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.

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 8^th edition (at this link), which will become effective beginning January 2018. For the most part, it is consistent with the 7^th 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 7^th 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 8^th edition, such pathological evidence is not used for staging.

The clinical stages are:

T category
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Clinically inapparent tumor that is not palpable
T1a	Tumor incidental histologic finding in 5% or less of tissue resected
T1b	Tumor incidental histologic finding in more than 5% of tissue resected
T1c	Tumor identified by needle biopsy found in one or both sides, but not palpable
T2	Tumor is palpable and confined within prostate
T2a	Tumor involves one-half of one side or less
T2b	Tumor involves more than one-half of one side but not both sides
T2c	Tumor involves both sides
T3	Extraprostatic tumor that is not fixed or does not invade adjacent structures
T3a	Extraprostatic extension (unilateral or bilateral)
T3b	Tumor invades seminal vesicle(s)
T4	Tumor 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
T2	Organ confined
T3	Extraprostatic extension
T3a	Extraprostatic extension (unilateral or bilateral) or microscopic invasion of bladder neck
T3b	Tumor invades seminal vesicle(s)
T4	Tumor is fixed or invades adjacent structures other than seminal vesicles, such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall
N category
NX	Regional lymph nodes were not assessed
N0	No positive regional lymph nodes
N1	Metastases in regional lymph node(s)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
M1a	Nonregional lymph node(s)
M1b	Bone(s)
M1c	Other 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 7^th 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.

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).

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.