Monday, March 27, 2017

Conflicting messages after surgery for high-risk patients from radiation oncologists and urologists

In spite of the data suggesting that brachy boost has better outcomes for high risk patients, it is being utilized less often and surgery is being utilized more often. After surgery, the high-risk patient is monitored by his urologist (Uro). If the urologist fears a recurrence, he may (1) refer his patient to a radiation oncologist (RO) for adjuvant or salvage radiation therapy (A/SRT), (2) refer his patient to a medical oncologist if he believes the recurrence is metastatic and incurable, or (3) he may continue to monitor the patient. The rate of utilization of A/SRT has been dwindling in spite of three major randomized clinical trials that proved that ART has better outcomes than waiting. If the patient does get to see a radiation oncologist, he may be advised to be treated soon, in conflict with the urologist advising him to wait. This puts the patient in a difficult situation.

Kishan et al. report the results of a survey among 846 ROs and 407 Uros. The researchers sought their opinions about under which conditions they would offer a high-risk post-prostatectomy patient A/SRT. For the purposes of their survey, they defined "adjuvant RT" as radiation given before PSA has become detectable, and "salvage RT" as radiation given after PSA has become detectable. "Early salvage RT" means PSA is detectable but lower than 0.2 ng/ml.

The following table shows the percent of ROs and Uros who agreed with each survey question:



RO
Uro
ART underutilized
75%
38%
ART overutilized
4%
19%
SRT underutilized
65%
43%
SRT overutilized
1%
5%



SRT when first PSA is detectable
93%
86%
ART when first PSA is undetectable
43%
16%
Early SRT when first PSA is undetectable
42%
43%
SRT when first PSA is undetectable
16%
41%



Recommend SRT if PSA is:


Detectable
15%
7%
2+ consecutive rises
30%
20%
>0.03-0.1
8%
8%
>0.1-0.2
13%
11%
>0.2-0.4
29%
35%
>0.4
5%
19%



Recommend ART if pathology report is adverse:


Positive margin
80%
47%
Extraprostatic Extension (pT3a)
60%
32%
Seminal Vesicle Invasion(pT3b)
68%
47%
Local organ spread (pT4)
66%
46%
Pelvic lymph node (pN1)
59%
29%
Gleason score 8-10
20%
20%
Prefer SRT
12%
25%



Recommend adjuvant ADT with ART if:


Positive margin
14%
12%
Extraprostatic Extension (pT3a)
15%
11%
Seminal Vesicle Invasion(pT3b)
29%
25%
Local organ spread (pT4)
36%
37%
Pelvic lymph node (pN1)
65%
46%
Gleason score 8-10
46%
28%
No ADT
22%
31%



Recommend whole pelvic A/SRT if:


Positive margin
6%
9%
EPE
12%
9%
SVI
25%
22%
pT4
30%
30%
pN1
82%
64%
GS 8-10
36%
24%
No role
12%
24%
Other
13%
3%

In contrast to Uros, ROs are more likely to believe that both ART and SRT are underutilized. Uros believe that are used about right. ROs often see patients too late if they see them at all.

When the first PSA is detectable, both kinds of doctors would recommend SRT. When the first PSA is undetectable, 43% of ROs would recommend ART nonetheless, while only 16% of Uros would recommend ART.

Most of the ROs would treat when they see 2 consecutive rises in PSA, or if the PSA was detectable and under 0.2. Most (54%) Uros would wait until PSA was over 0.2.

Over half the ROs would recommend ART to high risk patients demonstrating any of several adverse pathological features: positive margins, stage T3/4, or positive pelvic lymph nodes. The majority of Uros would not recommend ART to high risk patients with those adverse pathologies.

The majority (65%) of ROs would include adjuvant ADT if there were positive lymph nodes. Uros were less likely to recommend adjuvant ADT based on lymph node involvement and Gleason score.

While most of both groups would have added whole pelvic radiation for patients with positive lymph nodes, 82% of ROs would, but only 64% of Uros.

ROs, knowing that a locally advanced cancer can suddenly become metastatic, and therefore incurable, would like to give A/SRT as soon as possible. Uros, who treat patients for the combined effect of surgery and radiation on urinary and sexual function, would like to wait as long as possible. The patient is caught in the middle of this difficult decision. Some have recommended beginning neoadjuvant ADT at the lowest detectable PSA and extending that time for as long as needed  to give urinary tissues maximum time to heal. Whatever the high-risk patient may eventually decide is in his best interest, he should meet with an RO immediately after surgery to hear both sides of the issue. Uros are blocking access to information that the patient needs.

