Showing posts with label risk stratification. Show all posts
Showing posts with label risk stratification. Show all posts

Tuesday, March 27, 2018

Should perineural invasion influence active surveillance and radiation treatment options?

Perineural invasion (PNI) is a risk factor detected on a biopsy in 15%-38% of men with a prostate cancer diagnosis. It means that the pathologist saw nerves infiltrated with cancer cells. As they grow, tumors cause nerves to innervate them. The cancer infiltrates in and around small nerves that connect to nerve bundles (ganglia) outside the prostate, becoming a route of metastatic spread (see this link).  The data on whether it is independently prognostic for T3 stage after surgery are equivocal, although PNI is often the mechanism for extracapsular extension.  After considering Gleason score, PSA, stage, and tumor volume, PNI does not seem to add much to the risk of recurrence after surgery. PNI is not associated with higher surgical margin rates, and it is not considered sufficient to preclude nerve-sparing surgery. An open question is whether it raises risk enough to warrant more aggressive radiation options, like brachy-boost therapy, whole-pelvic radiation and long-term adjuvant ADT.

Peng et al. retrospectively examined the records of 888 men who were treated with external beam radiation at Johns Hopkins from 1993 to 2007. 21% of them had biopsy-detected PNI. Compared to men with no PNI, those with PNI had:

  • lower 10-year biochemical failure-free survival (40% vs 58%)
  • lower 10-year metastasis-free survival (80% vs 89%)
  • lower 10-year prostate cancer-specific survival (91% vs 96%)
  • similar 10-year overall survival (68% vs 78%)

It isn't surprising that PNI is associated with higher risk, but does it add any new information not already captured by Gleason score, stage, and PSA (i.e., the NCCN criteria for risk stratification)? After correcting for those other risk factors, PNI was still found to be associated with lower rates of biochemical failure-free survival, but not of metastasis-free survival, prostate cancer specific survival or overall survival.

PNI independently predicted for lower biochemical failure-free survival in low-risk and high-risk patients, but not for intermediate-risk patients.  Although it is a relatively rare finding among low-risk patients, when found, PNI also predicted for lower prostate cancer-specific survival. Biochemical failure in low-risk men with PNI differed according to whether they received adjuvant ADT or not:

  • 33% in men not treated with ADT
  • 8% in men treated with ADT

An earlier analysis of 651 men treated at the University of Michigan similarly found an association between PNI and biochemical failure-free survival, freedom from metastases, prostate cancer-specific survival, but not overall survival at 7 years after radiation treatment. They also found a more marked effect among high-risk patients. A meta-analysis of 5 studies among men who received EBRT found that PNI increased the risk of biochemical recurrence by 70%.

Although PNI may increase the risk associated with an unfavorable intermediate-risk or high-risk diagnosis markedly, brachy boost therapy is the best treatment for any such patient regardless of PNI, according to our best retrospective study and prospective studies like ASCENDE-RT. This study suggests that adding ADT may be beneficial for these patients. Low and intermediate-risk patients with PNI who opt for conventional IMRT may also benefit from the addition of short-term ADT.

(update 4/2020) In a ten-year follow-up of the TROG 03.04 RADAR  randomized trial, Delahunt et al. found that PNI detected at biopsy was independently associated (after adjusting for other risk factors) with later appearance of bone metastases.

Biopsy-detected PNI may have implications for active surveillance. Cohn et al. detected PNI in only 8.5% of 165 men selected for active surveillance. Within 6 months, they were given a confirmatory biopsy. AS was excluded at the confirmatory biopsy due to higher Gleason grade in 57% of men with PNI vs. 13% of men without PNI. PNI should not automatically exclude active surveillance, but it should be recognized as a risk factor in the decision. It would be interesting to know if there is an association between PNI and genomic risk (based on Oncotype Dx, Prolaris, or Decipher tests). It has yet to be determined whether PNI is still a significant risk factor after NCCN risk category, % core involvement, and genomic risk have been accounted for.

It is worth noting that PNI is not always reported on biopsy cores by pathologists, and there is no uniform method for quantifying it. Whether nerve infiltration is small or large, or outside or inside the nerve sheath, it is just reported as PNI, if it is reported at all. It will be difficult to include PNI as part of any risk stratification system until its reporting has been standardized.

Note: Thanks to Daniel Song for allowing me to see the full text of the study.

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)
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.


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, August 30, 2016

Risk Stratification for Radiation Therapy

Risk stratification involves assigning patients to categories based on diagnostic risk factors. The goal is to identify those patients who are more or less likely to respond to specific therapies (or active surveillance).  It is an aid to judgment for the patient and doctor, and helps assess prognosis and define the standards of care. It also provides for consistency between research studies so that they are more comparable. Because we depend on those studies for treatment guidelines, we don’t want to change the risk categories frequently.

In 1998, Anthony D’Amico introduced the most widely accepted risk stratification system. It has since been tweaked somewhat by consensus of the National Comprehensive Cancer Network (NCCN). It mainly relies on 3 risk factors – PSA (in 3 groups), Stage (in 3 groups), and Gleason score (in 4 groups) to create 3 risk categories (low, intermediate and high) with 2 sub-categories in each of the three. The “very low risk” sub-category also includes number of positive cores, highest % cancer in those cores, and PSA density. The “very high risk” sub-category also includes number of cores with Gleason score 8-10.

There are competing risk stratification systems. UCSF, for example, uses a system called the CAPRA score that includes age and % positive biopsy cores. Each risk factor is assigned points, and the points are summed to determine the risk category. It is also possible to use nomograms based on historical statistics to help with prognosis. While nomograms will always produce a risk probability as a%, those probabilities may, in some cases, be projected off of a very small dataset and their accuracy is questionable.

