Minimally invasive therapies

The establishment of guidelines, pharmacologic therapies, improved understanding of lower urinary tract symptoms (LUTS) versus benign prostate hyperplasia (BPH), respect for patient-centered goals, and improved discrimination of the patient with occult prostate cancer have empowered change in the management of LUTS. These new tools have allowed urologists to act on the recognized limitations of transurethral prostatectomy (TURP) as a historical gold standard and search for “ideal therapies” that provide durable, noninvasive treatments with an improved relief of symptoms at a decreased complication rate and cost and that simultaneously correct BPH-associated morbidities. Requisite to the chronic, progressive nature of BPH, the ideal therapy would also prevent future BPH-associated morbidities. These ideal therapies are not practical at this point in the evolution of therapy, thus the current goal of interventional therapy is to restore the comfort and well-being of patients.

Symptom progression is the bane of any treatment modality and is the most common manifestation of the progressive nature of BPH. Once a patient demonstrates symptom progression beyond watchful waiting or pharmaceutical therapy he requires counseling to evaluate appropriate treatment options in light of age-related risks, comorbid medical conditions, and the complexities associated with multiple medications. Potential risk factors have been identified for symptom progression, urinary retention, and prostate surgery such as prostate-specific antigen (PSA), obstructive symptom score, bother score, prostate volume, decreased flow rate, and increased postvoid residual (PVR) and transitional zone volume. Prostate volume and PSA were the best predictors of acute urinary retention, and PSA was the best predictor of prostate surgery (for all indications). Emerging literature suggests a relationship between the metabolic syndrome and the development of BPH, with a 56% increased total prostate annual growth rate and a 34% increased transition zone annual growth rate noted in men with metabolic syndrome compared with men without the metabolic syndrome. Prognostic parameters and their ability to predict progression may be important in the future of LUTS management and selection of therapy.

Patient selection for therapy has been difficult to assess in light of different patient expectations, payer sources, health care resources, and the evolution of technology. There is evidence that in the United States, the majority of men in a commercially available insurance plan chose watchful waiting in the first year, 18.7% of men chose an α-blocker, and only 2% of men chose a surgical or minimally invasive therapy. Race and social economic status may also play a role in patient treatment selection based on studies reporting that surgical intervention was more common in black men and black beneficiaries were 17% less likely to receive minimally invasive surgical treatment (MIST) than whites in 2005. Octogenarians have a significantly increased rate of surgical complications compared with younger patients (39% vs 22%, P <.05) and would theoretically benefit from minimally invasive therapies. However, the most frequent indications for surgery in octogenarians are urinary retention (55% of octogenarians vs 38% of younger men) or gross hematuria (7% vs 1.2%) and these indications are not associated with minimally invasive therapies as often as LUTS (38% of octogenarians vs 59% of younger men). There is evidence that the skill set of the urologist plays a significant role in the management options offered to patients as practitioners closer to completion of their residency training are more likely to include a minimally invasive technique. The most common minimally invasive therapies offered were transurethral microwave thermotherapy (TUMT) (55%) and transurethral needle ablation (TUNA) (33%).

A review of Medicare data from 1999 to 2005 indicated that the net result of all these influences resulted in a 44% increase in the total BPH procedures driven by a 529% increase in the number of MISTs (from 11,582 to 72,887). These data correspond to a 439% increase in the rate of MIST procedures from 136 to 678 procedures per 100,000 males during this period. During this same period the TURP rate decreased approximately 5% per year and by 2005 TURP accounted for only 39% of the surgical treatment procedures and MIST procedures accounted for 57%. Age, anesthetic risk, grade of obstruction, prostate volume, serum PSA value, treatment-related complication rate, presence of an indwelling catheter, and neurologic disorders should be taken into consideration when choosing an appropriate treatment.

