The most recent literature search was performed through March 2012. The following is a summary of the key literature to date.
An evidence-based approach to the analysis of data on the various treatment options for prostate cancer is problematic for the following reasons:
- The lack of controlled clinical trials comparing various different treatment options in homogeneous groups of patients. Thus far, the only randomized comparisons of alternatives for managing early-stage prostate cancer compared active surveillance (watchful waiting) with radical prostatectomy, (1) and external-beam radiation therapy (EBRT) with high-dose rate (HDR) brachytherapy with EBRT alone. (2, 3)
- Similar trials are limited to compare surgery with radiation or to compare different methods of radiation. In a recent review of 2,991 consecutive patients receiving a variety of therapies for localized prostate cancer, the authors concluded that it is still not possible to determine which of the treatment options leads to the best metastasis-free or overall survival (OS). Therefore, at the present time, there is no evidence-based gold standard of treatment, which limits the ability to assess emerging approaches. (4)
- The numerous patient variables, including tumor stage, size of tumor (i.e., percent positive biopsy score), Gleason score, and prostate-specific antigen (PSA) level.
- The indolent natural history of many early-stage prostate cancers, requiring prolonged follow-up to determine final patient outcomes.
- A variety of intermediate outcomes have been used, most commonly biochemical failure as evidenced by rising PSA levels.
- The evolving nature of radiation therapy. Over the past 10 years, major advances have occurred in the planning and delivery of radiation therapy, including conformal therapy and intensity-modulated radiation therapy (IMRT), both of which permit dose escalation. There are variables in the total dosage of radiation therapy, variations in the planning and delivery of radiation therapy, and multiple different combinations of therapy (i.e., EBRT plus brachytherapy). Fractionation of doses is another treatment variable that intends to balance the treatment effectiveness with both early and late morbidities to surrounding normal tissues.
- The role of dose escalation in radiation therapy of prostate cancer. A dose-response relationship in the treatment of prostate cancer is generally accepted among clinicians and physicists, and in fact serves as the scientific rationale of HDR brachytherapy, as well as other recent techniques for radiation planning and delivery (i.e., IMRT). While a few randomized controlled trials (RCTs) have examined this issue, the data suggest that dose escalation is associated with improved biochemical control. (5) However, data regarding the impact of total radiation dose on survival among patients with different prognostic factors are minimal. In addition, the optimal radiation therapy dose is unknown. (6)
Related policy No. 8.01.14, on conventional brachytherapy (using permanently implanted seeds), notes that while final health outcomes are not available, thus limiting scientific conclusions, conventional brachytherapy had become widely accepted by patients and physicians and may be considered a reasonable treatment option. Large case series of conventional brachytherapy have reported data on both morbidity and the intermediate outcome of biochemical relapse-free survival (RFS) (i.e., survival-free from increasing PSA levels). These studies show that conventional brachytherapy is associated with similar outcomes when compared with the alternative (EBRT). Therefore, given the uncertainty for choosing between the established treatment options of watchful waiting, radical prostatectomy, EBRT, or conventional brachytherapy, some may consider patient preference to be particularly appropriate in selecting conventional brachytherapy. Questions have also been asked about patient acceptance of HDR brachytherapy compared to low-dose rate (LDR) brachytherapy. Given these significant limitations, the following results have been reported for HDR as an adjunct to EBRT.
In 2011, Bannuru and colleagues analyzed 75 studies (10 RCTs and 65 nonrandomized comparative studies) on radiation therapy for clinically localized prostate cancer. (7) Radiation therapies included brachytherapy, high-dose rate (HDR) brachytherapy and EBRT (conformal radiation, intensity-modulated radiotherapy, or proton therapy). The authors found the evidence was insufficient to compare the effectiveness of different forms of radiation treatments. Additionally, the effects of radiation treatments on patient survival were unclear compared to no treatment or no initial treatment. However, evidence considered to be of moderate strength showed higher EBRT dosages were consistently associated with increased long-term biochemical control rates compared to EBRT delivered at lower dosages. Yamada and colleagues conducted a review of the literature and published consensus guidelines for HDR brachytherapy for the American Brachytherapy Society in 2012. (8) The authors reported dosing schedule differences and heterogeneous studies make HDR brachytherapy difficult to evaluate systematically. However, HDR brachytherapy was found to have favorable 5-year biochemical disease control ranging from 85-100% for low-risk, 83-98% for intermediate-risk, and 51-96% for high-risk prostate cancer.
