Are two PET radiotracers better than one?

There seem to be clinical trials of new PET radiotracers for the detection of prostate cancer all the time. In addition to the FDA-approved C-11 Choline, NaF18, FDG, and fluciclovine PET scans, most of the new PET scans target the PSMA protein on prostate cancer cells. On the horizon, we have seen some encouraging reports on PET radiotracers that target the Gastrin Releasing Peptide Receptor (GRPR) with a peptide called bombesin. GRPR, as the name implies, is ubiquitous in the stomach and intestines, but seems to show up in several different kinds of cancer cells as well.

Zhang et al. reported the results of a very small pilot study using a synthetic molecule that targets two different receptor proteins at the same time (also see this link). One part of the molecule (bombesin - BBN) targets the GRPR protein. The other part, called RGD, targets a protein called αvβ3. αvβ3 is a member of a family of proteins called integrins. These proteins are responsible for maintaining the structural integrity of cells. αvβ3 promotes cell adhesion, spreading and blood supply -- qualities vital to metastatic progression.

They used both the single Ga-68-BBN PET/CT and the dual Ga-68-BBN-RGD PET/CT to detect prostate cancer among 13 patients (4 newly diagnosed, 9 recurrent) with biopsy-proven prostate cancer. The dual PET radiotracer found cancer:

• In the prostates of 3 of the 4 men with newly diagnosed prostate cancer vs. 2 of the 4 men using the BBN-only radiotracer.
• 14 metastatic lymph nodes vs. 5 metastatic lymph nodes using the BBN-only radiotracer.
• 20 bone metastases vs. 12 metastatic bone metastases using the BBN-only radiotracer.

There were no toxic reactions.

While encouraging, it is still very early to draw conclusions. There is no confirmation that the extra "metastases" discovered were indeed metastases - they may be false positives. And there are no clues as to which kinds of prostate cancer the dual PET radiotracer is sensitive to, and which kinds are undetectable.

If confirmed by larger studies, it may be possible to not just detect the cancer, but to kill the detectable cancer cells as well with beta emitters like Lu-177 or alpha emitters like Ac-225.

SBRT for High Risk Prostate Cancer (update)

One of the more interesting developments in the use of radiation to cure high risk prostate cancer is to use SBRT (see this link). The standard of care remains external beam radiation with a brachytherapy boost. But SBRT, if successful for this purpose, may afford equal oncological outcomes with less toxicity and completion in only 5 treatments.

(update 11/18/2018) Alayed et al. reported the 5-year outcomes of 60 men treated with SBRT (which they call SABR) for high-risk prostate cancer at Sunnybrook Hospital in Toronto. The prospective pilot trial comprised 2 cohorts of 30 men each, treated as follows:

1. 40 Gy in 5 fractions to the prostate + 30 Gy in 5 fractions to the seminal vesicles
2. 40 Gy in 5 fractions to the prostate + 25 Gy in 5 fractions to the seminal vesicles AND the pelvic lymph nodes

12-18 months of adjuvant ADT were used in both groups.

Median follow-up was 5.6 years for Group 1 and 4.0 years for Group 2. The 5-year outcomes were:

• Biochemical failure was 15% in Group 1 and 0% in Group 2
• 4-year PSA was < 0.4 ng/ml for 63% of Group 1 and 93% of Group 2
• Late sexual and rectal side effects were worse for Group 1 than Group 2, urinary side effects were similar

This suggests that SBRT provides oncological outcomes that are similar to brachy boost therapy, while the side effects may be lower, especially if the dose to the seminal vesicles is 25 Gy/ 5 fractions. It also suggests that whole pelvic treatment is probably beneficial in high-risk patients and that toxicity is not higher.


Katz and Kang have presented the largest and longest follow-up trial of SBRT for high risk patients, with 98 patients and 8 years of follow up. Of those, 46 were treated with an SBRT boost following whole pelvic IMRT radiation, and 52 were treated with SBRT monotherapy. The 8-yr biochemical disease-free survival was 61%. This did not differ significantly whether they received the SBRT boost or monotherapy. It also did not differ significantly whether they received adjuvant ADT (55% did). Several different doses were used, but none had significantly better performance. Higher stage and higher grade cancers were cured equally well. Only patients with high initial PSA, perhaps indicative of metastases, fared worse than patients with lower initial PSA. Late Grade 2 rectal toxicity was higher for the combo IMRT+SBRT treatment. Late urinary and rectal toxicity were low (5% grade 2 + 3% grade 3 urinary, 7% grade 2 bowel toxicity), and transient, with none after two years.  This was reflected in patient-reported quality-of-life scores, which declined immediately after treatment but returned to baseline in less than a year.