A risk stratification system is created through a multistep process. The risk factors are assessed to find the ones that independently predict recurrence after treatment.  For example, stage, Gleason score and PSA, although they are somewhat correlated, independently predict recurrence. Those risk factors are then grouped such that the risk is about the same within the group, but is different between the groups. For example in the NCCN system, Gleason scores of 8, 9 and 10 are all roughly the same at predicting recurrence, but carry much greater risk than lower Gleason scores. Then the risk factors are combined (either by selection or by adding points) such that the risk is about the same within the risk category, but significantly different between risk categories.

D’Amico developed his risk stratification system based on data from patients treated from1989 to 1997. His dataset comprised 888 surgery patients treated at the University of Pennsylvania, as well as 766 patients treated with external beam radiation, 66 patients treated with LDR brachytherapy monotherapy and 152 patients treated with LDR brachytherapy plus ADT at the Joint Center for Radiation Therapy in Boston. He only looked at biochemical progression, which was defined as PSA≥0.2 ng/ml for surgery patients and 3 consecutive rises for radiation patients. External beam radiation was only 67 Gy – far below what is now considered curative. Biochemical recurrence after radiation has since been redefined because the previous definition over-predicted clinical recurrence. Radiation therapies did not include combined modalities, HDR brachytherapy, SBRT or proton therapy.

In 2007, Johns Hopkins validated D’Amico’s risk groups among 6,652 prostatectomy patients. In 2008, the Mayo Clinic validated D’Amico’s data among 7.591 patients treated with radical prostatectomy only. They also broadened outcome data to include clinical recurrence, evidence of systemic progression, overall and cancer-specific survival. I am not aware of any validation studies for external beam radiation or brachytherapy.

Because treatments and outcomes have changed so much for radiation therapies, it may be time to take another look at the risk stratification used for radiation therapy. An Italian group looked at data on 2,493 patients treated at 10 centers between 1997 and 2012. Patients were treated with a median dose of 76 Gy of EBRT and 62% also received ADT (almost half were high risk as defined by NCCN.) They call their risk stratification system the Candiolo Classifier. Like the CAPRA score system, it assigns points to each risk factor. Classification is based on the sum of those points.

They found that age and% positive cores at biopsy significantly added to their model’s ability to stratify the risk of patients. The following table shows the breaks that discriminated best, and the number of Candiolo points assigned to each risk factor.

Risk Factor
Candiolo  (points)
<70 (0)
≥70 (22)
% Positive Cores
1-20% (0)
21-50% (29)
51-80% (50)
81-100% (81)
<3 positive cores, ≤50% cancer in a core, and PSA density <0.15 ng/ml/g used in “very low risk” definition.
<50% positive cores used in “favorable intermediate risk” definition.
>4 cores with GS8-10 used in “very high risk” definition.
PSA (ng/ml)
<7 (0)
7-15 (42)
>15 (96)
Gleason scores
3+3 (0)
3+4 (35)
4+3 (48)
8 (76)
9-10 (106)
5+(5,4,or 3)
T1 (0)
T2 (17)
T3-T4 (58)

They defined 5 risk classes that discriminated well with risk of biochemical recurrence. The following table shows the biochemical progression-free survival (bPFS) for each risk class at 5 and 10 years. The relationship is similar for clinical progression-free survival, systemic (metastatic) progression-free survival, and prostate cancer specific survival.

Risk Class
5-yr bPFS
10-yr bPFS
Very Low
Very High

The Candiolo system beat the 3-tiered (low, intermediate and high risk) NCCN system in predicting all measures of progression after external beam radiation. For bPFS, its concordance index (a measure of how accurate its predictions are) was 72% vs. 63% for the NCCN system. It predicted metastases and prostate cancer survival with an accuracy of 80% vs. 69% for the NCCN system.

The Candiolo Classifier certainly seems to be an improvement, but should be validated by another group of researchers before it gains wider acceptance. Ideally, we would also have data on risk categories suitable for other kinds of radiation therapy, boost therapies, use of adjuvant ADT, and whole-pelvic radiation.

This “new, improved” system raises some interesting questions:

• The D’Amico/NCCN risk stratification system is based on antiquated data and a small dataset for radiation. Is it time for a make-over?

• Do we have to have a single risk stratification system against which all therapies should be assessed? It certainly facilitates comparisons between therapies if we have a single system. However, different risk factors (e.g., age and % positive cores) may be important in determining the risk associated with one therapy but not another.

• At what point has our ability to measure risk factors changed enough that the entire stratification system should be altered? The ability of multiparametric MRIs and advanced PET scans to more accurately assess stage and to target biopsy cores to more suspicious areas may increase the detected risk beyond what it was when the system was first set. Also, the Gleason scoring system and the AJCC staging system has changed over the years.

• How do we maintain comparability with older clinical trials and with our databases if we change our risk stratification? Many trials were established a decade or more ago with pre-set risk groups. When the data mature, will they be hard to analyze? A similar effect occurred when biochemical recurrence after radiation was redefined by the Phoenix consensus in 2005. In many studies, both definitions were presented for a while.

• Can a stratification system from Europe gain acceptance in the US and particularly by the NCCN? How do we get widespread agreement on which system is the “gold standard.” As far as I know, the CAPRA Score is only used by UCSF, even though it is an NCCN member.

• What is the role of other biochemical measures? PHI, 4KScore, PCA3, Oncotype Dx and Prolaris all measure risk. Should any of them be used in a risk stratification system? Should first-degree relatives who have had prostate cancer be included as a risk factor? What about African-Americans? And how should PSA be counted when the patient is taking 5ARis (Proscar or Avodart) for BPH?