, Amling CL, et al: Changing nature of high risk patients undergoing radical prostatectomy. J Urol 177:113-117, 2007.
7. Kuban DA, Levy LB, Tucker SL, et al: Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? (abstract 206). To be presented at the 50th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Boston, September 21-25, 2008.
8. Zelefsky MJ, Chan H, Hunt M, et al: Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 176(4 pt 1):1415-1419, 2006.
9. Kuban DA, Tucker SL, Dong L, et al: Long term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Bio Phys 70:67-74, 2008.
10. Merrick GS, Butler WM, Wallner KE, et al: Androgen deprivation therapy does not impact cause-specific or overall survival in high-risk prostate cancer managed with brachytherapy and supplemental external beam. Int J Radiat Oncol Biol Phys 68: 34-40, 2007.
11. Lee WR, Bae K, Lawton C, et al: Late toxicity and biochemical recurrence after external-beam radiotherapy combined with permanent-source prostate brachytherapy: Analysis of Radiation Therapy Oncology Group study 0019. Cancer 109:1506-1512, 2007.
12. Lawton CA, DeSilvio M, Lee WR, et al: Results of phase II trial of transrectal ultrasound-guided permanent radioactive implantation of the prostate for definitive management of localized adenocarcinoma of the prostate (Radiation Therapy Oncology Group 98-05). Int J Radiat Oncol Biol Phys 67:39-47, 2007.
13. Michalski JM, Winter K, Purdy JA, et al: Toxicity after three-dimensional radiotherapy for prostate cancer on RTOG 9406 dose level V. J Radiat Oncol Biol Phys 62:706-713, 2005.