Chapter 1 | Evolution from whole gland to focal therapy |
Chapter 2 | Mechanisms for cell death in ablative technologies |
Chapter 3 | Focal therapy as an alternative treatment for prostate and renal cancer |
Chapter 4 | Quality of life following whole gland treatment of prostate cancer |
Chapter 5 | Salvage radical prostatectomy |
Chapter 6 | Novel biomarkers in the diagnosis and treatment of prostate cancer |
Chapter 7 | From ‘incidentaloma’ to renal cancer |
Chapter 8 | Classification of small renal tumors before ablative therapy |
Chapter 9 | Impact of nephron sparing surgery on renal function |
Introduction
Nowadays, the treatment paradigm for localized prostate cancer (PCa) seems to distinguish patients with clinically relevant cancers (i.e. potentially life-threatening), who thus require treatment either in the form of traditional radical therapy or a contemporary less aggressive, organ-preserving approach, from the remainder who do not need any intervention at the time of diagnosis.
For a select group of patients with unifocal or unilateral PCa, alternative treatment options include focal therapy (FT) or subtotal glandular ablation with cryotherapy as a more established and proven technique. Other potential minimally invasive procedures that are non-surgical in nature that could also be utilized in the clinical setting include high-intensity focused ultrasound and interstitial laser ablation, which is currently undergoing clinical study. However, additional basic science research and large-scale randomized clinical trials with long-term oncologic follow-up and quality of life (QoL) outcomes are necessary before any conclusions can be made about the sustained efficacy of these minimally-invasive options.
This chapter evaluates the current trends for treating localized, low- and intermediate-grade PCa in a non-whole organ aggressive fashion, and in particular discusses focal therapy as a means of targeting the known cancer in selected low-risk cases, thus avoiding whole-gland therapy and its inherent potential complications regarding QoL. Traditional surgical, radiotherapy or hormonal therapeutic modalities are beyond the scope of this chapter.
A change of paradigm
Now is the prime time to explore new frontiers in imaging and FT of PCa. Almost every urology forum or congress includes a session devoted to the development of this concept. Seven international symposia dealing with this specific topic have been organized on an annual basis alternating between the in USA and Europe by the Duke Comprehensive Cancer Center and the Academic Medical Center, Amsterdam. Since 2008 this has involved the University of South California as well (www.focaltherapy.org). A cadre of clinicians and scientists has gathered at these different meetings including experts in prostate imaging, urologic pathology, basic scientists and molecular biologists, medical and radiation oncologists, urologists and industry leaders trying to improve current treatment modalities.4
Traditionally, PCa has been treated with whole-gland therapy, be it extirpative [radical prostatectomy (RP)], or in-situ therapy (external beam radiotherapy, brachytherapy, cryotherapy, among others). However, the recent trend that a proportion of cancers being diagnosed are unifocal, unilateral, or of lower malignant potential (clinically insignificant) has raised questions regarding the suitability of all patients for radical treatment (Ahmed 2012; Polascik and Mouraviev 2009). Ultimately, the treatment paradigm of managing localized PCa is to distinguish patients with clinically significant multifocal, bilateral cancer who require aggressive whole gland therapy from those with clinically relevant focal cancers who may benefit from either an organ-sparing approach or those who probably do not need any intervention at the time of diagnosis. The aim of this chapter is to critically analyze the current status of primary definitive therapy for the treatment of localized PCa with respect to therapeutic options limited to organ-sparing ablation and whether they can become potentially new frontiers in the treatment armamentarium for this malignancy.
Clinical parallels with other cancers
Many innovations have been accomplished in breast cancer over the last few decades. In the 1980s, the major debate in the local therapy of breast cancer was the rationale for the switch from radical mastectomy to the breast-conserving lumpectomy (Keynes 1981; Murley 1981; Langlands and Tiver 1982; Hayward et al. 1984; Russell 1985). In that light, the randomized National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 trial in 1976 was designed to answer the critical question whether lumpectomy with or without radiation therapy was as effective as total mastectomy for the treatment of invasive breast cancer (Fisher et al. 2002). Through 20 years of follow-up, that trial demonstrated that no significant differences were observed among these three groups of women with respect to disease-free survival, distant-disease-free survival, or overall survival. Lumpectomy followed by breast irradiation appears to be appropriate therapy for women with breast cancer, provided that the margins of resected specimens are free of tumor and an acceptable cosmetic result can be obtained (Fisher et al. 2002). The most important achievement of this trial was that the results proved the Halstedian concept of breast cancer biology and embraced an idea of breast conserving therapy (BCT) such as a lumpectomy as an alternative to mastectomy and to the use of immediate breast reconstruction. Ultimately, it took almost three decades for surgeon-oncologists to replace radical surgery for local stage breast cancer with new organ-preserving treatment principles.
