3-Dimentional Pathological Mapping of the Prostate (3DPM) in Prostate Cancer and Focal Therapy:
Prostate Cancer (PCa) is a multifocal disease with different patterns of cellular differentiation, these patterns are described with the modified classification of Dr Donald Gleason and are known are Gleason Score.
Usually these patterns co-exist since diagnosis.
As we tend to measure PSA levels for various reasons (screening) it is common to perform transrectal biopsies of the prostate under ultrasound guidance in patients with low PSA levels, and
1. to pick up a lesion of PCa and miss several others next to the previous one,
2. not to detect PCa although the presence of adverse PSA parameters,
3. to pick up only a microscopic focus of cancer and miss others in the rest of the gland, Jonathan Epstein at John Hopkins Hospital found that the patients that have only a microscopic focus of PCa detected at the 12 core transrectal biopsy have 45% chances to have insignificant cancer on the specimen of the radical prostatectomy leading to the conclusion that they were “overtreated” and possibly became incontinent or impotent. The same happens in 80% of the patients when a patient has less than 3 positive cores for PCa in the TRUS guided biopsies with less than 50% of the length of each core involved and Gleason Score ≤ 6 with PSAD: 0.15. But still 1/5 of the patients with microfocus of PCa detected are found to have extensive and aggressive disease that merits only radical treatment as any conservative management would not have been a reasonable choice.
4. to pick up not PCa but lesions that are called pre-cancerous lesions, that might evolve in PCa or they co-exist with PCa, these are the High Grade Prostate Intraepithelial Neoplasia (HG-PIN), the Atypic Small Acinar Proliferation (ASAP) and the Proliferative Inflammatory Atrophy (PIA) that apparently predict presence or development of PCa in 50% of the patients, who need to undergo repeated transrectal biopsies of the prostate,
5. not to have a comprehensive Gleason score representation from the biopsies.
Recent studies provided data according which if the patient meets some criteria to take in consideration not to undergo radical treatment as this will not affect either his length of life nor his quality of life. (link AUA criteria) Also, during the last 10 years there is the tendency to evolve the treatment of PCa according the pathway of treatment of breast cancer in other words with less aggressive and handicapping operations.
6. The query that rises is how to select the patients without jeopardising their safety?
The 3 Dimentional Pathological Mapping of the prostate (3DPM) is a novel biopsy technique that was described, developed and standardised as a protocol by Dr Winston E. Barzell in Sarasota Memorial Hospital (FL, USA) starting in 2002-2003 in order to be able to have extensive histological data for the selection of patients for Active Surveillance, Focal Therapy or Radical Treatment, himself as other clinicians as well (Dr Gary Onik) proved that without accurate histological data more than 50% of the PCa patients were directed towards a wrong decision regarding their treatment due to the non precise biopsy data obtained from standard transrectal guided biopsies.
Each patient deserves the best treatment regarding the disease and it is very unconfortable not to able to give some answers due to the lack of histological data. This tecnique provides an extensive sampling which turns the “probability” based discussion in “histology” based one with answers and an extremely accurate prediction of the natural history of each patient’s individual condition. Also it helps to pick up a very precise treatment in view of the novel trends which tend to cure PCa without turning the patient impotent or incontinent. In Greece nearly 25-40% of the cases of PCa detected are localised only in one lobe of the gland so theoretically could be eligible for focal treatment.
The 3DPM is performed under light 60-90 minutes general or spinal anaesthesia as a Day Surgery procedure and involves the use of transrectal obtained biopsies (or just the data from previous biopsies especially if performed by the author) and the saturation of the gland transperineally using special equipment and operator’s skills and a different ultrasound probe. Once the histopathologist examines under the microscope and reports the biopsies the surgeon performs a 3 dimentional reconstruction of the data and provides to the patient a stereotactic “map” of the histology of the prostate. These data can be discussed in order to “taylor” the treatment in the needs of each patient instead of offering a largely radical treatment to everyone.
The first ever presentation in Greece regarding the results of this technique was performed by Dr Karamanolakis in February 2010 at the 3rd International Congress on Controversies in Urology (poster CURY) where he presented the first results of his personal series and the impact in treatment management after his training at the Sarasota Memorial Hospital.
Prostate Cryoablation: Clinical Indications and Patient Selection
How cryosurgery works
Primary Cryoablation (Total Gland)
Total gland ablation of the prostate is the complete ablation of the prostate and periprostatic tissue with lethal ice at –40°C. It should be noted that Primary Cryoablation may be especially attractive for patients at risk for positive margins since the ice can be advanced beyond the prostate capsule. Additionally, Cryoablation is not limited by Gleason score. Finally, since the procedure can be performed under general or spinal anaesthesia it may be appropriate for patients who are unable to tolerate the risks of general anaesthesia or possible per- and post-operative complications.
