Long-term adjuvant ADT improves results of brachy boost therapy in unfavorable-risk prostate cancer patients

TROG 01.03 RADAR, begun in 2003, was a  (partly) randomized clinical trial to help optimize therapy of unfavorable-risk patients. It explored such topics as use of Zometa, radiation dose escalation, and optimal duration of androgen deprivation therapy (ADT) when given along with ("adjuvant" to) radiation therapy (RT).

• Zometa did not delay progression, which is similar to the STAMPEDE trial finding among men with metastatic hormone-sensitive prostate cancer when it was used without Celebrex. 
• The external-beam radiation (EBRT) doses they explored (66 Gy, 70 Gy and 74 Gy) were below today's standard of care (78 Gy-82 Gy), so have become irrelevant to current practice. 
• The assignment to various radiation doses was not randomized. 
• The benefit of long-term ADT (28 months vs 4 months) with dose-escalated EBRT in unfavorable-risk patients was proved by the DART 01/05 GICOR trial. 

Based on the Kishan et al. study, brachy boost therapy may be the preferred treatment option for high-risk patients So we will turn our focus to the only outstanding question that this major trial can still shed light on - what duration of adjuvant ADT is necessary when unfavorable-risk patients are treated with high dose rate brachy-boost therapy (HDRBBT)?

Joseph et al. reported the 10-year outcomes of the TROG 01.03 RADAR trial conducted at 24 sites in Australia and New Zealand. From 2003 to 2007, patients were randomized on 6 vs 18 months of adjuvant ADT . There were 1,051 evaluable unfavorable-risk patients defined as:

• Stage T2b-4 or
• Stage T2a and Gleason score≥7 and PSA≥10 ng/ml
• NCCN risk groups: 31% unfavorable intermediate-risk, 66% high-risk
• Patients with positive pelvic lymph nodes (stage N1) or distant metastases (stage M1) on a bone scan/CT were excluded

The HDRBBT treatment given to 237 patients consisted of:

• 46 Gy in 23 treatments of EBRT followed by 19.5 Gy in 3 HDR brachy treatments (biologically equivalent to 88 Gy if given as EBRT-only)
• All patients received 6 months of adjuvant ADT (Lupron) starting 5 months before EBRT 
• Half were randomized to get 12 extra months of ADT (total =18 months) 
• Pelvic lymph nodes were not treated

Distant progression (radiographic progression on a bone scan/CT) was the primary endpoint. The 10-year outcomes for those receiving HDRBBT were:

• 20% distant progression (25% less than 74 Gy EBRT)
• 2% local progression (71% less than 74 Gy EBRT)
• 15% bone progression (31% less than 74 Gy EBRT)
• 9% prostate cancer-specific mortality (25% less than 74 Gy EBRT)
• 23% all cause mortality (31% less than 74 Gy EBRT)
• Distant progression was reduced by 39% by the longer ADT treatment. It was statistically significant even after adjustment for potentially confounding risk factors.
• Longer ADT was beneficial independent of RT dose, whether EBRT or HDRBBT
• 13% of men receiving HDRBBT suffered urethral strictures vs 4% of men receiving 74 Gy EBRT (for full toxicity data, see this report)
• The cumulative incidence of transition to castration resistance was significantly lower in men receiving 18 months of adjuvant ADT with RT (in an earlier report)

This establishes the importance of adding long-term (18 months) ADT for all unfavorable risk patients receiving radiation as a primary treatment. The adjuvant ADT gave better outcomes independent of the radiation dose. The Nabid et al trial proved that 18 months is as useful as 36 months in high-risk patients. But rather than slavish adherence to a single number, NCCN recommends 18 months to 3 years of adjuvant, at the discretion of the doctor.

