Showing posts with label IMRT. Show all posts
Showing posts with label IMRT. Show all posts

Tuesday, August 30, 2016

Site of recurrence after primary radiation therapy

This is the first of a two-part commentary. In this part, we look at studies that identified the site of failure after primary radiation treatment. In next part, we will look at how SBRT is being used to treat such local recurrences.

Before any kind of treatment is given for a recurrence only detected via rising PSA, it’s important to assure that it is indeed only a local recurrence. If there are already distant metastases, local salvage treatment would only create side effects without cancer control. In the past, we only had bone scans and CT scans that could detect only the larger metastases. New imaging technologies are enabling us to better assess the recurrence site.

Hannequin et al. posted the results of their study (abstract 23) at last week’s Genitourinary Conference. The authors retrospectively looked at 89 patients treated in Paris, France between 2010 and 2014 with either brachytherapy (23 patients) or EBRT (66 patients) and who had a biochemical recurrence detected as a rising PSA of at least 2.0 ng/ml over its lowest level.  The patients were classified at diagnosis as favorable risk (28%), intermediate risk (39%) or unfavorable risk (33%). They all had an 18-FCH-PET scan and may have had a multiparametric MRI as well. In 20 patients (22.5%), no target lesion could be clinically identified. Among the 69 patients in whom a clinically detected recurrence was identified, the recurrence site was as follows:
  • ·      Local recurrence in 35 patients (51%)
  • ·      Lymph node recurrence in 22 patients (32%)
  • ·      Distant metastases in 12 patients (17%)
All of those 57 patients with local or lymph node recurrence (83%) were deemed eligible for salvage radiation, but only 17 (25%) could have it. The reasons for not having salvage radiation included advanced age, poor performance status, extensive disease, and patient refusal.

Zumsteg et al. published a retrospective analysis of 2,694 patients treated with external beam RT (IMRT or 3D-CRT) at Memorial Sloan Kettering Cancer Center between 1991 and 2008. The patient diagnosis and treatment characteristics were as follows:
  • ·      Risk category:
o   Low risk: 22%
o   Intermediate risk: 48%
o   High risk: 30%
  • ·      Median age: 69
  • ·      Adjuvant ADT received: 54%, median of 6 months
  • ·      Radiation dose received:
o   75.6 Gy (17%)
o   79.2-82.8 Gy (43%)
o   86.4 Gy (40%)

Local recurrence (prostate and seminal vesicles) was clinically detected mostly (71%) via biopsy, the rest radiographically (MRI or PET scan). Lymph node recurrences were detected by CT scan, and distant recurrences were clinically detected via biopsy, by radiographic response to ADT, or by rapidly rising PSA during the castrate-resistant phase. After 83 months of followup overall, and 111 months of followup on clinically recurrent patients:
  • ·      22.6% had a biochemical recurrence, defined as nadir+2
  • ·      17.6% had a clinically detected recurrence.
  • ·      Recurrence by risk category:
o   Low risk: 5.8%
o   Intermediate risk: 13.4%
o   High risk:  32.8%
  • ·      Recurrence by radiation dose:
o   75.6 Gy: 29.1%
o   79.2-82.8 Gy: 14.6%
o   86.4 Gy:  15.8%
  • ·      Recurrence was also higher in men under 70, higher stage, PSA>10, >50% positive cores.

Among those in whom a clinical recurrence was detected within 8 years of primary treatment, the site of the first recurrence was as follows:
  • ·      Local recurrence in 55%
o   74% in low-risk recurrent patients
o   68% in intermediate-risk recurrent patients
o   45% in high-risk recurrent patients
o   in 87% of local recurrences, it was the only recurrence site
  • ·      Pelvic lymph nodes (PLN) in 21%*
o   None in low-risk recurrent patients
o   in 38%, of PLN recurrences, it was the only recurrence site
  • ·      Abdominal lymph nodes in 9%
  • ·      Thoracic lymph nodes in 2%
  • ·      Bone in 34%
o   40% in high-risk recurrent patients
o   in 66% of bone recurrences, it was the only recurrence site
  • ·      Viscera in 2%
*Patients who presented with enlarged nodes were excluded, and no one received whole pelvic radiation.

The authors also note that a first isolated PLN recurrence was a rare event among all the men treated with EBRT, only occurring in 1.5% of them.

