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.

I-131-MIP-1095, a new radiopharmaceutical, in clinical trials at Memorial Sloan Kettering

There are few radiopharmaceuticals in clinical trials in the US (there are several in use in Germany), so when a new one is announced, we take notice. I-131-MIP-1095 has had a very limited clinical trial in Germany in 28 patients, and will now be tried in the US.

Like Lutetium 177, Iodine 131 is a beta particle emitter (see this link). It's beta particle energy is somewhat higher, so that it can penetrate greater distances through tissue - up to 3.6 mm, compared to 1.9 mm for Lu-177. This is an advantage in that it can destroy larger tumors, but it is a disadvantage in that it may destroy more healthy tissue, causing hematological and renal side effects. It is also similar to Lu-177 in that its uptake in human tissues can be detected using a gamma ray camera or SPECT detector. Because gamma ray detection does not afford the image quality that PET/CT does, it may be combined with a positron emitter, I-124. Lu-177 is sometimes combined with Ga-68 for the same purpose. This combination of therapeutic and diagnostic (sometimes called theranostic) may be useful in tailoring the dose to the patient based on individual uptake characteristics.

The molecule (or ligand) that the I-131 is attached to is MIP-1095. MIP-1095 is attracted to the PSMA protein on the surface of 95% of prostate cancer cells. Although it is highly specific for prostate cancer, there are other tissues that express PSMA, especially the salivary glands and lacrimal glands. It is excreted by the liver and kidneys, and may show up in the intestines, and the lower urinary tract. The dose to the kidneys may limit the amount of the pharmaceutical that may be given to the patient.

A group from the University Hospital Heidelberg, Zechman et al., treated 28 metastatic castration-resistant patients with I-131-MIP-1095 with the following results:

• In 61%, PSA was reduced by >50%. This is better than the response seen with Lu-177-PSMA-617 in these trials and in this one.
• PSA decreased in 21 of 25 patients, increased in 4.
• 85% had complete or moderate reduction of bone pain. 
• 25% had a transient slight to moderate dry mouth, which resolved in 3-4 weeks.
• White blood cell count, red blood cell count and platelets declined during treatment, but there were only 3 cases of grade 3 hematologic toxicity, often in patients with low blood counts at baseline.
• No renal toxicity was observed.
• The effective dose to cancer cells was higher than for Lu-177-PSMA-617, red marrow and kidney doses were similar, and liver dose was lower.

The clinical trial that is now recruiting at Memorial Sloan Kettering, is a Phase 1 trial to find the best dose of I-131-MIP-1095 among patients with metastatic castration-resistant prostate cancer. Doses will be administered 12 weeks apart for up to 5 cycles or until dose-limiting toxicity is observed (monthly assessments). Interested patients in the New York City metropolitan area should call the contacts listed on the bottom of this trial description.

We're still not very good at finding cancerous pelvic lymph nodes

(Updated)

Pelvic lymph node (PLN) detection is important because it is one of the first places prostate cancer travels to after leaving the prostate or prostate bed. Cancer cells in the interstitial fluid of the prostate drain out into sentinel LNs and then into many other LNs. The LNs act like filters, catching the errant cancer cells. Sometimes the white blood cells surround and destroy the cancer cells, but sometimes the cancer changes the white blood cells and lymph node tissue, creating a microenvironment that is more hospitable to cancer cells implanting themselves there and growing. It can take years for enough cancer cells to create such a hospitable habitat and grow to a size that can be detected with a scan. When it is detected there, it is called stage N1, and is called "locally advanced." In some cases, prostate cancer may still be cured if it is locally advanced. The standard ways of detecting cancerous pelvic lymph nodes (PLN) are via surgical removal or radiographic detection. Neither is very good.

CT Scan

The standard of care for detecting positive LNs is a pelvic CT scan with contrast. (Sometimes MRIs are used for this with no advantage other than billing for the hospital.) This is often done the same day as a bone scan for high risk patients. The CT detects the size of LNs, and suspicion of cancer is as follows:

• < 8 mm: not suspicious
• 8-11 mm: gray area
• ≥ 12 mm: suspicious

The problem with detection by size is that many small LNs may harbor cancer, and enlarged LNs may be enlarged due to infection or due to inflammatory processes in nearby cells. The problem with CT detection is that it's possible for a LN with cancer to be small, and the cytokines released by it to enlarge a nearby LN that does not bear any cancer. While a biopsy of an enlarged node may be difficult to perform, enlarged nodes that shrink with androgen deprivation is a sure sign that cancer was causing the enlargement.

