HDR Brachy Boost and Monotherapy for High-Risk Prostate Cancer

Three randomized clinical trials (Sathya et al. 2005, Hoskin et al.2012, and Guix et al.2013) established combination therapy of external beam radiation (EBRT) with a high dose rate brachytherapy (HDRBT) boost as a standard of care in the treatment of high-risk prostate cancer. In all three of those trials, the outcomes exceeded those from EBRT alone, but at a cost of higher toxicity.

In previous studies of this combination therapy for high-risk patients, freedom from biochemical relapse have ranged from 67-97% at 5 years, and from 62 -74% at 10 years. Late term genitourinary (GU) grade 3 toxicity ranged from 0-14.4% (median 4.5%); gastrointestinal (GI) grade 3 toxicity ranged from 0-4.1% (median .5%); chronic incontinence ranged from <1%-3.8%; urethral strictures ranged from .9-7.4% (median 4.5%); and erectile dysfunction ranged from 10-51% (median 31.5%).

It may be helpful to understand how large the effective doses of radiation were that were used in all of the aforementioned studies. The term “biologically effective dose” (BED) enables us to compare the cancer-killing power of the absorbed radiation across different radiation modalities. To provide a point of comparison, I show the BED as a % of the BED of a typical modern IMRT schedule, 80 Gy in 40 fractions (fx), which has a BED of 187 Gy.

Table 1 – Improved recurrence-free survival, but higher GU toxicity from boost therapy

Study	Modalities	Dose Schedule	BED Compared to 80 Gy IMRT	Freedom from recurrence among high risk	Follow up	Late grade 3 GU toxicity
Sathya et al. (2005)	HDRBT + EBRT	35 Gy over 48 hrs. +40 Gy/20 fx	-6%	71%	8.2 yrs median	14%
	EBRT only	66 Gy/33 fx	-17%	39%	8.2 yrs median	4%
Hoskin et al. (2012)	HDRBT + EBRT	17 Gy/2 fx + 35.75 Gy/13 fx	+15%	66%	7 yrs	11%
	EBRT only	55 Gy/20 fx	-17%	48%	7 yrs	4%
Guix et al. (2013)	HDRBT + EBRT	16 Gy/2 fx + 46 Gy/23 fx	+12%	98%	8 yrs	NA
	EBRT only	76 Gy/38 fx	-5%	91%	8 yrs	NA

Could equal oncological outcomes be accomplished but with less toxicity by using high dose rate brachytherapy as a monotherapy? The maturing of data from a clinical trial in Japan suggests it can be.

Yoshioka et al. (2015) have used HDRBT monotherapy on 111 high-risk patients treated from 1995 to 2012. Almost all of them (94%) received ADT as well. They evaluated 3 dosing schedules: 48 Gy/8 fractions, 54 Gy/9 fractions, or 45.5 Gy/7 fractions inserted over 4 to 5 days. 

With a median of 8 years of follow up, the authors report:

• ·      Biochemical no evidence of disease – 77%
• ·      Metastasis-free survival – 73%
• ·      Overall survival – 81%
• ·      Cause-specific survival – 93%
• ·      Late GU grade 3 toxicity – 1%
• ·      Late GI grade 3 toxicity – 2%

Unfortunately, they haven’t reported rates of erectile dysfunction. Other monotherapy series report ED rates of about 25%, and there’s no reason to suppose it would be particularly different for high-risk patients. They report no significant differences in oncological control or toxicity according to total dose or dose schedule used.

The biochemical control rates are well within the range seen for combination therapy at 5 to 10 years after treatment. At the same time, the rates of serious late term GU and GI side effects seem to be improved by the monotherapy.

Other recent studies have reported excellent results for HDRBT monotherapy for high-risk patients. Zamboglou et al. (2012) reported the monotherapy outcomes of 146 high-risk patients treated between 2002 and 2009. 60% received ADT as well. They evaluated 3 dosing schedules: 38 Gy in four fractions in one implant, 38 Gy in four fractions in two implants, and 34.5 Gy in three fractions in three implants. After 5 years, biochemical control was 93%, late grade 3 GU toxicity was 3.5%, and late grade 3 GI toxicity was 1.6%. The differences in toxicity among the dosing schedules were not statistically significant. Among previously potent men, only 11% lost potency sufficient for intercourse. The highest dose schedule did not have better oncological control or worse toxicity than the lower dose schedules.

