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Dr Adam Levinson
New Ablative Techniques in Urologic Oncology

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Release Date:

December 2013

Expiration Date:

December 2014

Estimated time to complete the educational activity:

1 hour

This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education.

Statement of Need:

Traditional management of clinically localized renal cell carcinoma and prostate adenocarcinoma has been total organ excision. Although this is oncologically effective, standard radical surgery is associated with significant treatment-related morbidity. Innovations in tissue ablation technologies offer the potential for effective treatment to limited target areas with improved side effects.

Target Audience:

This activity has been designed to meet the needs of urologists and supporting clinicians who treat patients with kidney and prostate cancer.

Educational Objectives:

After completing the activity, the participant should be better able to:

  • Review current ablative options for the treatment of prostate and kidney cancer.
  • Discuss renal ablation techniques and follow-up, as well as outcomes.
  • Describe complications following prostate cancer cryoablation.
Accreditation Statement:

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation:

Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Conflicts of Interest:

Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all our educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest.

The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity:

Name of Faculty Reported Financial Relationship
Jeffrey J. Tomaszewski, MD No financial relationships to disclose.
David Y. T. Chen, MD No financial relationships to disclose.

The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and the content manager at Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest.

Method of Participation:

There are no fees for participating in and receiving CME credit for this activity. During the period December 2013 through December 2014, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalandurologynews, and 4) complete the evaluation form online.

A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.

To reduce treatment-related morbidity, ablative technologies have been applied as a treatment for a number of malignancies, including lung, hepatic, testicular, prostate, and renal cancer.
Concomitantly, the widespread availability and utilization of cross-sectional imaging has led to an increase in the incidental detection of renal cancer,1 while prostate cancer screening practices have identified new opportunities for identifying smaller tumors with low probability of regional involvement and high likelihood of curability.

The traditional management of clinically localized renal cell carcinoma (RCC) and prostate adenocarcinoma has been total organ excision. Although this is oncologically effective, standard radical surgery is associated with significant treatment-related morbidity, especially in patients with comorbid conditions. Innovation in tissue ablation technologies offers the potential for effective treatments to limited target areas with improved side effect profiles. Herein we review current ablative options for the treatment of prostate and kidney cancer.

Kidney cancer

American Urological Association (AUA) guidelines recognize partial nephrectomy as the standard of care for managing the cT1a renal mass. Given the morbidity associated with partial nephrectomy, it may not represent the ideal treatment for all patients, especially among the elderly and infirm.

Several ablative technologies have been investigated, including cryoablation (CA), radiofrequency ablation (RFA), microwave thermotherapy,2 high-intensity focused ultrasound,3irreversible electroporation,4 and histotripsy.5 Only the first two modalities have achieved widespread use, with published reports of short to intermediate results, and these topics will be the focus of this review.

Cryoablation and 
radiofrequency ablation


CA is a thermal ablative technique that relies on the Joule Thomson phenomenon, whereby a highly compressed liquid (argon gas) expanding through a restricted orifice rapidly changes to a gaseous state and creates extreme cooling.6 When the extracellular fluid freezes, the osmotic pressure increases in the extracellular compartment; the resulting fluid shift causes cellular dehydration, accumulation of toxins within the cells, change in pH, and protein denaturation.6

Ice ball formation produces mechanical disruption of cellular membranes and blood vessel walls,7 leading to crystallization of the intracellular fluid. Endothelial damage indirectly triggers ischemia, thrombosis, and coagulative necrosis. All these effects synergize to result in cell death.6 Modern probes are capable of creating ice balls of widely varied sizes (3.1 × 3.6 cm to 4.5 × 6.4 cm), but the -40°C isotherm, the zone of lethal treatment, is generally smaller.7

Therefore, in clinical practice, the ice ball is usually extended 5 to 
10 mm beyond the tumor edge to ensure sufficient coverage of the target area. A double freeze-thaw cycle is associated with greater clinical efficacy compared with a single cycle,8 and renal CA is typically performed either laparoscopically or percutaneously.

Like CA, RFA can be performed percutaneously or laparoscopically, and the ideal approach depends on the condition of the patient, tumor location, and provider preference.9 Currently, there is insufficient evidence for what constitutes the ideal delivery method. RFA uses high-frequency monopolar alternating current delivered directly to the target tissue to generate thermal damage by converting radiofrequency waves into heat.10

When tissue reaches temperatures higher than 60°C, thermal dessication and coagulative necrosis lead to cell death through irreversible protein denaturation and cross-linking.10 The effectiveness of RFA depends on both the temperature and duration of treatment.7 A wide variety of RFA probes are available, with single-needle probes for small lesions, multiprobe array electrodes for larger areas (3-5 cm), and internally cooled electrodes to target the largest ablation volumes.11