Patients with fewer and smaller positive LNs have longer survival, so if the patient wants treatment for N1 prostate cancer, whether local or systemic therapy, it is best to use an alternative method of detection.

USPIO MRI

Ultra-small paramagnetic iron oxide (USPIO) particles accumulate in healthy LNs more than in cancerous LNs. The particles and their lack can be detected in LNs using MRI. Combidex (ferumoxtran) is a brand of USPIO that is now available for this purpose, but only at Radboud University in Nijmegen, The Netherlands. It can detect positive LNs with a diameter as small as 2 mm in some cases (see this link). It is better than a C-11 Choline PET scan, which has a size limit of 6 mm. (Update 2/7/23) Fortuin at al. reported on a new trial there comparing PSMA PET/CT to USPIO with MRI.  In the same 45 patients, all with high risk of cancerous LNs (before primary therapy or recurrent):

• PSMA PET/CT found 71 suspicious LNs in 25/45 (55%) patients -2.8 per patient
• USPIO w/ 3T MRI found 160 suspicious LNs in 33/45 (73%) patients - 4.8 per patient
• MRI only missed 19 of the PSMA-detected LNs, but found over twice as many, and upstaged ⅓ more patients

In 20 patients, they used a 7T MRI and found:

• 115 suspicious LNs in 17/20 (85%) patients - 6.8 per patient
• 91% were smaller than 5 mm (the PSMA PET/CT size limit)
• 63% were smaller than 3 mm (the 3T MRI size limit)

Most of the suspicious LNs were outside of the surgical pelvic LN dissection area.

The outstanding question is: what is the value of detecting every last cancerous LN?

PET/CT or PET/MRI

As we've seen, the currently best PET scan is the DCFPyL PET/CT, which has been approved in the US for high-risk and recurrent patients. Tumor to background ratios may be especially better than the Ga-68-PSMA PET/CT scans. DCFPyL detected 30% more positive LNs in the same patients. It has high specificity (95%) but low sensitivity (~ 40%). The Axumin (fluciclovine) PET/CT is less accurate (see this link). PET/MRIs, now available at a handful of US institutions will provide greater accuracy. Detection of small metastases (< 5 mm) is unproven even in the best of these scans.

Meredith et al. reported on 532 patients diagnosed with the Ga-68-PSMA  PET/CT after PSA recurrence following initial treatment with prostatectomy (425 patients) or RT (107 patients).

• Among those treated with primary prostatectomy, positive lymph nodes were detected in 68%.  
• Among those treated with primary RT, positive lymph nodes were detected in 40%.

(Update 11/14/17) Schmidt-Hegemann et al. reported on 129 patients diagnosed with the Ga-68-PSMA PET/CT:

• 20 patients were scanned before initial RT treatment
• 49 patients were scanned after PSA recurrence after prostatectomy
• 60 patients were scanned after PSA persistence after prostatectomy (PSA never became undetectable)

Positive pelvic lymph nodes were detected in:

• None in the pre-initial treatment group
• 16% in the PSA-recurrent group
• 33% in the PSA-persistent group
• Detection rates were about the same in patients with PSA< 0.05 ng/ml

Multiparametric MRI (mpMRI)

Multiparametric MRI is more specific than CT, but is no more sensitive at detecting positive LNs. In one study, only 57% were correctly staged with a DW-MRI.

Surgical pelvic lymph node dissection (PLND)

Surgical removal, or PLND, is usually performed at the same time as a prostatectomy. The surgeon looks for about 5-10 PLNs and removes them for pathological analysis. In the US, this isn't done routinely by most surgeons because it is usually negative (only about 5% of prostate cancer patients have PLN invasion when first diagnosed), there are often false negatives, and there are risks of lymphocele and lymphedema from it. There are two indicators that it may be advisable to perform a PLND:

1. Risk of PLN invasion is greater than 2% (or 2.6%) on a validated nomogram like this one based on PSA, Gleason score and stage, or,
2. Enlarged PLNs have been detected with CT or MRI

(Note: This recent nomogram based on European patients recommends ePLND when the risk of PLN invasion is at least 7%)

When cancer is found, sometimes wider removal of as many as 30 PLNs is performed, called extended PLND or ePLND. The hope is to find more infected LNs and remove them, all of them if one is lucky, but the ability to control cancer using ePLND is controversial and the subject of clinical trials. ePLND is difficult because LNs are nearly invisible, small, and difficult to find, obscured by more colorful tissue and sometimes hidden in the visceral fat. Unlike blood vessels, which branch out, lymph vessels are networked. ePLND yield may be increased by injecting a fluorescent liquid, called indocyanine green, into the prostate and letting it drain through the lymph vessels. Even so, this missed 24% of sentinel PLNs in one study. A magnetometer that finds iron oxide particles that accumulate in lymph nodes has been tried intraoperatively (see this link). Radiotracers that consist of a gamma emitter (Indium 111 or Technetium 99m) attached to a PSMA ligand have also been used intraoperatively for this purpose in some recurrent cases (see this link) . PET scans may be used to detect some of the larger nodes to be removed. ePLND is a more common practice in Europe than in the US.