The patient may wish to get more if:

• there are multiple high-risk features (e.g., GS9-10, PSA>20, T3/4, PNI, rare histology, genomic risk)
• there is suspicion of lymph node metastases, especially from advanced PET scans
• side effects are very tolerable

The patient may wish to get less if:

• there are lower risk features (e.g., GS 6-8, PSA<10, T2, no genomic risk)
• advanced PET scans (Axumin or PSMA) are negative
• side effects are onerous
• treatment is entirely extremely hypofractionated (HDR brachy or SBRT monotherapy)
• an additional systemic treatment (e.g., docetaxel, Zytiga, Xtandi, Erleada, or Nubiqa) is used experimentally

In an earlier observational meta-analysis (see this link), adjuvant ADT did not seem to add benefit to brachy boost therapy. This once again shows the limitation of observational studies. Only randomized clinical trials can provide the definitive proof we desire for decision-making.

Some patients think they can delay the transition to castration-resistance by eliminating or reducing the amount of ADT used with their RT. This shows that does not happen. Castration resistance is a consequence of genomic breakdown that always occurs as the cancer evolves. It may be facilitated by eliminating the hormone-sensitive cells and leaving only castration-resistant cells (this is called "competitive release"). By eliminating cancer cells as early as possible (before metastases have been detected) using HDRBBT and long-term adjuvant ADT, there is an opportunity to cure the disease. We are learning that cancer cells signal other cancer cells via extracellular vesicles to become like them. Even if it does not cure the patient, the profound reduction of the cancer load has a bigger effect on castration resistance than drug resistance does. This phenomenon was also noted in the TOAD randomized clinical trial (see this link). After there are metastases, an "evolutionary" personalized strategy (like this one) may be preferable.

Questions to ask a high dose rate (temporary implant) brachytherapist

HDR Brachy monotherapies doctor questions

1.        I assume we are talking about monotherapy only, without external beam radiation or hormone therapy – is that correct for my case?

2.       How many monotherapies have you performed? How many combined with external beam?

3.       How has your practice of HDR brachy changed over the years?

4.       What is your 5-yr freedom from recurrence rate for patients at my risk level? What proportion of your recurrences were local?

5.       What kind of urinary and rectal reactions can I expect? How long can I expect them to last? What medications or interventions do you typically give for that? Should I expect those symptoms to recur later?

6.       What is your rate of serious (Grade 3) adverse events? Do you see urinary strictures? Urinary retention requiring catheterization? Fistulas? Rectal bleeding requiring argon plasma or other interventions?

7.       What is the margin you will treat around the prostate? Is it less on the rectal side?

8.       What is the prescribed dose to the planned target volume?

9.       What is your treatment protocol? Number of insertions? Number of fractions? Dose per fraction? Can we vary those for convenience?

10.    What kind of imaging do you use for planning? MRI? CT? US?

11.      Do you increase dwell times in areas of known cancer?

12.    Do you use fiducials or Calypso transponders?

13.    In my treatment plan, what do you identify as “organs at risk” and what dose constraints do you put on them?

o    What dose will my penile bulb receive?

o    How do you limit urethral dose? (e.g., catheter)

14.    How long does each treatment take?

15.     How will I be immobilized/anesthetized during each treatment? What kind of analgesia is used?

16.    Are there any bowel prep or dietary requirements?

17.     Should I avoid taking antioxidant supplements?

18.    In your practice, among men who were fully potent, what percent remained fully potent 3-5 years later?

o    Have any men retained some ability to produce semen?

o    What is your opinion of taking Viagra preventatively?

19.    Do you monitor side effects with the EPIC questionnaire?

o    In your practice, what percent of men experience acute urinary side effects?

o    In your practice, what percent of men experience acute rectal side effects?

o    In your practice, what percent of men experience late term urinary side effects?

o    In your practice, what percent of men experience late term rectal side effects?

20.   What kind of PSA pattern should I expect following treatment?

21.    What is the median PSA nadir you are seeing in your practice, and how long does it take to reach that, on the average?

22.   In your practice, what percent of men experience biochemical recurrence?

o    What % of those have been local?

o    If there should be a biochemical (PSA) recurrence, what would the next steps be?

o    Have you ever used SBRT, brachy, or cryo for salvage after a local HDR brachy failure, and was that focal or whole gland?

23.   Are you open to email communications between us?

Why did biochemical control not translate into a survival increase after brachy boost therapy?