The optimal candidates for Primary Cryoablation are patients with:
- Biopsy confirmed local disease
- Low, medium or high-risk primary prostate cancer
- Stage T1 through T3
- Gland <,,,,,,,,,45cc is optimal (larger glands may be amenable to treatment if downsized using androgen ablation).
Salvage Cryoablation is indicated for those patients with localized disease who have failed a course of radiation therapy, either external beam, HDR, brachytherapy or a combination of radiation therapies. In the USA, Medicare has approved coverage for patients who meet one of the following conditions:
- Biopsy confirmed local disease and/or
- StageT2B, or below, and/or
- Gleason Score <,,,,,,,,, 9, and/or
- PSA <,,,,,,,,, 8ng/mL.
Cryoablation may be especially suited for use as a nerve sparing or focal therapy. The two clinical approaches are Nerve Sparing TCAP and Focal TCAP. The methodology used depends upon the believed extent of the patient’s disease. Regardless of the approach used, it is important to note that cryoablation has a proven ability to be repeated without increased morbidity unlike radiation or prostatectomy. Because a portion of the prostate is intentionally untreated extensive diagnostic biopsy and vigilant follow-up is essential for any partial gland procedure.
As focal therapy of prostate cancer we intend the subtotal ablation of the gland
that attempts to:
a. eliminate the cancer, yet
b. to preserve uninvolved tissue in an attempt to
c. maintain patient’s quality of life (QoL) in other words, normal erectile function, urinary control and bowel control.
This could be delivered through various modalities as demonstrated to this graphic.
This is something that two decades ago we could not even dream about it, as the early detection of this disease was not feasible. At the dawn of the 21st century, with all the accumulated knowledge and effective PSA trial or individual screening and safer extensive protocols of prostate biopsies led to:
- Stage migration
- Fewer tumours per prostate
- Smaller tumour volume.
It has been demonstrated with several analyses of demographic data that there was a gradual migration towards early detection of low stage, low grade disease from 1988 to 2006. This also created a shift towards increased frequency of unilateral lesions (especially pT2a = cancer in biopsy tissue only in one lobe of the gland) can lead to a significant change in the management paradigm in favour of organ-sparing focal unilateral ablation of the prostate on selected cases.
So, actually we have the opportunity to detect “microtumours” (small lesions) that they may have different tumour biology than larger tumours.
During the last years we had the chance to have the first results of large trial regarding “watchful waiting” and “active surveillance” as management of prostate cancer patients due to the fact that we recognised the importance of over-treatment of many of those patients.
According the CAPSure database 94% of men with low risk prostate cancer will still receive radical whole gland therapy. Combining the above in another demographic database study we realised that if expectant management is appropriate for low risk cancers then we have overtreated 10% of the patients with radical prostatectomy and 45% of the patients with radiotherapy. Focal treatment could also be considered as something intermediate for those patients that they are not happy to do nothing for their cancer but also think that radical treatment would be too much for their case.
Why we discuss this in 2010?
Because now we have widely available new technology, as we have re-evaluated our devices and concepts. We have better ablation devices, biopsy techniques and we wish to promote cancer imaging. Also, we have learned a lot from studies of other organs such as kidney cancer and mainly breast cancer and we have the awareness of those changing paradigms in current practice. There is a tendency in both sides of the Atlantic Ocean to spare the patients from complications associated with whole gland treatment (incontinence, impotence, changing in bowel habits). At last but not least, we tend to focus more on the issue of quality of life (QoL) because people live longer and they do wish to preserve their body functions as this is important especially for younger men, there is also a tendency in favouring minimally invasive techniques.
So, are we able to select amongst the patients with prostate cancer those that are eligible for receiving focal ablation of the gland without jeopardizing their cancer related survival?
Yes, as recently, the use of 3-dimentional transperineal mapping (3-DPM) biopsy for determining the extent of prostate cancer — when compared with the commonly used transrectal ultrasound (TRUS) biopsy — heavily impacted how patients` disease was managed in 70% of the cases. Combined with advanced imaging of the prostate it gives a pathological mapping of the organ in order to target the areas that we need to ablate. In other words it gives us the only actually available tool based on histological data in order to “tailor the treatment” on the individual cancer load and shape of the gland.
The concept of unilaterality actually seems to be the best way to guarantee a safety margin regarding achieving cancer care by ablating the focus/foci in one lobe (hemiablation) maintaining QoL for the patient as we spare a whole lobe with its vascular and nerve supply. In various series and the relative review papers we realized that 1 in 5 men diagnosed with prostate cancer had unilateral disease and was a perfect candidate for hemiablation (unifocality: 13-38% and unilaterality: 19-63%).