Kishan et al. presented early toxicity outcomes of the UCLA SBRT trial for high risk patients, which was described here and here. They treated 61 patients, 40 with adjuvant androgen deprivation therapy, 23 also received radiation to the pelvic lymph nodes. ADT and nodal radiation had no effect on toxicity.

After 1 year of median follow-up, the physician-reported toxicities were as follows:

• There were no grade 3 or higher toxicities
• Acute grade 2 urinary toxicity - 13%
• Acute grade 2 rectal toxicity - 7%
• Late grade 2 urinary toxicity  - 7%
• Late grade 2 rectal toxicity - 8%

At 12 months, the percent of patients who reported at least minimally detectable changes were:

• Urinary incontinence: 14%
• Urinary obstructive symptoms: 31%
• Bowel symptoms: 28%

There is also a recent report on SBRT boost therapy for high risk patients (see this link). Paydar et al. reported on 108 patients treated at Georgetown University,  59 of whom were high risk. The toxicities reported were as follows:

• Acute urinary toxicity - 18% grade 2 ,  1% grade 3
• Acute rectal toxicity - 7% grade 2
• Late urinary toxicity  - 40% grade 2, 6% grade 3
• Late rectal toxicity - 12% grade 2, 1% grade 3

SBRT boost therapy seems to increase toxicity significantly more than SBRT monotherapy. We will have to wait for reports of oncological outcomes to see whether the trade-off is worthwhile.

Vessel-sparing IMRT spares erectile function

While either nerve-sparing surgery or radiation can cause erectile dysfunction, the probability for that for any given patient is always worse after surgery. The recent ProtecT randomized clinical trial removed any doubt of that, if there ever really was any. While nerve-sparing surgery was introduced by Walsh in 1982, there has been no similar breakthrough in IMRT radiation delivery - until now.

Effects of treatments on erectile apparatus

The mechanism of erectile function is complex, involving the brain, hormones, neurotransmitters, enzymes, and nitric oxide, just to mention a few vital components. Nerve impulses must travel from the brain, through the spine, along the nerve fibers that surround the prostate and then along its length down to the corpus cavernosa (the spongy tissue inside the penis from the penile bulb to the glans). Surgery, even nerve-sparing surgery, usually disrupts the signal that must innervate the penis. "Nerve sparing" is not an all-or-nothing technique. If the cancer has grown out into the neurovascular bundles, only some of the nerves may be spared. Take away too little, and the cancer is not cured; take away too much, and permanent erectile dysfunction is assured. Sometimes surgeons send frozen slices of tissue for pathological analysis before deciding how much to remove.

When radiation causes erectile dysfunction, the mechanism is very different. Nerves are relatively impervious to radiation; however, blood vessels and other endothelial tissue may be affected. The blood that supplies the penis comes to it through the "pudendal arteries" that flow downwards on either side of the prostate (in the "neurovascular bundle"). The blood enters the penis at the penile bulb (the part that extends inside the pelvis) and engorges the tissue of the corpus cavernosa. Radiation may cause an inflammatory reaction in the linings of the blood vessels and in the tissue of the corpus cavernosa. Over a period of months, the inflammation may result in scar tissue that restricts blood flow, and the impedes the ability of the spongy tissue of the corpus cavernosa to expand and contract elastically.

For years, there has been somewhat conflicting evidence about whether radiation's effect on erectile dysfunction can be mitigated by reducing the dose to the penile bulb (see this link). Consequently, radiation oncologists set a dose constraint for the penile bulb, but that was not a full solution. Many radiation oncologists have wondered whether the dose to the pudendal arteries and to the other parts of the corpus cavernosa could be  restricted to preserve erectile function without sacrificing oncological effectiveness. Innovations in MRI-based planning and super-precise (sub-millimeter) beam delivery have enabled that.

Vessel-sparing IMRT

Spratt et al. at the University of Michigan conducted a clinical trial on 135 patients treated between 2001 to 2009 to see whether "vessel sparing" IMRT could better preserve erectile function while achieving equal cancer control. As others have, they used a T2 MRI to delineate the contours of the penile bulb and corpus cavernosa. Their innovation was to use contrast-enhanced MRI-angiography to delineate the pudendal arteries that run near the prostate apex. The MRI images were fused with CT scan images and dose goals were set based on those. Intermediate and high risk patients were treated with low dose rate brachy (seed) boost therapy before they received IMRT; low risk patients received IMRT alone. A treatment margin of 1 cm was set for patients receiving IMRT only. It was lowered to 0.5 cm for those receiving brachy boost therapy.

