Is Focal Therapy an Alternative to Active Surveillance?

Abstract

Because of the widespread use of prostate-specific antigen, urologists face an increasing number of patients with small-volume, low-grade prostatic carcinoma seeking the optimal therapeutic approach. Concerns about “overdiagnosis” of prostate cancer (PCa) and consequent overtreatment of clinically insignificant tumors in combination with the significant morbidity that traditional therapies carry have resulted in questioning the need for radical treatments of PCa for selected groups of patients with low-risk PCa. Active surveillance has been introduced as a conservative management option for PCa that closely monitors patients and treats them when progression is identified. Recently, because of technological advances, focal therapy has been introduced to optimize control of low-risk cancers while minimizing the adverse events of whole-gland therapy and the anxiety associated with delayed treatment. The rationales, merits, and limitations of both active surveillance and focal therapy are highlighted in this article.

Introduction

P rostate cancer (PCa) is now recognized as one of the most important medical problems facing men, with an estimated 192,280 new cases for 2009 in the United States. PCa represents the second most lethal tumor among men, with 27,360 expected deaths in 2009.¹ Because many cases of PCa will not become clinically significant, the widespread implementation of prostate-specific antigen (PSA) reflects the low mortality-to-incidence ratio. The introduction of aggressive biopsy and rebiopsy regimens and extended prostatic biopsy schemes seem to significantly contribute to the detection of minimal or indolent, non–life-threatening prostatic tumors.

“Overdiagnosis” of PCa, defined as the diagnosis of cancers that will not be diagnosed clinically during life,² has unquestionably occurred and represents a challenge for both patients and clinicians. Ideally, only potentially curable patients with clinically significant PCa should undergo treatment. At present, active treatment of newly diagnosed PCa remains the gold standard, even considering earlier detection of PCa.³ More conservative management strategies have been proposed, including active surveillance and, more recently, focal therapy for carefully selected patients with localized PCa.

The Active Surveillance Option

Active surveillance (AS) is the new term for the conservative management of PCa and represents an active decision not to treat the patient immediately, to follow him with close surveillance by PSA determinations, and to rebiopsy and treat at predefined, not scientifically based thresholds that classify progression. In these cases, the treatment options are intended to be curative.³

The underlying principle of AS was the reduction of the overtreatment ratio in patients with clinically confined low-risk PCa, without giving up treatment with curative intent, in contrast to the watchful waiting (WW) strategy.

Rationale for AS

Patients' overtreatment

Many authors have attempted to identify “clinically insignificant” or “low-risk” PCa based on biopsy and clinical criteria. The gold standard for clinically insignificant tumors is a radical prostatectomy specimen that contains less than 0.5 cc of Gleason 6 or less PCa.⁴ Low-risk tumors include clinical T_1–2a disease, with a PSA level of less than 10 ng/mL and biopsy Gleason score of 6 or less.⁵

Data from the large Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database demonstrated a significant increase in the proportion of patients with low-risk tumor characteristics from 27.5% in 1990 to 1994 to 45.8% in 2004 to 2006; in addition, there are significant, ongoing trends toward more favorable characteristics within the low risk category.⁶

In the PSA era, more PCa is detected at earlier stages, and this stage migration correlates with considerable lead-time bias because tumors are diagnosed well before they would otherwise become clinically evident. The rate of overdetection is suggested to be as high as 50%, meaning that up to one-half of PSA-detected cancers may be clinically insignificant.⁷ These data suggest that a lot of the men with localized PCa would not, in fact, benefit from a definitive treatment.

In the AS approach, patients with favorable tumor characteristics, in terms of T stage, Gleason score, and PSA level, are closely monitored using serum PSA levels and repeated prostate biopsies. The choice between radical treatment on the one hand or continued observation on the other is based on evidence of disease progression during this monitoring determined by PSA doubling time and Gleason score progression to >6 at rebiopsy.³

Reduced morbidity

Surgery and radiotherapy provide excellent long-term cancer control in low-risk PCa, but they carry significant morbidity in terms of early complications (ie, wound infection, bleeding, rectal problems, hospital stay, gastrointestinal-urinary toxicity) and long-term adverse effects on sexual and urinary function that can influence the quality of life. In the only randomized study of radical prostatectomy vs watchful waiting, men who were randomized to surgery had a 35% absolute increase in the risk of erectile dysfunction and a 28% absolute increase in the risk of urinary leakage.⁸

The Prostate Cancer Outcomes Study results for treatment harms and patient satisfaction indicated that external-beam radiation therapy (EBRT) was also associated with urinary leakage occurring daily or more frequently (12%) and erectile dysfunction (43%).⁹ In addition, bowel urgency was more frequent with EBRT (3%) compared with radical prostatectomy or surveillance.⁹ These figures underscore the significant morbidity that is associated with surgery or radiotherapy and the impact on a man's lifestyle.

