Focal Therapy - Brief Overview and Focal Cryo Experience at PIOA

Duke K. Bahn, MD • Prostate Institute of America (www.PIOA.ORG) • Ventura, California (805) 585-3082  or  (888) 234-0004

 

DrBahn

 

INTRODUCTION: The progression of clinically localized prostate cancer is usually slower than other cancers, and has confounded the development of a national consensus regarding the optimal treatment for the disease. In addition, most of the observers believe that screening with PSA can result in the over-treatment of prostate cancer. However, the justification for PSA screening and treatment is still accepted by most experts due to the estimated 27,540 death from this disease last year in the United States. Although some prostate cancers are aggressive, the relatively slow growing nature of clinically localized prostate cancer has refuted the current established treatment options for the disease. This argument is supported by the fact that about one third men over 50 years of age will display incidental prostate cancer at autopsy, but only 10 – 16% will develop invasive prostate cancer during their life time, and only 2.5% will die from it.
Current treatment options for prostate cancer (PC) are either active surveillance or radical intervention treating the entire prostate (surgery, radiation, and others). Radical therapy may maximize the cancer control, but with a certain degree of sexual and urinary complications which may seriously affect quality of life. Active surveillance will not impact a patient’s sexual and urinary function, but it can carry the psychological burden of missing the window of opportunity for cure for some men.
This article reviews many forms of novel approaches that are called “focal therapy” or “subtotal therapy”. The goal of this approach is not only to achieve the same level of cancer control as seen in radical therapy, but also to maintain few or no complications in a selected group of men who have early stage organ- confined disease.  

 

DrBahn_CDUS

Dr Bahn has been targeting prostate cancer with color Doppler ultrasound for almost 2 decades.

DEFINITION OF FOCAL THERAPY:
Focal therapy is a generic term for destroying the tumors only by treating a portion of the prostate, and leaving the prostate gland intact. There is no consensus of opinion on the method of focal therapy. Some researchers treated only areas of known cancer while others have tried to treat the entire one half of the prostate that showed tumor involvement. There was also an attempt to treat the entire gland excluding the neurovascular bundles. Therefore, some advocate the term “subtotal therapy” instead of “focal therapy”. But “focal therapy” is the most common term, now spanning over a decade of research.

The advantages of focal therapy include:
1. It is a minimally invasive procedure using highly accurate imaging to target and destroy only the cancerous tissue within the prostate.
2. The side effects (mainly urinary and sexual dysfunctions) are far less frequent and severe than other conventional therapies.
3. If it fails, other currently available treatment options remain viable. In other words, it will not burn the bridge behind you.
4. It usually performed as an out-patient basis, if not an overnight hospital stay.
5. Recuperation from the procedure is mostly uneventful and quick.


The disadvantages of focal therapy include:
1. It is not widely available. The patient may need to travel to find an expert.
2. Parts of the procedure may not be covered by insurance for some men. The patient should ask about cost, insurance, etc.

 

TARGETED FOCAL (SUBTOTAL) CRYOABLATION
Focal (subtotal) cryotherapy is defined as the less than complete ablation of the prostate gland with freezing or ice.
A known tumor site (lobe) is aggressively treated, but the contralateral (opposite side) lobe of prostate tissue and surrounding structures are spared. This method offers targeted local cancer control, while preserving urinary continence and sexual potency for most. (See Table 1)
In the PSA era, many cancers are detected at an early organ contained stage, and may be confined in one lobe of the prostate. As many as 35% of clinically localized prostate cancers are unifocal and may be candidates for focal therapy. A tumor less than 0.5cc is used as a criterion for low-volume disease; this may not require any type of intervention. Others argue that even tumors smaller than 0.5 cc may be clinically aggressive and may require intervention. It is indeed a burden to identify the proper candidates for focal therapy.

 


PATIENT SELECTION FOR FOCAL CRYOABLATION:
Optimal patient selection criteria are not clearly defined nor agreed upon within the urology field. However, it is essential that the patient have unifocal (1 focus lesion) or unilateral (1 side of gland) prostate cancer. We perform a color Doppler transrectal ultrasound and staging biopsy (in addition to the initial extended blind biopsy that usually was already performed by the patient’s physician). Some centers advocate more invasive saturation biopsy to confirm the known tumor site but more importantly to reconfirm the absence of any additional tumor in the other lobe. If an unexpected clinically significant cancer is found in the other lobe by repeated biopsy, the patient is excluded as a candidate for focal therapy. In general, low-risk prostate cancers are preferred but moderate to high-risk cancers in men with medical co-morbidities can also be considered. Only unilaterality, not pre-operative PSA level or tumor differentiation (Gleason grade), are the defining issue. Men with extracapsular extension or seminal vesicle invasion can also have focal therapy.
Focal cryotherapy can also be offered as a salvage therapy (failure after any type of organ preserving treatment, such as radiation, cryotherapy, HIFU, and photodynamic therapy) as long as the recurrent disease is unilateral in location.