TUMT

Microwave as a therapy for the prostate has evolved since first introduced by Yerushalmi and colleagues in 1985. Microwave frequencies fall within the range of 300 to 3000 MHz and are absorbed as they propagate through tissue, producing changes in the tissue that result in heat. Analogous to ultrasound, higher frequencies do not penetrate the tissue so deeply. Similar to ultrasound, increasing the energy output (capacity to perform work) of the microwave signal increases the amount of power (work/time) that irradiates the tissue. When the prostate tissue absorbs this energy, heat is produced, thus the more energy absorbed, the greater the heat created. In TUMT, an external power source creates microwaves between the frequencies of 900 and 1100 MHz. All approved units employ a microwave antenna incorporated into a urethral catheter. Continued improvement in antenna design has refined the focus of the energy within the prostate transition zone, and resultant treatment temperatures have progressed sequentially from less than 45°C (hyperthermia) to greater than 45°C (thermotherapy) (the minimum temperature to destroy prostate cells reliably), to temperatures greater than 70°C (thermoablation). Thermoablation produces cavities in the prostate and is reported to result in greater improvements in symptoms and objective parameters. The goal of microwave therapy is to provide efficacious treatment with less patient risk than that of TURP.

Patients who are potential candidates for TUMT should meet the criteria for treatment according to the American Urological Association (AUA) guidelines for BPH. This would include men with moderate-to-severe LUTS of BPH who failed medical therapy, do not want medical therapy, or cannot or will not consider surgery. A patient’s decision to undergo TUMT is typically determined by his perceived balance between a one-time method requiring minimal anesthetic, reduced risks compared with TURP, and an improved efficacy compared with medical therapy. However, urologists must recognize that there is an array of microwave devices and that these design differences affect appropriate patient selection. Urologists must be familiar with factors such as antenna length and design that determine the location of the preferential focus and the minimum and maximum size of the prostate that can be reliably treated.

The rapid evolution of technology and the inherent differences in device design preclude grouping outcomes of all devices into a single conclusion without careful understanding of the individual device characteristics. For example, the limited energy output of the Prostasoft 2.0 produced an initial symptomatic improvement, but the objective parameters failed to improve compared with baseline, and up to 66% of men required supplemental treatment. In contrast, the higher energy output of the Prostasoft 3.5 was associated with a decrease in the international prostatic symptom score (IPSS) of 11 points (from 20 to 9.3) and an increase in the maximum urinary flow rate of 5 mL/s (9.4 mL/s to 14.6 mL/s) at 6 months after treatment. The higher energy microwave was also associated with a longer indwelling urinary catheter time of 18 days but was not associated with serious complications. Additional investigators have noted similar improvements with other higher energy devices (Targis, Prostate Solutions Inc.), reporting significant symptomatic improvement up to 24 months. In these studies, the mean maximum flow rate increased from 7.3 mL/s to 14.5 mL/s at 6 months, the mean PVR decreased from 199 mL to 34.8 mL at 6 months, and both parameters remained stable at 12 months. The authors also noted that the prostate volume decreased from 57 cm ³ to 42 cm ³ , cavitation was observed in 77% of patients and only 13% of patients required retreatment within 1 year. High-energy devices also allowed clinicians to expand the indications for the device. Originally, TUMT was thought to be insufficient therapy for patients presenting with urinary retention despite the general patient characteristics most attractive to the use of a minimally invasive therapy. Many of these patients were older, had a larger prostate volume, and had more surgical comorbidities. However, the high-energy TUMT devices have reported a catheter-free rate of 82% to 91% in selected patients, although most also must continue medical therapy.

Although it can be difficult to recruit patients to sham controlled and randomized clinical trials, a limited number of these studies involving TUMT are available. When compared with sham (the catheter was placed but the antenna was not powered), there was a reported average decrease in symptom scores of 11 points (compared with 5 points with sham) at 6 months in 220 patients. When high-energy TUMT was compared with terazosin (52 participants), the literature indicates that α-blockers provide a more rapid improvement in IPSS, peak flow, and quality of life (QOL) at 2 weeks compared with TUMT, although by 4 months TUMT demonstrated superior outcomes (IPSS score 35%, Q _max 22%, QOL 43% better in TUMT compared with α-blockers), was associated with fewer adverse events (7 of 51) compared with α-blockers (17 of 52), and TUMT maintained its effectiveness compared with terazosin for at least 18 months. Newer α-blockers are associated with fewer side effects and a randomized investigation of neoadjuvant and adjuvant α-blockade combined with TUMT demonstrated highly significant improvement in symptoms as early as 2 weeks after therapy compared with TUMT alone, and at 12 weeks the 2 groups exhibited comparable symptom reduction. Thus, earlier relief of symptoms may be possible and may improve patient satisfaction with TUMT.

