Monday, October 15, 2018

Low Dose Rate Brachytherapy Monotherapy at the Mayo Clinic

The Mayo Clinic reported the 10-year oncological results on 974 consecutive low and intermediate risk patients treated with low dose rate brachytherapy (I-125 seeds) monotherapy from 1998 to 2013.

Patients were treated as follows:

  • 90% of the prostate received 159 Gy (median dose) of 1-125 seeds
  • 26% received some ADT (mainly to shrink the prostate)


Patient characteristics (number (%)) were as follows:

  • Gleason 6: 783 (80%)
  • Gleason 3+4 :153 (16%)
  • Gleason 4+3:  38 (4%)
  • Stage T 2b or 2c: 24 (2.5%)
  • PSA ≥ 10: 93 (10%)
  • Low risk: 693 (71%)
  • Intermediate risk: 281 (29%)


While they did not routinely collect data on the percent of positive biopsy cores, they did define an "unfavorable intermediate risk" cohort as having Gleason 4+3 or multiple intermediate risk factors.

With median follow-up of 6 years, there were only 45 cases of biochemical failure, and 10 deaths from any cause. The 10-year biochemical recurrence-free survival was:

  • 85% overall
  • 90% among low risk men
  • 74% among intermediate risk men


The following hazard ratios were significant on multivariate analysis:

  • Gleason score 4+3: 7.0
  • Use of ADT: 0.3
  • PSA (per unit increase): 1.17
  • Unfavorable intermediate risk : 3.75


Predominant Gleason pattern 4 also affected the rate of distant metastases and prostate cancer-specific survival. Use of ADT did not. Local recurrence was only 2%.

Radiation dose was consistently escalated, so the effect of dose differences failed to meet statistical significance. Patient selection has changed over the years. Low risk men are routinely steered towards active surveillance. Multiparametric MRI is now used to stage intermediate risk candidates in order to find those where cancer is likely to have escaped the prostate capsule or penetrated the seminal vesicles -- those patients may be offered multimodal radiation with both external beam therapy and a brachy boost. While use of monotherapy was rare among those with GS 4+3, it is probably much rarer today. Monotherapy seems to be sufficient in favorable intermediate risk men.

This study had similar results to those reported by Cleveland Clinic (see this link). It also affirms that monotherapy is all that's needed for favorable intermediate risk (see this link), and that brachy boost therapy is needed for unfavorable risk patients (see this link). These are reflected in current guidelines (see this link). The use of ADT beyond cytoreduction does not seem to be necessary, at least in high risk men receiving brachy boost therapy (see this link). This study did not address the toxicity of brachytherapy, which should be discussed with one's brachytherapist.

With thanks to Brian Davis for allowing me to read the full text of his study.

Friday, October 12, 2018

ASTRO, ASCO, & AUA strongly endorse a shortened course of IMRT for primary therapy

It will come as no surprise to my readers that moderately hypofractionated IMRT (first-line radiation delivered in 20-26 treatments or fractions instead of the conventional 40-44 fractions) received strong endorsement from all of the major US organizations of physicians who treat prostate cancer. The American Society for Radiation Oncology (ASTRO), in collaboration with the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) issued the new guidelines, which are also supported by the Society of Urologic Oncology (SUO), European Society for Radiotherapy & Oncology (ESTRO), and Royal Australian and New Zealand College of Radiologists.

A hypofractionation task force issued the new evidence-based guidelines. They divided their guidelines into two parts: (1) moderately hypofractionated IMRT (20-26 fractions); (2) ultrahypofractionated IMRT (4-5 fractions), usually called SBRT, SABR, SHARP, or CyberKnife (I will refer to it as SBRT). They strongly support moderate hypofractionation. They conditionally support SBRT, because of the moderate degree of evidence published by their cut-off date of March 31, 2017. They may revisit those guidelines after further review.

The following guidelines were strongly endorsed based on high quality evidence with strong consensus:

1A: Low risk men who refuse active surveillance should be offered moderately hypofractionated IMRT.

1B: Intermediate risk men should be offered moderately hypofractionated IMRT.

1C: High risk men should be offered moderately hypofractionated IMRT.

