Showing posts with label intermediate risk. Show all posts
Showing posts with label intermediate risk. Show all posts

Monday, March 19, 2018

Escalated radiation dose doesn't improve 8-year overall survival in intermediate risk men (but does it matter?)

Last week, we saw that escalated dose did not improve 10-year overall survival in high-risk men (see this link). The latest published findings of the randomized clinical trial (RTOG 0126) prove that 8-year overall survival was not improved in intermediate risk men who received a higher radiation dose. In both studies, we are left wondering whether that matters.

Michalski et al. reported the results of RTOG 0126, a randomized clinical trial (RCT) designed to prove that escalated dose improves survival in intermediate risk men. It was a very large trial:
  • 1499 men
  • 104 sites in the US and Canada
  • Patients treated from 2002 to 2008
  • Median age was 71
The patients were all intermediate risk, defined as:
  • Stage T1b-T2b, and
  • Gleason score ≤ 6 and PSA ≥10 and <20 (16%), or
  • Gleason score = 7 and PSA < 15 (84%)
  • 71% were Gleason score 3+4
The treatment consisted of:
  • either low dose 70.2 Gy/ 39 treatments 
  • or high dose 79.2 Gy/ 44 treatments
  • delivered using 3D-CRT (66%) or IMRT (34%)
  • none had adjuvant ADT, but they may have had salvage ADT or other salvage therapies if RT failed
After a median follow-up of 8.4 years:
  • 8-year overall survival was 75% for the low-dose group vs. 76% for the high-dose group (not significantly different)
  • 8-year prostate cancer mortality was 4% for the low-dose group vs. 2% for the high-dose group (not significantly different)
  • 8-year biochemical failure was 35% for the low-dose group vs. 20% for the high-dose group (significantly different)
  • 8-year local progression (felt with DRE) was 6% for the low-dose group vs. 3% for the high-dose group (significantly different)
  • 8-year distant metastases (bone scan/CT detected) was 6% for the low-dose group vs. 4% for the high-dose group (significantly different)
  • 8-year salvage therapy was 22% for the low-dose group vs. 14% for the high-dose group (significantly different)
Toxicity outcomes were as follows;
  • Acute grade 2+ urinary toxicity was 17% for the low-dose group vs. 17% for the high-dose group (not significantly different)
  • Late-term grade 2+ urinary toxicity was 7% for the low-dose group vs. 12% for the high-dose group (significantly different)
  • Acute grade 2+ rectal toxicity was 5% for the low-dose group vs. 7% for the high-dose group (not significantly different)
  • Late-term grade 2+ rectal toxicity was 15% for the low-dose group vs. 21% for the high-dose group (significantly different)
In a separate analysis of the high-dose group:
  • Acute grade 2+ urinary and rectal toxicity was 15% among those treated with 3D-CRT vs. 10% among those treated with IMRT (a significant difference)
  • Late-term grade 2+ urinary toxicity was not significantly different among those treated with 3D-CRT vs. IMRT
  • Late-term grade 2+ rectal toxicity was 22% among those treated with 3D-CRT vs. 15% among those treated with IMRT (a significant difference)
This RCT raises many important questions about the design of clinical trials and the validity of conclusions drawn from them. Dr. Michalski addressed some of these concerns in an audio interview presented with the published study. This was an enormous undertaking, running almost two decades from design to reporting, and coordinating the treatments and reporting of 1,500 men in over 100 sites spread throughout Canada and the US.

The results show that dose escalation was not needed to increase 8-year survival in these intermediate risk patients. But this probably won't change practice for a number of reasons.

The intervening endpoints are of considerable importance to patients: the anxiety associated with rising PSA, the toxicity of all the salvage therapies, and the pain and possible crippling due to metastases all impact quality of life.