When compared with the historical gold standard, TURP, the magnitude and durability of the symptom score and the maximum flow rate improvements were greater after TURP. However, TURP was associated with a 9.4% to 19.9% complication rate, and required an anesthetic, postoperative hospitalization, and a 2% yearly re-operation rate. In contrast, TUMT resulted in a lower incidence of retrograde ejaculation, erectile dysfunction, TURP syndrome, clot retention, transfusion requirement, was rarely was associated with strictures but had a 7% yearly re-operation rate, and the average catheter time with high-energy TUMT was 3 to 14 days. Similarly, the ProstaLund Feedback Treatment (ProstaLund Operations AB, Uppsala, Sweden) has been compared with TURP and has not shown inferior outcomes, but selection and reporting bias and a limited number of patients inhibit meaningful use of these data. Few trials have directly compared TUMT with other minimally invasive procedures, although short-term studies of individual procedures suggest similar improvement in symptoms and flow rate.

Limitations imposed by the lack of large-scale multi-institution trials were addressed in a pooled analysis of 6 multicenter studies of cooled thermotherapy, involving 541 men whose baseline measures were comparable across the studies. At 3 months, the AUA symptom score had improved by a mean of 11.6 (55%), Q _max by a mean of 4.0 (51%), and QOL by a mean of 2.3 (53%). These improvements were maintained for 48 months with only slight attenuation (corresponding mean changes of 43%, 35%, and 50%) and were highly statistically significant ( P <.0001–0.01). A satisfactory level of improvement (at least 25%) was observed at all points in more than 85% of patients for AUA symptom score and QOL and in more than 65% of patients for Q _max . This large, long-term pooled analysis confirms the results observed for TUMT in smaller and shorter-term studies.

There is evidence that TUMT results in relatively small changes in PSA (mean decrease of 0.27 ng/mL at 1 year) and prostate volume (mean decrease of 3.80 cm ³ at 1 year), supporting the concept that prostate volume reduction is not a significant factor in symptom relief and that prostate function is unaltered after TUMT. In the absence of a well-defined mechanism of action and the observation that TUMT is associated with an increased retreatment rate compared with TURP it becomes clear that prognostic parameters indicating long-term response are critical to the success of this technology. Ideally, these parameters that would improve patient selection because they would predict men at risk for retreatment and thus reduce the risks and expense associated with exposure to serial treatments. When investigators examined the prognostic value of age, PSA, and prostate volume, they found that improvement occurred in all subgroups of patients, but a PSA level greater than 4 ng/mL was observed to predict an unsatisfactory symptom score and maximum urinary flow rate at 3 or more years in patients who initially demonstrated a satisfactory response to treatment. For the first time, the authors offered prognostic indicators for eventual failure in the patient after initial success, adding to the previous studies where PSA was an identified risk for deterioration in symptoms and flow rate, episodes of acute urinary retention, and prostate growth in all response groups. Logically, patients with elevated baseline PSA levels may need more careful long-term follow-up to assess the need for retreatment.

During the procedure patients commonly experience mild perineal warmth, mild pain, and a sense of urinary urgency. However, only 5% of patients reported their pain as being severe during Targis therapy. It is the authors’ experience that all patients required a prostate anesthetic block and pretreatment oral analgesics.

The main risks of TUMT include urinary retention, infection (1%–13%), and postoperative pain. The increased risk for infection following TUMT may be related to the length of catheter dwell time and necrotic tissue sloughing. Erectile dysfunction following TUMT appears to be related to the energy protocol of the device used, with higher-energy TUMT protocols resulting in a greater incidence of erectile dysfunction (18.2%) compared with low-energy protocols (no reported incidence). Retrograde ejaculation occurs less often in TUMT compared with the reported rate for TURP (0%–28% of patients after TUMT, 48%–90% of patients after TURP). Overall, patients’ sexual satisfaction appears to be greater among those who have undergone TUMT rather than TURP, with 55% of patients undergoing microwave thermotherapy reported as being very satisfied, compared with a 21% rate among patients after TURP. Clinicians are cautioned that the risk of acute myocardial infarction is not negligible using TUMT. TURP and TUMT are associated with a higher incidence of mortality caused by acute myocardial infarction, (especially more than 2 years after therapy) compared with the general population. A recent report also indicates that the risk of hypertension and cerebrovascular accident is also increased with TUMT. Other rare complications have been reported following TUMT; these include, but are not limited to, bladder perforation, bowel irradiation, chronic pain, urethral injury, prostatitis, urethral tear, anal irritation, and urethral stricture. Some patients have experienced serious injuries following TUMT, including damage to the penis and urethra, and have required colostomies or partial amputation of the penis. In December 2000, the US Food and Drug Administration issued a warning about these injuries and identified the following risk factors that may contribute to these side effects;