 


METHODS:
The cryoablation procedure uses extremely cold temperature (ice) to ablate the tissue. The third generation technology uses argon gas for cooling and helium for warming. It consists of two freeze and thaw cycles after the placement of a urethral warming device. Under general anesthesia or spinal block, cryoprobes are placed percutaneously under ultrasound guidance at strategic locations to be frozen. If seminal vesicle invasion is present, it would also be frozen by placing one of the probes in the lumen of the seminal vesicle. Usually 2-4 cryoprobes are used, depending on the size of the lesion and the size of the prostate. (See Figure 1) A single probe may be placed in the contralateral lobe close to the urethra and external sphincter in case heating is necessary to protect these organs (simultaneous heating and cooling). This can be a useful technique if the prostate gland volume is small. This combination of aggressive freezing at targeted locations within the prostate while maintaining the integrity of the urethra, external sphincter, and contralateral lobe, including the neurovascular bundle, is the premise of focal cryoablation.

 

Cryotherapy is an outpatient based procedure performed as same day surgery. However, if the patient visits from long distance he will have overnight observation in the hospital and discharged following day with a Foley catheter in place. The catheter is usually removed in 3-5 days. (See Figure 1)
As a follow up PSA levels should be checked once every three months for one year and every six months thereafter. Biopsy is encouraged at one year, two years, five years, and anytime there is a PSA elevating trend.

 

RESULTS:
Based on multiple publications in the literature (See Table 1.), the overall oncologic outcome of focal cryoablation therapy is encouraging. We recently published focal cryotherapy data for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow up of 3.7 years (1-8.5 years). Complete follow up was available in 70 patients. No patient died or developed metastasis. Pre-cryotherapy PSA was 5.9 ng/ml and Gleason score was 6 (n=30) and 7 (n=43). More patients had Gleason 7 (Intermediate risk) than Gleason 6 (Low risk) cancers. Post-cryotherapy mean PSA was 1.6 ng/ml (70% reduction). Of 48 patients undergoing post-cryotherapy biopsy, 36 (75%) had negative biopsies and 12 had positive biopsy for cancer. Reviewing the 12 cases with positive biopsies, 11 cancers were seen in untreated lobe and one in the treated lobe. Complete urinary continence and potency sufficient for intercourse were documented in 100% and 86% of patients, respectively. Matched-pair comparison of focal cryotherapy and robot assisted laparoscopic prostatectomy revealed similar oncologic outcome, defined as needing salvage treatment.
DISCUSSION:
Appropriate patient selection and standardized follow-up protocols remain controversial issues in focal therapy for prostate cancer. In our opinion, image visibility of prostate cancer is extremely important for proper patient selection, precise cancer mapping that allows accurate therapeutic targeting. We believe the encouraging oncologic outcomes (cancer responses) of our study were a result of accurate TRUS-based sextant and color Doppler targeted biopsy and mapping.
Follow-up biopsies in the treated side confirmed no evidence of cancer in 98% (47 of 48). Ohori et al reported that the index (primary) lesion typically accounts for 80% of the tumor bulk, with the remaining 20% comprising smaller secondary lesions. Removing or destroying the index tumor might eliminate the possibility of distant metastasis in the future and overall tumor burden by 90%.
Similarly, Villers et al. reported that 80% incidental cancers were <0.5 ml. In our series, the follow-up systemic biopsies from the untreated, contralateral, previously negative lobe revealed newly diagnosed cancers in 11 patients: most were small volume Gleason 6, but two were Gleason 7 = 3+4 and one was Gleason 7 = 4+3. However, 8 of 11 patients elected to undergo active surveillance for these newly diagnosed relatively low risk cancers. Consequently, only 4 (5.7%) of 70 patients underwent salvage treatment. Three patients chose focal cryotherapy and one had radiation therapy. In matched-pair radical prostatectomy series, 6 patients (8.8%) underwent salvage therapy.

Given the potential for cancer mutifocality (more than 1 tumor) and/or bilaterality (both sides of prostate), as well as potential under-diagnosis at the entry biopsy, follow-up biopsies for the untreated lobe are mandatory.
Following focal cryoablation, current PSA criteria have a limited role in predicting local recurrence in the treated lobe or progression in the untreated lobe. It is noteworthy that in our series, even patients with biopsy-proven recurrence had well controlled PSA levels (range: 0 – 1.5ng/ml). In other words, our mandatory post-cryotherapy biopsies revealed cancer before a significant PSA rise. Interestingly, percent decrease of PSA from pre to post-cryotherapy was
70%. Since untreated tissue remained in the contralateral lobe, this 70% PSA decrease after hemi-ablation seems a reasonable benchmark to indicate successful ablation of the index lesion, based on prior data that the index cancer accounts for 80% of entire cancer volume in a given patients.
A major limitation of our study includes the fact that 22 patients (33%) refused follow-up biopsy, mainly due to their negligible post-treatment PSA level (<1 ng/ml).

 

 