Even the most thorough ePLND misses positive PLNs. In one recent study, almost a quarter of positive LNs would have been missed even if ePLND had been used. Metastases don't just stick in sentinel LNs (the first ones that drain from the prostate). This is unlike breast cancer, for example. Cancer may accumulate in a LN without being detectable in all the LNs upstream from it.

The definition of the PLN field  of whole pelvic radiation as defined by a consensus of radiation oncologists missed 44% of the positive LNs, in this study. A study of LN failures after whole pelvic radiation therapy found that more than half had a failure above the treated area.

Clearly, there is no imaging modality that will find all metastatic cells in the PLN area. Failure of either ePLND or whole pelvic radiation to adequately treat the pelvic LNs that are most likely to be positive is problematic. As the coverage/dissection area expands, so does the risk of side effects. Lymphedema and lymphocele may result from ePLND. Late-term damage to the upper bowel is a risk of increasing the radiation field (see this link).

Such risks must be balanced against the evidence for benefits of treatment. The success of pelvic radiation in various settings was discussed here, and early results from the STAMPEDE clinical trial among N1 patients are encouraging.

Is once ever enough?

When Jeff Demanes at the California Endocurietherapy Center, then in Oakland, CA, started doing high dose rate brachytherapy (HDRBT) as a monotherapy (i.e., without any additional external beam therapy or hormone therapy), he arbitrarily chose a treatment schedule of 42 Gy delivered in 6 treatments or fractions. The first 3 fractions were given in one overnight hospital stay after a single insertion of the catheters, which stayed in place for all 3 fractions. Then the whole process was repeated a week later. At the same time, Alvaro Martinez, then at William Beaumont Hospital in Detroit, MI, arbitrarily chose 38 Gy in 4 fractions (twice a day for two days). Although the biologically effective dose (BED) is somewhat higher for the 4-fraction schedule, they had equally excellent oncological and quality-of-life outcomes. This established that prostate cancer responded to fewer larger doses (hypofractionation) -- an intrinsic quality of the cancer, called a low alpha/beta ratio.

Over the years, alternative treatment schedules that might be more convenient for patients were tried. Last year, we saw that 27 Gy delivered in 2 fractions afforded equivalent outcomes to a high fraction schedule (see this link). Several new studies show that HDRBT can be delivered in just a single fraction without causing any extra side effects for the patient. A single fraction translates to a much lower cost treatment, with the added convenience of no prolonged hospital stays, less time under anesthesia, and quicker recuperation. It also means that a patient can travel to a central location for a one-day treatment with no costs incurred for hotels, and without taking a week off from work.

Morton et al. at Sunnybrook Cancer Center in Toronto randomized 170 low- and intermediate-risk patients to either the one- or two-dose schedule. With median follow-up of 20 months, they reported:

• Acute grade 2 urinary toxicity: 51%; grade 3 in one patient
• No significant difference between the 1- and 2-dose schedule
• Acute grade 2 rectal toxicity: 1%
• Chronic grade 2 urinary toxicity: 31%; grade 3 in one patient 
• No significant difference between the 1- and 2-dose schedule
• Chronic grade 2 rectal toxicity: none
• There was no grade 3 rectal toxicity.
• Grade 2 ED rates were 29% for the 2-fraction arm, 11.5% for the single fraction arm.
• Sexual domain scores on the EPIC questionnaire declined by twice as much in the 2-fraction arm.

(note: physician-reported toxicities may be higher when patients are probed about specific issues using the EPIC questionnaire.)

(Update 11/16/2017) In an update, 8 of the 87 (9%) of the patients treated with a single fraction were found to have a local recurrence, and 7 of those 8 patients still had cancer in exactly the same place that was treated initially, and it was more aggressive than the initial Gleason score. Close inspection of the treatment plan showed that the dose received in that place was very high. While the authors conclude that the dose needed to be even higher, I believe it is more likely that the degree of fractionation was inadequate for the reasons explained below (cancer cells in the "S-phase" of mitosis and hypoxia).

(Update 9/15/2020) In a longer-term update of the same trial, a third suffered biochemical failure within 5 years, and 78% were biopsy-confirmed local failures. They also held a trial among 60 patients who received a single fraction of HDR brachytherapy but with a focal boost of at least 23 Gy to the largest prostate tumor. Those patients fared no better.