• •
  

  Incorrect placement or undetected migration of the treatment catheter or the rectal temperature sensors

  
  
• •
  

  Failure of the physician to remain with the patient throughout the entire treatment duration

  
  
• •
  

  Failure to pause treatment when the patient is communicating serious pain

  
  
• •
  

  Oversedation of the patient, which compromises his ability to communicate pain

  
  
• •
  

  Treatment of patients who have undergone prior radiation therapy to the pelvic area

  
  
• •
  

  Treatment of patients whose prostate sizes are outside the ranges specified in the labeling

  
  
• •
  

  Leakage from the balloons used to retain the urethral catheter or the rectal temperature sensor in the correct anatomic position

Of all nonablative thermal therapies, TUMT is the best documented. The literature has reported that TUMT is safe when properly supervised by a physician and is an effective minimally invasive alternative treatment for symptomatic BPH. TUMT can be performed in a 1- to 2-hour office visit without intravenous sedation, but the urologist must be cognizant of the reports concerning myocardial infarction, hypertension, and stroke when using this therapy as an alternative for patients who are at high surgical and anesthetic risk. It is not effective for patients with a large median lobe or a very large prostate, and it results in less significant improvement in urinary flow patterns than TURP. Cost-effectiveness analysis has suggested that TUMT has lower costs, but long-term analysis of the cost-benefit scheme in light of the risk for serial treatments is required.

TUMT

Microwave as a therapy for the prostate has evolved since first introduced by Yerushalmi and colleagues in 1985. Microwave frequencies fall within the range of 300 to 3000 MHz and are absorbed as they propagate through tissue, producing changes in the tissue that result in heat. Analogous to ultrasound, higher frequencies do not penetrate the tissue so deeply. Similar to ultrasound, increasing the energy output (capacity to perform work) of the microwave signal increases the amount of power (work/time) that irradiates the tissue. When the prostate tissue absorbs this energy, heat is produced, thus the more energy absorbed, the greater the heat created. In TUMT, an external power source creates microwaves between the frequencies of 900 and 1100 MHz. All approved units employ a microwave antenna incorporated into a urethral catheter. Continued improvement in antenna design has refined the focus of the energy within the prostate transition zone, and resultant treatment temperatures have progressed sequentially from less than 45°C (hyperthermia) to greater than 45°C (thermotherapy) (the minimum temperature to destroy prostate cells reliably), to temperatures greater than 70°C (thermoablation). Thermoablation produces cavities in the prostate and is reported to result in greater improvements in symptoms and objective parameters. The goal of microwave therapy is to provide efficacious treatment with less patient risk than that of TURP.

Patients who are potential candidates for TUMT should meet the criteria for treatment according to the American Urological Association (AUA) guidelines for BPH. This would include men with moderate-to-severe LUTS of BPH who failed medical therapy, do not want medical therapy, or cannot or will not consider surgery. A patient’s decision to undergo TUMT is typically determined by his perceived balance between a one-time method requiring minimal anesthetic, reduced risks compared with TURP, and an improved efficacy compared with medical therapy. However, urologists must recognize that there is an array of microwave devices and that these design differences affect appropriate patient selection. Urologists must be familiar with factors such as antenna length and design that determine the location of the preferential focus and the minimum and maximum size of the prostate that can be reliably treated.