The median age of the men at treatment was 71, and they were screened for good performance status. The actuarial life expectancy in the US for a 71 year-old men is 14 years. This implies that they ought not make a decision based on expected survival for only 8 years. Also, as radiation-treated men get treated at a younger age, the gap will become more pronounced. According to the Memorial Sloan Kettering Life Expectancy Nomogram, a 71 year-old intermediate-risk man in good health has only a 8% probability of succumbing to prostate cancer in 10 years (vs 3% in 8 years in this study), and 12% at 15 years if he had no treatment whatever. At the same time, his probability of dying from other causes is 30% in 10 years, and 51% in 15 years. The overall survival improvement may not become apparent until median survival is reached in 15 years. And differences in prostate cancer survival are difficult to discern when numbers are this low. But it is difficult and costly to track patients for 15-20 years. We have to look to surrogate endpoints.

While 8-year overall survival and prostate cancer-specific survival did not improve, all the intervening endpoints did. Biochemical failure, local progression, distant metastases, and use of salvage therapies were all worse in the low-dose group.  It is very costly and difficult to run an RCT long enough to see a survival difference in men with localized prostate cancer. As we've seen, the few RCTs that have run the longest for each type of therapy have been single institution studies with much smaller sample sizes. Distant metastasis-free survival is probably a better surrogate endpoint if the study can't run for 15-20 years. There were enough metastatic events to see a difference. A recent analysis by the ICECaP Working Group of 12,712 patients in 19 clinical trials of radiation in localized prostate cancer showed that 5-year metastasis-free survival was almost perfectly correlated with overall survival. By reducing the time needed to accumulate data, this might increase the relevance of such trials while reducing their costs.

As Dr. Michalski points out, survival in both groups was much better than expected when the study was designed in 2001. This is largely because life-extending salvage therapies (e.g., docetaxel, GnRH agonists, Zytiga, Xtandi, Xofigo, and Provenge) have become prevalent in the interim.

Toxicity was markedly reduced by the introduction of IGRT/IMRT technology that became increasingly available, especially in the US, in the last 20 years. With the improvement in beam accuracy and the knowledge of the dose/toxicity relation of organs at risk, tighter dose constraints for organs at risk have been utilized. Because of the technology changes, a high-dose regimen today is probably no more toxic than a low-dose regimen. So, if there is little toxicity cost to the more effective treatment, why not use it? Rapidly adopted changes in radiation technology in the last 20 years, especially the shift from 3D-CRT to IMRT, render many of the findings irrelevant to today's standard practice.

Another RCT reported by Nabid et al. at the 2015 Genitourinary Conference had similar findings. They found that 10 year overall survival was no different for higher dose (76 Gy vs 70 Gy) or the addition of short-term ADT. Biochemical failures were actually worse in the higher dose group, but only if short-term ADT was not used with it. Zaorsky et al. conducted a meta-analysis of dose escalation trials in intermediate risk men and arrived at a similar conclusion. A contrary finding was noted by Kalbasi et al. in their analysis of the National Cancer Database. They found that there was a significant survival increase associated with higher dose (hazard ratio = 0.84). In fact, for every 2 Gy increase in dose, there was an 8% reduction in the hazard of death in intermediate-risk patients. Being retrospective, their analysis suffers from selection bias - it may be that the frailest patients got lower doses. However, they did include more unfavorable intermediate risk patients, including those treated with adjuvant ADT.

We are now recognizing that unfavorable intermediate risk patients may benefit from adjuvant ADT and higher doses, whereas the favorable intermediate risk patients may not. EORTC 2291 and the Nabid et al. trial established that short term (6 month) ADT markedly improved progression-free survival. Several retrospective studies (like this one and this and this) suggest that the benefit is limited to those with less favorable disease characteristics. It may well be that higher doses are necessary to overcome the radioresistance of high volumes of Gleason pattern 4.

The degree to which RTOG 0126 is irrelevant to contemporary decision-making is heightened by the success of hypofractionated IMRT and SBRT in intermediate risk patients. Both provide much higher biologically effective doses, equal efficacy to conventional IMRT, and about the same toxicity. Also, their cost is lower and patient convenience is higher. Unless a patient has an anatomical abnormality such that dose constraints cannot be met, it is hard to come up with a reason why higher biologically effective doses should not be used.

Note: Thanks to Dr. Howard Sandler for allowing me to see the full text of the study.

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.