HDR brachytherapy with external-beam radiation therapy (EBRT)
Randomized, controlled trials
Hoskin and colleagues reported on a European single-center randomized trial of 220 patients that was conducted between 1997 and 2005, which compared 55 Gy of EBRT to 35.75 Gy of EBRT with HDR brachytherapy. (3) With a median follow-up of 30 months, the authors noted an improvement in actuarial biochemical RFS, as well as a lower incidence of acute rectal discharge. In 2012, Hoskin et al. subsequently reported on longer term follow-up of 218 patients from this Phase III trial. (2) Seventy-six percent of patients also received androgen-deprivation therapy (ADT). Biochemical relapse-free survival was greater in the combination treatment group after 4 years, with a median time to relapse of 116 months versus 74 months in the EBRT-only treatment group. Estimates of biochemical relapse-free survival for the combination group at 5, 7, and 10 years were 75%, 66%, and 46% versus 61%, 48% and 39% for the EBRT-only group, all respectively (p=0.04). However, overall survival (OS) was not significantly different between treatment arms. Estimates of OS for the combination group at 5, 7, and 10 years were 88%, 81% and 67% versus 89%, 88% and 79% for the EBRT-only group, all respectively (p=0.2). Severe urinary symptoms (26-31%) and bowel events (6-7%) were not significantly different between groups at 5 and 7 years. Erectile dysfunction rates were not reported.
Non-randomized, comparative studies
In a case series at William Beaumont Hospital (WBH) in Royal Oak, Michigan, Martinez and colleagues reported on 472 patients with intermediate- to high-risk prostate cancer (PSA level of ≥10 ng/mL and/or a Gleason score of ≥7, and/or clinical stage ≥T2b) treated with pelvic EBRT and an HDR boost using ultrasound guidance during the period of 1992 to 2007. (9) Patients received a hypofractionated regimen of pelvic EBRT delivered in 23 fractions of 2 Gy for a total dose of 46 Gy over a 5-week period. Initially, HDR brachytherapy consisted of 3 implants of 5.5 Gy, 6.0 Gy, and 6.5 Gy each. Subsequently, the HDR brachytherapy dosages were changed to 2 implants using 8.25 Gy, 8.75 Gy, 9.5 Gy, 10.5 Gy, and 11.5 Gy to achieve dosages equivalent to the 3 implant dosages delivered initially in the study. EBRT was not delivered on the days the patients received HDR brachytherapy boost (for example, on days 5 and 15 when 2 implants were used). The authors reported the 10-year results were significantly better in the groups that received higher dose levels (i.e., >268 Gy biologically equivalent dose), using the Phoenix definition for biochemical failure (43.1% vs. 18.9%), clinical failure (23.4% vs. 7.7%), and distant metastasis (12.4% vs. 5.7% - all respectively). Biologically equivalent dose (BED) is calculated to obtain a more significant measure of the dose absorbed by the prostate tissue rather than simply the quantity of radiation dose delivered. In this study, BED was calculated with an alpha/beta ratio of 1.2 Gy. Overall survival at 10 years was better in the higher dose group, but the difference was not statistically significant. Adverse events included grade 3 genitourinary (GU) and gastrointestinal (GI) tract complications of 2-3% and less than 5%, respectively.
Researchers at WBH reported on the outcomes of a series of 207 patients treated between 1991 and 2000. (10) All patients had poor prognostic factors, which included tumor stage T2B, a Gleason score of 7, or a PSA greater than 10 ng/mL. External-beam radiation therapy was alternated with HDR radiation therapy as a boost. At a mean follow-up of 4.7 years, overall biochemical control rate was 74%, but was 85% if one poor prognostic factor was present, 75% if 2 were present, and 50% if all 3 were present. Late toxicity was minimal. The authors suggest that these results are similar or better than other treatment alternatives for prostate cancer with poor prognostic features.