Key patient and treatment characteristics included:

• Age = 63 (median)
• Baseline erectile function: IIEF score ≥ 16 (mild or no ED)
• Risk: Low - 39%, Intermediate - 53%, High -9%
• Gleason score: 3+3 - 44%, 3+4 - 33%, 4+3 - 13%, 8-10 - 9%
• Treatment: IMRT alone - 39%, brachy boost - 61%
• Dose: IMRT - 75.6-79.2 Gy, brachy boost - 110 Gy I-125 seeds + 45 Gy IMRT
• Pelvic dose: 45 Gy (high risk only)
• 6-month ADT: yes -33%, no - 67%

Potency preservation

During a median follow-up of 8.7 years, patients filled out questionnaires and doctors evaluated their erectile function at 2 years and 5 years. They were also queried about their use of erectile medicines and aids. Their responses were matched to the results of the PROSTQA study, matched for age, baseline potency, and other sexual risk factors. The percent of men who had erections firm enough for intercourse 2 years after treatment were:

• 78% if they had vessel-sparing IMRT
• 42% if they had conventional IMRT
• 24% if they had nerve-sparing prostatectomy

Other measures of erectile function at baseline, 2 years and 5 years included:

• No sexual aid use: 88%, 47%, 44%
• IIEF score ≥16 (no or mild ED): 100%, 70%, 67%
• High/very high confidence in getting and keeping an erection: 63%, 40%, 33%
• Potent without aids: 80%, 45%, 35%
• Potent with aids: 20%, 41%, 53%
• Impotent: 0%, 14%, 12%

As we've seen in other studies, most of the radiation-induced ED will show up within the first two years, and probably within 9 months of treatment. This was shown for 3D-CRT in the ProtecT clinical trial,  for brachytherapy, for SBRT,  and EBRT. Perhaps the authors will make an attempt to separate the effect of patient aging in a future analysis. The University of Michigan should be able to accomplish this using their age-adjusted sexual domain EPIC scores.

It's worth noting that potency preservation was no different for those who had the brachy boost or IMRT only. It was better for younger men, men with higher baseline performance, and those who did not have adjuvant ADT.

Oncological outcomes

At 5 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 100%
• High risk: 98%

At 10 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 89%
• High risk: 88%

One could not ask for better outcomes!

Conclusion

It appears that vessel-sparing IMRT is a vast improvement over conventionally targeted IMRT in terms of preservation of erectile function, and based on this, should be adopted as standard practice for all patients who might benefit. Interestingly, potency preservation is similar to that reported for SBRT (see this link) and for high dose rate brachytherapy (see this link). That is not at all surprising because both of those therapies use much narrower margins than those used for IMRT, typically 2-3 mm vs. 10 mm for IMRT, and the biologically effective dose to the vascular tissue of the pudendal arteries are lower. With SBRT, intra-fractional motion is tracked, thus avoiding dose to nearby structures. With HDR brachytherapy, the gland is immobilized with catheters that prevent doses to the nearby vessels and organs. Hopefully, equally excellent results can be achieved with hypofractionated IMRT,  but that remains to be proved in future trials. With salvage IMRT, the entire prostate bed is treated, so I do not know if radiation to the pudendal arteries can be similarly avoided.

Anyone planning on having IMRT should forward a copy of this study to his radiation oncologist, and ask to discuss it at their next meeting. Of course, for men who are low risk, active surveillance will cause no erectile dysfunction and no loss of ejaculate.

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only (Redux)

In August, Kishan et al. showed a preliminary analysis of oncological outcomes among Gleason score 9 and 10 patients treated with brachy boost therapy (EBRT+BT), external beam radiation therapy alone (EBRT) or surgery (see this link). Because of the limited sample size, some of the differences were not large enough to be statistically significant. Kishan et al. have now expanded their analysis to include 1,001 patients treated between 2000 and 2013, who were treated at several of the top institutions in the US: UCLA, Fox Chase, Cleveland Clinic, Mt. Sinai, and Wheeling Hospital. So far, only an abstract of the study has been presented at the GU Conference. The patient characteristics were as follows: 

• 324 were treated with radical prostatectomy (RP).
• 347 were treated with EBRT only.
• 330 were treated with EBRT + BT (BT was either low dose rate or high dose rate).
• All patients were Gleason 9 or 10 on biopsy.

Treatment specs

• Among the RP patients, 40% had adjuvant or salvage radiation therapy (68 Gy).
• Among radiation patients, 90% had adjuvant ADT
• Median dose of EBRT was 78 Gy.
• adjuvant ADT continued for 18 months, median.
• Median equivalent dose of EBRT+BT was 90 Gy
• adjuvant ADT continued for 12 months.