1D: Moderate hypofractionation should be offered regardless of patient age, comorbidity, anatomy, or urinary function. However, physicians should discuss the limited follow-up beyond five years for most existing RCTs evaluating moderate hypofractionation. *

1E: Men should be counseled about the small increased risk of acute gastrointestinal (GI) toxicity with moderate hypofractionation. Moderately hypofractionated EBRT has a similar risk of acute and late genitourinary (GU) and late GI toxicity compared to conventionally fractionated EBRT. However, physicians should discuss the limited follow-up beyond five years for most existing RCTs evaluating moderate hypofractionation.*

The following guidelines were strongly endorsed based on moderate quality evidence with strong consensus:

7A: Image guidance (e.g., fiducials, transponders, cone beam CT, etc.) should be used for both moderate hypofractionation and SBRT.†

8A: 3D-CRT should not be used with hypofractionation.§

The following guidelines were conditionally endorsed based on moderate quality evidence with strong consensus:

2A: 60 Gy in 20 fractions or 70 Gy in 28 fractions are suggested for moderate hypofractionation.

2B: No variation in treatment regimen by patient age, comorbidity, anatomy, or urinary function.

3A: Low risk men who refuse active surveillance should be offered SBRT

4A: The SBRT dose for low and intermediate risk men should be 35 Gy - 36.25 Gy in 5 fractions.**

4B: SBRT doses of 36.25 Gy in 5 fractions should not be exceeded outside of a clinical trial or registry.**

5A: At least two dose-volume constraint points for rectum and bladder should be used for moderate hypofractionation or SBRT: one at the high-dose end (near the total dose prescribed) and one in the mid-dose range (near the midpoint of the total dose).


The following guidelines were conditionally endorsed based on low quality evidence with strong consensus:

3B: Intermediate risk men should be offered SBRT, but should be encouraged to do so in a clinical trial or registry.**

3C: High risk men should be not be offered SBRT outside of a clinical trial or registry.

4C: Daily SBRT treatment is not recommended due to increased risk of toxicity.

5B: Normal dose/volume constraints used in the reference study should be adhered to for both moderate hypofractionation and SBRT


The following guideline was strongly endorsed based on low quality evidence with strong consensus:

6A: Planned target volume definition of the reference study should be adhered to for both moderately hypofractionated IMRT and SBRT.††


* While most of the hypofractionation trials did not report beyond 5 years of follow-up (see Table at this link), some did. The Archangeli et al. trial reported survival outcomes out to ten years. (I believe the guideline authors erred about this.) M.D. Anderson published an eight-year update after the close of the task force review. As we saw in our review of RTOG 0126, survival does not become a useful endpoint for perhaps 15-20 years for men with localized prostate cancer, and surrogate endpoints, such as 5-year recurrence-free survival or metastasis-free survival must be used instead. Kishan et al. proposed that for ultrahypofractionated regimens, 3-year PSA may be an excellent surrogate endpoint. The ProtecT clinical trial showed that adverse effects of radiation almost always show up in the first two years.

† For the disaster that can ensue when fiducials are not used with SBRT, see this link. The guidelines should state that intra-fractional motion tracking should be used with SBRT.

§ In the recently presented (not published in time for these guidelines) randomized clinical trial of ulrahypofractionated RT vs conventionally fractionated RT, they did use 3D-CRT in both arms. There was no difference in 5-year biochemical recurrence-free survival or 6-year toxicity.

** In a large, multi-institutional clinical trial (too late to make it into these guidelines), Meier et al. reported excellent 5-year oncological and toxicity outcomes using 40 Gy in 5 fractions. In SBRT dose escalation trials, both Zimmerman at UT Southwestern (reported here) and Zelefsky at MSKCC (I've heard from his patients) found that 45 Gy in 5 fractions gave excellent oncological and toxicity outcomes. The task force neglected the fact that prescribed doses are reported differently by different ROs. Alan Katz, for example, reports a prescribed dose of 35 Gy to the planned target volume (the prostate plus the margin around it), but the clinical target volume (the prostate itself) gets about 38 Gy, while the margin gets considerably less.

†† Smaller margins are possible when fiducials are used for intra-fractional tracking. Tighter margins cause less toxicity to organs at risk.

Sadly, the effect of hypofractionation on erectile function was seldom reported and was not part of the task force's analysis.