Tuesday, August 30, 2016

SBRT Boost Therapy

Recently we have seen evidence of improved cancer control in high-risk patients treated with external beam radiotherapy with a brachytherapy boost to the prostate. This has been demonstrated with both HDR brachytherapy boost and with LDR brachytherapy boost. Can the same cancer control be obtained with IMRT and an SBRT boost to the prostate?

Anwar et al. reported the outcomes of 48 intermediate and high-risk patients treated with SBRT boost therapy between 2006 and 2012 at UCSF. 71% (34 patients) were high risk, 39% (14 patients) were intermediate risk.

The treatment consisted of:
  • ·      IMRT: 45-50 Gy in 25 fractions to the entire pelvis if the risk of lymph node involvement was > 15%, otherwise with a 1 cm margin.
  • ·      SBRT boost: 9.5 or 10.5 Gy in 2 fractions to the prostate, seminal vesicles + a 2 mm margin, 0 mm on the rectal side.
  • ·      Heterogeneous planning was used to mimic HDR brachytherapy dosimetry.
  • ·      Gold fiducials were used for daily (IMRT) and intra-fractional (SBRT) image tracking.
  • ·      Intermediate risk patients had 4-6 months of adjuvant hormone therapy.
  • ·      High-risk patients had up to 2 years of adjuvant hormone therapy
After a median of follow-up of 42.7 months, they reported the following results:
  • ·      5-yr  biochemical no evidence of disease: 90%
  • ·      PSA nadir (median): 0.05 ng/ml
  • ·      2 patients had a PSA bounce over 2 ng/ml, which declined with longer followup
  • ·      4 patients had a clinical recurrence outside of the radiation field
  • ·      Local control (within the radiation field) was 100%.
  • ·      Acute toxicity:
o   Urinary, grade 2: 17%
o   Rectal, grade 2: 10%
  • ·      Late toxicity:
o   Urinary, grade 2: 25%; grade 3: 1 patient
o   Rectal, grade 2 or higher: none

Clearly, these are excellent results for cancer control.  The table below shows outcomes in similar trials of SBRT boost treatments and of SBRT monotherapy.

SBRT boost
SBRT boost
SBRT monotherapy
SBRT boost
Risk levels treated (# of patients)
Intermediate (14)
High (34)
High (45)
High (52)
High (41)
Relative BED*
ADT used
Biochemical Disease-free survival
90% at 5 years
70% at 5 years
68% at 5 years
92% at 4 years
Late-term urinary toxicity

* Biologically Effective Dose for cancer control relative to 80 Gy in 40 fractions

Compared to these other small trials, Anwar et al. used significantly higher effective radiation doses and got perhaps better control (remembering that almost a third were intermediate risk), but late-term urinary toxicity was high. Lin et al. used lower doses, had similar control in their all high-risk group trial at 3 years, and none suffered from late-term urinary toxicity. Katz treated consecutive high-risk patients with SBRT boost and with monotherapy, respectively, but had the same cancer control in both groups, and the late-term urinary toxicity was not significantly different. Katz concluded that the SBRT boost accomplished nothing compared to the monotherapy, and also found that ADT use did not contribute to cancer control in his patients. He treated all subsequent high-risk patients with SBRT monotherapy only and without ADT.

We can also look at the Anwar outcomes next to those of a recent LDR brachy boost therapy trial and an HDR monotherapy trial in the table below.

SBRT boost
LDRBT boost
HDR-BT monotherapy
Risk levels treated (# of patients)
Intermediate (14)
High (34)
Intermediate (122)
High (276)
Intermediate (103)
High (86)
Relative BED*
ADT used
Biochemical Disease-free survival
at 5 years
High Risk-83%
at 7 years
High Risk-87%
at 4 years
Late-term urinary toxicity
25% Grade 2
2% Grade 3
NA Grade 2
18% Grade 3
19% Grade 2
10% Grade 3

SBRT boost therapy seems to provide similar rates of cancer control, but with less late term urinary toxicity compared to brachy boost therapy or HDR-BT monotherapy.

In an interesting twist, Memorial Sloan Kettering Cancer Center is running a clinical trial of SBRT supplemented with an LDR-BT boost to the prostate in intermediate-risk men (NCT02280356). I would guess that this would have considerable toxicity, but the clinical trial will prove or disprove that hypothesis.