Oncological outcomes

After a median follow-up of 4.8, 6.4 and 5.1 years for EBRT, EBRT+BT and RP, respectively, the oncological outcomes were as follows:

• The 10-year rates of distant metastases were
  • 39.9% for RP 
  • 34.2% for EBRT
  • 19.7% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.
• The 10-year rates of prostate cancer-specific mortality (PCSM) were
  • 20.3% for RP
  • 25.2% for EBRT
  • 14.1% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.

The authors conclude:

Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. 

Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While this does not prove causality (only a randomized clinical trial can do that) it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy with ADT will probably be the best choice.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

Pelvic lymph node treatment area is seldom wide enough

A Mayo Clinic study sought to determine exactly where the recurrences were after failure of prostatectomy. Parker et al.  studied recurrence in 41 patients who received a post-prostatectomy C-11 Choline PET/CT scan between 2008 and 2015, and at least one recurrence site was identified (median = 2). They were all candidates for whole pelvic salvage radiation, using at least 45 Gy of external beam radiation. They classified their recurrence sites as:

1. IF (in-field) if the recurrence site would receive at least 45 Gy
2. EOF (edge of field) if the recurrence site would receive less than 45 Gy (inadequate dose)
3. OOF (out of field) if the recurrence site would not receive any radiation

They identified 121 recurrence sites. A sizeable minority (43%) of the recurrence sites were within the whole pelvic radiation field; however, when they looked at how many of the patients were adequately treated for all their recurrence sites, a disturbing picture emerges:

• Only 12% had IF recurrences
• 24% had EOF recurrences (median dose - 10 Gy)
• 88% had OOF recurrences.
• 15% had both EOF and OOF recurrences.
• 10% had both IF and OOF recurrences.

It should be mentioned that the patients did not receive the PET scans until their PSA reached a median of 3.1 ng/ml (C-11 Choline PET isn't much good at PSAs lower than 2 ng/ml.) This occurred a median of 15 months after biochemical failure (PSA≥ 0.2 ng/ml). And biochemical failure occurred a median of 24 months after prostatectomy. We know that waiting this long is sub-optimal.

A similar study at Memorial Sloan Kettering looked at the site of failure after first-line radiation therapy to the prostate only (including seminal vesicles in some). They used CT scans (mostly) to detect sites of failure among 60 patients who had their first failure in the pelvic area. Spratt et al. found that, among those patients, only 42% would have the first detected lymph node metastasis treated by the standard pelvic lymph node radiation field. They found that by expanding the field to include the common iliac lymph nodes would treat 93% of recurrences.

A study at University Hospital Munich used F-18 or C-11 Choline PET scans to determine the site of lymph node involvement in 32 high-risk patients, and in 87 patients who were biochemically recurrent after prostatectomy. Location of lymph node involvement was similar for both groups, with 39% of pelvic LNs missed by the standard treatment field.

A similar study at the University of Kansas, using C-11 Acetate PET scans found that over half of all positive pelvic lymph nodes would have been missed by the standard radiation field. Notably, 78% of all positive lymph nodes were smaller than 1 cm, and therefore would have been missed if only a CT scan were used to identify them.

A similar study found that 39% of pelvic LNs would have been missed.

(Update 5/2019) De Bari et al. used a PSMA PET scan to identify sites of recurrence after prostatectomy failure. They found:

• 75% of patients had a nodal relapse outside of the traditional (RTOG) field
• To cover 95% of the nodal relapses, the radiation field size would have to be expanded to include the para-aortic lymph nodes up to T12-L1

The other common method of treating pelvic lymph nodes is via extended pelvic lymph node dissection (ePLND).  In one recent study, almost a quarter of positive LNs would have been missed even if ePLND had been used.

It is possible that as advanced PET scans gain wider use, detection of smaller pelvic LN metastases will be possible. Jelle Barentsz at Radboud University Hospital in Nijmegen, Holland claims he can detect LN metastases as small as 2 mm using USPIO MRI. Even so, we are far from being able to detect all micrometastases in the pelvic area. If the goal is curative therapy, it is necessary to treat what we can't see as well as what we can see.

Unfortunately, it is not always as simple as expanding the radiation treatment field or increasing the number of pelvic LNs dissected surgically. As the treated area is widened, the risk of side effects increase. Lymphoceles and lymphedema are potentially crippling side effects of surgical excision. Damage to the enteric tissue of the small bowel and vascular damage become risk factors with wider radiation treatment fields. For anatomical reasons, not everyone is a good candidate.

(Update 9/1/20) NRG Oncology expanded its recommendation for the treatment of pelvic lymph nodes (see this link).

Such risks have to be balanced against the evidence for the potential benefit of such 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.

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.