CONCLUSION:
Imaging visibility on scanning is necessary to achieve precise cancer mapping. Focal cryotherapy represents a modification of the whole gland approach and appears to offer acceptable oncologic effectiveness with reduced treatment related adverse events. The risk of incomplete eradication of cancer is likely to be small in appropriately selected men. It is precisely those types of patients who are presently confounded by the choice between active surveillance and a more complex whole-gland treatment. There are other competing technologies that can be applied to focal or subtotal therapy. Some of them are not ready for clinical use, but are intriguing. The most important component in any focal therapy is the precise imaging. Without clear identification of the tumor, its location and stage of the disease, focal therapy can be a blind approach with potential for suboptimal outcome.
Other Competing Focal Ablation Technologies
HIGH INTENSITY FOCUSED ULTRASOUND (HIFU)
In HIFU, ultrasound beam is focused at a small fixed point to create high power that produces heat ranging from 80 to 100 degrees C. It is proven to be lethal temperatures that will create tissue ablation. It has been applied towards organ-confined, localized prostate cancer treatment as a primary treatment or as salvage therapy (after failed any organ preserving therapy, such as radiation, cryoablation, etc). Recently the help of MRI scan is applied to enhance the targeting the cancer in addition to the ultrasound imaging. It is a quite popular procedure in Europe and Asia. This technology just received the FDA clearance, although patients should still ask about insurance coverage and costs.
HIFU is performed as an outpatient procedure, usually under spinal anesthesia. Real-time ultrasound imaging guidance and/or magnetic resonance guidance is used to position the probe and to monitor the procedure. Pulses of HIFU are directed at the targeted section of the prostate, inducing tumor necrosis.
A few published outcome data show fairly good cancer control and acceptable rates of complications. The study populations in the studies are all small and all had short follow up. One study reported the treatment failure (defined as any positive biopsy and/or need for salvage therapy prompted by rising PSA levels) was observed in 42%. Other studies reported the rates of positive biopsy at 12 months were in the range of 8-23%. The sexual and urinary dysfunction rates are fairly low (< 10%).

 


FOCAL BRACHYTHERAPY: LOW-DOSE RATE (LDR) AND HIGH-DOSE RATE (HDR)
LDR brachytherapy is typically used to treat the entire prostate by implanting permanent radioactive seeds that allow the delivery of high dose radiation to the prostate while limiting the collateral damages. The use of whole-gland brachytherapy for localized prostate cancer has been well established. Focal LDR brachytherapy is to target the cancerous area only in the prostate while sparing the rest of the prostate tissue. It will further reduce the radiation toxicity related complication. It usually performed under transrectal ultrasound guide.
HDR brachytherapy (temporary placement of radioactive material in the prostate) can be also used as a focal therapy modality. There is only limited information in the literature related to the clinical outcome of focal brachytherapy, either as LDR or HDR.

 

PHOTODYNAMIC THERAPY (PDT) OR VASCULAR-TARGETED PHOTODYNAMIC THERAPY (VPD)
This technique describes the destruction of a target tissue via the administration of an inactive, light sensitive agent (photosensitizer) and the local application of light in the presence of oxygen. The photosensitizer absorbs a laser light and transfers this energy to the tissues, creating cell destruction. One recently developed photosensitizer has a tendency of staying within the tumor vascular network. Due to this reason, when PDT is applied, extensive vascular damage is created that leads to tissue necrosis. It is referred to “Vascular-Targeted PDT.” One small study of 13 patients who had salvage VPD reported 8/13 biopsies negative at 6 months. Two patients experienced urethro-rectal fistulae. This therapy is not approved for prostate cancer in the US, but there are a few clinical trial sites.
NANOKNIFE
NanoKnife technology is known as an Irreversible Electroporation. Instead of using extreme heat or cold, the NanoKnife system uses electrical currents to treat the tumors. The device known as the NanoKnife passes an electrical current through the tumor. The expected electric injury is a creation of permanent nano-meter sized very small holes (pores) in the tumor cells, leading to the death of the cells. Ultrasound or other imaging techniques such as CT or MRI is used to focus the electric current precisely on the tumor. One study in the literature reported about 75% disease free survival at 10 years.

 

SUGGESTED READING
1. Bahn DK, et al: Focal prostate cryoablation: Initial results show cancer control and potency preservation. J of Endourology. Vol 20, No 9, p688-692, Sept. 2006
2. Onik G, et al: “Male lumpectomy”:focal therapy for prostate cancer using cryoablation. Urology. 2007 Dec;70 (suppl):16-21
3. Jones JS. Et al: Focal or subtotal therapy for early stage prostate cancer. Current treatment options in oncology. Springer, Boston. Vol 8, No 3, June 2007
4. Gillett MD et al: Tissue ablation technologies for localized prostate cancer. Mayo Clin Proc Dec 2004;79(12):1546-1555
5. Polascik TJ et al: Focal therapy for prostate cancer. Current opinion in urology 2008, 18:269-274
6. Lambert EH et al: Focal cryosurgery: Encouraging health outcomes for unifocal prostate cancer. Urology. 69(6), 1117-1120
7. Bahn DK et al: Focal cryoablation of prostate: A review. The ScientificWorld Journal (2008) 8, 486-491
8. Nguyen H, Bryan BS et al: Focal cryotherapy in the treatment of localized prostate cancer. Cancer Control 2013, Vol 20, No 3
9. Bahn DK, de Castro Abreu A, et. al: Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. European Journal of Urology 2012:62 (1):55-63
10. Babaian RJ, Donnelly B, Bahn DK, et al.: Best practice statement on cryosurgery for the treatment of localized prostate cancer. J Urol. 2008;180(5):1993-2004
11. De Castro Abreu A, Bahn DK, et al: Salvage focal and salvage total cryoablation for locally recurrent prostate cancer after primary radiation therapy. BJUI 2013:112, 298-307
12. Tong W, G Cohen, et al: Focal low-dose rate brachytherapy for the treatment of prostate cancer. Dovepress, April 2013




Dr Fred Lee, 1930 - 2016

DrFredLee

PAACT mourns the loss of Dr Fred Lee, the Father of color Doppler ultrasound for prostate, and a pioneer in cryotherapy in the USA.  He was a true advocate at heart, and helped hundreds of patients in his clinic in Rochester, Michigan.