The first randomized clinical trial to prove that brachy boost (BB) therapy had better oncological outcomes among high risk patients was Sathya et al. (2005). After 5 years, 36% of those high-risk patients who received the brachy boost had a PSA recurrence vs. 66% of those who received external beam radiation (EBRT) only. In an update, the authors report that overall survival was not significantly different in the two groups. This seems to call into question whether PSA recurrence is a useful surrogate endpoint for survival, or if it is, under what circumstances?

Dayes et al. provided a 14-year median update on the original study and added further comments in this "Beyond the Abstract" essay. The 104 patients in the original study who were treated between 1992 and 1997 had the following characteristics and treatments:

• Median age was 66
• 60% were high risk, 40% intermediate risk
• All had a negative pelvic lymph node dissection, negative bone scan and CT
• Brachy boost (BB) comprised 35 Gy of Ir 192 over 48 hours plus 40 Gy of EBRT in 20 fractions for a total of 75 Gy [sic].
• EBRT-only compromised 66 Gy delivered in 33 fractions using 2DRT (an outmoded external beam technology).
• None received androgen deprivation as part of their radiation therapy, nor afterwards unless PSA reached 20 ng/ml.

As of the update on the 104 patients (with only 5 lost to follow-up):

• Mortality from any cause was 67% among the BB patients, 77% among the EBRT-only patients -- not significantly different
• Prostate cancer-specific mortality was 18% among the BB patients, 23% among the EBRT-only patients - not significantly different
• Incidence of metastases was 20% among the BB patients, 28% among the EBRT-only patients - not significantly different
• Improvement in PSA control was maintained: 47% higher rate of biochemical recurrence-free survival among the BB group

There was a biopsy given 2 years after treatment to 87 of the 104 men in the original study

• In the BB group, 24% had a positive biopsy and 6% were metastatic
• In the EBRT-only group, 51% had a positive biopsy and 6% were metastatic

The authors conclude:

Despite ongoing benefit with respect to biochemical disease control, long term follow up out to 2 decades failed to demonstrate improvements in other important outcomes such as development of metastatic disease, deaths from prostate cancer and deaths from any cause. 

Increased biochemical (PSA) control usually translates into increased survival later on. That correlation is well-characterized. So why did it not in this case?

This study, with a sample size of only 104 (51 BB, 53 EBRT-only), was not large enough to detect statistically significant survival differences. We note that directionally there was an improvement in survival even though the difference wasn't big enough for 95% confidence. Also, 40% were intermediate risk patients who are slower to have detectable metastases and are more likely to die of other causes. By contrast, the ASCENDE-RT trial of LDR brachy boost therapy recruited 398 men, 30% were intermediate risk, and may eventually be able to demonstrate overall survival differences with longer follow-up.

We have to acknowledge that the doses delivered in this study were below what is now considered curative, and the findings here are to a large extent irrelevant. I am at a loss to explain how a hot iridium implant could be left in a patient for 48 hrs without doing serious damage or cooking the prostate to a crisp.  Perhaps they used cooler implants back then.  I can only trust that Dr. Sathya is correct in not making a correction for the lack of fractionation, which would be typical. It seems the BB dose was sub-optimal as demonstrated by the fact that in a quarter of men, the cancer was left alive in the prostate. EBRT-only was worse - leaving cancer alive in the prostates of twice as many men. Although they dissected some pelvic lymph nodes that they could find, we now know that even with improved modern lymph node detection methods, we miss 44% of positive lymph nodes (see this link). The 6% who were metastatic might have been caught with some of our new PET scans. So, in both groups, there was a lot of cancer left behind. Many high-risk radiation patients today would have had whole-pelvic radiation and would have had hormone therapy for up to two years. This highlights the importance of expanding the treated area, using escalated doses, and adding systemic therapy when the probability is high that the cancer might have escaped the prostate.