The site of recurrence was strongly correlated with prostate cancer-specific mortality. Compared to locally recurrent prostate cancer, the risk of prostate cancer death after a median of 111 months of followup was:
  • ·      4.2 times higher for lymph recurrences
  • ·      8.1 times higher for bone recurrences
  • ·      9.6 times higher for multi-organ/visceral recurrences
In fact, after accounting for the site of recurrence, only the Gleason score, but none of the other risk factors (e.g., PSA kinetics, stage, age, time to recurrence), predicted prostate cancer mortality. This, and the fact that a first recurrence site was often the sole recurrence site, suggests that there are different types of prostate cancer (phenotypes) with characteristic patterns of spreading and characteristic virulence.

The authors draw 3 conclusions:
“1) The prostate is the most common initial site of recurrence in patients in all risk groups with an increasing absolute incidence that correlates with increasing NCCN risk group.  

2) Isolated PLN relapse is rare in all patients, including those at high risk treated without elective PLN irradiation, at least when using CT for detection.

3) Tumors in many patients display a tropism for specific anatomical compartments and these anatomical patterns of recurrence independently predict prostate cancer specific mortality after clinically detected recurrence.

Unfortunately, their report doesn’t show the time to first recurrence broken down by recurrence site. It may be that the much shorter followup in the French study (patients were treated 2-6 years ago) may explain the lower incidence of bone metastases in that study. Detection methods may explain the differences as well.

In both studies, more than half of the recurrences after primary radiation therapy were local and were at least potentially treatable with salvage therapies. That may not hold true for other kinds of radiation. There isn’t a lot of data on recurrence sites, but the higher biologically effective doses available with SBRT, HDR monotherapy, and multi-modal radiation may be better able to overcome the more radio-resistant cells. In a recent commentary, we saw that a novel kind of radiation, called Carbon Ion Radiotherapy, could kill cancer cells even in a low-oxygen (hypoxic) tumor environment.

The table below shows the range of biologically effective doses for various radiation modalities, and the percent of local failures in all treated patients (not just those with a recurrence), broken out by risk group where available.

Percent Local Failures by Risk Group

EBRT
SBRT
HDR brachy monotherapy
EBRT+HDR brachy boost
Relative biologically effective dose*
.89-1.02
1.06-1.17
1.27-1.36
.97-1.17
Low Risk
4%
0.9%

2.5%
1%
Intermediate Risk
9%
2.6%
1%
High Risk
15%
7%

9%
Followup
9 years
6/7 years
10 years
4 years
Reference

*Relative to 80 Gy of IMRT for cancer control

The local failure rates seem to be higher for EBRT than for SBRT, HDR brachy monotherapy, or HDR brachy boost therapy. Only a randomized comparative trial can decide what relative role biologically effective doses, radiation intensity, patient selection, and detection techniques play in determining the extent of local control. It would be useful to know as well whether genetic tests like Prolaris or Oncotype Dx can predict local response to radiation, and whether there are identifiable subtypes that metastasize to lymph nodes, bones or viscera. Better detection of local and distant recurrence is needed as well.

In the next commentary, we will look at how SBRT is being used in salvage treatment of those isolated local recurrences.


written January 13, 2016





Adverse Effects of Primary IMRT


A recent commentary listed some of the most common adverse effects of prostatectomy, some of which (e.g., perceived penile shrinkage, climacturia, Peyronie's, stress incontinence) are seldom mentioned by urologists to prospective patients, and are not routinely included in standardized quality-of-life questionnaires. In the interest of providing equal time to the potential adverse effects of radiation, below is a list of such effects, ranked by approximate incidence, for primary IMRT.

This list only applies to primary IMRT and not to salvage treatments, which may have a very different side effect profile. These data are not purely for IMRT – they include some patients treated with 3D CRT as well. Some patients in these studies may have had adjuvant ADT, so it is impossible to distinguish the effects of radiation from the effects of concurrent hormone treatment. None of this applies to SBRT or brachytherapy.

Most of the data on acute side effects are pulled from the Sanda et al. study, which represents the patient-reported outcomes at 9 of the top US institutions, and is not indicative of community practice. Many of the late-terms side effects are given as their absolute incidence. Acute side effects are given as increases over baseline function (indicated by “+”). Unless otherwise specified, they are acute side effects (within 3 months of treatment), rather than late-term or chronic side effects. Acute side effects are typically transient. Contrary to “common knowledge,” new side effects rarely emerge after 2 years.