 

Dr Lee often joked that his close friend Dr Duke Bahn was his student, but also became his teacher.  Duke Bahn remembers Fred Lee with the same fondness, stating that  “Dr. Fred Lee was a true humanist with virtue. His remarkable contribution to prostate cancer diagnosis and treatment can’t be properly described in a short sentence.

 

He had been a close friend and a contributor to PAACT since its inception. He touched many lives with love and compassion. His incredibly wonderful spirit will be in their hearts and minds forever.

 

I have been extremely blessed to know Fred as a mentor, colleague, and more importantly a good friend. We lost a big star in prostate community. I will miss him dearly.”

 

PAACT President Rick Profit also remembers Dr Lee – “I first met Dr Lee shortly after I began working at PAACT in October of 2000, a meeting which blossomed into a friendship, personal and professional. Often I would personally take patients to Dr. Lee’s office to have him perform his magic with the color Doppler ultrasound to determine if there was evidence of prostate cancer, which would usually result in a targeted biopsy. Dr. Lee was always a patient’s doctor, his patients always came first regardless of cost or the ability to pay. To the best of my knowledge, every man I ever took to Dr. Lee for CD-TRUS benefited greatly from the care, attention, and expertise of his diagnostic skills – and his generosity to see these men at NO CHARGE. As a bonus of seeing me, he would never let me leave without a complimentary look at my prostate as well. Dr. Lee was a great friend and will truly be missed, not only by me, but by so many more as well.  You will be missed, but never forgotten, my dear friend.”

 

A Memorial Service honoring Dr Lee’s life will be held at 3:00 PM on Saturday, February 20th at the
First Unitarian Universalist Church of Ann Arbor ((4001 Ann Arbor Saline Road, Ann Arbor, MI 48103).   
Any questions can be directed to the church

(734) 666-6158.  The service is open to the public.

 

If you would like to leave comments for his family, you can sign Dr Lee’s memorial guestbook here.

 

RIP, wonderful Dr Lee.




Male Lumpectomy: Focal Therapy is the future of PC Treatment Gary Onik, MD 2014

GARY ONIK, MD • THE ONIK PROSTATE CANCER CENTER – AVENTURA, FL
CONTACT: KAREN BARRIE, MS (847) 502-1414 OR EMAIL: BARRIEMEDMARKETING@GMAIL.COM

INTRODUCTION
For both patients and doctors, current prostate cancer management reminds me of Oliver Hardy saying to Stan
Laurel, “This is another fine mess you have gotten me into!” Relying on radical treatments with high morbidity, we seem to have abandoned the basic tenets of cancer therapy:
1. Find it early.
2. Stage it as accurately as possible.
3. Treat it aggressively, appropriate to its stage and tumor aggressiveness.

We find ourselves in a paradoxical situation. Early detection of prostate cancer has become difficult, if not impossible, due to new guidelines against routine PSA screening. Why did the U.S. Preventive Services Task Force, a volunteer panel of medical professionals, rule against wide use of a simple and effective screening tool? First, men with suspicious or rising test results are sent for an unpleasant diagnostic procedure (TRUS biopsy) that has been proven to miss up to 30% of cancers. Those with negative biopsies later have repeat biopsies, while expense (and anxiety) mount up. Second, this protocol finds too many less aggressive cancers—and the cure may be worse than the disease.  A dilemma between overtreatment vs. no treatment occurs when patients diagnosed with low-to-moderate risk cancer are counseled to defer treatment in favor of active surveillance, a strategy for which many patients don’t have the psychological tolerance—they worry that a time bomb is ticking in their bodies. This worry may well be justified by a recent UCLA study showing how prostate cancer cells are a moving target. (1) Yet this advice is given so men can hold off on the risks of overtreatment: urinary and sexual side effects. So we don’t go looking for cancer because we might find it, over treat it, and damage men’s quality of life?  Can you think of any other cancer for which early detection is discouraged and treatment delayed? It is extremely rare to suggest that other cancers (breast, liver, lung, kidney, liver, etc.) can simply be monitored!  My twofold thesis addresses this dilemma by offering a safe and effective middle ground:

A. For diagnosis, there is an alternative to TRUS biopsy that is extraordinarily accurate, painless, and does not involve puncturing the rectal wall. It is the 3D Transperineal Prostate Mapping Biopsy (3D-PMB), which is more disease-specific for low, moderate and high-risk cancers than MRI-guided targeted biopsies. It improves prostate cancer management decisions by up to 70% because it allows matching the treatment to the disease, and it provides specific localization for precise targeting. In short, it meets the first and second tenets of cancer therapy.

B. For treatment, there is an effective FDA-approved minimally invasive procedure that satisfies the third tenet of cancer therapy, to the major benefit of the patient.