An international group of investigators reported on the use of HDR brachytherapy as an adjunct to conformal EBRT with or without androgen-deprivation therapy in a case series of 611 patients. (11) A total of 209 patients were treated at WBH, and thus it is likely that there are overlapping patients with the study reviewed above. While the authors reported that adjunctive HDR was associated with excellent long-term outcomes in terms of biochemical control, disease-free survival and cause-specific survival, interpretation of the findings is limited due to the absence of a control group.
Investigators from the California Endocurietherapy (CET) Cancer Center reported on outcomes (median follow-up of 7.25 years) of 209 consecutive patients with localized prostate cancer treated with HDR brachytherapy combined with EBRT. (12) The PSA progression-free survival (PFS) rate was 90%, 87%, and 69% for the low-, intermediate-, and high-risk groups, respectively.
Phan et al. reported on a case series of 309 patients treated with EBRT (40 to 45 Gy) and HDR brachytherapy (22 to 24 Gy). (13) At a median follow-up of 59 months, the 5-year biochemical control rate was 86% and OS was 91%; rates were higher for those with lower-risk disease. However, these results are difficult to interpret without having a comparison group.
In a retrospective analysis, Deutsch and colleagues compared patients who had received HDR brachytherapy and IMRT to those who had received ultra-high dose IMRT alone for low- to high-risk prostate cancer. (14) In the HDR and IMRT treatment group, 160 patients received 3 fractions of HDR dosages of 5.5-7.0 Gy, delivered once on the day of implant and twice on the next day, followed with IMRT 1 month later at a dose of 45.0–50.4 Gy. The ultra-high dose IMRT group of 470 patients received 86.4 Gy delivered in 48 fractions with 5 to 7 beams of 15-MV photons. In the only outcome measured in this analysis, overall, the HDR and IMRT group had statistically significant improvement in the 5-year PSA RFS (PSA nadir + 2) compared to IMRT alone (97.7% vs. 82%, respectively; p< 0.0001). The authors hypothesized the higher BED in HDR and IMRT (229 Gy) may have translated to better outcomes than the highest BED of IMRT alone (190.08 Gy). When the risk groups were separated out, the PSA-relapse survival for HDR plus IMRT over IMRT remained significant in the intermediate-risk group (98% vs. 84%, respectively; p=0.001). However, improvement was not significant in the low-risk group (100% vs. 98%) or the high-risk group (93% vs. 71%, both respectively; p=0.23). The authors noted having fewer patients in the low- and high-risk groups may have influenced results. Additionally, androgen-deprivation therapy may have confounded the outcomes in the high-risk group.
In another retrospective comparison of HDR brachytherapy and IMRT compared to IMRT alone, Wilder et al. found no significant differences in 3-year biochemical disease-free (PSA nadir + 2) survival between treatment groups in low-, intermediate-, and high-risk patients (100% vs. 100%, 98% vs. 100%. and 93% vs. 67%, all respectively). (15) The rates of toxicity incidence were reported to be similar in both treatment groups. In this study, 240 patients received HDR boost at 5.5 Gy twice on the day of implant and again 1 week later totaling 22 Gy followed by IMRT of up to 50.4 Gy administered 1-4 days later. The 44 patients in the IMRT-alone group received 79-81 Gy. The BEDs calculated at an alpha/beta ratio of 1.5 Gy were 213.6 Gy in the HDR and IMRT group versus 174.2-178.2 Gy in the IMRT-alone group. The authors noted longer follow-up is needed to further understand the roles of HDR and IMRT in prostate cancer treatment.