In general, urinary, rectal and sexual adverse effects will be worse among men whose function is impaired before treatment, and those with certain comorbidities. Radiation dose, image guidance techniques, margins, anatomic differences, and sensitivity to radiation contribute to individual variances in side effects. Most of the side effects are attributable to inflammation (cystitis, urethritis, proctitis), spasms (diarrhea, bladder spasms), and the destruction/fibrosis of vascular and other tissues (ED, urinary retention). There are treatments available for many of these adverse effects. Patients are advised to discuss them with their doctors.

Loss of semen (5 yrs) 89%

Fatigue 32%
Sexual function- big/moderate problem (1 yr) 31%
Frequent urination +18%
Vitality/hormonal function – big/moderate problem (1 yr) 18%
Bowel urgency  +15%
Bowel frequency +14%
Urinary irritation or obstruction – big/moderate problem (1 yr) 14%
Bowel/rectal function – big/moderate problem (1 yr) 11%
Dysuria (pain while urinating) +11%
Weak stream +10%

Leaking >1x per day +9%
Rectal pain +5%
Fecal incontinence +5%
Dribbling +4%
Urinary incontinence – big/moderate problem (1 yr) 4%
Any pad use +3%
Bloody stools +2%

Other rare effects with <1% incidence:
Rectourethral fistula
Bladder neck contracture requiring surgical intervention
Second primary pelvic cancer
------------

Sources:

Prospective evaluation of the prevalence and severity of fatigue in patients with prostate cancer undergoing radical external beam radiotherapy and neoadjuvant hormone therapy.

Quality of Life and Satisfaction with Outcome among Prostate-Cancer Survivors (Sanda et al.)

Preliminary Toxicity Analysis of 3DCRT versus IMRT on the High Dose Arm of the RTOG 0126 Prostate Cancer Trial

Radiotherapy-induced second primary cancer (RTSPC) risk is low and may differ by radiation technique.

Urorectal fistulae following the treatment of prostate cancer

Second primary cancers after radiation for prostate cancer: A systematic review of the clinical data and impact of treatment technique

Monday, August 29, 2016

How long is long enough? Length of follow-up on clinical trials for primary treatments

Many of us are faced with the difficulty of choosing a primary therapy based on data from clinical trials with follow-up shorter than our life expectancy. How can we know what to expect in 20 or 30 years? This is quite apart from the fact that most published studies only tell us how the treatment worked for a chosen group of patients treated by some of the top doctors at some of the top institutions – they never predict for the individual case that we really want to know about; i.e., “me.” The issue of length of follow-up is particularly problematic for radiation therapies, although it may be too short for surgery and active surveillance studies as well. How can we make a reasonable decision given the uncertainty of future predictions?

I may have missed some studies, but the longest follow-up studies I have seen for each primary therapy treatment type are as follows:

• HDR brachy monotherapy - 10 years (
CET/Demanes)
• HDR brachy+EBRT - 15 years (
Kiel, Germany)
• IMRT - 10 years (
MSKCC)
• LDR brachy monotherapy - 12 years (
UWSeattle & Mt. Sinai)*
• LDR brachy+EBRT - 25 years (
RCOG)
• Protons- 10 years (
Loma Linda)
• SBRT - 9 years (
Katz)
• Robotic RP - 10 years (
Henry Ford Hospital, Detroit)
• Laparoscopic RP - 10 years (
Heilbronn, Germany)
• Open RP - 25 years (
Johns Hopkins)
• Active Surveillance - 20 years (
Toronto)

*Mt. Sinai published a study with longer follow-up (15 years); however, all patients were treated from 1988 to 1992, before modern methods were used, and such results are irrelevant (see below) for decision-making today.

On a personal note, I was treated at the age of 57 and had an average life expectancy of 24 years, possibly more because I have a healthy lifestyle and no comorbidities. So there were no data that could help me predict my likelihood of cause-specific survival and quality of life out to the end of my reasonably expected days. What's more, the therapies with the longest follow-up (open RP, brachy boost) also have the highest rates of serious side effects. With my low-risk cancer, there seemed little need to take that risk with my quality of life.