THE MALE LUMPECTOMY
This article describes our latest results with both 3D-PMB and focal cryotherapy (cryoablation, or simply cryo, meaning lethal freeze). Our data validates the advantages of what I first termed the Male Lumpectomy.  I now have long term results (average follow up of 10 years) with focal cryotherapy for prostate cancer or the Male Lumpectomy. I first presented this idea in a 2002 paper (2) demonstrating that we could effectively locate and target a prostate tumor without having to destroy, remove or irradiate the whole gland. By isolating and treating just the tumor and a surrounding safety margin, we generate competitive (actually better) efficacy in controlling cancer while preserving healthy tissue to markedly lower morbidity (side effects).
That paper started the ball rolling. Focal prostate cancer therapy is now carried out in some manner in major U.S.
cancer centers, including MD Anderson, Johns Hopkins, Sloan Kettering, Duke and NYU to name a few. Textbooks
cover the subject and annual medical meetings on this topic are convened. The results are consistent: good cancer control, yet low side effect risks.
My own study data offers compelling evidence that mapping biopsy and focal cryo provide a combined clinical approach that completely changes the current paradigm, meeting the highest cancer treatment standards, and bringing it fully in line with the best therapies for local treatment of any other tumor. Additionally, this approach greatly reduces the high economic costs of conventional prostate cancer treatments (robotic prostatectomy and radiation therapy), as well as the long term personal quality of life costs (with their own associated management dollars).

MATERIALS AND METHODS
In our practice, we stage patients for focal therapy using 3D Transperineal Prostate Mapping Biopsy (3D-PMB).
Transrectal ultrasound (TRUS) guided biopsy is not enough to guide focal therapy. 3D-PMB is carried out under general anesthesia (so it’s painless). Unlike a transrectal biopsy, which takes prostate samples through the rectal wall, 3D-PMB is done through the perineum (the skin between the scrotum and rectum). A grid, like that used in brachytherapy, is placed against the skin, and ultrasound guides the position of needles into the gland. Note that while ultrasound cannot distinguish important differences in normal and cancerous tissue, it clearly shows the placement of biopsy needles.  Tissue samples taken throughout the gland are separately marked with the grid coordinates so their precise location is identified in the pathology report. This is what gives a threedimensional
or holographic map of any cancers, even very small ones that might be found. We are able to take far more samples than the 10-12 commonly taken in a TRUS biopsy. 3D-PMB also has the advantage of more accurate Gleason scores since there’s little risk of missing a tumor core where the more dangerous cells tend to be.

A study we published in the most prestigious cancer journal in the world (Journal of Clinical Oncology) compared the results of TRUS biopsy vs. 3D-PMB in over 180 patients (3).  What we found was sobering. Compared to TRUS biopsy, 3D-PMB found 50% more cancer on the opposite side of the gland. It also raised the Gleason score in approximately 25% of patients. Additionally, a 3D-PMB is safer than TRUS biopsy because it is a sterile procedure, greatly lowering the chance for life threatening sepsis (infection with colon bacteria) and debilitating prostatitis that are significant risks in TRUS biopsy. Identifying the exact location of each specimen allows exact treatment targeting of the tumor, including its location, size and shape.

Some clinicians are using MRI guided biopsies to guide focal therapy. Studies comparing MRI to mapping biopsy or prostatectomy specimens show that it misses 25% of significant cancers (4) and is only 28% specific, meaning that 72% of the time what it reads as cancer is not (5). While I support advanced multiparametric MRI of the prostate as an adjunct resource, only 3D-PMB can give the thorough tissue map necessary for long term cancer control as demonstrated by my data.

What about the concern that biopsies spread cancer? There is absolutely no credible clinical evidence that this happens.  Why is this important? Fears of “track seeding” have been sadly overplayed by a handful of doctors who feed patients’ wishful thinking that prostate cancer can be clinically diagnosed and staged by imaging alone. In fact, MRI or color Doppler is not specific enough to make an accurate diagnosis of prostate cancer, meaning it often OVER estimates less aggressive cancer, and is not sensitive enough in identifying very small but significant cancers. Anyone who tells you, based solely on imaging, that you have cancer is doing you a great disservice—especially if they proceed to treat you.  It is my conviction that any physician who treats based on imaging and/or rising PSA without biopsy confirmation is committing the grossest kind of malpractice. In the last month I encountered two patients who had been offered radiation without biopsy confirmation of cancer. I was appalled, as this violates the universal medical ethic, “Above all do no harm” (primum non nocere).

In our practice, we originally theorized that perhaps 25-30% of prostate cancer cases would be amenable to focal therapy.  Our experience, confirmed by another study (6), showed that as many as 94% of patients qualify for a focal approach. In other words, focal therapy is more than a “niche” treatment—many more men may benefit, especially when their disease is accurately diagnosed and staged, and when the treatment is done by an expert.

Once you have located the tumor there are a number of ways to kill the cancer. We mainly use cryotherapy (cryoablation or simply “cryo”) to carry out the focal therapy. Cryo is the only ablation modality that has Level One evidence of superiority over beam radiation in eradicating cancer (compared in a randomized study) (7). Another excellent reason to use cryo comes from evidence of a specific tumor immunologic effect when a cancer is frozen. This effect has been shown in animal models to prevent metastatic disease and to cause regression of distant prostate cancer metastases (spread) in patients. Our cancer control results with medium and high risk patients are so much better than reported data with radical prostatectomy or radiation that an immunologic explanation for these results must be considered. Heat-based therapies such as laser and HIFU denature (destroy beyond recognition) tumor proteins (antigens). It is these antigens on the surface of cells that scatter into the body. Since they are not intact cells they cannot spread or cause cancer, but they are helpful because they appear to trigger this immunologic
effect (8, 9). I predict it will take at least a decade to see if heat-based ablation gets the same immunologic results. Personally, I don’t want to deprive my patients of this potential benefit, particularly when there is no advantage I can see, as yet, to other ways of killing the tumor.