(Update 3/12/2021) Gomez-Itturiaga et al. reported the results of 44 low and intermediate-risk patients treated with a single 19 Gy fraction of HDR brachytherapy. After 4 years of median f/u, 14 patients (32%) experienced biochemical relapse, and 11 were confirmed to have relapsed in the dominant lesion. 

Hoskin et al. at Mt. Vernon Hospital, Middlesex, UK treated 165 patients: 115 with the 2-dose schedule, 24 with a single 19 Gy dose, and 26 with a single 20 Gy dose.

• At two weeks after treatment, severe prostate/urinary symptoms were higher among those who received the 20 Gy dose.
• Acute catheter use was higher among those getting a single dose (21% and 29% for 19 Gy and 20 Gy, respectively) compared to those receiving the split dose (3%)
• By 12 weeks after treatment, all scores were at baseline or better.
• Acute grade 3 urinary symptoms occurred in about 9% of patients.

Update: Hoskin et al. updated their study:

• 4-year biochemical recurrence-free survival was no different for the single fraction group (94%)
• Late term serious side effects were 2% urinary and none for rectal

Prada et al. reported on 40 low- and intermediate risk patients treated in Spain with a single 19 Gy fraction. They also all received a hyaluronic acid rectal spacer. With 19 months of median follow-up:

• There was no acute or chronic grade 2 or higher urinary or rectal toxicity
• Biochemical control at 32 months was 100% for low risk patients, and 88% for intermediate risk patients.

In an update on 60 patients, they reported that 6-year biochemical control was only 66%.

Siddiqui et al. treated 68 low and intermediate-risk patients at William Beaumont Hospital with a single dose of 19 Gy using HDRBT. With median follow-up of 3.9 years, the outcomes were as follows:

• Acute grade 2 urinary toxicity: 12.1%
• Acute grade 2 rectal toxicity: none
• Chronic grade 2 urinary toxicity: 14.7%
• Chronic grade 2 rectal toxicity: 3%
• There was no grade 3 toxicity.
• They did not report ED rates.
• 5-year disease-free survival: 77%
• 5-year biopsy-proven local failure:19%

The authors conclude:

Higher than expected rates of biochemical and local failure, however, raise concerns regarding the adequacy of this dose. Additional investigation to define the optimal single-fraction HDR brachytherapy dose is warranted, and single-fraction treatment should not currently be offered outside the context of a clinical trial.

(Update 11/23/2019) Barnes et al. reported the outcomes of a single 19 Gy fraction on 28 patients who were primary low-risk (14), and favorable intermediate-risk (10). After 2 years of median follow-up:

• 3-yr biochemical failure-free survival was 81%
• Acute grade 2 urinary toxicity=18%; grade 3 urinary=4% (1 case)
• Late-term grade 2 urinary toxicity= 18%; none grade 3
• No grade 2 or higher rectal toxicity, acute or late-tern

In addition to patient convenience, there is another reason that toxicity may be lower with a single dose: every time the patient moves between fractions, the catheters are dislocated into a slightly different position. Such movement puts radiation in areas that were not part of the pre-treatment simulation, so that organs at risk (e.g., bladder, rectum, and urethra) may receive a higher dose than planned. Use of fiducials and cone-beam CT between each fraction can mitigate this effect.

The sexual side effects deserve closer scrutiny; but otherwise, so far, so good. So why not just treat all patients with one dose of 19 Gy? For that matter, why not do that with SBRT? That would only entail a single painless, anesthesia-less short treatment - one and done, why not?

Radiobiological reasons for fractionation

The big outstanding question is whether cancer control will be as good with a single dose. At 10 years after treatment, Demanes reported biochemical control of 99% among low-risk patients, and 95% among intermediate-risk patients using his 6-fraction regimen. Most of the above studies of single-fraction HDRBT had only had very short follow-up. The longest follow-up was the Prada et al. update, which showed that after 6 years, biochemical control was only 66%.  However, the 4-year Hoskin et al. update showed biochemical control at 94%. It's unclear why those two studies would be so different. The William Beaumont Hospital trial of single dose HDRBT already had 7% biochemical failures at 3 years, and the Washington University study found a 19% failure rate at  3 years. Is this just patient selection, or does it reflect a failure of the treatment?

It's worth reviewing the reasons why fractionated radiation can fail; it's called the 5 R's of radiobiology: repopulation, repair, redistribution, re-oxygenation, and radioresistance.