Even though BB wasn't curative for many high risk patients, it is disappointing that death was not delayed by reducing the tumor burden. There are several clinical trials of treating the prostate (with surgery or radiation) even after metastases have been detected, thereby hoping to prolong survival by reducing the load of cancer cells. Metastasis-directed radiation is sometimes given in this hope as well. Both of those therapies decrease PSA, at least temporarily. But only treating PSA serves no purpose if that is the only outcome. If this study is any indication, the cancer will catch up and replace the killed cells with no net survival benefit. I hope that is not the case.

Revised ASCO/CCO brachytherapy guidelines

The publication of the ASCENDE-RT clinical trial (discussed here) has led to a revision in the brachytherapy guidelines (available here) issued by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO). The guidelines are for patients who choose radical therapy rather than active surveillance. They based their guidelines only on randomized clinical trials that included brachytherapy as an option.  They exclude high dose rate brachytherapy (HDR-BT) as a monotherapy because it has not been proven in a randomized clinical trial.

Their guidelines suggesting which therapies are suitable are stratified by patient risk level:

Low Risk

• Low dose rate brachytherapy (LDR-BT) alone
• External Beam Radiation Therapy (EBRT) alone, or
• Radical prostatectomy (RP)

Intermediate Risk

For favorable intermediate risk patients (no Gleason score> 3+4, no more than half the cores positive, PSA<10, and stage<T2b):

• LDR-BT alone

For other intermediate risk patients:

• EBRT with or without androgen deprivation therapy (ADT) and a brachy boost (LDR-BT or HDR-BT) to the prostate.

High Risk:

• EBRT and ADT and a brachy boost (LDR-BT or HDR-BT)

They make the following qualifying statements:

• Patients should be counseled about all their management options (surgery, EBRT, active surveillance, as applicable) in a balanced, objective manner, preferably from multiple disciplines.
• Recommendation for low-risk patients is unchanged from initial guideline, because no new randomized data informing this question have been presented or published since.
• Patients ineligible for brachytherapy may include: moderate to severe baseline urinary symptoms, large prostate volume, medically unfit, prior transurethral resection of the prostate, and contraindications to radiation treatment.
• ADT may be given in neoadjuvant, concurrent, and/or adjuvant settings at physician discretion. It is noted that neoadjuvant ADT may cytoreduce the prostate volume sufficiently to allow brachytherapy
• There may be increased genitourinary toxicity compared with EBRT alone.
• Brachytherapy should be performed at a center following strict quality-assurance standards.
• It cannot be determined whether there is an overall or cause-specific survival advantage for brachytherapy compared with EBRT alone, because none of the trials were designed or powered to detect a meaningful difference in survival outcomes.

Neither the patient nor the doctor should take these to be their only options. ASCO/CCO only included options for which there is Level 1 evidence; that is, evidence from  randomized comparative clinical trials. Patients, doctors and insurance providers should make treatment decisions based on the full array of available clinical data, understanding that higher level evidence carries more weight.

Less treatment regret with SBRT and when patients are fully informed at UCLA

There is growing recognition that the patient's satisfaction or regret with his treatment decision is more than just a matter of whether he is happy with the oncological outcome. Satisfaction/regret is the product of many variables, including how well he understood his options, his interactions with his doctors, the side effects he suffered and when he suffered them, his expectations about the side effects of treatment, and cultural factors.

Shaverdian et al. explored the issue of treatment regret with patients treated at UCLA with three kinds of radiation therapy: Intensity Modulated Radiation Therapy (IMRT), Stereotactic Body Radiation Therapy (SBRT), and High Dose Rate Brachytherapy (HDR). Questionnaires were sent to 329 consecutive low or favorable intermediate risk patients treated from 2008 to 2014 with at least one year of post-treatment follow-up. There was a high (86%) response rate. The number of responses were:

• IMRT -  74 patients
• SBRT - 108 patients
• HDR  -   94 patients

Patient characteristics were similar across treatments. The only significant differences were:

• HDR patients were a median of 5 years younger
• IMRT patients disproportionately African- American and Asian-American
• Length of follow-up was longer for IMRT patients
• HDR patients were more likely to be taking medication for erectile dysfunction.