FOCAL CRYO RESULTS
In our practice, we now have clinical data on a total of 70 patients who underwent focal cryo. All have at least 8 years
follow-up (ranging from 8 to 18 years with a mean follow up of 10.1 years). 41 patients were Gleason 6 or less, 24
were Gleason 7 (6 patients 4+3, 18 patients 3+4) and 5 were Gleason 8 or greater. 15 patients had a PSA of 10 or greater.  We stratified the 70 patients using the D’Amico system. Thus,  29 patients were low risk, 32 medium risk, and 9 high risk
.OnikFocalTx2014_Table 1

Overall actuarial survival was 66/70 (94%), meaning 4 patients died from other causes. Disease specific survival
was 64/64(100%), meaning no patients died from prostate cancer. This is a rather remarkable statistic given that the
majority of patients in this series (41) were medium to high risk. It certainly illustrates that patients who are appropriate candidates for focal therapy are not taking a greater risk of death in choosing this avenue.

Overall Biochemical Disease Free Survival (BDFS, meaning no rise in PSA) was 89% (62/70). When broken down by risk level, BDFS for low risk patients was 90% (26/29), for medium risk patients 88% (28/32) and for high risk patients 89% (8/9).  These again are rather remarkable results. For comparison, a 2012 article by Ginsburg, et al., looking at results of robotic radical prostatectomy with over 1100 patients had an overall BDSF of 72% at 5 years (10). See Table 2.

OnikFocalTx2014_Table 2

In my experience in a tertiary referral practice, having interviewed patients who have already seen surgeons, it is
unusual to encounter a patient who has had explained to him what a “positive margin” is. For those who are unclear, after the gland is removed, the cut margins of the gland are stained and microscopically examined for tumor. If tumor is found at the cut margin the implication is that there is residual cancer left in the patient. This is called a positive margin. It leads to a high rate of disease progression. In Ginsburg’s study positive margins occurred in 27.3% of patients, which the authors describe as in keeping with national statistics. Our results, with selective tumor destruction while preserving healthy, functional prostate tissue, hold great promise for patients who might otherwise undergo surgery, with its risks of short and long term urinary and sexual side effects, only to experience a rising PSA within years of the treatment.

Why all risk levels of patients would have the same cancer control results, might have two possible explanations:

1. Focal cryo has an ability to treat extracapsular disease.  Patients at high risk for positive margins at prostatectomy
have a better chance of local control with ablative therapy.  This was very well illustrated by one of our patients who had a T4 lesion already invading the bladder, a PSA of 200 and a Gleason score of 10. He is now 8 years out from his cryo with no evidence for recurrence. We also have used a localized removal of urethral tissue in some patients who had tumor next to the urethra, when we were afraid that the urethral warmer might prevent a completely destructive freeze at that site.

2. A cryoimmunological response must also be considered for these remarkable results in medium and high risk patients.  Based on the human and animal data, it’s likely that in some patients there is exposure of tumor antigens at the time of the procedure that acts as an in vivo cancer vaccine, preventing later metastasis from occurring.

A WORD ABOUT RECURRENCE
Choosing radiation or RP as a first or primary treatment limits future options. Neither has a good fallback position
should local disease recur. Hormone ablation is not curative, and the side effects are unpleasant. However, when focal cryo patients are retreated they do extremely well. The ability to retreat patients with local recurrences by repeat freezing, or even RP or radiation, means that our patients have less chance of untreated local residual cancer that can later spread.

In our series, 10% of patients (7/70) were retreated with cryo to the opposite side of the original procedure. (In other words, a second cancer later occurred in previously biopsy-negative and therefore untreated tissue.) All 7 (100%) are biochemical disease free (BDF). Two patients with local recurrence underwent radiation and both are BDF. One patient underwent RP and radiation and is now on ADT (hormone ablation). In total, 14% of patients (10/70) had a local recurrence that required re-treatment, and 90% of those 10 patients (9/10) remain BDF.

Bilateral disease (cancer on both sides of the gland at initial treatment) was not a barrier to successful focal therapy. In our series, 28.5% (20/70) of patients had bilateral multifocal disease (more than one tumor location) that required bilateral cryo. Of those, 95% (19/20) were BDF.

FOCAL CRYO SIDE EFFECTS (MORBIDITY)
The hope for low morbidity associated with focal therapy has been confirmed by our results. All patients were continent (with no pads) immediately after the first procedure (100%).  One recurrent patient converted to a second whole gland freeze, resulting in mild stress incontinence requiring pads while playing golf. Other authors confirm these continence results (11).

As to potency, focal therapy did extremely well. 58/70 patients were potent preoperatively (pretreatment baseline
function). 54/58 (94%) were potent postoperatively with or without the use of oral agents, to their satisfaction, within 6 months. However, 11 patients were ultimately rendered impotent by additional treatment (7 by additional cryo, 4 by a combination of ADT, radiation or radical prostatectomy).  Interestingly, 4/12 preoperatively impotent patients were potent after the procedure. This was due to the immediate potency rehab protocol that we provide, if needed. 43/58 patients (74%) therefore ultimately retained potency. Again, these results are consistent with other focal therapy series.  No other complications were noted. Blood loss was virtually zero. No rectal fistulas were seen and no patient needed a further procedure for urinary obstruction.

