Showing posts with label monotherapy. Show all posts
Showing posts with label monotherapy. Show all posts

Wednesday, September 28, 2016

Brachytherapy alone is enough for favorable intermediate risk patients

RTOG 0232 was a large clinical trial conducted to determine whether low dose rate brachytherapy (BT) alone was of equal benefit compared to external beam radiation therapy with a brachytherapy boost (EBRT+BT) in intermediate risk patients.

The study was conducted at 68 cancer centers in the US and Canada from 2003 to 2012. 588 intermediate risk men were treated. For the purposes of this study, “intermediate risk” was defined as:
  • Stage T1c – T2b, and
  • Either Gleason Score of 7 and PSA less than 10 ng/ml, or
  • Gleason score of 6 and PSA between 10 and 20 ng/ml
They did not collect detailed data and report separately those who would now be classified as “favorable intermediate risk” by the Zumsteg definition (Gleason score 3+4, less than half the biopsy cores positive, and otherwise low risk). However, Howard Sandler, the Principal Investigator, wrote:
It was deliberately a favorable intermediate group largely. At the time (2002) we felt that combination therapy was mandatory for the more advance patients and we weren’t comfortable randomizing to brachy alone for those patients.

So it is important that we do not generalize their findings to unfavorable intermediate-risk or high-risk patients.

The patients were treated as follows:
  • BT: 145 Gy of I-125 seeds or 125 Gy of Pd-103 seeds
  • EBRT+BT: 45 Gy of EBRT and a boost with 110 Gy of I-125 seeds or 100 Gy of Pd-103 seeds
After 5 years of follow-up:
  • Progression-free survival was 85% for EBRT+BT patients, 86% for BT patients (no difference)
  • Acute grade 3 (serious) side effects were suffered by 8%  in each group.
  •  Late-term grade 3 (serious) side effects were higher (12%) in the EBRT+BT compared to 7% in the BT group
o   Urinary side effects: 7% in the EBRT+BT group vs. 3% in the BT group
o   Rectal side effects: 3% in the EBRT+BT group vs. 2% in the BT group

So, the addition of external beam radiation added nothing to cancer control, at least out as long as 5 years. While side effects were low for both groups, combination therapy increased them.

We saw recently in an analysis of the patients at Cleveland Clinic who were treated exclusively with BT only (see this link, especially the section on intermediate risk), that progression-free survival was very good for “low intermediate risk” patients. Furthermore, Drs. Stone and Zelefsky agreed that the combination therapy is unnecessary for this group, especially when treated with a sufficient brachytherapy dose. Radiotherapy Clinics of Georgia has built a business out of treating even low-risk patients with the combination therapy. This is now proved to be an overtreatment that is needlessly toxic.

Monday, August 29, 2016

High Dose Rate Brachytherapy (HDRBT) monotherapy – 10 year results

Reporting ten-year results for any radiation therapy is a rare privilege. It’s especially exciting for high dose rate brachytherapy (HDRBT) monotherapy because, based on what was known about prostate cancer radiobiology at the time it was first tried, it should not have worked. Well, it exceeded all expectations, forced radiation oncologists to rewrite the textbooks, and paved the way for new radiation technologies.

HDRBT had been used as an adjunct to external beam radiation since 1986 at Kiel University in Germany, at the Seattle Prostate Institute in 1989, at William Beaumont Hospital near Detroit in 1991, and at the California Endocurietherapy Center in Oakland in 1991. The “boost” delivered to the prostate capsule yielded some of the best oncological results at the time. Galalae et al have recently reported the 15-year results from Kiel. It was tried in the era before dose escalation, when external beam alone could not reliably deliver curative doses, and raising the dose was highly toxic with the technology available at the time.

The first trial of the monotherapy began in Osaka, Japan in 1995. Jeff Demanes (then in Oakland) and Alvaro Martinez (at William Beaumont Hospital near Detroit) tried using it as a monotherapy in 1996 in some of their favorable risk cases. The technique involves inserting about a dozen or more narrow tubes called catheters up through the perineum. These serve as the guides for radioactive Iridium 192 needles, and hold the prostate rigidly in place. The process is monitored by cone beam CT, and the dwell times of the radioactive needles are calculated by computer and controlled robotically. Unlike “seeds,” areas outside of the prostate capsule, like the seminal vesicles, may be treated, and nothing is left inside. Also, there is no limit on prostate volume as there is with seeds. Some readers may be interested in a comprehensive review of HDR brachytherapy monotherapy written by Demanes and Ghilezan last year.

There does not seem to be a single best schedule for fractionation and implantation. Demanes started in 1996 with two catheter implants a week apart with three fractions delivered during each implant. He now offers other dosing schedules. Martinez recently reported on a single implant with just two fractions, all in one day.