Thursday, March 23, 2017

Prostate Cancer Staging Update

The standard staging manual for prostate cancer is a consensus issued by the American Joint Committee on Cancer (AJCC). They have now issued the 8th edition (at this link), which will become effective beginning January 2018. For the most part, it is consistent with the 7th edition.

How is it used?

Staging refers to where the cancer is located in relation to the organ of origin. The purpose is to create a standard for staging that is used universally. Because universal use is important, AJCC excludes staging techniques that are not accessible everywhere – it must be available to large university teaching hospitals as well as to doctors in individual community practice. This means that such sophisticated diagnostic tools as multiparametric MRIs and advanced PET scans are excluded.

It is used in clinical practice to help assign patients to risk categories for treatment and prognosis, and it is used in clinical trials for similar purposes. Standardization is critical – every doctor reviewing the charts of patients understands that the AJCC stage means exactly the same thing. AJCC also wants to keep staging categories fairly consistent across different kinds of cancers (e.g., stage T2 means organ-contained for every cancer). Because inter-comparability over time and across cancers is an important part of its use, it is conservative – it doesn’t change all that much from edition to edition.

AJCC staging is one of several decisive parameters used for risk stratification (see below) and for determining probability of recurrence using nomograms. In the US, most of the risk stratification systems, including NCCN and CAPRA and the MSK and Han/Partin nomograms, use the AJCC system. It has been adopted in Canada, Europe and most of the rest of the world.

Clinical staging and pathological staging

AJCC distinguishes between clinical staging and pathological staging. For prostate cancer, clinical staging is determined at the time of diagnosis. Pathological staging, if it is done, is determined from the prostatectomy pathology findings. Clinical stages are usually designated by a “cT” before the number, while pathological stages are designated by a “pT” (T is German for Tier).

Clinical stages

For clinical stages, the T stage is only based on DRE findings. This represents a change from the 7th edition, which allows for the staging based on imaging results, if reliable enough. T stage is never based on biopsy results.

Clinical extraprostatic extension (stage cT3a)
Clinical staging is cT1c or cT2a in over 95% of newly diagnosed cases. So, if stage cT2a or less is used as a cutoff, clinical T stage has low negative predictive value (i.e., a low T stage is not a good indicator of risk), but good positive predictive value (i.e., a high T stage is prognostic for recurrence after treatment). Ultrasound and MRIs are not very good at identifying small areas of extraprostatic extension. Epstein, at Johns Hopkins, has identified cancer mixed with extraprostatic tissues in biopsies taken from the apex. Eastham, at MSK, has identified cancer mixed with extraprostatic tissues in biopsies taken from the base. As of the 8th edition, such pathological evidence is not used for staging.

The clinical stages are:
T category
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
T1Clinically inapparent tumor that is not palpable
T1aTumor incidental histologic finding in 5% or less of tissue resected
T1bTumor incidental histologic finding in more than 5% of tissue resected
T1cTumor identified by needle biopsy found in one or both sides, but not palpable
T2Tumor is palpable and confined within prostate
T2aTumor involves one-half of one side or less
T2bTumor involves more than one-half of one side but not both sides
T2cTumor involves both sides
T3Extraprostatic tumor that is not fixed or does not invade adjacent structures
T3aExtraprostatic extension (unilateral or bilateral)
T3bTumor invades seminal vesicle(s)
T4Tumor is fixed or invades adjacent structures other than seminal vesicles, such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall
Pathological stages
T category
T2Organ confined
T3Extraprostatic extension
T3aExtraprostatic extension (unilateral or bilateral) or microscopic invasion of bladder neck
T3bTumor invades seminal vesicle(s)
T4Tumor is fixed or invades adjacent structures other than seminal vesicles, such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall
N category
NXRegional lymph nodes were not assessed
N0No positive regional lymph nodes
N1Metastases in regional lymph node(s)
M categoryM criteria
M0No distant metastasis
M1Distant metastasis
M1aNonregional lymph node(s)
M1bBone(s)
M1cOther site(s) with or without bone disease
Pelvic lymph node (N) staging

Pelvic lymph nodes get their own stage. They may be staged using enlarged lymph nodes on imaging (clinical staging), or based on dissection (PLND) and biopsy (pathological staging). The definition of “pelvic lymph node” includes the following groups: pelvic, hypogastric, obturator, iliac, and sacral (lateral, presacral, or promontory [ie, Gerota]). Recent studies have shown that the definition should probably be enlarged to include the common iliac nodes (see this link and this one). For the current edition, those lymph nodes are classified as M1a rather than N1.