While we may be tempted to wait for longer follow-up, (1) we don't always have that luxury, and (2) there very likely will not
 be any longer follow-up. Not only is follow-up expensive, there are also the problems of non-response, drop-outs, and death from other causes. The median age of patients in radiation trials is typically around 70, so many will leave the study. The 10-yr Demanes study, for example, started with 448 patients, but there were only 75 patients with 10 years of follow-up. The “10-year” study of IMRT at MSKCC started with 170 patients, but only 8 patients were included for the full ten years! After the sample size gets this small, we question the validity of the probability estimates, and there is no statistical validity in tracking further changes. (It is worth noting that IMRT became the standard of care without longer term or comparative evidence.)

An even bigger problem is what I call
 irrelevance. Technological and medical science advances continue at so brisk a pace that the treatment techniques ten years from now are not likely to resemble anything currently available (another argument for active surveillance, if that's an option). Dose escalation, hypofractionation, IGRT technology, intra-operative planning, VMAT, variable multi-leaf collimators, on-board cone-beam CT, and high precision linacs - all innovations that have mostly become available in the last 15 years - have dramatically changed the outcomes of every kind of radiation therapy, and made them totally incomparable to the earlier versions. Imagine shopping for a new MacBook based on the performance data of the 2000 clamshell iBook. By the time we get the long-term results, they are irrelevant to the decision now at hand.

What we want to learn from long-term clinical trials are the answer to two questions: (1) Will this treatment allow me to live out my full life? and (2) what are the side effects likely to be? To answer the first question, researchers look at prostate cancer-specific survival. It’s not an easy thing to measure accurately – cause of death may or may not be directly related to the prostate cancer. We usually look at overall survival as well. For a newly diagnosed intermediate risk man, prostate cancer survival is often more than 20 years, so we can’t wait until we have those results to make a decision. Taking one step back, we look at metastasis-free survival, but that is often over 15 years. Sometimes there is clinical evidence of a recurrence before a metastasis is detected (e.g., from a biopsy or imaging). More often, the only timely clue of recurrence is biochemical – a rise in PSA over some arbitrary point. That point is set by consensus. Researchers arrived at the consensus after weighing a number of factors, especially its correlation with clinically-detected progression. Biochemical recurrence-tree survival (bRFS), or its inverse, biochemical failure (BF), is the most commonly used surrogate endpoint.

We might be comfortable if outcomes seem to have reached a plateau. For some of the above studies, we are able to look at some of the earlier reported biochemical failure rates compared to those measures reported at the end of the study (ideally broken out by risk group).
  • ·      In the Demanes Study, the 10-year results are virtually unchanged from the 8-year results.
  • ·      In the Kiel study of HDR brachy boost, the 5-, 10- and 15-year BF was 22%, 31%, and 36%.
  • ·      In the RCOG study of LDR brachy boost, the 10-, 15-, 20- and 25-year BF was 25%, 27%, 27%, and 27%
  • ·      In the Mt. Sinai study of LDR brachy, the 8- and 12-yr BF was 12% and 10% for low risk; 19% and 16% for intermediate risk; 35% and 36% for high-risk patients.
  • ·      In the MSKCC study of IMRT, the 3-, 8- and 10-yr BF was 8%, 11%, and 19% for low risk; 14%, 22% and 22% for intermediate risk; 19%, 33% and 38% for high risk patients.
  • ·      In the Katz SBRT study, the 5- and 7-year BF was 2% and 4% for low-risk, 9% and 11% for intermediate-risk, and 26% and 32% for high-risk patients.
  • ·      For comparison, the 5- 10- 15- and 25- year recurrence rates for prostatectomy at Johns Hopkins were 16%, 26%, 34% and 32%.

For most of the therapies, HDR & LDR brachy monotherapy, LDR brachy boost therapy, and SBRT, the failure rates remained remarkably consistent over the years. However, for surgery and IMRT, failure rates increased markedly in later years. Most of us can’t wait 25 or more years to see if a therapeutic option remains consistent or not, and for radiation, the results would almost assuredly be irrelevant anyway.