The rapid evolution of technology and the inherent differences in device design preclude grouping outcomes of all devices into a single conclusion without careful understanding of the individual device characteristics. For example, the limited energy output of the Prostasoft 2.0 produced an initial symptomatic improvement, but the objective parameters failed to improve compared with baseline, and up to 66% of men required supplemental treatment. In contrast, the higher energy output of the Prostasoft 3.5 was associated with a decrease in the international prostatic symptom score (IPSS) of 11 points (from 20 to 9.3) and an increase in the maximum urinary flow rate of 5 mL/s (9.4 mL/s to 14.6 mL/s) at 6 months after treatment. The higher energy microwave was also associated with a longer indwelling urinary catheter time of 18 days but was not associated with serious complications. Additional investigators have noted similar improvements with other higher energy devices (Targis, Prostate Solutions Inc.), reporting significant symptomatic improvement up to 24 months. In these studies, the mean maximum flow rate increased from 7.3 mL/s to 14.5 mL/s at 6 months, the mean PVR decreased from 199 mL to 34.8 mL at 6 months, and both parameters remained stable at 12 months. The authors also noted that the prostate volume decreased from 57 cm ³ to 42 cm ³ , cavitation was observed in 77% of patients and only 13% of patients required retreatment within 1 year. High-energy devices also allowed clinicians to expand the indications for the device. Originally, TUMT was thought to be insufficient therapy for patients presenting with urinary retention despite the general patient characteristics most attractive to the use of a minimally invasive therapy. Many of these patients were older, had a larger prostate volume, and had more surgical comorbidities. However, the high-energy TUMT devices have reported a catheter-free rate of 82% to 91% in selected patients, although most also must continue medical therapy.

Although it can be difficult to recruit patients to sham controlled and randomized clinical trials, a limited number of these studies involving TUMT are available. When compared with sham (the catheter was placed but the antenna was not powered), there was a reported average decrease in symptom scores of 11 points (compared with 5 points with sham) at 6 months in 220 patients. When high-energy TUMT was compared with terazosin (52 participants), the literature indicates that α-blockers provide a more rapid improvement in IPSS, peak flow, and quality of life (QOL) at 2 weeks compared with TUMT, although by 4 months TUMT demonstrated superior outcomes (IPSS score 35%, Q _max 22%, QOL 43% better in TUMT compared with α-blockers), was associated with fewer adverse events (7 of 51) compared with α-blockers (17 of 52), and TUMT maintained its effectiveness compared with terazosin for at least 18 months. Newer α-blockers are associated with fewer side effects and a randomized investigation of neoadjuvant and adjuvant α-blockade combined with TUMT demonstrated highly significant improvement in symptoms as early as 2 weeks after therapy compared with TUMT alone, and at 12 weeks the 2 groups exhibited comparable symptom reduction. Thus, earlier relief of symptoms may be possible and may improve patient satisfaction with TUMT.

When compared with the historical gold standard, TURP, the magnitude and durability of the symptom score and the maximum flow rate improvements were greater after TURP. However, TURP was associated with a 9.4% to 19.9% complication rate, and required an anesthetic, postoperative hospitalization, and a 2% yearly re-operation rate. In contrast, TUMT resulted in a lower incidence of retrograde ejaculation, erectile dysfunction, TURP syndrome, clot retention, transfusion requirement, was rarely was associated with strictures but had a 7% yearly re-operation rate, and the average catheter time with high-energy TUMT was 3 to 14 days. Similarly, the ProstaLund Feedback Treatment (ProstaLund Operations AB, Uppsala, Sweden) has been compared with TURP and has not shown inferior outcomes, but selection and reporting bias and a limited number of patients inhibit meaningful use of these data. Few trials have directly compared TUMT with other minimally invasive procedures, although short-term studies of individual procedures suggest similar improvement in symptoms and flow rate.

Limitations imposed by the lack of large-scale multi-institution trials were addressed in a pooled analysis of 6 multicenter studies of cooled thermotherapy, involving 541 men whose baseline measures were comparable across the studies. At 3 months, the AUA symptom score had improved by a mean of 11.6 (55%), Q _max by a mean of 4.0 (51%), and QOL by a mean of 2.3 (53%). These improvements were maintained for 48 months with only slight attenuation (corresponding mean changes of 43%, 35%, and 50%) and were highly statistically significant ( P <.0001–0.01). A satisfactory level of improvement (at least 25%) was observed at all points in more than 85% of patients for AUA symptom score and QOL and in more than 65% of patients for Q _max . This large, long-term pooled analysis confirms the results observed for TUMT in smaller and shorter-term studies.