So far, trials of SBRT boost therapy are too small to draw anything but provisional conclusions. There is a larger trial nearing completion at Georgetown University Hospital next month. Based on these pilot studies, SBRT boost therapy seems to be capable of providing good cancer control in high-risk patients and may be able to accomplish that with less toxicity than brachytherapy-based treatments. As we’ve seen, SBRT monotherapy and HDR brachy monotherapy are emerging therapies for high-risk patients as well. It would certainly be a lot more convenient to accomplish the same cancer control, at lower cost, and with perhaps less toxicity using just 5 SBRT monotherapy treatments instead of 27 treatments with SBRT boost. Only a randomized comparison clinical trial can tell us whether one therapy is better than another. The most appropriate radiation dose level, dose constraints, the size of margins, lymph node treatment, and whether adjuvant ADT provides any benefit are variables yet to be determined.

This is an area of active investigation. If readers are interested in participating in a clinical trial of SBRT boost therapy, below is a list of open trials and their locations:

Fountain Valley, CA (NCT02016248)
Sacramento, CA (NCT02064036)
San Francisco, CA (NCT02546427)
Miami, FL (NCT02307058)
Park Ridge, IL (NCT01985828)
Boston, MA (NCT01508390)
Madison, WI (NCT02470897)
21st Century Oncology- Scottsdale, AZ, Ft. Myers and Plantation, FL, Farmington Hills, MI, Myrtle Beach, SC (NCT02339948)
Sydney, Australia (NCT02004223)
Gliwice, Poland (NCT01839994)

Poznan, Poland (NCT02300389)

EBRT works better with ADT for intermediate/high-risk prostate cancer

The EORTC trial 22991 compared EBRT + short-term ADT vs. EBRT alone in intermediate and high-risk men. The preliminary report by Bolla et al. was posted at the 2016 GU Conference. There are more details of the clinical trial available here. There were 819 patients in the European multi-institutional study:
  • ·      407 received EBRT only, 403 received EBRT+6 months of ADT
  • ·      Radiation dose: 70, 74, or 78 Gy (at discretion of each institution)
  • ·      Pelvic node radiation: at discretion of each institution
  • ·      75% intermediate risk, 25% high risk

After a median follow-up of 7.2 years,
  • ·      5-year biochemical progression-free survival was 82.5% with the ADT, 69.3% without it.
  • ·      Improvement was irrespective of radiation dose.
  • ·      5-year clinical progression-free survival was improved by 7.9 percentage points.
  • ·      Late urinary toxicity was 5.9% with the ADT, 3.6% without it (not statistically significant)
  • ·      Severe sexual function impairment was 27.0% with the ADT, 19.4% without it (statistically significant)
  • ·      Symptoms of hormone treatment, sexual activity and functioning were impaired at 6 months with ADT, but there was no difference at 2 years.

The authors conclude:
The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQOL or sexual function.”

Unfortunately, this preliminary report doesn’t break out the intermediate and high-risk men separately.

We have previously looked at the DART 01/05 clinical trial that proved that at escalated radiation doses, long-term (28 months) androgen suppression improved cancer control better than short-term (4 months), at least for high-risk men. The benefit of longer duration ADT was not established for intermediate risk men at 5-year follow-up.

Nabid et al. focused on intermediate risk men and found a clear benefit to adding 6 months of ADT rather than none (after 10 years of follow-up).

It now seems clear that short-term androgen suppression improves results in intermediate risk men, while longer androgen suppression is necessary in high risk men. It would be helpful to know whether the improvement in intermediate risk men was only among the subgroup classified as “unfavorable intermediate risk.” ADT seems to have a more powerful effect than radiation dose, but it is unclear if that effect is maintained with therapies like SBRT and brachy boost that treat with much higher biologically effective doses. We are getting closer to defining an optimal duration of adjuvant ADT by risk level, and future trials using genetic classification data may provide better definition.