Repopulation doesn't apply when cancer is slow-growing as prostate tumors are. It is a consideration for rapidly growing tumors, like head and neck cancers. In such cancers, ablation of some tumor tissue may actually speed up the growth of the rest. Very frequent treatments (hyperfractionation) is needed in such cases.

Repair refers to the fact that the cancer that was not lethally damaged can re-grow between treatments and even during treatments. This may be a problem for low dose rate brachytherapy because the prolonged damage may be sublethal. Some researchers in Sweden recently questioned whether the relatively long CyberKnife treatments (which may take an hour per fraction) may allow for some to occur during each treatment. (This concern would not apply to SBRT delivered on other platforms or to HDRBT.)

Redistribution refers to cell cycles that cancer cells go through as they duplicate their DNA and divide in a process called mitosis. One phase of the cell cycle, called the S-phase, is where DNA repair and replication occurs. Cells are less sensitive to the lethal effects of radiation during the S phase, and some portion of cancer cells are in the S-phase at any given moment. Fractionation increases the odds that cancer cells will not be in the S-phase across all the times radiation hits them. With a single dose, the odds of some cells being in a radioresistant phase are higher.

Re-oxygenation refers to the fact that oxygen is required for radiation to kill cancer cells. Tumors are relatively hypoxic (low oxygen environments) compared to healthy tissue, because their blood supply is often malformed and leaky. This means that cancer cells in the center of a large tumor may lack the oxygen needed for radiation to kill them. With each fraction, the radiation kills the cells at the surface of the tumor that may have a better blood supply. And with repeated fractions, layers of surface cells are stripped away until the tumor is gone. A single dose may not be optimal when the index tumor is large.

Radioresistance means that some kinds of cells, particularly those that don't replicate quickly, like nerves and muscle, are inherently less subject to lethal radiation damage. Like many slow-growing tissues, prostate cancer is known to be radioresistant. That's why dose escalation has been necessary to cure it. 19 Gy in a single dose actually exceeds the biologically effective dose of 42 Gy in 6 fractions, so it is probably more than enough to overcome any radioresistance.

It may not be feasible to deliver 19 Gy in one fraction to every patient. Because of variations in individual pelvic anatomy, visceral fat and prostate size, a large single dose may violate the dose constraints for organs at risk.

It will be a few more years before the above clinical trials have matured enough to tell us whether the single dose treatment is adequate for the job. Until then, it is prudent to use a fractionated treatment schedule.

Can brachytherapy spread prostate cancer?

In an earlier commentary (see this link), we looked at the available evidence that invasive procedures, including surgery, biopsy, and brachytherapy, could spread prostate cancer. There have been very few cases reported where it is likely that brachytherapy has spread prostate cancer: 5 cases from seeds migrating to the lungs (see this link), and one case where a catheter probably spread the cancer to the bladder wall during high dose rate brachytherapy (see this link).

Tsumura et al. report the results of their study to determine whether circulating tumor cells (CTCs) were dislodged from the prostate into systemic circulation by brachytherapy. They took blood samples from 59 patients before and immediately following brachytherapy.

• 30 patients were treated with a combination of hormone therapy, external beam radiation, and high dose rate brachytherapy (HDRBT) for high risk or locally advanced prostate cancer.
• 29 low- and intermediate-risk patients were treated with low dose rate brachytherapy (LDRBT) as a monotherapy.

The blood samples were analyzed using CellSearch technology. They found that:

• None of the samples taken before brachytherapy had any CTCs
• CTCs were detected immediately after brachytherapy in 7 patients (11.8%), 13.3% among LDRBT patients, 10.5% among HDRBT patients.
• There was no statistically significant association with risk category, clinical stage, tumor volume, Gleason score, PSA, prostate volume, needle concentration, age, hormone therapy or type of brachytherapy.

While it is too soon to know whether those CTCs will cause a recurrence in the 7 brachytherapy patients, a similar study done by Eshwege et al. before and after prostatectomy suggests that they will not. In that study, there was increased risk of recurrence only if CTCs were found before the prostatectomy. The additional shedding of tumor cells during the procedure did not correlate with recurrence within 5 years.

Even high risk/advanced prostate cancer cells are not capable of survival outside of the prostate environment. To metastasize, they must first undergo a series of genetic alterations called epithelial-to-mesenchymal transition (EMT). Some researchers believe that small numbers of such metastatic-capable cancer cells may exist in small numbers within the prostate. If so, it seems to be a rarity.