Ralph Waldo Emerson is misquoted as saying, “Build a better mousetrap, and the world will beat a path to your door.” An important criterion for decision-making when there is only limited data is our answer to the question: Is this a better mousetrap? Arguably, robotic surgery was only an improvement over open surgery, and not an entirely new therapy requiring separate evaluation. It has never been tested in a randomized comparison, and I doubt we will ever know for sure. Arguably, IMRT was simply a “better mousetrap” version of the 3DCRT technique it largely superseded and didn’t need a randomized comparison to prove its worth. Was HDRBT monotherapy just an improvement over HDRBT+EBRT? Was SBRT just an improvement over IMRT, or should we view it as a variation on HDRBT, which it radiologically resembles by design? There are no easy answers to any of these questions. However, as a cautionary note, I should mention that proton therapy was touted as more precise because of the “Bragg peak effect,” yet in practice seems to be no better in cancer control or toxicity than IMRT.

There is also the problem of separating the effect of the therapy from the effect of the learning curve of the treating physician. Outcomes are always better for patients with more practiced physicians. The learning curve has been documented for open and robotic surgery, but less well documented for radiation therapies. Patients treated early (and perhaps less skillfully) in a trial are over-represented in the latest follow-up, and there may be very little follow-up time on the most recently (and perhaps more skillfully) treated patients.

So when do we have enough data to make a decision? That comfort level will vary among individuals. I was comfortable with 3-year data based on choosing a theoretically “better mousetrap”, and many brave souls (thank God for them!) are comfortable with clinical trials of innovative therapies. In the end, everyone must assess for himself how long is long enough. For doctors offering competing therapies and for some insurance companies, there never seems to be long enough follow-up. I suggest that patients who are frustrated by those doctors and insurance companies challenge them to come up with concrete answers to the following questions:
  • ·      What length of follow-up do you want to see, and why that length?
  • ·      What length of follow-up was used to determine the standard of care?
  • ·      Do you need to see prostate-cancer specific survival, or are you comfortable with an earlier surrogate endpoint?
  • ·      What is the likelihood of seeing longer term results, and will there be any statistical validity to them if we get them?
  • ·      Have outcomes reached a plateau already?
  • ·      What evidence is there that toxicity outcomes change markedly after 2 years?
  • ·      Will the results still be relevant if we wait for longer follow-up?
  • ·      Is the therapy just a “better mousetrap” version of a standard of care?
  • ·      Are my results likely to be better now that there are experienced practitioners?

Sunday, August 28, 2016

LDRBT, IMRT and SBRT Quality of Life


Some of the leading lights in radiation oncology have collaborated on a study by Evans et al. of patient-reported quality of life (QOL) following various primary radiation treatments for prostate cancer. They analyzed three monotherapies (all without hormone therapy): low dose rate brachytherapy (LDRBT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT). It did not include high dose rate brachytherapy or proton therapy.

Because this study was so far-reaching in its scope and its findings, it is worth taking a close, detailed look at it. I will break it into three parts. In the first part, we’ll look at the basis of the study – how the study was designed and carried out, and what does it purport to tell us. In Part 2, we will look at some of the more important findings of the study. And in Part 3, we will discuss the implications and caveats of its findings, and draw conclusions.

PART 1. THE BASIS OF THE STUDY

The purpose of the study was to evaluate three primary radiation therapies – LDRBT, IMRT and SBRT – with respect to the patient-perceived side effects of those treatments, and to do so in a standardized and consistent manner. While this was a prospective study, it was not a randomized comparison, which is the gold standard for doing that. However, it does provide the doctor and patient with more information on what they can reasonably expect, across those treatments, than we’ve ever had before.

Data was provided by several of the top institutions in the US:

LDR or IMRT
Michigan (2 sites)
Mass General
Beth Israel Deaconess
MD Anderson
Cleveland Clinic
Washington University (St Louis)

SBRT
Georgetown
21st Century (2 sites)

The number of patients in the two-year follow up:
  • ·        LDRBT: 243 patients
  • ·        IMRT: 140 patients
  • ·        SBRT: 272 patients


I don’t know how they selected which doctors and medical centers to include. In addition, the study was done with the assistance of the PROSTQA Study Consortium, a blue-ribbon panel of top researchers. They previously published much of this data on IMRT and LDRBT in 2008 (see this link). The SBRT data are new. Their results are a good indicator of outcomes from top practitioners at major treatment centers, and are not a good indicator of expected outcomes in community practice. I’m sure that many patients have favorite doctors whose work was not represented in this study, and they will argue that these results are not representative.