Monday, August 29, 2016

Brachy boost may lower mortality in high-risk patients

 The ASCENDE-RT randomized clinical trial demonstrated that the combination of external beam radiation with a brachytherapy boost (EBRT+BT) significantly reduced biochemical progression-free survival. A new data analysis suggests that the benefit may extend to prostate cancer survival as well.

Xiang and Nguyen searched the SEER database to identify 52,535 high- and intermediate-risk patients who were treated with EBRT+BT or EBRT alone in 2004-2011. Of that total, 20% received EBRT+BT, and one-third were high risk. They matched patients for risk factors, and adjusted for other variables that affect survival. By 8 years after treatment, the adjusted prostate cancer-specific mortality was:
  • ·      1.8% for EBRT+BT
  • ·      2.7% for EBRT
  • ·      5.4% for EBRT+BT among high-risk patients
  • ·      7.6% for EBRT among high-risk patients
  • ·      Mortality was not significantly reduced among intermediate-risk patients

The authors conclude:
BT boost was associated with a moderate reduction to PCSM in men with localized unfavorable-risk prostate cancer. Those most likely to benefit are younger patients with high-risk disease.”

Of course, this was a database analysis and not a randomized clinical trial, so the findings are provisional until better data are available. The mortality numbers are small, reflecting the long natural history of prostate cancer progression even among high risk patients, and the fact that at modern dose levels, both the monotherapy and the combined modality may cure or delay progression for a long time. As we’ve seen, the combined modality approach does increase the side effects of treatment. The fact that there is so far no discernable survival benefit for intermediate risk patients, should dissuade those with “favorable intermediate risk” prostate cancer from pursuing boost therapy. Each unfavorable risk patient will have to assess for himself whether the added toxicity is worthwhile.

Hypofractionation – no long-term effect on quality of life

Reducing the number of radiation treatments had no long-term differential effect on urinary, rectal or sexual quality of life, according to a study from Fox Chase Cancer Center that was recently presented at the ASTRO meeting.

These findings compliment their 2013 report of equivalent rates of cancer control from the two treatment schedules. Between 2002 and 2006, they randomly assigned 303 patients to either hypofractionation or conventional fractionation:
  • ·      Hypofractionation: 70.2 Gy in 26 fractions (2.7 Gy per fraction)
  • ·      Conventional fractionation: 76 Gy in 38 fractions (2.0 Gy per fraction)
  • ·      High-risk patients received long-term adjuvant ADT; some intermediate risk patients received short-term ADT (there were no low risk patients).
  • ·      Mean age was 67 years in both groups.
  • ·      Patients evaluated their quality of life using the EPIC and IPSS questionnaires

The findings that were presented at ASTRO or included in a Medscape article about it were:
  • ·      Urinary irritative symptoms declined by less than the amount considered to be minimally clinically detectable at both 3 years and 5 years, and were not different between the two groups.
  • ·      Urinary continence symptoms declined by 7% at 3 years and by 9% at 5 years in the hypofractionated group. Compared to the conventionally fractionated group, it was significantly different at 3 years but not significantly different at 5 years. (The EPIC categories that are lumped together as “urinary incontinence” may not mean what most people mean by the term. It may include patient perception of any leaking or dribbling, as well as any pad use. The decline was large enough to be noticeable, but were not very large. The fact that they were not significantly different between the two groups at 5 years may speak to common age-related declines.)
  • ·      Patients with poor baseline genitourinary function had worse quality of life outcomes with hypofractionated radiation than with conventionally fractionated radiation
  • ·      Bowel symptoms declined by less than the amount considered to be minimally clinically detectable at both 3 years and 5 years, and were not different between the two groups.
  • ·      Sexual function declined by a clinically detectable degree at both 3 years and 5 years, but was not different between the two groups.
  • ·      Baseline function was an important predictor of long-term quality of life outcomes.

These findings echo the results just reported in the CHHiP trial in the UK. While caution is warranted among men with poor baseline urinary, rectal and sexual function, these two studies provide strong Level 1 evidence that hypofractionated radiation is not inferior to conventionally fractionated radiation. Most patients should be able to complete primary IMRT treatments in about 5 weeks rather than 8 weeks, and at considerably reduced cost.

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.