Nadir PSA predicts survival after radiation and androgen deprivation for unfavorable risk patients

If a treatment isn't working, we want to know as quickly as possible so we can try a salvage therapy while it can still make a difference. We want a measure of effectiveness, called a surrogate endpoint, that will predict survival, and we usually turn to PSA as our best early indicator. But there are different ways of defining mortality, and different measurements utilizing PSA. In an analysis of a randomized clinical trial (available here), the researchers sought to answer these questions for unfavorable risk patients who were treated with external beam radiation (EBRT) + androgen deprivation (ADT).

The purpose of the randomized clinical trial (NCT00116220) was to determine whether adding 6 months of androgen suppression improved freedom from biochemical failure over radiation therapy alone. This was a secondary analysis of the data. The details of the study were as follows:

• All patients were "unfavorable risk," defined as PSA between 10 and 40 ng/ml or Gleason score ≥7 or extracapsular extension or seminal vesicle invasion.
• Men were screened for minimal of no comorbidities.
• Median age was 72.
• They all received 70.2 Gy of 3D-CRT at 6 hospitals in the Boston area between 1995 and 2001
• Half (78 men) got 6 months of ADT with the radiation; half (79 men) had radiation without ADT
• PSA was evaluated every 3 months for 2 years, every 6 months for 3 years, and then annually.
• When PSA climbed above 10 ng/ml they received salvage ADT.

In selecting the kind of "mortality" they wanted to use as the gold standard endpoint, the researchers selected "age-adjusted all-cause mortality (ACM)" rather than "prostate cancer-specific mortality." This was a reasonable choice for several reasons:

• It is often difficult to discern whether  prostate cancer was the final cause of death. Men may die of kidney or liver failure or other final causes that are consequences of their prostate cancer. 
• Prostate cancer has been found to be associated with other causes of death. 
• The men in this study were only included if they had no or minimal comorbidities that might contribute to their death. 
• Men were eventually diagnosed with metastatic castration-resistant prostate cancer, and most had received chemotherapy.
• The mortality was age-adjusted for actuarial death rates. 
• Follow-up was long enough (16.5 years, median) so that even slow-killing prostate cancer would be a significant cause of mortality.

They examined 4 PSA-related metrics as potential surrogate endpoints:

1. PSA failure, defined as nadir + 2.0 ng/ml
2. PSA nadir > 0.5 ng/ml
3. PSA doubling time < 9 months
4. Time to PSA failure < 30 months

They had several criteria for inclusion. Basically, they wanted to find metrics that predicted mortality, and that continued to make a difference in survival time after the effect of the adjuvant ADT no longer extended survival. All but "PSA failure" met their criteria. Of the remaining 3 metrics, PSA nadir > 0.5 ng/ml had the largest effect in explaining survival.

The following table shows the percent of 8-year all-cause mortality for each surrogate endpoint, when it was met and when it wasn't, and the percent of the treatment effect (adjuvant ADT) explained by each metric.

	Percent mortality at 8 years		Percent of treatment effect explained by metric
Endpoint achieved:	YES	NO
PSA failure	32.5%	11.8%	NA
PSA nadir > 0.5 ng/ml	47.4%	13.6%	104%
PSA doubling time < 9 mos.	40.7%	14.1%	43%
Time to PSA failure < 30 mos.	39.4%	15.3%	41%

If the PSA nadir was over 0.5 ng/ml, it predicted the biggest difference in mortality. It also explained essentially all of the treatment effect of the added ADT.

Before anyone gets worried that their PSA is over 0.5 ng/ml, we must remember what "nadir" means. Because this analysis was done in hindsight, nadir is the lowest PSA ever achieved after treatment. It was not, in this case, the lowest value achieved so far. It often takes 5 or more years to achieve the nadir after radiation. For those who received adjuvant ADT with their radiation, the nadir will be achieved while they are still on ADT, and the PSA may rise above the nadir as the effect of the ADT wears off.

A nadir of only 0.5 ng/ml among those taking ADT in this clinical trial suggests that the ADT was not working completely. I assume that ADT was begun 2 months before the EBRT, continued during the 2 months of EBRT, and was continued for 2 months after that (6 months total). If the first PSA was taken 3 months after EBRT completion, the effect of the ADT had not worn off yet. Some of the cancer must already have been castration resistant. Patients received a bone scan, but some must have already had metastases that were too small to be detected by it. We see this reflected in how quickly the metric predicted mortality. In as quickly as one year from the start of treatment, mortality was 20% among those who had already reached a nadir, and it was over 0.5 ng/ml vs. 0% in those who hadn't reached it. At year one, the percent who had met the endpoint was negligible for the other endpoints. Clearly, patients with a PSA that never goes down below 0.5 ng/ml after radiation +ADT are at greater risk.