It is worth noting that conventionally fractionated IMRT became the standard of care without any comparative clinical trials. The longest running single institution dose-escalated IMRT trial (at MSKCC) had 10 years of follow-up on a small sample size (n=170). By contrast, Alan Katz is expected to report 10-year SBRT outcomes this year on 515 patients. The task force is holding SBRT to a higher standard that by this time next year, it should have the published results to meet.

While the task force endorsed moderate hypofractionation, we will have to see whether radiation oncologists (ROs) follow their guidelines. Because ROs are reimbursed by the number of fractions they give, they will be understandably reluctant to reduce the number of fractions. It remains to be seen whether insurance companies will enforce a limit. It is a clear benefit to the patient in terms of convenience and cost.

Thursday, October 11, 2018

I-131-MIP-1095 will enter a phase 2 randomized clinical trial

As I reported last year, a new radiopharmaceutical has entered the pack. I-131-MIP-1095, a powerful beta-particle emitter attached to a PSMA-targeted ligand, will enter a multicenter phase 2 randomized clinical trial. Progenics®, the manufacturer, put out a press release, which can be read here.

They will be testing a combination of I-131-MIP-1095 with enzalutamide (Xtandi) in patients who are metastatic, castration resistant, have not yet had chemotherapy, and who have become resistant to Zytiga. It is hoped that Xtandi will radiosensitize the cancer to the radiopharmaceutical with a resultant PSA decrease.

120 evaluable patients will be recruited; half will get the radiopharmaceutical + Xtandi, half will get Xtandi alone. All patients will be screened using DCFPyL PET/CT to assure that their metastases are PSMA-avid. The primary endpoint - the percent who have greater than 50% PSA reduction - will be collected for a year. Secondary endpoints - radiographic response, progression-free survival, and overall survival - will be reported at the end of two years.

The other two major radiopharmaceuticals in clinical trials are Lu-177-PSMA-617 and Ac-225-PSMA-617. Lu-177-PSMA-617 has entered phase 3 randomized clinical trials in the US with about 30 test sites expected. So far, recruiting has begun in Omaha NE, Albuquerque NM, Kettering OH and Houston TX and at UCLA, Tulane, Mayo, and Indiana University. There are also various phase 1 and 2 clinical trials in the US and internationally.

I recently reported about the very promising outcomes of Ac-225-PSMA-617 in Germany. Patients report that they are combining Ac-225-PSMA-617 and Lu-177-PSMA-617 to get the advantages of each. Weill Cornell in NYC is investigating Ac-225-J591 in a phase 1 trial.

Wednesday, October 10, 2018

What to expect after prostate radiation (acute side effects)



Urinary, rectal and sexual side effects of treatment are usually mild and transient, although they may be worse if you are especially sensitive to radiation, are an older man, or had symptoms before you started radiation therapy. Some side effects described below may occur in many men starting anytime from a week to a month after treatment and continuing for weeks or months. The duration and intensity vary greatly between men.

If any of those symptoms interfere with your day-to-day living, call your doctor. He may be able to prescribe medication that can help alleviate those symptoms.

Urinary

Total incontinence is uncommon. There may be some leakage or dribbling. Other common side effects are irritation, burning or bleeding while urinating, feeling like you have to urinate immediately even when you know your bladder isn’t full, having to wake up several times during the night to urinate, or having to urinate frequently during the day. You may pass small amounts of blood or blood clots; however, if you are bleeding copiously when you urinate, contact your doctor immediately.

A rare but potentially serious side effect is urinary retention. If you find that you can’t urinate even though your bladder feels full, go to the Emergency Room of the nearest hospital immediately and tell them you are suffering from urinary retention. They must catheterize you to allow the urine to flow out.

Rectal

There may be a feeling like you have to pass a stool but you cannot, and this feeling may recur often. This is called tenesmus. You should be aware that that feeling is from inflammation in your rectum (proctitis), not from actual stool there, and if you strain, you may create hemorrhoids. You may have frequent bowel movements. There may be blood in your stools or blood may drip out. Hemorrhoids may occur. Sometimes stool may leak out, especially when you are passing gas. Stool may be loose, or it may be especially hard.

If you have diarrhea for more than a few days, call your doctor. If the bleeding is copious, call your doctor.