High-dose rate brachytherapy as monotherapy
Publications on use of high-dose rate (HDR) as monotherapy for treatment of prostate cancer are fewer than those that report its use as combined modality therapy (CMT) with EBRT. Demanes et al. reported on a prospective case series of 298 patients with previously untreated low- to intermediate-risk localized prostate cancer (median value PSA of 6.0 ng/mL) treated with HDR brachytherapy as monotherapy between 1996 and 2005 at CET and WBH. Each facility used a different treatment protocol. (16) At CET, a total of 42 Gy in 6 fractions of 7 Gy were delivered using computed tomography (CT) images for treatment planning. WBH used a total of 38 Gy delivered in 4 fractions of 9.5 Gy with ultrasound images used for treatment planning. At 8 years’ follow-up, the authors reported 99% local control, 97% biochemical control (using the Phoenix definition defined as PSA nadir + 2), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% overall survival. Grade 2 urinary frequency or urgency was transient in 10% of patients, while grade 3 urinary retention was experienced in 3% of patients. Gastrointestinal tract toxicity was reported to be less than 1%. The authors attribute the low rate of adverse effects to the precision of HDR dosimetry and concluded HDR monotherapy is safe and effective in this population. In a study from the same institutions, Martinez and colleagues reported on a nonrandomized study comparing 454 patients treated with either palladium-103 seed LDR brachytherapy (206 patients) or HDR brachytherapy as monotherapy (171 patients) received at WBH during the period of 1993 through 2004. (17) The patients at WBH selected which treatment option they received. Also included in the study analysis were 77 patients who received HDR brachytherapy as monotherapy at CET during the period of 1996 through 2002. All of the patients selected for this study were low to intermediate risk and had PSA levels equal to or less than 12 ng/mL, Gleason scores of equal to or less than 7, and clinical stage T1c-T2a disease. The HDR brachytherapy dosages were the same as in the Demanes et al. study above (9.5 Gy x 4 at WBH and 7 Gy x 6 at CET). Treatment outcomes at 5 years included biochemical control rates (PSA nadir + 2) of 89% in the LDR group at WBH, 91% in the HDR group at WBH, and 88% in the HDR group at CET. Overall and cause-specific survival rates at 5 years were not statistically different between groups. The HDR groups experienced statistically significant lower rates of dysuria, urinary frequency/urgency, and acute rectal pain. Rates of diarrhea, rectal bleeding, and acute urinary incontinence and retention were similar. Most toxicities were grade 1 in both groups, but more grade 3 acute GU toxicities were seen in the LDR group. Potency was 30% in the LDR group and 20% in the HDR groups. The authors of this study concluded HDR brachytherapy as monotherapy is an acceptable choice for treatment of favorable risk prostate cancer. It is likely that there are overlapping patients with the studies reviewed above that were conducted at WBH. However, the authors do not comment on this.
Corner et al. published results of a Phase II study of HDR brachytherapy as monotherapy in 110 patients treated with 3 regimens: 34 Gy in 4 fractions, 36 Gy in 4 fractions, and 31.5 Gy in 3 fractions. (18) At 6 months, 2 patients had grade 3 bladder toxicity, and 1 patient had grade 2 gastrointestinal (GI) tract toxicity. No PSA relapses have been detected, although the median follow-up was just 12 months among the 55 patients who received 31.5 Gy. The authors concluded that these early results suggest an excellent biochemical response with no differences seen in acute and late toxicity among the 3 regimens. Grills and colleagues reported on a series of 149 patients with early-stage prostate cancer who were treated with either permanent or temporary (HDR) brachytherapy monotherapy at one center. (19) In this series, patients selected which of the 2treatments they would receive. Treatments were given between 1999 and 2001. The authors note lower acute grade 1 to 3 symptoms in the HDR group, but many of these symptoms were grade 1. The reported rates of grade 2 and 4 chronic genitourinary (GU) toxicity did not vary and were 23%. The impotence rate was 16% in the HDR group and 45% in the LDR group. Levels of biochemical control were similar in the 2 groups with median follow-up of 35 months. Given the non-random assignment of patients in this single institution study, additional confirmatory trials may be useful.
Salvage HDR brachytherapy
Data on using HDR in the salvage treatment following failed prior radiation therapy are limited. In 2012, Jo and colleagues reported on 11 patients with radiorecurrent local prostate cancer who received salvage high-dose rate brachytherapy with EBRT (n=10) or proton beam (n=1). (20) During mean follow-up of 29 months (range 18-41 months), PSA levels remained low in 7 patients but rose in 4 patients. No grade 3 adverse events were reported.