CONCLUSIONS
The long term results of focal cryoablation, within the limitations of our data, is significantly superior to traditional
RP and radiation. Unanticipated is that patients at high risk for recurrence have a much higher disease free survival than that reported with robotic RP and with better quality of life.  Repeat treatment for localized recurrence does not appear to negatively impact patient disease specific or BDF survival, perhaps accounts for improved results in high and medium risk patients. Patients treated with bilateral multifocal disease appear to do as well as those with unilateral tumors. Most striking, all grades and PSA levels appear to have excellent results compared to other therapies. When including all risk levels of disease and bilateral disease, the overwhelming majority of patients would be eligible for this approach when appropriately diagnosed, staged, and treated by an
experienced cryosurgeon.

The Male Lumpectomy achieves these results with minimal morbidity in terms of incontinence and potency. The
safety and long term efficacy of focal cryoablation is now established, though this is not to say that further study is
not needed. Enough evidence is available, however, that I would have no qualms about offering this option to qualified patients. Future investigators now have the data to have a comfort level to conduct comparative Level One evidence studies between focal therapy, robotic RP and the various forms of radiation.

This data also sets the bar high for focal therapy. When developing this approach, we tried to optimize every step
of the procedure to give us the theoretically best outcomes possible with our current knowledge. All of the important
aspects of our methods for selecting and performing focal therapy are supported by Level One data as being the best
way to carry out this mission (3D-PMB for diagnosis and staging, cryo for the ablation). Since we are dealing with
peoples’ lives, anyone carrying out focal therapy should adhere to the principles we have outlined in selecting and
performing the procedure. Based on my experience there will be a plethora of focal therapy methods being touted in
the near future. It’s going to take other investigators another ten years to figure out if their method can produce the same results. As a patient, you will be challenged to sort out proven treatments with a published, peer-reviewed track record vs. “the latest” innovations without long-term results.

We have been going down the same path with prostate cancer for so long. Despite the best efforts of urologic surgeons and radiation therapists to improve the results of their traditional treatments, little progress has been made in improving survival and lowering complications. Focal therapy gives us a new, exciting and hope-filled alternative road to take. It will be the responsibility of the medical community to thoroughly compare focal therapy as we have outlined it, honestly and fairly, with traditional therapies. If this is accomplished I am confident that we will have embarked on a new era in prostate cancer management.

REFERENCES
(1) Stoyanova T, Cooper A, Drake J et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proceedings of the National Academy of Sciences, published online Dec. 2013. at http://www.pnas.org/content/early/2013/11/25/1320565110.full.pdf+html
(2) Onik GM, Narayan P, Vaughn D, et al. Nerve sparing cryosurgery for the treatment of primary prostate cancer: a new approach to preserving potency. Urology. 2002 Jul;60(1):109-14.
(3) Onik, G. Miessau M, Bostwick DG Three-dimensional prostate mapping biopsy has a potentially significant impact on prostate cancer management. J Clin Oncol. 2009 Sep 10;27(26):4321-6. 2009 Aug 3.
(4) Delongchamps et al. Multiparametric MRI is helpful to predict tumor focality, stage, and size in patients diagnosed with unilateral low-risk prostate cancer. Prostate Cancer and Prostatic Diseases (2011) 14, i232–237.
(5) Abd-Alazeez1 A, Kirkham HU, Ahmed M et al. Performance of multiparametric MRI in men at risk of prostate cancer before the first biopsy: a paired validating cohort study using template prostate mapping biopsies as the reference standard. Prostate Cancer and Prostatic Disease (2013), 1–7.
(6) Singh PB, Anele C, Dalton E, et al. Prostate cancer tumour features on template prostate-mapping biopsies: Implications for focal therapy. Eur Urol. 2013 Oct 6. http://www.ncbi.nlm.nih.gov/pubmed/?term=singh+anel
e+prostate
(7) Donnelly BJ, Saliken JC, Brasher, PMA et al. A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer. Cancer 2010;116:323-330.
(8) Ablin et al. Cryobiology, 8:271, 1971.
(9) Waitzl R, Solomon S, Petre E et al. Potent Induction of Tumor Immunity by Combining Tumor Cryoablation with Anti–CTLA-4 Therapy. Cancer Res; 72(2) January 15, 2012.
(10) Ginzburg S, Nevers T, Staff I et al. Prostate cancer biochemical recurrence rates after robotic-assisted laparoscopic radical prostatectomy. JSLS 2012;16:443-50.
(11) Bahn E, Abreu AL, Gill I et al. Focal cryotherapy for clinically unilateral, low intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. Eur J Urol 2012 July;62(1)55-63.




20+ YEAR SURVIVORS, 2013

Letters from Six PC Patients – Fall 2013 Newsletter
(FOR PATIENT CONTACT INFORMATION, PLEASE CALL PAACT AT 616-453-1477)

You asked for input from prostate cancer survivors of twenty years. My experience may be of interest and could convince others that “cancer” is just a word – not a sentence.

In 1991 at age 57, during a routine annual physical my doctor was concerned about a PSA reading of 5.7.  A subsequent MRI revealed aggressive tumors in both sides of the prostate gland. I had no previous indication or symptoms such as middle of the night bathroom visits so my immediate reaction was shock/horror.