Five other prospective randomized trials have confirmed that survival is equivalent after BCT followed by adjuvant therapy and mastectomy Arriagada 1996; Blichert-Toft et al. 1992; Poggi et al. 2003; van Dongen et al. 2000; Veronesi et al. 2002). Although the local recurrence after BCT has been a great source of concern for both patients and physicians, 5the consensus conference on breast conservations established a goal for BCT as a 10-year local recurrence rate between 5% and 10%, less than 1% per year (Schwartz et al. 2006). Since these initial trials were conducted, the extent of surgery has been decreasing while local control has been increasing. The reasons for this explanation include various factors such as changes in local treatment (advance imaging, biomarkers, careful patient selection, novel image-guided targeted ablation, etc.), addition of boost radiation therapy and improvements in systemic therapy [implementation of new drugs – aromatase inhibitors, taxanes and anti-human epidermal growth factor receptor 2 (HER2) agents]. The prevailing theory was that the surgeon had to remove the gross disease and that moderate-dose radiation or systemic therapy would eradicate residual ‘subclinical disease’ while preserving the cosmetic result. Implicit in this theory was the assumption that the extent of ‘subclinical disease’ was limited and similar in all patients.
The importance of both endocrine therapy and chemotherapy to maintaining local control is also well documented in prospective randomized trials. The majority of women with invasive breast cancer now receive some form of adjuvant systemic therapy in addition to surgery and radiation therapy. Since these trials were conducted, more effective systemic therapy has become available. As survival has increased as a result of improved systemic therapy, a parallel decrease in local recurrence rates has been observed.
Another location with strong evidence-based arguments against an organ-removing surgery for clinically localized disease is a kidney cancer. The majority of kidney cancers are is renal cell carcinoma (RCC), for which the open procedure (radical nephrectomy) was regarded as the ‘gold standard’ treatment in the 1960s and 1970s. With the introduction of advanced imaging techniques such as CT scanning and/or MRI, detection of small renal masses and thus small RCCs became more frequent. This had an effect (Novick 1977) that rebounded on the surgical approach in the late 1970s when Novick et al. developed an improved open partial nephrectomy technique making it suitable for healthy patients with small renal tumors or even for patients with a solitary kidney or compromised renal function. Recently, Lane et al. reported on the 10-year outcomes of laparoscopic nephrectomy and open partial nephrectomy (Table 1.1) (Lane 2013).
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6The cancer control data were excellent in carefully selected patients with limited risk of recurrence for cT1 renal cortical tumors. Overall survival at 10 years was driven by patient factors such as age, comorbidity and operative indication, and by cancer factors such as predicted recurrence-free survival but not by the choice of operative technique, which depends on surgeon preference and experience.
Contemporary radical treatment of prostate cancer
With the widespread adoption of screening programs and detection of early stage PCa, focal targeted therapy may assume a more prominent role between the two management extremes of radical treatment (RP, etc.) and no treatment (such as active surveillance). It is very important, especially for the relatively young cohort of patients (e.g. in mid-fifties and sixties who are still potent and keen to preserve bodily functions such as continence and erectile function), to maintain QoL after PCa treatment. During the last decade, several pathologic and clinical studies have been undertaken to better understand the role and place of organ-preserving ablative technologies, taking into consideration the conceptual promise of using targeted ablation as a ‘male lumpectomy’ in select, appropriate candidates (Emberton 2013; Mouraviev 2010).
Eradication of cancer at an early stage offers the best chance for reducing cancer morbidity and mortality. Since the introduction of PCa screening in the United States with prostate-specific antigen (PSA) testing and digital rectal examination (DRE), the clinical characteristics of the average patient at presentation has changed, including a younger age at diagnosis, increased incidence of non-palpable cancers and decreased serum PSA. This happened in parallel with the development of various biopsy techniques and schemes with subsequent changes in sampling methods and tissue diagnosis interpretation (Figure 1.1). In general, the trend shows an increasing proportion of low-risk disease at the time of diagnosis with a consequent marked decrease in the high-risk group and less apparent changes in the intermediate group over the last 7 years in a large pooled cohort of patients (Cooperberg 2004).