Changes from the 7th edition

The major changes are:
  • T stage based on DRE only. Imaging is never used. (Nor is biopsy)
  • Dropped the term “extracapsular” in favor of “extraprostatic.”
  • No pathological T2 subcategories.

Risk stratification

AJCC has its own risk stratification system that uses the TNM staging data as well as PSA and Gleason Grade Groups. They designate their risk categories with roman numerals (e.g., IVB) and refer to them as “Prognostic Stage Groupings.” This may lead to some confusion; for example, a man with stage pT4, N0, M0, any PSA, and Grade Group 1-4 is “Stage Group IIIB,” while “Stage Group IV” refers to patients with any T stage but with N1 or M1. A patient hearing a doctor say, “You are stage four,” may be curable or incurable, depending on whether the four is the Arabic numeral (4) or the Roman numeral (IV). Fortunately, the most common risk stratification system in the US is the NCCN, which uses the designations “low risk,” “intermediate risk” or “high risk,” with sub-categories for each. Risk stratification systems may include many other risk factors beyond stage, grade and PSA. It is a complex topic which will be dealt with at a later time.

Judgment

While there are very good reasons for the staging rules established by AJCC, they do not replace judgment. MRIs, PET scans, genetic data, and detailed biopsy findings, while not part of the AJCC system, should not be ignored if available. The clinician seeing a moderate bulge on an MRI that he could not feel on a DRE is justified in treating the patient as if he has extraprostatic extension, and possibly recommending against surgery and for brachy boost radiation. AJCC staging is an aid to judgment, not a replacement for judgment.

Tuesday, March 21, 2017

No need to go through 38-44 treatments with IMRT anymore

There have been several hypofractionation trials maturing in the last couple of years. With minor exception, they all tell the same story: external beam radiation therapy (EBRT) can be completed in less time without loss of efficacy or increase in toxicity. Hypofractionation means completing EBRT in fewer treatments or fractions using higher doses per fraction.

Catton et al. now report the 5-year outcomes of a multi-institutional, multinational (27 centers in Canada, Australia and France) randomized clinical trial (called the “PROFIT” trial) among 1,206 intermediate-risk patients treated from 2006 to 2011. All patients received radiation doses now considered curative: 78 Gy in 39 fractions (conventional fractionation - CFN) or 60 Gy in 20 fractions (hypofractionation - HFN). The doses are biologically equivalent for cancer control, no ADT was allowed. After median follow-up of 6.0 years:

  • 5-year freedom from biochemical or clinical failure was 85% in both groups
  • Acute urinary toxicity, grade 2: 27% in both groups; grade 3:4% in both groups 
  • Acute rectal toxicity, grade 2: 16% for HFN*, 10% for CFN; grade 3: <1% in both groups 
  • Late term urinary toxicity, grade 2: 20% for HFN, 19% for CFN; grade 3+:2% for HFN, 3% for CFN Late term rectal toxicity, grade 2: 7% for HFN, 11% for CFN*; grade 3+: 1% for HFN, 3% for CFN 
*Difference between arms was statistically significant, but not meaningful

The table below summarizes the key oncological and late-term toxicity outcomes of the various hypofractionation trials:

Randomized Clinical Trial
Risk Groups
Fractionation
5-yr bPFS
Urinary toxicity
Grade 2+
Rectal toxicity
Grade 2+
Ref.
PROFIT
100% intermediate
60 Gy/20fx
78 Gy/39fx
85%
85%
22%
21%
8%
14%
1
Fox Chase
67% Intermediate, 33% high
70.2 Gy/26fx
76 Gy/38fx
77%
79%
22%
13%
18%
23%
2
CHHiP
73% intermediate, 15% low, 12% high
60 Gy/20fx
74 Gy/37fx
91%
88%
12%
9%
12%
14%
3
MD Anderson
71% intermediate, 28% low, 1% high
72 Gy/30fx
75.6 Gy/42fx
96%
92%
16%
17%
10%
5%
4
RTOG 0415
100% low risk
70 Gy/28fx
73.8 Gy/41fx
94%
92%
30%
23%
22%
14%
5
HYPRO
>70% high, <30% intermediate
64.6 Gy/19fx
78 Gy/39fx
81%
77%
41%
39%
22%
18%
6, 7
Cleveland Clinic
49% low, 51% intermediate
70 Gy/28fx
78 Gy/39fx
94%
88%
1%
2%
5%
12%
8