The data show that focal cryoablation is as good for prostate cancer control as any other treatment, including surgery, radiation and hormone therapy, but it is less invasive and traumatic for patients, preserves sexual and urinary function and has no major complications in expert hands.
With cryoablation, the urologist insert some probes through the skin, using imaging to guide / target the needle to the tumour or to a certain part of the prostate that has the cancer, the probe then circulates extremely cold gas to freeze and destroy the cancerous tissue. This minimally invasive treatment targets only the cancer itself, sparing healthy tissue in and around the prostate gland rather than destroying it, as traditional approaches do.
Minimally invasive urologists that practice focal treatment tailor that treatment to each patient`s disease. Instead of removing the entire prostate, or freezing the entire gland or using radiation on the entire prostate, we can find out where the cancer is and just destroy that part.
We`ve reached a tipping point: treating only the tumour instead of the whole prostate gland is a major and profound departure from the current thinking about prostate cancer. We also have found the way to avoid under-treatment of the candidates for focal therapy thanks to the 3-DPM biopsy protocol.
You can go home on the same day of the procedure, and you can repeat the treatment, if needed, in later years as it is necessary to undergo periodical follow-up in order to have a surveillance of the remaining tissue.
Calling focal cryoablation a male lumpectomy reflects the origins of this approach in the breast-sparing surgery that replaced radical mastectomy as the preferred treatment for breast cancer.
Unlike breast lumpectomy, a surgical lumpectomy for prostate cancer is not technically feasible, so to treat just a portion of the prostate, minimally invasive cryoablation is needed.
Cryoablation (or cryo or cryotherapy) spares as much as possible of the prostate gland and its neurovascular bundles, limiting the side effects of bladder control problems (incontinence) and erectile dysfunction (impotence) that result from more radical prostate cancer treatments. It also represents an advantage over "watchful waiting," because all treatment options are preserved.
Any risks are fewer and lesser in intensity than surgery, so if you have the equivalent chance of cancer being cured with far less chance of having any complications, why wouldn`t you choose it?
A study of involved 120 men who had focal cryoablation over the past 12 years, including testing the levels of prostate-specific antigen (PSA) in the blood, of those patients, 112 (93%) had no evidence of cancer — in spite of 72 being labelled medium to high risk for cancer recurrence. There were no local recurrences in the areas we treated, and with the ability to re-treat the 7% of patients who developed a focus of cancer at a different site in the gland, cryoablation was 100 percent effective in local control of the patient`s disease.
They reported that 85 percent of the men retained sexual function. Of those who did not have previous prostate surgery, all remained continent. Incontinence becomes a big issue with many patients. For some it`s a more important side effect than impotence.
The 3-D transperineal biopsy complements the focal cryoablation approach because earlier detection of smaller tumours increases the likelihood that a small tumor can be treated using cryoablation.
In another study, restaging of 180 patients who had previously undergone TRUS mapping biopsies who were considering conservative management for their cancer. The results showed that 70% of the men would have their management changed by the new information provided by 3-DPM mapping.
Through mapping, more than 50% of men who were diagnosed with cancer on one side of the prostate gland with traditional TRUS biopsy had undetected cancer on the other side as well in various studies including my personal series.
Management of prostate cancer is in great part determined by the Gleason score, a cancer ranking method indicating tumour grade and stage and the extent and location of a patient`s disease. When we restaged those men in an American series, we found that 22 percent of them experienced an increase in their Gleason score — meaning that they had a more aggressive cancer than was originally thought from their original biopsy. The 3-D mapping biopsy provided life-saving information.
This biopsy technique allows us to map the location of the tumor with tremendous precision and has the potential to greatly affect the decisions we make about treating prostate cancer.
The data are unequivocal. If you`re doing `watchful waiting,` get mapped.
If you`re having radiation or hormone therapy or thinking about getting a `nerve-sparing` radical prostatectomy, get mapped.
If TRUS doesn`t show all the cancer that`s present, you`re not going to have the proper treatment.
With 3-D transperineal mapping, a grid placed over the perineum (the area of skin between the rectum and the scrotum) allows an urologist to accurately map the location of each biopsy core removed. The cores are taken through the skin rather than through the rectum, allowing many more cores to be removed — about 50 or more compared to 10-12 in a TRUS biopsy.
The mapping grid also allows the location of the tumour to be known much more precisely, allowing an surgeon to cryoablate (freeze) only the tumour and not the whole prostate gland.
Controversy surrounds the treatment of prostate cancer, which usually grows slowly and initially remains confined to the prostate gland.
Growing evidence of overdetection and overtreatment in many men with low-risk tumours has led to a concept in the medical community of "watchful waiting" or observing a man`s disease progression prior to initiating treatment.