Sexual

Semen will usually dry up soon after treatment, although there may be small amounts of fluid. Occasionally, you may see some blood in that fluid or a few drops of blood may drip out after orgasm.

You may notice that, over time, erections are not as hard or as long-lasting. To protect the blood vessels supplying your penis with blood, your doctor may have prescribed Viagra or a similar medication. You should continue to take that medication for at least 6 months after the end of treatment, even though it seems like you don’t need it.

Testosterone levels often drop following radiation, but may eventually return to normal levels. Because of this, you may notice a drop in the level of your sexual desire/libido. Some men experience difficulty reaching orgasm.

If any of the symptoms are bothersome, you may want to consult with a doctor who specializes in Sexual Medicine.


For a list of all side effects, long-term and acute, see:
Adverse Effects of Primary IMRT


Sunday, September 30, 2018

Survival benefit to debulking the prostate with radiation in men with low metastatic burden

The term "debulking" denotes the radical treatment (via prostatectomy or radiation) of the cancerous prostate after distant metastases have been discovered. This first randomized clinical trial of debulking with external beam radiation found that there was no overall survival benefit.

Results of the STAMPEDE randomized clinical trial were published in the Lancet. Like the HORRAD trial (see below), they found there was no survival benefit to radiation debulking among all newly diagnosed men with metastases (Stage M1). Unlike the HORRAD trial, they utilized higher radiation doses.

Newly diagnosed men were treated with standard of care (which at the time meant ADT and docetaxel in 18% of the men) and were randomized to no radiation debulking or hypofractionated radiation, consisting of either:
  • 55 Gy in 20 daily treatments, or
  • 36 Gy in 6 weekly treatments (note: this bioequivalent dose is 15% higher)
However it made a big difference in survival if the men were oligometastatic (1-3 distant metastases). After 37 months median follow-up:
  • Survival increased by 32% (hazard ratio = 0.68) in 819 oligometastatic men
    • 3 yr survival was 81% with debulking vs 73% without debulking
  • No survival increase among the 1,120 polymetastatic men (defined as visceral metastases or 4 or more bone metastases with at least 1 outside the axial skeleton)
Survival increases were also noted among men with only pelvic lymph node metastases (N1M0), in whom whole pelvic radiation may be curative.

Adverse events from the radiation were generally mild:
  • 5% had grade 3 (serious) or higher acute urinary or rectal side effects
  • 4% had grade 3 (serious) or higher late-term urinary or rectal side effects

Based on this and their other randomized clinical trials, men with lower metastatic burden should be treated with ADT+Zytiga, followed in 2 months with local hypofractionated radiation. Men with higher metastatic burden should be treated with ADT+docetaxel (it is unknown whether Zytiga adds any additional benefit). Metastasis-directed therapy is under investigation.

BoevĂ© et al. reported the results of 432 men with bone metastases at 28 centers in the Netherlands from 2004 to 2014 (the HORRAD trial). They had received no previous treatments. They all had PSA > 20 ng/ml at the start of treatment and were under 80 years of age. They were randomized to receive either:
  1. Lifelong ADT (an LHRH agonist, starting with 4 weeks of an anti-androgen)
  2. Lifelong ADT + external beam radiation therapy (EBRT) 
The EBRT dose was 70 Gy (35 treatments of 2 Gy each) or 57.8 Gy (19 treatments of 3.04 Gy each), which are biologically equivalent. No whole pelvic radiation or brachy boost therapy was given.

After 47 months median follow-up, the median overall survival was:

  • 45 months in the group that received ADT + EBRT
  • 43 months in the group that received ADT only
The difference was not significant

The authors also looked at survival differences based on:
  • Number of bone metastases (<5, 5-15, >15)
  • PSA at diagnosis (greater or less than 60 ng/ml)
  • Gleason score
  • Stage
  • Age
  • Performance status
  • Painful bone metastases

None made any significant difference in survival.

The time to PSA progression was slightly longer among those who received EBRT (15 months vs. 12 months), but the statistical significance vanished after correction for patient characteristics.

These disappointing results conflict with several retrospective database analyses. This once again illustrates that only prospective randomized clinical trials can prove a causal relation, and that observational studies are confounded by the vagaries of patient selection; i.e., patients who receive debulking in actual clinical practice are the ones who would do better anyway. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor  plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference.