There is evidence that TUMT results in relatively small changes in PSA (mean decrease of 0.27 ng/mL at 1 year) and prostate volume (mean decrease of 3.80 cm ³ at 1 year), supporting the concept that prostate volume reduction is not a significant factor in symptom relief and that prostate function is unaltered after TUMT. In the absence of a well-defined mechanism of action and the observation that TUMT is associated with an increased retreatment rate compared with TURP it becomes clear that prognostic parameters indicating long-term response are critical to the success of this technology. Ideally, these parameters that would improve patient selection because they would predict men at risk for retreatment and thus reduce the risks and expense associated with exposure to serial treatments. When investigators examined the prognostic value of age, PSA, and prostate volume, they found that improvement occurred in all subgroups of patients, but a PSA level greater than 4 ng/mL was observed to predict an unsatisfactory symptom score and maximum urinary flow rate at 3 or more years in patients who initially demonstrated a satisfactory response to treatment. For the first time, the authors offered prognostic indicators for eventual failure in the patient after initial success, adding to the previous studies where PSA was an identified risk for deterioration in symptoms and flow rate, episodes of acute urinary retention, and prostate growth in all response groups. Logically, patients with elevated baseline PSA levels may need more careful long-term follow-up to assess the need for retreatment.

During the procedure patients commonly experience mild perineal warmth, mild pain, and a sense of urinary urgency. However, only 5% of patients reported their pain as being severe during Targis therapy. It is the authors’ experience that all patients required a prostate anesthetic block and pretreatment oral analgesics.

The main risks of TUMT include urinary retention, infection (1%–13%), and postoperative pain. The increased risk for infection following TUMT may be related to the length of catheter dwell time and necrotic tissue sloughing. Erectile dysfunction following TUMT appears to be related to the energy protocol of the device used, with higher-energy TUMT protocols resulting in a greater incidence of erectile dysfunction (18.2%) compared with low-energy protocols (no reported incidence). Retrograde ejaculation occurs less often in TUMT compared with the reported rate for TURP (0%–28% of patients after TUMT, 48%–90% of patients after TURP). Overall, patients’ sexual satisfaction appears to be greater among those who have undergone TUMT rather than TURP, with 55% of patients undergoing microwave thermotherapy reported as being very satisfied, compared with a 21% rate among patients after TURP. Clinicians are cautioned that the risk of acute myocardial infarction is not negligible using TUMT. TURP and TUMT are associated with a higher incidence of mortality caused by acute myocardial infarction, (especially more than 2 years after therapy) compared with the general population. A recent report also indicates that the risk of hypertension and cerebrovascular accident is also increased with TUMT. Other rare complications have been reported following TUMT; these include, but are not limited to, bladder perforation, bowel irradiation, chronic pain, urethral injury, prostatitis, urethral tear, anal irritation, and urethral stricture. Some patients have experienced serious injuries following TUMT, including damage to the penis and urethra, and have required colostomies or partial amputation of the penis. In December 2000, the US Food and Drug Administration issued a warning about these injuries and identified the following risk factors that may contribute to these side effects;

• •
  

  Incorrect placement or undetected migration of the treatment catheter or the rectal temperature sensors

  
  
• •
  

  Failure of the physician to remain with the patient throughout the entire treatment duration

  
  
• •
  

  Failure to pause treatment when the patient is communicating serious pain

  
  
• •
  

  Oversedation of the patient, which compromises his ability to communicate pain

  
  
• •
  

  Treatment of patients who have undergone prior radiation therapy to the pelvic area

  
  
• •
  

  Treatment of patients whose prostate sizes are outside the ranges specified in the labeling

  
  
• •
  

  Leakage from the balloons used to retain the urethral catheter or the rectal temperature sensor in the correct anatomic position

Of all nonablative thermal therapies, TUMT is the best documented. The literature has reported that TUMT is safe when properly supervised by a physician and is an effective minimally invasive alternative treatment for symptomatic BPH. TUMT can be performed in a 1- to 2-hour office visit without intravenous sedation, but the urologist must be cognizant of the reports concerning myocardial infarction, hypertension, and stroke when using this therapy as an alternative for patients who are at high surgical and anesthetic risk. It is not effective for patients with a large median lobe or a very large prostate, and it results in less significant improvement in urinary flow patterns than TURP. Cost-effectiveness analysis has suggested that TUMT has lower costs, but long-term analysis of the cost-benefit scheme in light of the risk for serial treatments is required.