Because this was not set up as a randomized comparison of treatments, differences in patient selection may skew the results. Importantly, the LDRBT cohort is 5 years younger (65 years, median) than the other two groups (69 years, median). In all quality-of-life studies, younger patients do better. They are less likely to suffer deleterious effects of radiation, and they are more resilient in their recovery. Paralleling the difference in age at baseline, the baseline sexual QOL was best for LDRBT, and the baseline prostate symptom scores were best for LDRBT, followed by IMRT and SBRT.

The instruments they used to evaluate quality of life were EPIC-26 and SF-12. Patient-reported assessments have an advantage over physician-reported toxicity reports. The physician data depends on the patient to voluntarily tell the doctor about all adverse events, which is useful for highest grade events (3 or 4), but is less reliable for low grade events (1 or 2) that the patient might never bring to the doctor’s attention. Some men “tough it out,” some see their PCP instead (who may be more accessible), and some worry about even the most minor events. The survey instruments used here are standardized and validated, and guide the patient through a detailed assessment of the QOL issues that have been found to matter most. Patients filled them out at baseline, at 1-2 months, 6, 12, and 24 months. EPIC scores are based on scale of 0 (worst) to 100 (best). Although they also measured such qualities as general physical and mental status, and vitality/well-being, none of these were impacted by treatments.

IMRT and LDRBT patients were treated from 2003 to 2006; SBRT patients from 2007 to 2011. Contemporary best practice was observed as follows:

·        LDRBT: 144 Gy prescribed dose for I-125, US-guided, transperineal placement, I-125 or Pd-103 used, and 3-5 mm margins (more details here)
·        IMRT:76-79 Gy in 1.8-2.0 Gy increments, and 0.5-1.5 cm margins.
·        SBRT: 35-40 Gy in 5 fractions, fiducials or Calypso image guidance, and 3-5 mm margins.

There were two kinds of urinary problems that were measured: urinary incontinence (leakage, dribbling, control & pad use) and urinary irritation/obstruction (frequency, pain/burning, weak/incomplete). Bowel issues comprised urgency, frequency, leakage, bleeding and pain. The sexual domain comprised ability to have erections, their firmness, and frequency when needed; also, quality of orgasms and overall sexual function.

All of the study’s findings relate to how much patient evaluations changed compared to their baseline evaluations in the urinary, rectal and sexual quality of life domains. We expect that the radiation therapies that do the least damage will show the least deterioration in the patient perceptions in each domain.

Because the study was not randomized, and it did not attempt to match triplets of patients on their demographics and co-morbidities, we have the difficulty of comparing results in different kinds of patients. The analysis of patient characteristics across treatments revealed only one real glaring discrepancy – LDRBT patients were 5 years younger than the rest. The authors made some attempt to restore comparability by only looking at sexual scores among patients who were 60 years of age or older, but such analyses were limited in their published results. In my opinion, they ought to have computed age-adjusted scores in all domains. The failure to do so will compound the difficulties in interpreting results as they carry their tracking into the future when the aging of the study population has greater effects.


PART 2. DETAILED FINDINGS

In this part we’ll look at the results of their analysis. The authors did a great job of compiling a vast amount of information. Even so, in some cases, I wish more of the information had been presented (I was able to see the full text). Perhaps they will reveal more of the details in future analyses of this rich database.


Change from Baseline

The following table shows the EPIC score change from baseline after two years among patients having each kind of therapy. The last column shows, for reference, the minimum amount of change that has been found to be clinically important for that set of symptoms.


LDRBT
IMRT
SBRT
Urinary- irritative/obstructive
-6*
+2
0
5-7
Urinary - incontinence
-6*
-5*
-3
6-9
Bowel
-7*
-8*
-1
4-6
Sexual†
-24*
-21*
-14*
10-12
* Change is statistically significant
†Among those with scores over 60 at baseline (to help compensate for age-related differences).

Sexual status was the domain that was most affected by all the treatments. For LDRBT, it had the greatest deterioration. Deterioration in urinary and bowel scores were statistically significant and clinically meaningful in patients who had LDRBT. IMRT also had its greatest impact on sexual status, and not much different from LDRBT. Other than sexual status, only IMRT bowel scores deteriorated meaningfully; urinary status returned to near baseline. SBRT had the smallest change in sexual status, albeit large enough to be meaningful. Bowel and urinary status returned to baseline.