Renal ablation follow-up

Although no specific post-CA protocol has been widely implemented, computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used for follow-up imaging. Initially, tumor size may increase due to peri-tumoral hemorrhage, but tumor periphery can be hard to differentiate from surrounding fibrosis and stranding.6 Post-CA, any enhancement greater than 10 HU or an interval increase in tumor size is suspicious for inadequate tumor ablation or recurrence. On T1-weighted MRI, 61% of adequately treated tumors are isointense to renal parenchyma, whereas 95% are hypointense on T2.6,12

Radiologic absence of disease may not serve as a surrogate for clinical cure; 3.6% of post-RFA biopsies are positive six months following treatment.13

Post-RFA, imaging plays an important role in tumor localization, real-time monitoring of the ablation zone, and follow-up. RFA is typically monitored with ultrasound, and ablation zones are seen as hyperechogenic areas created by vaporization of interstitital fluid. A follow-up contrast enhanced CT or MRI is typically used to ensure a lack of enhancement within treated tissue, and a thin enhancing rim representing either inflammation or hemorrhagic granulation tissue may be seen in early follow-up.14

Given the difficulty in determining the extent of the coagulation zone, the goal of RFA is to ablate a 1 cm margin of normal tissue surrounding the tumor on all sides; however, preservation of normal surrounding renal parenchyma limits margin size.9


Renal ablation outcomes


While some have suggested follow-up for CA series is too limited to draw meaningful conclusions about oncologic efficacy,15 intermediate oncologic outcomes with follow-up ranging from 9 to 36 months suggest excellent local control (95%-100%) and cancer-
specific survival (95%-100%) in patients with single sporadic renal masses.16-18 Following RFA, short- and intermediate-term oncologic outcomes reveal recurrence-free rates of 90%-96.8 % in patients with mean tumor volumes of 2.0-3.2 cm.15

In the 2009 AUA guideline for the management of clinically localized stage I RCC, a meta-analysis revealed total recurrence-free survival of 87.6% and 85.2% for CA and RFA with a mean follow-up of 26.2 months and 39.3 months, respectively.15 A recent meta-analysis of 20 studies with a total of 457 cases revealed a pooled proportion of clinical efficacy of 89% (95% CI 0.83-0.94) for CA and 90% (95% CI 0.86-0.93) for RFA.15

In review of 2,104 tumors, the reported overall complication rates ranged from 0.9%-16.2%,6with hemorrhage (1.1%-16.2%), perinephric hematoma (1.6%-4.4%), and urine leak (1.2%-7.1%) most commonly reported. Increasing anatomic tumor complexity and “nearness” to the renal hilum as objectified by R.E.N.A.L. nephrometry score is associated with an increased risk of complications following CA.19

Following RFA, the most common minor complication is pain and paresthesias at the probe insertion site, while most major complications are secondary to thermal injury to the renal collecting system 
(UPJ obstruction, urine leak). A meta-
analysis of 11 studies revealed a complication rate of 19.0%,15 while renal function following RFA is typically preserved.20

Local recurrence-free rates similar


Unfortunately, no prospective comparative trial exists to determine the ideal treatment modality when considering RFA and CA.21 As opposed to RFA, CA has also been shown to be effective in the treatment of tumors larger than 3 cm in greatest dimension.22 RFA is limited in the treatment of central renal masses, given thermal sink effects originating in the highly vascular renal hilum.23 Conductive relative cooling at the central ablation margin results in local failures in up to a third of such masses.24

A recent large series clearly demonstrates no differences between the technologies with regard to complication and local recurrence-free rates.15, 23 The debate about which technology is more effective is essentially over, 
with RFA and CA demonstrating equal efficacy and morbidity.25

Long-term data on oncologic efficacy and more rigorous head-to-head trials are needed to determine the role of CA and RFA in the management of small renal tumors.

Prostate Cancer

PSA screening has led to increased detection of less aggressive and potentially clinically insignificant prostate tumors, and many patients show similar outcomes whether they elect active surveillance or radical whole gland therapy. There is little to no difference in overall and prostate cancer (PCa)-specific survival after a median of 10 years of follow-up.26

However, the recognized urinary, bowel, and sexual function adverse effects commonly resulting from radical treatment27 have driven interest in ablative therapies aimed at reducing morbidity while maintaining oncologic efficacy.28

Furthermore, as 20%-30% of PCa patients recur after standard treatment, ablative therapy for local retreatment, such as salvage cryoablation (SCA) may be as effective as traditional options but with less toxicity.29 A number of investigational approaches exist for targeted prostate ablation: in-bore 
laser ablation30 and photodynamic therapy,31 but only CA and high-
intensity focused ultrasound (HIFU) have more substantial data and will 
be the primary modalities reviewed.