Decision-making process

Those that chose IMRT spent less time making their decision. The percent that spent less than a month making their decision was:

• IMRT: 47%
• SBRT: 31%
• HDR:  12%

Although most patients felt they had learned enough about the treatment options before making their decision, those who chose IMRT were least likely to say so:

• IMRT: 83%
• SBRT: 91%
• HDR: 86%
• 11% of the IMRT patients wished they had learned more about active surveillance.

There was widespread agreement that they had worked mutually with their doctors to arrive at a decision.

• IMRT: 85%
• SBRT: 91%
• HDR: 84%

Treatment regret

The percent who felt that they would have been better off with a different choice was least for SBRT:

• IMRT: 19%
• SBRT: 5%
• HDR: 18%
• This rate of treatment regret for IMRT and HDR is similar to the rate expressed for surgery (see this link).

Of those who expressed treatment regret, the biggest reason for it (36%) was because they could have had better sexual function. 72% of those with treatment regret would have chosen active surveillance if they had it to do over again.

 
After correcting for patient characteristics, the factor most associated with treatment regret was whether they had learned enough about other treatments. Those with treatment regret were 53 times as likely (odds ratio) to say that they had not learned enough. The next biggest factor predicting treatment regret was whether the long-term side effects were worse than expected (odds ratio = 42). Expectations and the disappointment of those expectations have a large impact on treatment regret. Those who chose IMRT were 11 times more likely to have treatment regret than those who chose SBRT, and those choosing HDR were 7 times more likely to experience treatment regret compared to SBRT. The table below shows the odds ratio for all statistically significant factors.

	Relative impact on treatment regret  (odds ratio)
Decision-Making Factors
Learned enough about treatments	53
Mutually worked with physicians	16
Doctors fully informed me	11
Side Effects
Short-term side effects worse than expected	8
Long-term side effects worse than expected	42
Bowel function	8
Sexual function	5
Urinary function	5
Treatment
IMRT vs SBRT	11
HDR vs SBRT	7
HDR vs IMRT	1

While IMRT was the highest cost treatment, it also gave the lowest value to the patient. Conversely, SBRT, the lowest cost treatment, provided patients with the highest value. To increase value to patients, doctors must assure that patients are fully informed about all their treatment options, and the side effects that they may reasonably expect. Patients should be encouraged to take their time investigating options, especially active surveillance.

All patients in this study were treated at UCLA, which has a policy of fully informing patients of all their options and expected outcomes. It is impossible to entirely separate the effect of superior patient counseling on the part of the physician from the superior treatment outcomes as the reasons for increased patient satisfaction. Perhaps if this questionnaire were used across multiple institutions those effects could be distinguished. Because UCLA is a nationally-renowned tertiary care center, these results are not at all applicable to what goes on in the community setting. If expanded, we would like to see comparisons with other treatment modalities: surgery (robotic and open), low dose rate brachytherapy, active surveillance, proton beam therapy, hypofractionated IMRT, and focal ablation therapies. It would also be instructive to compare the value attached to adjuvant treatment modalities (e.g., brachy boost therapy and hormone therapy) given to patients with more advanced disease and in the salvage setting. It is a good start, however, and provides a validated questionnaire by which treatment centers can assess their performance and set goals for improvement. We would love to see this "report card" expanded nationally.

Questionnaire

For those who have been treated and would like to see how your treatment falls on the treatment regret questionnaire, I've copied it below. It may also be useful for those who have not yet been treated to help assure you minimize your treatment regret.

Prostate Cancer Patient Voice Questionnaire

This questionnaire is designed to better evaluate your treatment experience so that we can continue to improve the quality of the care we provide. To help us get the most accurate measurement, it is important that you answer all questions honestly and completely.