Outcomes

Reported outcomes from several studies on AS are promising, but there is the limitation of the rather short follow-up, especially when the long natural history of the disease is taken into account. In general, 20% to 35% of men will receive delayed treatment with curative intent at a median follow-up ranging from 24 to 64 months.¹⁰ In one of the largest studies (299 patients) with perhaps the longest median follow-up (8 years) in which 65% of patients remained free of treatment, the overall survival rate was 85%, and the disease-specific survival rate was 99.3%.¹¹

Considerations

Undertreatment

The undertreatment consideration arises mainly from the potential clinical understaging of PCa patients and consequently from the uncertainty of compromising the opportunity for cure if treatment is delayed. Nearly 25% of patients with low-risk cancer who might be thought to be ideal candidates for AS will have either a higher Gleason score or greater cancer volume at evaluation of a radical prostatectomy specimen or at immediate repeated biopsy.^12,13 Therefore, it is of utmost importance to closely monitor patients to identify early signs of potential disease progression.

Different follow-up protocols of patients undergoing AS have been proposed, and the detection of PCa progression still remains a challenge for physicians.¹⁰ The most appropriate timing of repeated biopsy, the number of core samples necessary, and optimal progression criteria are still to be determined to correctly identify in a timely manner men in whom there is progress to more aggressive cancer.

Low acceptance

Data from the CaPSURE national registry showed that of the 2156 men with low-risk localized PCa included in the registry between 1990 and 2001, only 197 (9.1%) elected AS for initial disease management.⁶ The use of AS remained relatively constant (9.3%) between 2002 and 2006, despite the increasing interest in the role of AS.⁶ These data indicate that AS has not gained the expected popularity among patients and physicians and surveillance has been resisted in many constituencies because of concern about the inaccuracies of clinical staging and grading.

Psychological impact

It seems reasonable that living with a PCa diagnosis, especially when treatment with curative intent is deferred, can produce considerable stress and anxiety. There are only a few publications that directly address AS as opposed to WW, although some characteristics might be shared by both groups. A systematic review of monitoring programs found that up to 50% of men abandoned monitoring within 2 years, largely because of anxiety related to increasing PSA levels rather than objective evidence of disease progression.¹⁴ In addition, Latini and associates¹⁵ showed that anxiety can be an independent factor in driving surveillance patients toward active intervention.

In a randomized trial from Scandinavia, however, that compared radical prostatectomy with WW, worry, anxiety, and depression were similar between the two arms.⁸ Burnet and coworkers¹⁶ showed that AS for managing localized PCa was not associated with greater psychological distress than immediate radical treatments. Contemporary data suggest that men who are undergoing traditional WW for PCa generally have very stable quality of life indices.^17,18 It seems that patients who knowingly select AS and appreciate the indolent natural history of good-risk PCas remain adherent to the surveillance protocol and may avoid much of these adverse psychological effects.

Focal Therapy

Focal therapy for PCa is an individualized treatment that selectively ablates known disease and preserves existing functions, with the overall objective of minimizing lifetime morbidity without compromising life expectancy.¹⁹

Rationale for focal therapy

The concept of organ-sparing treatment has proven its efficacy for selected tumors of the breast, skin, bladder, and kidney. The driving forces behind the development of focal therapy for PCa include all the arguments in favor of AS but also the considerations regarding expectant management. Recent stage migration toward low-risk PCa, overtreament of biologic insignificant tumors with radical prostatectomy at the additional expense of nonnegligible morbidity, undertreatment of patients improperly selected for AS, and the relatively low acceptance of AS as a result of the psychological burden of delaying treatment of a malignant disease represent the main reasons that have fueled the concept of focal therapy. Last but not least, the technological advances that provide the ability to perform prostate-sparing ablation are now available.

Four modalities appear to have the most clinical promise for PCa focal therapy, including highintensity focused ultrasound, cryotherapy, radiation therapy (RT) (external beam RT [EBRT] and brachytherapy), and photodynamic therapy (PDT) (Table 1).

Table 1.