Many patients, however, feel uncomfortable with this strategy and may proceed to radical or aggressive treatment. When men must choose between `watchful waiting` and high-morbidity whole-gland treatments (like surgery and radiotherapy), a lumpectomy-type treatment, which has so markedly changed the management of breast cancer for women, is a welcome `middle ground` addition for those with prostate cancer.
Interventional cryoablation for prostate cancer is not experimental. This is a treatment option that doctors should discuss with their patients early on.
Most people don`t realize that you can surgically remove the whole prostate and, in 20% of the cases, the cancer can be left (called a positive margin).
Doctors should discuss cryoablation with patients early on, he advised, noting that recently the American Urological Association issued a best practice statement that indicated that cryotherapy is an option for men who have clinically organ-confined prostate cancer of any grade with negative metastatic evaluation. Since this interventional treatment is not widely known to doctors and patients, individuals will need to pursue it on their own.
1. Abstract 75: "Focal Therapy for Prostate Cancer — 120 Patients With Up to 12-Year Follow-up," G. Onik, Center for Safer Prostate Cancer Therapy, Orlando, Fla., SIR 34th Annual Scientific Meeting March 7-12, 2009.
2. Abstract 198: "3D Prostate Mapping Biopsy Has a Potentially Significant Impact on Prostate Cancer Management," G. Onik, M. Miessau, Center for Safer Prostate Cancer Therapy, Orlando, Fla., SIR 34th Annual Scientific Meeting March 7-12, 2009.
3. 3rd World Congress of Controversies in Urology February 25-28, 2010. (poster CURY)
Table 1: AUA Guidelines for proposed clinical definition of prostate cancer suitable for AS or focal therapy.
PSA<10ng/ml and PSAD<0.15ng/ml/ml
Either transperineal mapping biopsy or, if transrectal, number of cores adjusted to volume of the gland: 10 cores minimum +2 cores for every 10ml of prostate >40ml, to a maximum of 18 cores.
Imaging (MRI with or without MRSI)
Single, biopsy proven lesion on imaging.
PSA: prostate-specific antigen, PSAD: prostate-specific antigen density, MRI: magnetic resonance imaging, MRSI: magnetic resonance spectroscopy imaging.
* Defined as 1 of 12 regions of prostate (left or right, apex or middle or base, anterior or posterior).
Table2: EAU Guidelines for AS.
1. Different series have identified several eligibility criteria for enrollers:
- Clinically confined PCa (T1-T2)
- Gleason score ≤ 7
- PSA <15-20 ng/mL (5).
2. Moreover, different criteria were applied to define cancer progression, although all groups used:
- a PSA doubling time with a cut off ranging between ≤ 2 and ≤ 4years
- Gleason score progression to ≥ 7 at re-biopsy, at intervals ranging from one to four years.
Summary of deferred treatment
In presumed localised PCa (Nx-N0, M0):
- Stage T1a: well and moderately differentiated tumours. In younger patients with a life expectancy of <10 years, re-evaluation with PSA, TRUS and biopsies of the prostatic remnant is recommended (level of evidence: 2a).
- Stage T1b-T2b: well and moderately differentiated tumours. In asymptomatic patients with a life expectancy of > 10 years (level of evidence: 2a).
In presumed localised PCa (Nx-N0, M0):
- stage T1b-T2b patients who are well informed and have well differentiated (or Gleason 2-4) PCa and a life expectancy of 10-15 years
- all patients not willing to accept side-effects of active treatment
- well informed, asymptomatic patients with high PSA levels for whom cure is unlikely (level of
In locally advanced disease (stage T3-T4):
- asymptomatic patients with well or moderately differentiated cancer, PCa and a short life expectancy
(level of evidence: 3)
- PSA < 50 ng/mL and PSA doubling time > 12 months (level of evidence: 1).
Table 3: Deferred treatment or Active surveillance according SELCN Guidelines:
This term is used to describe a treatment that includes an active stand point to postpone treatment until required.
In presumed localized disease (N0, Nx M0)
- T1a well and moderately differentiated disease. In younger patients with Life expectancy over 10 years re-evaluation with PSA follow up and TRUS guided rebiopsy is recommended
- T1b all patients with a life expectancy of >10 years or good performance status should have PSA monitoring and TRUS guided rebiopsy after 3-6 months.
- T2 disease well and moderately differentiated with life expectancy of <10 years and asymptomatic.
- Presumed localized disease all staging and gradings if patient is unwilling to accept side effects of active treatment.
- Locally advanced disease (T3-T4). Asymptomatic patients with well or moderately differentiated tumours and short life expectancy in metastatic disease.
Deferred treatment for metastatic disease is only acceptable in asymptomatic patients with a strong wish to avoid treatment related side effects. The MRC trial has highlighted the risk of developing symptoms (pathological fractures and spinal chord compression) without receiving the possible benefit from hormonal treatment. These patients need close follow up.