Because this trial began over a decade ago, it does not include radiation doses now considered to be curative (around 80 Gy). Nor does it include brachy boost therapy, which was shown to be superior to EBRT alone in high risk patients in the ASCENDE-RT randomized clinical trial. It is also unknown what effect whole-pelvic radiation or metastasis-directed therapy might have had, or whether prostatectomy with or without extended pelvic lymph node dissection (ePLND) may have increased survival.

This clinical trial began before CHAARTED, STAMPEDE, and LATITUDE clinical trials proved that early treatment with docetaxel and abiraterone improves survival in newly diagnosed metastatic men. It is unknown what effect debulking may have in men pre-treated with those systemic therapies.

Many of these unknowns are being explored in current clinical trials. The recently announced randomized clinical trial of debulking at MD Anderson will allow for either EBRT or surgery. This clinical trial in Canada allows for treatment with surgery, HDR brachytherapy, chemotherapy, and SBRT to metastases. This clinical trial in Europe allows for treatment with  docetaxel, and abiraterone. This clinical trial in Germany randomizes patients to prostatectomy + ePLND or best systemic therapy.

Because radiation and prostatectomy have adverse effects, this study should make patients cautious about having any kind of debulking outside of a clinical trial.

Sunday, September 2, 2018

Free Randomized Clinical Trial of Ga-68-PSMA-11 PET indicator at UCLA

UCLA is now running a randomized clinical trial of the Ga-68-PSMA-11 PET indicator for men  with a recurrence (PSA≥ 0.1 ng/ml) after prostatectomy who are considering salvage radiation therapy (SRT). They are expanding and adding a control arm to the trial they did earlier (see this link) that found that the PSMA-based PET scan was able to change treatment decisions in about half the men.

Here are the trial details and the contact info:
https://clinicaltrials.gov/ct2/show/NCT03582774

UCLA normally charges $2650 for the PET indicator, so this is an opportunity to save some money. If a patient is randomized to the control group, he may still get an Axumin PET scan when his PSA is confirmed above 0.2 ng/ml, which is covered by Medicare and most insurance. The Axumin PET scan only detects cancer in 38% of patients if their PSA is in the range of 0.2-1.0 ng/ml, while the Ga-68-PSMA-11 PET scan detects cancer in about 27%-58% of recurrent men whose PSA is between 0.2 and 0.5. UCLA recently completed another free clinical trial comparing Axumin to Ga-68-PSMA.

I'm told that the NIH trial of another PSMA PET indicator, DCFPyL, has a waiting list of 2-3 months, and they are no longer taking patients whose PSA is below 0.5 ng/ml. It is possible to pay for PSMA-based PET scans in Germany and Australia. The newest and perhaps most accurate PSMA-based PET indicator, F(18)-PSMA-1007, is in clinical trials in Germany (see this link).

This trial is not open to men who have already had SRT, have known metastases, have had ADT within the last 3 months, or who cannot have radiation for any reason.

Monday, August 13, 2018

Salvage Radiation Dose: Decision-Making Under Uncertainty

A large, well-done, confirmed randomized clinical trial (RCT) is the only evidence that proves that one therapy is better than another. According to current consensus, this is deemed "Level 1a" evidence. But this high level of evidence is seldom available. This is especially true of prostate cancer because it takes so long to achieve acceptable endpoints like overall survival, prostate cancer-specific survival, and metastasis-free survival. Such studies are very expensive and difficult to carry out.

Alexidis et al. analyzed the National Cancer Database for men treated with adjuvant or salvage radiation therapy (SRT) after prostatectomy failure from 2003 to 2012. SRT with doses above 66.6 Gy were labeled "high dose," and SRT with doses above 70.2 Gy were labeled "very high dose." Between 2003 and 2012:

  • High dose SRT utilization increased from 30% to 64%
  • Very high dose SRT utilization increased from 5% to 11%
  • Utilization of high and very high dose rates was greatest at academic centers, lowest at community centers.