Current Focal Therapy Modalities

Modalities	Mechanism of action	Imaging	Studies
Cryotherapy	“Freeze rupture,” necrosis, and vascular thrombosis	TRUS	Best studied focal therapy Several case-series studies
HIFU	Thermal induced protein denaturation and coagulative necrosis	TRUS MRI	Two feasibility studies
RT -EBRT -Brachytherapy	DNA damage, cell damage, and apoptosis	CT TRUS	Feasibility studies
PDT	Light activated, oxygen-dependent cytotoxic and vasculotoxic reactions	TRUS MRI	Two Phase I/II studies

TRUS = transrectal ultrasonography; HIFU = high intensity focused ultrasound; MRI = magnetic resonance imaging; RT = radiation therapy; EBRT = external beam radiation therapy; CT = computed tomography; PDT = photodynamic therapy.

Under the umbrella of focal therapy, several approaches can be found, including local application of therapy to a specific focus, ablation of one-half of the prostate (hemiablation), and ablation of nearly the entire prostate (near-total ablation) leaving only a rim of nonmalignant parenchyma adjacent to a neurovascular bundle that one would intentionally want to protect.²⁰ Subtotal prostate ablation seems to be an attractive option, especially for patients with monofocal or unilateral PCa who are willing to preserve their quality of life in terms of sexual, urinary, and bowel function.

Outcomes

Analysis of the outcomes from the available focal treatment modalities is beyond the scope of this article and will be presented in detail in the following articles of this issue. To date, only uncontrolled case series carried out in single institutions have reported their early results. Table 1 indicates the volume and type of studies. In general, preliminary experience has shown promising results regarding the feasibility and efficacy of focal therapy as a treatment option for patients with low-risk PCa. Given the long natural history of the disease, longer term data are needed to prove the oncologic efficacy of focal therapy. A review of these very limited data from case series (mainly for cryotherapy studies) has demonstrated potency preservation (with or without the use of 5-phosphodiesterase inhibitors) in three-quarters of treated patients and a continence rate of nearly 100%.²¹

Considerations

Unifocality and unilaterality

One of the greatest considerations regarding the use of focal therapy has been the concern about the multifocality of PCa. In a comprehensive review of 12 contemporary radical retropubic prostatectomy series with 2988 patients in total, Meiers and associates²² found that the reported incidence of multifocal PCa ranged from 67% to 87%. Similarly, Wise and colleagues²³ reported a 17% frequency of unifocal tumors after examining 486 RP specimens.

Mouraviev and coworkers²⁴ analyzed 1184 paraffin-embedded radical prostatectomy specimens from patients with clinically localized PCa focusing on the potential applicability of the hemiablation technique. Completely unilateral cancers were detected in 227 (19.2%) patients. The majority of unilateral tumors were low volume, with a percentage of tumor involvement less than 5% (72%) and with Gleason score less than 7 (61%). These findings indicate that almost one in five patients who are treated with radical prostatectomy would be amenable to focal therapy treating one lobe of the prostate (hemiablation).²⁴

The argument in favor

Pathologists have noted that many radical prostatectomy specimens contain a large tumor (the ‘index lesion’) and smaller, satellite tumors. Ohori and colleagues²⁵ evaluated 961 radical prostatectomy specimens from patients with clinically confined PCa. Extracapsular extension (ECE) was found in 16% of patients, and the index lesion was responsible for the ECE in 86% of the cases. When patients with a PSA level less than10 ng/mL were analyzed, it was found that only 18% of cancers were unifocal, but the largest focus of cancer (index lesion) represented an average of 80% of all cancer present. In this subgroup of patients, ECE was present in 28% of patients, of which 92% arose from the largest cancer.²⁵ In addition, Wise and associates²³ found that progression-free survival was associated with index cancer volume but not with secondary tumor characteristics. Similar results have been reported by Noguchi and coworkers²⁶ who evaluated the prognostic value of secondary cancers in multifocal, localized PCa.

Based on these studies, it seems that in a significant proportion of patients with multifocal disease, the index tumor is the responsible one for the total cancer volume and the potential ECE whereas nonindex tumors are unlikely to affect overall disease progression. Therefore, the concept of biologically unifocal disease has been introduced, suggesting that targeting an index cancer has the potential to dramatically decrease total tumor volume and eliminate the most likely source of ECE.²⁷ Other studies, however, indicate that some secondary lesions (20%) have adverse pathologic findings in terms of size, extraprostatic extension, grade, or margins, whereas the long-term relevance of secondary tumors in terms of growth, need for treatment, and metastatic potential is still uncertain.²⁸

Optimal biopsy schemes and imaging

The future success of focal therapy will depend on adequate prostate sampling at biopsy and accurate characterization of the spatial distribution of tumor into the prostate. Systematic reviews of the literature have suggested the use of 12-core prostate biopsy schemes that add laterally directed cores to the standard sextant scheme at the initial biopsy for PCa detection.^29,30 These biopsies schemes have not focused on laterality or focality of PCa, because this information is not necessary for whole-gland therapy. Therefore, the question is how many cores are sufficient or necessary to reliably identify and characterize unifocality or unilaterality of PCa.