Figure 1.1: This patient underwent 6 sessions with negative standard 10 −12 core random biopsies. After MRI, two targeted biopsies found a ventral cancer on the right side with Gleason score 6. (a) Colour overlay MRI consisting of the apparent diffusion map and anatomical T2 weighted images. Red/purple colour indicates restricted diffusion, which may be a sign of cancer. (b) Whole-mounted histology slide with the index tumor demarcated on the right side. Courtesy of E. Rud et al., Oslo University Hospital.
According to the risk stratification of D'Amico et al., the low-risk group encompasses men with PSA < 10 ng/mL, Gleason score less than 7, and clinical (c) T1c or T2a stage (D'Amico et al. 2003). A recent review 7of 6,652 patients treated with RP for clinically localized PCa from 1984 to 2005 revealed a mean age at surgery of 58 years with a median preoperative PSA of 6 ng/mL. At the time of diagnosis, 61% of patients in the overall cohort presented with stage cT1c tumors and 63% with a Gleason score of 6 or less, which comprised a pool of nearly 60% of men being classified as having low-risk features. In the 1998 to 2005 time frame, 72.6% of tumors were stage cT1c and 67.7% of men were classified as low risk (Hernandez et al. 2008).
A total of 5,343 patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database were evaluated from 1989 to 2001 (Cooperberg 2004). Overall, 37.5% of patients were low risk during the years of study, the proportion increasing from 29.8% in 1989–1992 to 45.3% in 1999–2001. In a more recent period (1995–2007), 42% of patients presented with low-risk features. Socio-demographic factors associated with a more favorable classification on multivariate analyses were age younger than 60 years, education beyond high school, and income greater than $50,000, while nonwhite race was associated with high-risk disease.
The more indolent biologic behavior of these tumors has paved the path to more selective therapies. An International Consortium Panel defined focal PCa as being less than stage T2b, with no Gleason pattern 4 or 5, detected by systematic biopsies (with 10 transperineal cores preferred), and with no more than two positive adjacent sectors in a patient with low PSA density < 0.15 ng/mL/g (Sartor et al. 2008). Nowadays, a higher proportion of men are presenting with pathologic stage T2a or T2b tumors, i.e. having unilateral disease. This trend was noted by Polascik et al., reviewing 3,676 men undergoing RP at the Duke Prostate Center from 1998–2006 (Polascik et al. 2000). The patients were classified and divided based on date of surgery as within the early PSA era (1988–1995), transitional PSA era (1996–2000), or contemporary PSA era (2001–2006). Pathologic (p) T2a or T2b stage disease was found in 14.3% of the overall cohort. This represented an increase from 8% in the early PSA era to 17% in the transitional and contemporary eras. However, within the latter two groups, the proportion of stage pT2a tumors increased from 4% to 13%, signifying an overall trend toward a smaller volume of disease. When this trend was correlated by measuring the percent of tumor involvement (PTI), analysis demonstrated a shift to lower tumor volume over time. The number of glands with stage PTI ≤ 5% significantly increased from 10% during 1988–1995 up to 37% in 2001–2006 with a subsequent decline in larger volume (PTI > 15%) disease (Polascik et al. 2000).
Caso et al. (2010) determined the adequacy of T2 PCa sub-staging as an independent predictor of biochemical disease-free survival (bDFS) after RP, from the Duke Prostate Center database based on men who had pT2 PCa (1990 cases) (Polascik et al. 2000). PSA recurrence was defined as a single value > 0.2 ng/mL. Kaplan-Meier curves compared differences in bDFS between T2 sub-divisions. The mean age at surgery was 62 years, and 16% of patients were African-American. Median 8prostate weight was 40 g [interquartile range (IQR) 31–52] and median preoperative PSA was 5.6 (IQR 4.2–7.8). The pathological Gleason score was < 6 in 57%, 7 in 38%, and > 8 in 5% of cases; pathological T stage distribution was 18% T2a, 6% T2b, and 76% T2c; and PTI was < 5% in 43%, between 5.1 and 10% in 24%, between 10.1 and 15% in 10%, and >15% in 19% patients, respectively. In total, 366 (18.4%) patients had a biochemical recurrence after a median of 4.6 years (IQR 2.1–8.2) follow-up. The bDFS was significantly higher for pT2a disease than for pT2b and pT2c in univariate analysis (Polascik et al. 2000).