Hypofractionation has demonstrated equal efficacy and side effects compared to conventional fractionation. Hypofractionation requires greater care on the part of the radiation oncologist. He must use advanced image guidance with placement of fiducials or radio transponders and localization with cone beam CT, set tighter margins, lower dose constraints for organs at risk, assure adequate bladder filling and lack of bowel distension at each treatment, use fused MRI/CT images if possible, and have very rapid linacs to minimize intrafractional motion. With this much cumulative level 1 evidence, it is hard to justify the use of conventionally fractionated EBRT anymore. Patients should not have to endure 38 or more treatments, and pay the extra cost of that, even if insurance or Medicare is willing to pay. Patients should shop for radiation oncologists who have experience with hypofractionation, or preferably, with extreme hypofractionation (SBRT).

Wednesday, March 15, 2017

Brachy Boost: The gold standard for progression-free survival of high risk prostate cancer

Several randomized clinical trials have established the superior oncological outcomes of the combination of external beam radiotherapy with a high dose rate brachytherapy boost (see this link). Last year, the results of the first randomized clinical trial of the combination of external beam radiotherapy with low dose rate brachytherapy, the ASCENDE-RT trial, was presented at the 2015 Genitourinary Conference (reported here). We now have the full details of the oncological outcomes (toxicity outcomes will be reported separately).

Morris et al. reported on 398 intermediate (31%) and high risk (69%) patients treated at 6 facilities in British Columbia and Toronto. All patients received 12 months of androgen deprivation beginning 8 months before radiation therapy. and continuing 4 months after the start. Androgen deprivation consisted of a GnRH agonist (Eligard or Suprefact) with an antiandrogen (bicalutamide or flutamide) given for the first 4 weeks. The radiation treatment was either of:
  • EBRT-only: 78 Gy in 39 fractions using 3D-CRT
  • Brachy boost: 46 Gy in 23 fractions of EBRT (3D-CRT) + 115 Gy of I125 seeds
It is worth noting that the brachy boost dose used in this trial is compared to an EBRT dose that is considered to be high enough to be curative by today's standards.

With 6.5 years of median follow-up, the 9-year biochemical progression-free survival (bPFS) was:
  • 85% for the brachy boost cohort vs. 65% for EBRT only
  • The hazard ratio was 2.3 (i.e., those getting EBRT only were 2.3 times as likely to relapse compared to those getting the brachytherapy boost)
  • Among those with high-risk prostate cancer, 9-year bPFS was 83% for the brachy boost cohort vs. 62% for EBRT-only.
  • Among those with intermediate-risk prostate cancer, 9-year bPFS was 94% for the brachy boost cohort vs. 70% for EBRT-only.
  • Among those who did not relapse, the median nadir PSA was 0.01 ng/ml (54% undetectable) for the brachy boost cohort vs. 0.25 for EBRT-only (8% undetectable).
  • In this length of follow-up, metastases, prostate cancer-specific mortality, and overall mortality were rare events, and were not statistically significantly different. Median age was 68.
This analysis did not address toxicity outcomes, but, as previously reported, the improved oncological outcomes came at the expense of toxicity:
  • Late term Grade 2 or higher genitourinary (GU) toxicity was higher for the brachy-boost group. 
  • Late term Grade 3 GU toxicity reached 19% for the brachy-boost group vs. 5% for the EBRT-only group. 
  • Late term gastrointestinal (GI) toxicity was similarly mild for both groups.
The use of 3D-CRT rather than IMRT (which is now the more prevalent form of EBRT) probably affected toxicity, especially with the wider field of the brachy-boost therapy.

This should establish brachy boost therapy (using either a high dose rate or low dose rate brachy boost) as the gold standard for oncological control for high risk prostate cancer. Perhaps equivalent outcomes with less toxicity may be achievable for both high risk and intermediate risk patients using high dose rate brachy monotherapy, SBRT monotherapy, or SBRT boost therapy. But for now, those are experimental approaches in high risk patients. The optimal duration of ADT use has yet to be defined. Patients with pre-existing urinary conditions should approach boost therapy with caution.

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.

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

Friday, March 10, 2017

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.

Tuesday, March 7, 2017

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.





Thursday, March 2, 2017

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.




Monday, February 13, 2017

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.

Friday, February 3, 2017

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.