Ongoing Clinical Trials
An April 2012 search of online site ClinicalTrials.gov identified several active studies on HDR brachytherapy for prostate cancer treatment. The National Institutes of Health (NIH) is studying the quality of HDR brachytherapy implants in an estimated 112 prostate cancer patients (NCT00924027). In this study, the primary outcome will be adequacy of the implant in targeting the tumor volume with the prescribed dosage. The Mayo Clinic, Virginia Commonwealth University, and the National Cancer Institute are conducting studies to demonstrate the safety of combining HDR brachytherapy with EBRT in the treatment of prostate cancer patients. The National Cancer Institute study (NCT00091390) has enrolled 110 patients. The Virginia Study (NCT00243321) has been completed, and the Mayo study (NCT00714753) was terminated due to slow accrual. In a pilot study at Memorial-Sloan Kettering Cancer Center, HDR brachytherapy will be studied in 20 patients as definitive therapy for intermediate-risk prostate cancer (NCT00573833). In a Phase III, prospective, multi-center, randomized trial, 1,520 patients with intermediate-risk prostate cancer will be studied to compare dose-escalated radiotherapy (EBRT or EBRT with HDR or LDR brachytherapy) with or without short-term androgen deprivation therapy (NCT00936390). In NCT000913939, HDR brachytherapy delivered with magnetic resonance imaging (MRI) guidance will be studied in 60 patients who have either locally advanced or locally recurrent after EBRT prostate cancer. In NCT00807820, MR spectroscopy will be used to deliver HDR brachytherapy to the dominant intraprostatic lesion in 56 patients.
At Memorial-Sloan Kettering Cancer Center, high-dose rate brachytherapy as salvage therapy will be studied for locally recurrent prostate cancer in 40 patients previously treated with EBRT (NCT00604526).
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received from 2 physician specialty societies (4 reviews) and 2 academic medical centers while this policy was under review for March 2009. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. There was generally strong support for use of HDR (as monotherapy and with EBRT) as an option in the treatment of prostate cancer.
High-dose rate temporary prostate brachytherapy is a technique of delivering a high-intensity radiation source directly to the prostate gland for the treatment of prostate cancer. Based on data from published studies and clinical input, its use may be considered medically necessary combined with EBRT in the treatment of patients with localized prostate cancer. While data on HDR monotherapy are more limited, given what is known about temporary and permanent brachytherapy and based on existing data and clinical input, HDR monotherapy may also be considered an option. While quality studies differentiating superiority of any type of radiation technique are not available, the available evidence for use of HDR prostate brachytherapy as monotherapy or in conjunction with EBRT in the treatment of localized (organ-confined) prostate cancer is sufficient to conclude treatments result in improvement in net health outcome.
Because published data are still limited and clinical trials are ongoing, use of HDR in the treatment of prostate cancer as salvage therapy is considered investigational.
Practice Guidelines and Position Statements
The National Comprehensive Cancer Network (NCCN) guidelines (v.3.2012) for the treatment of prostate cancer indicate HDR brachytherapy combined with EBRT ( 40-50 Gy) may be used instead of LDR brachytherapy to increase the dose of radiation for intermediate- to high-risk patients. (21) Boost regimens commonly used include 9.5-10.5 Gy x 2 fractions, 5.5–7.5 Gy x 3 fractions, and 4.0-6.0 Gy x 4 fractions.
The American Brachytherapy Society (ABS) Prostate High-Dose Rate Task Group (22) provides the following patient selection criteria for monotherapy: clinical stage T1b-T2b and Gleason score equal to or less than 7, and/or PSA equal to or less than 10 ng/mL. For HDR boost, ABS patient selection criteria includes: patients with high-risk features such as T3-T4, Gleason score 7-10, and/or PSA greater than 10 ng/mL or patients with bulky T1-2b tumor. The ABS published a review of the literature and consensus guidelines for HDR brachytherapy in 2012 as noted above. (8) The ABS recommends HDR brachytherapy with or without EBRT for various risk levels of localized prostate cancer especially for intermediate- or high-risk patients as a boost with EBRT. The ABS guidelines note HDR brachytherapy is contraindicated in patients who have a preexisting rectal fistula, are unable to tolerate anesthesia and/or have no proof of malignancy. HDR monotherapy is considered investigational for high-risk patients by the ABS. HDR monotherapy as salvage treatment is only recommended for use in specialty centers or Institutional Review Board-approved protocols.
Medicare National Coverage
Brachytherapy sources and services for administration and delivery of brachytherapy are covered by Medicare.