Minimal Clinically Detectable Change

The authors also looked at what% of patients suffered a minimal clinically detectable (MCD) change in each of those components of their quality of life over time. The typical pattern was a sharp increase at 1 or 2 months (acute effects). In all but sexual scores, that was followed by improvement. Predictably, urinary irritation/obstructive were most impacted, reaching about 90% at two months for LDRBT, and significantly better at all time points for IMRT and SBRT. The proportion who had MCD bowel symptoms and sexual symptoms was consistently more favorable for SBRT than for LDRBT or IMRT.

As a measure of the severity of symptoms, the authors looked at the % of patients who suffered an MCD increase of twofold or more over baseline after two years:

LDRBT
IMRT
SBRT
Urinary (all)
45%
25%
18%
Bowel
25%
30%
11%
Sexual†
35%
33%
20%
None of the above
34%
40%
65%
All of the above
8%
7%
2%

In general, large clinical deteriorations in QOL were about twice as frequent for LDRBT compared to SBRT, with IMRT falling in the middle.

Symptom Severity over Time

As another measure of symptom severity, the table below shows the% change versus baseline in the proportion who rated their symptoms as moderate to severe, at 1-2 months and at 2 years:

LDRBT
IMRT
SBRT

2 mos.
24 mos.
2 mos.
24 mos.
1 mo.
24 mos.
Urinary (all)
+33%
+7%
+27%
+3%
+8%
-3%
Bowel
+14%
+6%
+16%
+6%
+7%
-2%
Erectile dysfunction†
+21%
+19%
+11%
+16%
+5%
+11%
† inability to have erections, among patients of all ages

Moderate to severe acute urinary and rectal side effects increased markedly for LDRBT and IMRT. For SBRT, they increased much less and returned to slightly better than baseline levels.

Keeping in mind that LDRBT patients were a median of 5 years younger than the other two groups, the increase in erectile dysfunction among LDRBT patients is troubling.  As we saw in a recent study, the deterioration occurs earlier than was previously thought. For SBRT, in contrast, there was only a +5% increase in erectile dysfunction severity at two months after treatment, but that increased to +11% by two years. Nevertheless, that was still lower than the other two therapies.

PART 3. DISCUSSION

In this section, we will make an attempt to explain the findings of the study and draw whatever conclusions we can from them.

We have seen a very consistent pattern across all the measures of QOL and in all of the domains: LDRBT patients did worst, SBRT patients did best, and IMRT patients were in between. Why should that be? Let’s examine a few hypotheses:

Patient selection/non-random

This was not a randomized comparative trial, so it is possible that the LDRBT patients selected were, for some reason, more prone to the damaging effects of radiation. This argument is weakened by the fact that they were 5 years younger, and their urinal, rectal and erectile function at baseline were better than in the other two groups.

Better practitioners not represented

Some of the top LDRBT practitioners like Peter Grimm, Michael Zelefsky, Brian Moran, and Gregory Merrick, to name a few, were not represented here. One could also argue in the other direction that some of the most experienced SBRT practitioners, like Christopher King, Alan Katz, and Debra Freeman, were not represented here. Their results might have increased comparative favorability of the SBRT results still further. However, the results do seem to be comparable to those reported by Katz and the 8-institution consortium.

Time of treatment

IMRT and LDRBT results were based on best practice in 2003-2006, while SBRT was based on patients treated in 2007-2011. There were technological improvements in both modalities since then that might make their outcomes more comparable to SBRT. As radiation technology continues to evolve, it becomes problematic to choose among them based on past performance.

Hypofractionation spares healthy tissue

Hypofractionation (SBRT or HDRBT) – radiation applied in fewer treatments (or fractions) – has been found to kill cancer cells more efficiently than normal fractionation (IMRT) or continuous fractionation (LDRBT). Because prostate cancer is especially susceptible to hypofractionation (technically, we say it has a low alpha/beta ratio of about 1.5), and because healthy nearby early-responding tissues are less susceptible (they have a higher alpha/beta ratio of about 10), healthy tissues are better spared by it.

A convenient measure for comparing the dose seen by nearby healthy tissues is something called the biologically effective dose (BED). We can compute for each modality the maximum BED experienced by nearby early-responding tissues that are responsible for acute side effects. With SBRT (7.5 Gy X 5 fractions), the BED to those tissues is 30% less than the dose from IMRT (1.8 Gy X 44 fractions). For LDRBT (144 Gy I-125 Rx dose), the maximum BED to those tissues is 56% greater than the dose from IMRT. ). Making comparisons solely on BED is problematic because LDRBT radiation is extremely short range, so a lower proportion of the bladder and rectum surface may be exposed to that maximum dose.