The authors decry the fact that this doubling of high dose SRT took place in the absence of RCTs that would definitively establish proof. They point out that the evidence for it is based on observational studies (see, for example, King and Kapp and Ohri et al.), which are fraught with confounding due to stage migration,  selection bias and ascertainment bias. Stage migration was the result of better imaging becoming increasingly available to rule out SRT from patients already harboring occult distant metastases. Also, three randomized clinical trials published in the middle of the observational period convinced many radiation oncologists that earlier SRT led to better tumor control than waiting. Selection bias occurred because the patients selected to get higher doses of radiation were healthier and those whose cancer was less progressed -- they would have done better regardless of the dose. Ascertainment bias resulted from the longer observational period for patients treated in 2003 vs. 2012 - the opportunity for treatment failure increases with the amount of time that has passed. The authors also doubt that biochemical recurrence-free survival (which is what was used in observational studies) is a good enough surrogate endpoint for overall survival. They are right that all these factors may be confounding the previous retrospective analyses, and the only way to know with certainty is to conduct a trial where patients are randomized to receive high or low SRT doses,  and follow patients long enough so that median survival or at least metastasis-free survival is reached in the low dose group.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened. Unfortunately, many patients were treated with three-dimensional conformal radiation therapy (3D-CRT), which had higher toxicity than the IMRT in widespread use now. Also, it uses freedom from biochemical failure (not yet reported) as its surrogate endpoint.

So, what is a patient to do in the absence of Level 1a evidence? Should he accept the higher doses with possibly added toxicity and better tumor control, or should he go for a lower dose with possibly less toxicity and less tumor control?

As a compromise, Mantini et al. recently reported 5-year biochemical disease-free survival (bDFS) and other outcomes for patients who received higher dose SRT (70.2 Gy vs. 64.8 Gy) depending on their post-operative pathology. They also may have received (depending on pathology) whole pelvic radiation and adjuvant hormone therapy. Those patients who received the higher dose had equivalent 5-yr bDFS in spite of their worse disease characteristics. Those who received only 64.8 Gy still had a 5-year bDFS as high as 92%. We do not know how many of those recurrent men with favorable disease characteristics actually needed any SRT. They were all treated with 3D-CRT and toxicity was not reported.

The other thing we can do when our information is imperfect is go through the Bradford Hill checklist. It can give us more confidence if we have to make a decision based on less than Level 1 evidence. The factors that ought to be considered are:

  • Strength of Association (larger associations are more likely (but not necessarily) causal)
  • Consistency of Data (independent studies all lead to the same conclusion)
  • Specificity (a very specific population is differentially affected)
  • Temporality (the effect has to occur after the cause)
  • Biological gradient (too some extent, more drug/radiation dose leads to more effect) 
  • Plausibility (one can come up with a plausible explanation)
  • Coherence (lab studies demonstrate a plausible mechanism for the observed effect)
  • Experiment (has the effect been prevented by modifying the cause)
  • Analogy (similar factors may be considered)


Unfortunately, the authors did not refer to Dr. King's more recent analysis of SRT dose/response, which we discussed in depth here. He looked at 71 studies, demonstrating consistency. While it is not Level 1 evidence, it is Level 2a evidence. In it, he observes that the salvage radiation dose response conforms exactly to the primary radiation dose response.  In other words, the prostate tumor is equally radio-resistant whether it is in the prostate or the prostate bed. This increases the plausibility of a dose effect of SRT. What's more, dose escalation was proven to be beneficial for biochemical recurrence-free survival, metastasis-free survival, and freedom from lifelong ADT use, for primary radiation in intermediate risk men by a RCT (RTOG 0126). So, we also have greater confidence in SRT dose escalation by analogy.

RTOG 0126 did not find an increase with higher dose in 8-year overall survival or cancer-specific survival. This calls into question whether these longer-term effects are really useful endpoints if we are to be able to obtain and use the results of any clinical trial in a reasonable time frame.

Dr. King proposed a randomized clinical trial of 76 Gy vs. 66 Gy for SRT. Meanwhile, he is routinely giving his SRT patients at UCLA 72 Gy. Dr. Zelefsky at Memorial Sloan Kettering Cancer Center and other eminent radiation oncologists have also upped the radiation dose to 72 Gy. Such doses seem to be safe and effective, but it is one of many factors in the SRT treatment decision that must be carefully considered by patients and their doctors.