Name: _______________________________________

Today’s Date (please enter date when survey completed): Month ________ Day_______ Year________

Question 1:
What is the highest level of education you have received? 
a) Less than high school
b) Graduated from high school
c) Some college
d) Graduated from college 
e) Postgraduate degree

Question 2:
How much time did you think about your diagnosis and treatment options before deciding on your treatment?
a) Less than 1 month 
b) 1-2 months
c) 2-4 months
d) 4-6 months
e) Over 6 months

Question 3:
Do you believe you learned enough about the different treatment approaches for treating prostate cancer before undergoing treatment? (circle all that apply)

1. a)  Yes
   
2. b)  No, I wish I had learned more about intensity
   modulated radiation therapy (IMRT)
   
3. c)  No, I wish I had learned more about stereotactic body
   radiation therapy (SBRT)
   
4. d)  No, I wish I had learned more about brachytherapy
5. e)No, I wish I had learned more about active surveillance
6. f) No, I wish I had learned more about surgical treatments
7. g) Other (please specify): _______________________ ___________________________________________

Question 4:
How true or false has the following statement been for you? “I felt that I worked with my doctors to mutually decide on the best treatment plan for me.”
a) Definitely false
b) Mostly false
c) Neither true nor false 
d) Mostly true
e) Definitely true

Question 5:
During the past 4 weeks, how much of the time have you wished you could change your mind about the kind of treatment you chose for your prostate cancer? 
a) None of the time 
b) A little of the time 
c) Some of the time 
d) A good bit of time 
e) Most of the time

f) All of the time

Question 6:
How true or false has the following statement been for you during the past 4 weeks?
“I feel that I would be better off if I had chosen another treatment for my prostate cancer.”
a) Definitely false
b) Mostly false
c) Neither true nor false 
d) Mostly true
e) Definitely true

Question 7:
If you do have regret about your treatment, which one of the following most accurately describes the reason why you have regret?

1. a)  I could have had fewer urinary symptoms with another treatment.
   
2. b)  I could have had fewer rectal symptoms with another treatment.
   
3. c)  I could have had better sexual function with another treatment.
   
4. d)  I could have had a less costly treatment.
   
5. e)  I could have had another more effective treatment.
   
6. f)  I could be better off now without having had any active treatment.
   
7. g)  Other (please specify): _______________________ ___________________________________________
   

Question 8:
If you do have regret about your treatment, which one of the following most accurately describes the treatment you now wished you had received?

1. a)  I would rather have had surgery (robotic or open prostatectomy).
   
2. b)  I would rather have had stereotactic body radiation therapy (SBRT).
   
3. c)  I would rather have had Brachytherapy.
   
4. d)  I would rather have had Intensity Modulated Radiation Therapy (IMRT).
5. e) I would rather have gone forward without active treatment (Active Surveillance).
6. f) Other (please specify):__________________________________________________________________

Question 9: 
This question asks about the short-term side effects. While undergoing treatment, were the short-term side effects you actually experienced less than or more than you had originally expected?
a) The side effects I actually experienced were exactly as I had expected.
b) The side effects I actually experienced were significantly less than I had expected. 
c) The side effects I actually experienced were slightly less than I had expected.
d)  The side effects I actually experienced were slightly more than I had expected.
e)  The side effects I actually experienced were significantly more than I had expected.

Question 10: 
This question asks about the long-term side effects. After completing treatment, were the long-term side effects you actually experienced less than or more than you had originally expected?

1. a)  The side effects I actually experienced were exactly as I had expected.
   
2. b)  The side effects I actually experienced were significantly less than I had expected.
   
3. c)  The side effects I actually experienced were slightly less than I had expected.
   
4. d)  The side effects I actually experienced were slightly more than I had expected.
   
5. e)  The side effects I actually experienced were significantly more than I had expected.
   

Question 11:
How strongly do you agree or disagree with the following statement? 

“Based on my experience, I believe my doctors fully informed me about possible side effects before I started treatment.”
a) Strongly disagree
b) Disagree
c) Neither agree nor disagree 
d) Agree
e) Strongly agree

Question 12:
Overall, how big a problem have your urinary, bowel, and sexual functions been for you during the last 4 weeks? (circle one number on each line) 

             (0) No problem  (1)Very small problem (2)Small problem  (3)Moderate problem (4)Very big problem 
Urinary function  0 1 2 3 4 
Bowel function    0 1 2 3 4 
Sexual  function   0 1 2 3 4 

note: Thanks to Dr. King for allowing me to review the full text.