Hoskin et al. (2012) reported the monotherapy outcomes of 86 high-risk patients treated between 2003 and 2009. Almost all of them (92%) received ADT as well. They evaluated 4 dosing schedules: 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, and 26 Gy in two fractions. After 4 years, biochemical control was 87%, late grade 3 GU toxicity was 12%, and late grade 3 GI toxicity was 1%. It is not clear why GU toxicity was higher than in the other two studies. They did not report erectile dysfunction. Although higher rates of strictures, ranging from 3-7%, and urinary toxicity occurred on the most aggressive dosing schedules, the differences were not statistically significant on this sample size. Similarly, the difference in recurrence-free survival at the lowest dose was not statistically significant.

Table 2. Clinical trials of HDRBT monotherapy for high risk

Study	Dose Schedule	BED Compared to 80 Gy IMRT	Freedom from recurrence among high risk	Follow up	Late grade 2+ GU toxicity	Late grade 3+ GU toxicity
Yoshioka et al. (2015)	48 Gy/8 fx	+29%	77%	8 yrs	NA	1%
	54 Gy/9 fx	+45%			7%
	45.5 Gy/7 fx	+30%			6%
Zamboglou et al. (2012)	38 Gy/4 fx/1 implant	+49%	97%*	5 yrs	9% retention 9%incontinence	3% retention 1% incontinence
	38 Gy/4 fx/2 implants	+49%	94%*	5 yrs	7% retention 5% incontinence	2% retention <1%incontinence
	34.5 Gy/3 fx/3 implants	+60%	95%*	3 yrs	5% retention 8% incontinence	1% retention 1% incontinence
Hoskin et al. (2012)	34 Gy/4 fx	+21%	77%	5 yrs (median)	33%	3%
	36 Gy/4 fx	+35%	91%	4.5 yrs (median)	40%	16%
	31.5 Gy/3 fx	+35%	87%	2.8 yrs(median)	34%	14%
	26 Gy/2 fx	+35%	NA	.5 yrs (median)	NA	NA

*across all risk groups, high risk only was 93%

Within all three published studies, there were no statistically significant dose-response relationships in terms of either oncological control or toxicity. However, looking across the three, it may be that the higher doses provided better control at the cost of some higher toxicity. I hope someone will do a meta-analysis on the full data sets to confirm that. Larger studies will be needed to determine whether toxicity increases with the more aggressive dosing schedules. All the control rates were within the range of the combination therapies, and all of the toxicities were acceptable. Evidently, all of the studies applied enough radiation to effectively kill the high-risk cancer. Nor did the dosing schedule used have an impact on results. HDR brachy monotherapy as currently practiced uses anywhere from a single fraction to nine fractions, and anywhere from a single implant to three implants.

It is difficult to draw conclusions about the use of ADT. All three studies utilized high rates of adjuvant ADT – over 90% in two of the studies. The study with the lowest rate of ADT utilization, Zamboglou et al., at 60%, also used the highest radiation doses. Although Demanes et al. found that ADT had no incremental benefit when used with combination therapy, that study was in the early years (1991-1998) when relatively low radiation doses were used. Until there is a randomized clinical trial of its use with HDRBT monotherapy, it will be hard to walk away from using ADT.

Unlike low dose rate brachytherapy (seeds), HDRBT can treat areas outside of the prostate, including the prostate bed and the seminal vesicles. However, to my knowledge, it has not been used to treat pelvic lymph nodes, which would be impossible to find using current imaging technology. In all three studies, patients were screened for evidence of lymph node involvement. Clearly, HDRBT monotherapy is not a good choice if LN involvement is suspected. There are calculators for predicting such risk based on Gleason score, PSA and cancer volume. High-risk patients may have a statistically high risk for LN involvement without showing evidence, but even the “high risk” levels are not very high, so treatment remains controversial. One clinical trial (Lawton et al.) demonstrated a benefit to full-pelvic IMRT coupled with neoadjuvant ADT, and there is a current clinical trial that allows for a brachy boost (RTOG 0924) that may confirm that finding.

SBRT is radiologically identical to HDRBT, and as discussed in a recent article, its use for high-risk patients is also being explored. Both of these treatments have the potential to provide excellent cancer control while minimizing the side effects of treatment, and with a considerable time and cost advantage over IMRT-combo treatments. I encourage high-risk patients to enroll in clinical trials for both alternatives. HDRBT monotherapy for high risk is part of a clinical trial at Stanford (NCT02346253).