Dose constraints

Radiation oncologists set strict dose constraints for the bladder, urethra, rectum, and sometimes to the penile bulb, limiting the volume of those organs that receive potentially toxic doses. However, there is only so much that doses can be limited if they are to effectively kill the cancer in the prostate. I don’t know what dose constraints were set for the three modalities examined in this study. We can only assume that they used best practices.

Imaging

The imaging of the pelvic organs both in planning and in the application of radiation makes a large difference in toxicity. This is where SBRT shines. SBRT commonly uses a fused image of a CT and MRI with fiducials or transponders in place for planning. This helps to precisely predetermine, down to less than a millimeter, where all the beams will be directed. These practices can be used with IMRT as well. However, with IMRT, the images are aligned only once per session, whereas with SBRT, the images are aligned continually throughout the session. We recently saw how disastrous SBRT could be without intra-fractional motion tracking. LDRBT seed placement is commonly accomplished under ultrasound image guidance, using computerized intra-operative planning. The ultrasound can help the doctor see where the needles are going, but it can’t see the seeds well. Even stranded seeds tend to move, the prostate is moved by each needle insertion, and the prostate swells throughout the procedure, so that it is impossible to know where their final position will be. An image is obtained about a month later, after the swelling subsides, to check for major discrepancies in seed positions and to give an after-the-fact reading of the doses absorbed by organs at risk.

Late term effects

This study tracked patients for two years, which is long enough for most of the late-term side effects to show up. However, some will inevitably show up even later. Some tissues, particularly some in the bowel, are “late responding” to radiation damage. Late responding tissues are relatively more sensitive to the concentrated radiation of SBRT (they have an alpha/beta ratio of 3-5), so it is possible that SBRT’s advantage will decrease with longer follow up.

CONCLUSIONS

Although one can quibble over methodological issues in comparing the modalities, SBRT certainly provides excellent quality of life to treated patients. SBRT also is the most convenient of the treatments, requiring only five short visits, no intrusive procedures (other than fiducial placement), and no anesthesia. LDRBT is the winner on cost of treatment, with a $17,000 median Medicare reimbursement, followed by SBRT ($22,000) and IMRT ($31,000). However, a full cost analysis should also include the costs of managing the side effects of treatment, which seem to be much lower for SBRT and higher for LDRBT. Based on the findings of this study, and approximately equivalent oncological control for the 3 modalities in favorable risk patients, it is hard to justify IMRT. Availability is an issue: IMRT is available everywhere, while there is less access to excellent practitioners of SBRT (usually as CyberKnife®) and LDRBT. Some insurance still will not cover SBRT, although that is less often a barrier now.

An oft-heard argument against SBRT is that there’s not enough long-term data. SBRT is the youngest of the three modalities, used against prostate cancer since 2003. The longest-running SBRT study, has 7 years of follow up on 515 patients. For comparison, robotic prostatectomy has been used since 2000, and has never been proven superior to open surgery in a randomized comparative trial. IMRT, likewise, has never been evaluated in a comparative randomized trial, and in its current form, using dose escalation and precision IGRT techniques, was only begun in the mid-1990s. The longest-running IMRT study, at Memorial Sloan Kettering, has 10 years of follow up on 170 patients. LDRBT has been used, in some form, for over a hundred years. However, in its modern form with dose escalation and intra-operative planning methods, there are no studies older than 15 years that have any decisional value. I have often bemoaned the problem of “irrelevance” in long-term clinical studies: by the time we get the results, technology and practice have changed so much that the results have become irrelevant in making decisions among the best available therapies.

While this study raises the hypothesis that SBRT may be superior to IMRT and LDRBT, it is prudent for the patient to keep them all in his consideration set at least until the results of randomized comparative trials become available. This study should influence patients and clinicians to give serious consideration to SBRT.

Later this year, we will have the early results from Sweden of a randomized clinical trial of SBRT versus IMRT in intermediate-risk patients. There are several more comparative trials that are scheduled for completion in the coming years. If they confirm the results of this study, it will be difficult to justify IMRT as first-line therapy. Unfortunately, as far as I know, there are none planned comparing SBRT and LDRBT. There are few institutions that offer both modalities (Memorial Sloan Kettering is an exception), so randomization would be problematic.