Cryoablation

Over the past decade, prostate CA has been increasingly used for primary, salvage, and focal therapy of PCa. Current cryotherapy systems represent third generation cryotechnology that achieve tissue destruction via direct cellular and vascular injury, apoptosis induction, and immune mediated cytotoxicity (as described above).32

A trans-rectal ultrasound probe and perineal template are used to define the anatomical configuration of the prostate and 
facilitate localization of the cryoprobes into appropriate distribution for sufficient gland coverage.32 Thermosensors can be applied to monitor the treatment and temperature at surrounding margins, such as the external 
sphincter and Denonvilliers fascia.

A warm saline urethral irrigation is used to prevent urethral damage and minimizes post-treatment urinary morbidity.32 
CA is started at the anterior region and progresses posteriorly, and commonly an additional 2-4 mm zone of freezing into the periprostatic tissues is obtained, to achieve a wider margin of treatment.32

A recognized limitation of prostate CA is defining success of treatment. There is no accepted standard for determining efficacy. As prostate CA by design leaves the periurethral region untreated, residual benign prostate in that location can produce PSA, and so undetectable PSA levels are uncommonly seen after prostate CA. In a series of 590 patients with a mean follow-up of 5.4 years treated for primary prostate CA, using a PSA nadir of 0.5 ng/mL as a threshold for recurrence, the biochemical disease-free survival (BDFS) rate was 61%, 68%, and 61% for D’Amico low-, intermediate-, and high-risk groups, respectively, with an overall BDFS of 62% at seven years.32,33

However, using the ASTRO definition, BDFS dramatically improved to 92%, 89%, and 89%, respectively, with a combined seven-year BDFS rate of 89.5%.32, 33 Similarly, examination of PSA nadir levels among 2,427 patients following whole gland prostate CA revealed that a PSA nadir of 
0.6 ng/ml or greater was associated 
with significant risks of biochemical failure (29.5%, 46%, and 54% in 
low-, intermediate-, and high-risk groups, respectively) within the first 
two years.34

Following primary prostate CA, 10-year BDFS rates (median follow-up 12.5 years) of 80.6%, 74.2%, and 45.5% for low-, intermediate-, and 
high-risk patients, respectively, have been reported, and the overall negative biopsy rate at 10 years was 76.96%.35

Complications


Complications following prostate CA include urinary incontinence, erectile dysfunction, voiding dysfunction, and fistula formation. Rates of clinically significant incontinence range from 4.8%-7.5%,36, 37 with the highest rates reported among patients with apical disease or those undergoing SCA (7.9%-10.2%).38 ED rates are high, with 72%-93% of men reporting worsening function after therapy.37

Following SCA, ED occurs in 72%-86%,39 and while these rates are partly contributable to preexisting ED from primary treatment, the introduction of third-generation technology has not significantly improved the rates of ED.32 Voiding dysfunction (3%-4%) is largely attributable to urethral sloughing, which is dramatically minimized with the use of urethral warming catheters.36 Rates of prostatorectal fistulae have fallen secondary to use of the urethral warmer and in contemporary series range from 0%-0.5%.36

High-intensity focused ultrasound


With HIFU, high-energy ultrasonic beams are delivered into the prostate via a transrectal approach. The acoustic energy is converted into thermal energy, causing coagulative necrosis.7 While prostate HIFU is approved and widely available in Europe, Japan, and other countries worldwide, it has not gained FDA approval and is currently only available in the U.S. within clinical trials. Similar to prostate CA, the best means to assess the efficacy of prostate HIFU remains undefined.

Among 1,002 patients treated with HIFU for localized PCa, eight-year biochemical-free survival rates (by Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001).40 At 10 years, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively.40

Severe incontinence and bladder outlet obstruction were initially significant but have improved with refinement in the technology and experience, from 6.4% and 34.9% originally to 3.1% and 5.9%, respectively. Other groups have reported urethral stricture, impotence, epididymitis, and urinary incontinence in 16%, 14%, 4%, and 0.8%, respectively.7

Salvage treatment

Prostate salvage HIFU shows promise, but current follow-up is limited, ranging from 3 to 39 months, and with reported DFS rates of between 25% to 54%.41 Morbidity following salvage HIFU is higher compared with primary HIFU treatment, including urinary incontinence (49.5%), rectourethral fistula (3%-12.5%), bladder neck contracture or urethral stricture (10%-20%), UTI (1%-6%), and prolonged urinary retention (6%).41 Salvage HIFU remains a promising treatment alternative in patients who have localized failure after radiation therapy.

Given the high risk of complications associated with salvage therapy, careful selection of patients is imperative. Long term follow-up and prospective multicenter randomized controlled trials are required to assess whether these encouraging results are truly equivalent to those observed after other salvage treatments such as radical prostatectomy, brachytherapy and CA.

Although extirpative surgery remains the standard of care for most urologic malignancies, some patients may benefit from the reduced morbidity of minimally invasive ablative therapies that are quickly establishing themselves as viable primary treatment options.

Source: http://www.renalandurologynews.com/cme-articles/new-ablative-techniques-in-urologic-oncology/article/324846/

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