The authors recommend that patients whose PSA never achieves a nadir below 0.5 ng/ml after EBRT plus 6 months of ADT should be recommended for clinical trials of early use of second-line hormonal agents, chemotherapy, and other new therapies. This is a logical implication, but it is not likely to occur very often because standard of care has changed since this clinical trial began.

The DART 01/05 GICOR randomized clinical trial proved that among high risk patients, 28 months of adjuvant ADT was superior to the 6 months of adjuvant ADT that were used in the present study. It is less likely that the nadir will stay above 0.5 ng/ml with the longer course of ADT and with the escalated radiation dose (of about 80 Gy) that is now standard of care. So while a nadir > 0.5 ng/ml in this situation is still an endpoint indicating elevated risk, few patients will be observed to exhibit it.

SpaceOAR hydrogel - is the difference worthwhile?

SpaceOAR hydrogel is spacer injected between the rectum and the prostate that increases their separation. This allows less radiation targeted at the prostate to hit the rectum. They published an interim 15-month report in 2015, and now Hamstra et al. have published their final report based on 3 years of follow-up.

The clinical trial was conducted at 20 participating institutions between 2012-2013 among patients who were to receive IGRT/IMRT as their first-line therapy for low- or intermediate-risk prostate cancer. Additionally, no more than 50% of biopsy cores were positive, ADT was not used, and prostates larger than 80 cc were excluded. The test was "single blinded:" physicians implanted the gel at the same time fiducials were implanted, but patients did not know if they received the spacer. All patients received 79.2 Gy of IMRT with 5-10 mm margins. 149 men were randomly assigned to the Spacer group. The Control group comprised 73 men.

While the researchers report physician-assessed toxicity data, they also collected patient-reported quality-of-life outcomes. Patient-reported outcomes are not subject to reporting bias, and are collected using well-validated questionnaires (EPIC). Patients did not know if they received the spacer. Patients filled out comprehensive questionnaires at baseline, 3 months after treatment, and then at month 6, 12, 15 and 36. On the EPIC questionnaires, a minimally important difference (MID) has been previously found to be a decline of 5 points, 6 points, and 11 points for rectal, urinary and sexual side effects, respectively. The researchers also reported the percent of patients whose quality-of-life scores declined significantly to a level that was at least twice as great (2X MID).

Acute toxicity

The change at 3 months compared to baseline represents the acute effects of radiation. This is the period of maximal deleterious effect of radiation on rectal and urinary quality of life. After 3 months, quality of life typically improves. The exception to this rule is sexual quality of life, which may continue to deteriorate, largely due to age (see this link).

At 3 months, the percent of patients who were bothered by any bowel-related side effect (moderate or big bother) was 9.4% among the Spacer group, and 5.7% among the Control group. The difference was not statistically significant. The only component (components included such morbidities of diarrhea, blood in stools, urgency, frequency, etc.) of bowel bother that was statistically significant was bowel pain, which was reported as a moderate or big bother by 6.8% of the Spacer group and none of the control group. The spacer made bowel pain worse rather than better.

Physician-reported grade 2 acute toxicity at 3 months was exactly the same (4%) for both the Spacer and the Control group. The spacer had no effect on any but the mildest acute toxicity.

Urinary scores were not significantly affected by the spacer. Among the Spacer group, 22.8% evaluated their urinary-related side effects as a moderate or big bother. Among the Control group, 17.1% evaluated it as a moderate or big bother. The difference between the two groups was not statistically significant, nor were any of the components of urinary function (e.g., pain, urgency, waking up to urinate, weak stream, frequency, etc.).

Bothersome sexual effects were also not significantly different between the Spacer and Control group, and at 3 months, were similar to baseline.

Late-term toxicity

At 36 months after treatment, 2.2% of the men in the Spacer group evaluated their bowel function as a big or moderate bother. This compares to 4.4% in the Control group -- not a statistically significant difference. None of the components of rectal bother were significantly better in the men who received the Spacer, although the scores were directionally better in almost every component. Quality of life in the rectal domain for both the Spacer and Control groups were close to their baseline values.

This low rate of bothersome rectal toxicity was confirmed by physician reports of rectal toxicity. Ignoring mild rectal side effects (i.e., grade 1, like blood spots on toilet paper or loose stool) that patients often do not bother to report to their doctors, we see that physician-reported grade 2 or higher rectal adverse events occurred in only 6% of patients, all in the Control group. Only one patient suffered a serious (grade 3) rectal injury in the Control group. It's worth noting that even this small number was an increase from the 15-month report. At 15 months, there was only one patient who had grade 2 or greater rectal toxicity. Late-term rectal toxicity is not a major issue with modern-day radiation.