My G.P referred me to an urologist who gave me a Lupron injection which he said would shrink the tumors and make them easier to remove during surgery which he said would be necessary for me to survive. When I asked him about possible down-side of the radical prostatectomy he warned me that I would be most certainly impotent and incontinent. At that time I had recently married so the shock/horror effect went up two notches!!!

I paid that urologist the $500 for the Lupron injection, wished him a nice day and left in a hurry.

During the next few weeks I spent a lot of time on the phone seeking information from specialists all over the U.S.A.
about prostate cancer in general and the possible treatments available. Each one of these doctors insisted that their
specialty, – be it cryosurgery, freezing the tumors, Palladium seed implants , chemical castration, radical prostatectomy, etc. etc., was the only way to go. I had several conversations with the late and great Lloyd Ney who was enormously helpful and encouraging.

I eventually found a urologist surgeon in St. Petersburg Florida, who advised me that using his nerve sparing technique a radical prostatectomy would not only remove the tumors but there was a good chance that incontinence and impotence might be avoided. At this point I was desperate to do something positive so went ahead with the radical. I just wanted that little suckers out of there!

The surgery went well up to a point. I had no incontinence problems, but aft er three months there was no sign of a return to normal sexual life. We then tried injections directly into the penis, which worked very well, but aft er several months the clinical procedure was so lacking in spontaneity and was causing malformation so that was abandoned.

Finally I accepted the urologist suggestions that a penile implant would be a better solution. This was done almost
two years after my original surgery.  The big day finally arrived and both my partner and I were pleased with the results and that has been the case ever since.

My PSA after surgery was 0.01 and has remained at that number since 1991.  I test religiously every six months and even though my results are good I always attend the doctor’s office with a slight foreboding.

I have never forgotten the help and advice I received from Lloyd Ney and others at the PAACT, and I try to maintain financial contribution to the funds from time to time.  I regularly advise people to be tested as I was and several who
have taken my advice had learned that they have the disease but have been able to take advantage of treatments which were not available to me twenty years ago. I exercise regularly, swim every day and try to keep a healthy diet
PT/Florida

———————————————————————————————————————————-
To whom it may concern,
On page 18 of the summer issue it listed a request for Survivors of 20+ years. I guess I qualify as I started combating
cancer in 1985, Sarcoma.  Then Prostate Cancer in 1992 that has been back 9 times. Thanks to Cryo, Brachytherapy, and 6 treatments of TomoTherapy, I am still here. With a lot of praying also!!!!

Medical Treatments:
October 1985—Node/Tumor removal around left Spermatic cord (benign then malignant by AFIP 2 months later)
April 1986—Left orchiectomy (didn’t get desired margins – Sarcoma)
May 1986—External Beam Radiation
March 1992—Prostate Cancer determined – Biopsy – Gleason Score 3 + 4 = 7
May 1992—Megace started
October 1992—Radical aborted as it has spread out of capsule
December 7, 1992—Megace stopped and Antineoplastons started (Dr. Burzynski– Houston, TX)
January 16, 1995—Cryoablation of prostate as had lost effectiveness to Antineoplastins
May 25, 1995—Stopped Antineoplastins as PSA = 0
March 1999—Brachytherapy as PSA rising
July/September 2005—TomoTherapy of right lymph node as scan showed tumor there and PSA rising
July 5, 2007—Urostomy – Dr. Andrews – Mayo Clinic
April/May 2008—TomoTherapy of right lymph node as C-11 acetate showed tumor there.
December/January 2010—TomoTherapy of left seminal vesicle as biopsy showed tumor there
July/August 2011—TomoTherapy of right lymph node as scan showed tumor back
July/August 2012—TomoTherapy of bone in right hip as P/C-11 acetate showed tumor there
November 2012-January 2013—TomoTherapy of tumor just starting in L-4
November 2012-January 2013—TomoTherapy of two lymph nodes as C-11 showed cancer in both
As you can see, I was a test subject in many treatments, however the most important is TomoTherapy.
If you need any more information, just let me know.
RG/Arizona
——————————————————————————————————————————–
I will hopefully be a 20 year survivor the end of this year.
WR/New York
——————————————————————————————————————————–
The last issue of PAACT’s newsletter suggested survivors 20+ years with Prostate Cancer be encouraged to send a note.  With a PSA in December 1991 of 50, followed by radical surgery and radiation in January 1992 and a year of Lupron in 2011. I’ll be 86 in December, 23 years with Prostate Cancer.  I’m still very active.

MC/California

———————————————————————————————————————————-

In my journey of Prostate Cancer PAACT has played an important role. I praise GOD for all your help and
information, which helped me stand up to my urologist and ask for what I had wanted/learned through PAACT.
My cancer is still under control, diagnosed in 1999.

Yours sincerely,
RN/Missouri

———————————————————————————————————————————-
March 1992—PSA 15.3, positive biopsy, age 70
May 1992—Radical prostatectomy
1992-1996—PSA 0 – 0.15
Late 1996 – Mid 1997 PSA 0.39 – 0.54
1997—Started Casodex 50 mg/day PSA to 0.08
In recent years have tried different dosages of generic Casodex: 0, 25, and 50 mg/day, also 50 mg every other day.
1997-2013 PSA minimum 0.02, PSA max 1.00
Last tested on 6-17-2013 PSA was 0.55, present age 91 ½, visit urologist 2 times a year
RH/Indiana