The skeptics did not believe it could work. Demanes was delivering only 42 Gy of radiation (7 Gy in each of 6 fractions), while the typical external beam dose was about 70 Gy (delivered in 1.8 Gy or 2.0 Gy doses) at the time. It was conventional wisdom that prostate cancer responded best to many small doses of radiation in exactly the same way that all other cancers do. Radiobiologists express this as a quantity called the alpha/beta ratio, which they believed would be about 10 for prostate cancer. This would result in a biologically effective dose (BED) 15% lower than the external beam dose that many believed was already too low.

It is now widely accepted that the alpha/beta ratio for prostate cancer is about 1.5. This means that Demanes was delivering a BED to the cancer that was actually almost 50% higher than the prevalent external beam doses of the time (and is still about 37% higher than the current dose-escalated IMRT BED). It also means that those doses were very sparing of the early-responding healthy tissues of the bladder and rectum (which do, in fact, have an alpha/beta ratio of about 10). Those tissues were receiving from HDRBT a dose that was effectively 15% lower in its biological impact. This was the best of all possible situation: higher dose to cancer cells, lower dose to healthy tissue. As a result of Demanes’s work, Christopher King at Stanford in 2003 used Accuray’s new CyberKnife platform to mimic the prostate HDRBT treatment using external beam radiation. Others have experimented with less extreme forms of shorter, more intense dose schedules, called hypofractionation. IMRT hypofractionation has now proved its efficacy and safety in a large-scale randomized clinical trial (see my recent report).

Hauswald et al. reported the 10-year results on 448 favorable risk patients treated by the California Endocurietherapy Cancer Center (now at UCLA) from 1996 to 2009. The patient characteristics were as follows:
  • ·      288 low risk, 160 intermediate risk
  • ·      76% Gleason score ≤6, 20% Gleason 3+4
  • ·      Median age: 64
  • ·      Only 9% received neoadjuvant ADT
  • ·      Median prostate volume: 33 cc (range: 9-134 cc)
  • ·      Median follow up: 6.5 years

The ten-year results were as follows:
  • ·      Biochemical progression-free survival: 98%

o   Low risk: 99%
o   Intermediate risk: 95%
  • ·      Local control: 100%
  • ·      Distant metastasis-free survival: 99%
  • ·      Prostate cancer specific survival: 99%
  • ·      Overall survival: 77%
  • ·      None of the outcomes were statistically different for low risk or intermediate risk groups.
  • ·      Late grade 2 GU toxicity: 10%; grade 3: 5%; 1 patient had grade 4.
  • ·      Late grade 2 GI toxicity: 1%; no grade 3 or 4
  • ·      60% of previously potent patients were able to have erections suitable for intercourse, with or without medication (at median age of 69)

The potency preservation rate reported for HDRBT, at 69-89%, is the highest reported for any radical therapy. As we’ve seen in other radiation studies, and contrary to popular wisdom, any decline in erectile function typically occurs within the first nine months. Subsequent declines are mostly attributable to normal aging.

The ten-year cancer control rates on these favorable risk patients was remarkably high, and late toxicity was low. Such patients are often good candidates for active surveillance, but for those who are not, HDRBT is certainly a good alternative. Perhaps the most interesting use is as a monotherapy even among men with unfavorable risk prostate cancer. We recently saw that early investigations of this use are encouraging.

The impressive ten-year results reported here are a testimony to the pioneering achievements of Dr. Demanes, who is retiring soon from active practice. His California Endocurietherapy Center at UCLA, which will continue to operate, is one of only a small number of centers where patients can get HDRBT monotherapy. The economics are such that it is not especially attractive for radiation oncologists to enter this specialty, but we hope that it will remain a treatment option for prostate cancer patients for many years to come.

Sunday, August 28, 2016

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

Dose Schedule
Compared to 80 Gy IMRT
Freedom from recurrence among high risk
Follow up
Late grade 3 GU toxicity
Sathya et al. (2005)
35 Gy over 48 hrs.
+40 Gy/20 fx
8.2 yrs median
EBRT only
66 Gy/33 fx
8.2 yrs median
Hoskin et al. (2012)
17 Gy/2 fx + 35.75 Gy/13 fx
7 yrs
EBRT only
55 Gy/20 fx
7 yrs
Guix et al. (2013)
16 Gy/2 fx + 46 Gy/23 fx
8 yrs
EBRT only
76 Gy/38 fx
8 yrs

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

Dose Schedule
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

8 yrs

54 Gy/9 fx
45.5 Gy/7 fx
Zamboglou et al. (2012)
38 Gy/4 fx/1 implant
5 yrs
9% retention
3% retention
1% incontinence
38 Gy/4 fx/2 implants
5 yrs
7% retention
5% incontinence
2% retention
34.5 Gy/3 fx/3 implants
3 yrs
5% retention
8% incontinence
1% retention
1% incontinence
Hoskin et al. (2012)
34 Gy/4 fx
5 yrs (median)
36 Gy/4 fx
4.5 yrs (median)
31.5 Gy/3 fx
2.8 yrs(median)
26 Gy/2 fx
.5 yrs (median)

*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).