Saturation biopsy techniques may ultimately be necessary to support decision-making regarding focal therapy. Transperineal “mapping” biopsies performed every 5 mm using a brachytherapy template to direct the needle seem to provide more accurate information regarding spatial tumor distribution and unilaterality of PCa because clinically significant index tumors <1 cm can be reliably identified for focal ablation.³¹

A transperineal three-dimensional mapping biopsy of the prostate is well tolerated and provides superior staging information compared with conventional transrectal ultrasonography (TRUS) biopsy.^31,32 Using transperineal mapping, reported Gleason upgrading (compared with TRUS biopsy) ranged from 16% to 43.5%, and the incidence of bilateral disease (previously determined as unilateral by TRUS biopsy) ranged from 47% to 55%.^31,32

At this time, there is no radiologic modality that can image the exact localization of small-volume PCa. Previous studies reported a variable sensitivity of MRI in localizing disease within the prostate with higher spatial and contrast resolution than TRUS or CT but low specificity.^33,34 Kirkham and coworkers³⁵ reviewed the current data on the efficacy of MRI at detecting and characterizing cancer within the prostate by analysis of the different magnetic resonance sequences available. High-grade and large tumors have been detected significantly more often with both T₂ sequences and spectroscopy. Estimation of size has been improved by dynamic contrast and spectroscopy, but errors of >25% are common. Recently, functional imaging techniques, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, and magnetic resonance spectroscopic imaging (MRSI), have been introduced and evaluated the capability to detect and localize prostate cancer.

Villers and colleagues³⁶ reviewed the current status of MRI techniques in identification of organ-confined PCa with regard to focal therapy and AS. Significant progress in accuracy for cancer detection, volume estimation, intraprostatic location, and extraprostatic extension has been achieved, making MRI the most readily available and useful imaging method, although there is room for further improvement.³⁶ Cost and limited access to these advanced MRI techniques keep them investigational.³⁷ Table 1 provides the imaging modality that the available focal therapeutic options use for tumor localization and treatment guidance and monitoring.

Difficulty in follow-up

There is a lack of standardized follow-up protocols for patients with focal therapy.³⁸ Because a variable amount of prostate tissue is left untreated in focal therapy, absolute values of PSA will be insufficient for verifying and monitoring treatment success. PSA kinetics after treatment to define biochemical recurrence also needs to be clarified.

The position of follow-up TRUS biopsies should be determined, Because positive biopsies in cases where only the index tumor has been ablated may be the result of the presence of secondary insignificant cancers and not treatment failure. In addition, MRI/MRSI may identify the lesion created by ablation and may have a potential role in follow-up protocols.

Future Perspectives –Conclusions

There is a large gap between the “do-nothing” approach (as expressed by WW) and radical treatment for low-risk PCa. As a result, the concept of AS came to replace WW and has narrowed the gap. AS offers a radical treatment option to patients who show signs of progression. Therefore, there is still room for minimally invasive therapies that have good oncologic results and less morbidity. Does focal therapy represent a “middle ground alternative” between the extremes of radical treatments and expectant management? Current, but limited, evidence suggests that focal therapy may play this role of the middle ground alternative.

It is inevitable, however, that successful adoption of focal therapy relies on optimal patient selection. Further research on imaging and pretreatment prognostic indicators is necessary, stressing the need for an interdisciplinary scientific collaboration.

Advances in imaging will allow physicians to precisely identify, target, and destroy PCa foci. The introduction of functional magnetic resonance technology has provided reasonable hopes. Incorporation of molecular biology in the selection of PCa patients should be the next step. Development of molecular markers for aggressiveness of individual PCa will predict with better accuracy the likely natural history of a given patient's tumor. Proteomic studies are now under way and are expected to identify new prognostic markers.

Last but not least, the patient's preference should have a decisive role in treatment choice. The premise of focal therapy that the morbidity is substantially low is very appealing to patients. It is essential, however, that the physician present the available data and highlight the remaining uncertainty. At present, the advisability and applicability of an emerging therapy such as focal therapy depend on an estimate of risk regarding extension and severity of disease and treatment response. Patients also should be informed that no long-term data on focal therapy efficacy exist and that there are potential risks of salvage strategies in case of treatment failure.

Ongoing research on focal therapy should be standardized and be part of clinical trials. Only well-constructed clinical trials with long follow-up comparing different management strategies for localized PCa will be able to provide all the necessary data to define the position of focal therapy in the therapeutic armamentarium of urologists.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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