Late-term urinary scores were not statistically significantly different for Spacer (4.4% big/moderate bother) and Control (8.9% big/moderate bother). Both were improved from baseline. The only component that was significantly worse was urinary frequency (18.2% vs 4.6%). It is unclear why any urinary side effects would be affected at all by a rectal spacer. It may be an artifact of the low sample size at 36 months - just 46 in the Control group, and 94 in the Spacer group.

There were no differences in overall sexual bother between Spacer and Control groups, or in any of its components. In the Control group, big/moderate sexual bother increased from 35.2% at baseline to 41.3% at 3 years. In the Spacer group, big/moderate sexual bother increased from 23.6% at baseline to 28.6% at 3 years. In both cases, sexual bother peaked at 1 year after treatment.

The following table shows the percent of patients in the Spacer and Control groups whose scores in each domain (rectal, urinary and sexual) declined by the minimally important difference (MID) or by at least twice the minimum (2x MID), which would be clinically significant to the patients.

*statistically significant difference between Control and Spacer with 95% confidence

We notice that the spacer moderated the declines in the rectal scores. There was a 16 percentage point improvement in late term rectal evaluations due to the spacer. However, we also saw that the relative decline was not very bothersome to the patients (96% did not find it even moderately bothersome).

What is perplexing here is why the urinary scores would have declined more without the spacer -the clinically notable difference (2x MID) was statistically significant.The dose received by the bladder and urethra was unaffected by the rectal spacer. There was also a rather sudden increase in both urinary and rectal MIDs at the 3-year mark. At all prior time points, there were no statistically significant differences between the Control and Spacer groups. Many respondents were lost to follow-up at 36 months (and over a third were lost) and data may become erratic as sample size gets small.

Is it worthwhile to treat all patients? 

The cost of the SpaceOAR hydrogel injection is about $2,500. IMRT patients should not expect any amelioration of bothersome acute rectal symptoms. A cost/value analysis depends upon which toxicity numbers one wants to focus upon.

1. Even if the difference were statistically significant (and it's not), only 2.2% would avoid bothersome late-term rectal symptoms by using the gel. So to spare one patient bothersome rectal symptoms, 45 patients would have to be treated at a cost of over $90,000. 
2. If we focus on the late-term toxicity improvement, 6% avoided late-term grade 2 or higher rectal symptoms by using a spacer. To spare one patient such symptoms, 17 patients would have to be treated at a cost of $42,500.
3. If we use the 2x MID difference as our guide, 16% would avoid low grade late-term rectal symptoms. So to spare one patient those symptoms, 6 patients would have to be treated at a cost of $15,000. 

Some would argue that even though the symptoms are relatively mild, late-term symptoms are often longer-lasting. Each patient has to decide for himself. Patients who are interested should obtain pre-approval from their insurance. It has been provisionally approved, but Medicare approval is expected in 2018.

Safety must be considered as well. The risks are not large, but neither are they non-existent. In addition to the dangers of anesthesia and infection, there is a small danger that the injection will penetrate the rectal wall or cause a rectal ulcer. Such dangers are small, and undoubtedly diminish with clinician experience.

Rather than treat all radiation patients, it would be much more efficient to identify the patient characteristics that increase the risk of late-term rectal toxicity. The presence of visceral fat, anatomic abnormalities, medications (e.g., anticoagulants and antihistamines), comorbidities (e.g., inflammatory bowel disease and diabetes), smoking, and the microbiome may play a role. There may also be a genetic component, like mutations in DNA repair genes, that renders a patient more susceptible to lasting damage from radiation. Further analysis may help explain why there was no benefit in terms of acute toxicity, and why even this small benefit took 3 years to show up. Dr Hamstra mentioned that analysis is ongoing, and they plan a follow-up presentation at ASTRO next year.

The researchers are to be congratulated on this very well executed randomized clinical trial. There are too few trials like this. In fact, Daniel Hamstra boasted:

"I think this is better than any other study ever performed for prostate cancer.  I know of no phase 3 trials testing a new technique or study which randomized patients and reported benefits for toxicity and QOL.  IMRT has not done it.  Image guided therapy has not.  Proton therapy has not.  Robotic surgery has not.  Nor has any surgical technique.  If you go back to the original Dutch 3D conformal trial published 15 years ago they showed reduced toxicity with 3D conformal RT as compared to 2D RT (but did not collect QOL).  So, this is really a landmark study in that it was randomized (and blinded in that the patients did not know which arm they were on until the end of the trial).

Note: Thanks to Daniel Hamstra for allowing me to read the full text, and responding to my questions.