To predict tumor unilaterality, Mouraviev et al. retrospectively analyzed the results of 1184 men who had undergone RP between 2002 and 2006 and had clinically localized cancer (cT1c or cT2) and PSA < 10 ng/mL (Mouraviev 2007). Patients exhibiting adverse pathologic prognostic factors, such as seminal vesicle invasion and lymph node involvement were excluded from the analysis, as were those who had prior transurethral surgery or neoadjuvant therapy of any kind. Completely unilateral cancers were found in 19.2% of patients, i.e. in 1 of 5 men, who potentially could avoid an organ extirpative procedure thus preserving the contralateral lobe. Multivariate analysis was performed to determine which factors independently predicted an unilaterality: non African-American race, pathologic Gleason score < 7, negative margins, and < 10% tumor involvement all demonstrated a significant correlation (Sartor et al. 2008). This pathological background paved a road toward a concept of potential hemiablation of the prostate as an alternative to RP in a select cohort of patients while keeping intact the other lobe of the prostate, and subsequently relying on careful monitoring to prevent tumor development de novo or potentially missed tumors.
Results from the CaPSURE database estimated that in the years 1999–2001 only 8% of men were monitored with watchful waiting (now known as ‘active surveillance’) (Cooperberg 2004). Certainly, at least a subset of low-risk patients is being over-treated, with subsequent declines in QoL without improved survival from their therapy. However, it is also clear that after long-term follow-up (> 10 years) there are advantages in terms of metastases-free disease and cancer-specific mortality in patients treated with radical surgery versus those that have opted for watchful waiting. A middle-ground approach in which the most aggressive tumor is ablated while a substantial portion of the gland is spared offers promise for oncologic control with maximal preservation of functions.
Tumor growth and the need to intervene early
According to historical perspective of tumor growth kinetics, there are two established models which are exponential and Gompertzian expansion. It has been proven over a few decades that PCa tumors are frequently slow growing as they undergo exponential expansion. 9From the very beginning of tumorigenesis (log phase) the small mass of tumor does not multiply extensively. The hypothesis behind this phase is that ‘pre-cancer’ cells are being thoroughly prepared for the next phase and are accumulating various mutations. Thus cell death outweighs the growth of new dividing cells, keeping the same size of the tumor with no clinical manifestations, remaining subclinical and undetectable for several or even many years. When angiogenesis factors are thought to be expressed, the tumor acquires its own blood supply; this fuels cancer growth to enter the logarithmic (log-phase) period, the tumor becoming large enough to be detected and treated. Theoretically, this can be explained as being due to increase of the growth fraction (ratio of dividing to total cells) with a predominance of dividing cells over the dying cells.
However, even upon reaching its maximum rate, the tumor's growth fraction does not necessarily mean that the tumor will become larger and clinically detectable with conventional diagnostic tools. Interestingly enough, while the reduction in cell number in the log-phase in response to a dose of effective chemotherapy is relatively small, the fractional cell killing rate would be significantly higher than later in tumorigenesis. Then, in the plateau phase, tumor growth slows down as the fraction decreases and a large proportion of cells are dying due to space and nutrient limitations, and blood supply and ‘protective’ genomic mutations are causing the death of many cancer cells. When a tumor approaches 30 doublings (1 × 109 cell), the tumor becomes clinically detectable and comprise 1 g or 1 mL of tissue or equivalent to a tumor that is 1-cm in diameter. In this phase, a 50% reduction in tumor mass represents only a one-third log decrease in tumor volume (Tisman 2013). For example, a tumor mass containing 8 × 1010 cells that is reduced to half its volume by chemotherapy still contains 4 × 1010 cells. Finally, further terminal tumor growth up to 35–40 doublings represents a tumor volume of 1000 mL or tumor diameter of 10 cm (Figure 1.2) (Tisman 2013). These tumors usually result in extensive metastases with damage to vital organs and subsequent patient death.
Briefly summarizing the aforementioned classic description of tumor kinetics, one point that needs to be stressed is that the duration of tumorigenesis from initiation takes several years and for three-quarters of that period the tumor is still clinically undetectable. We have to take into consideration that these tumor kinetic data are becoming dated and need to be revisited in light of novel discoveries in whole- and single-cell genome sequencing and advanced imaging technologies. We now have in our armamentarium different genomic signatures and tools such as multiparametric MRI which we expect will shift the diagnosis of PCa toward an earlier stage disease, thereby identifying small sized lesions (< 0.5 mL) allowing us to intervene early and more efficaciously.10
Figure 1.2: Prostate cancer kinetics: explanation is in the body of the text (based on Tisman 2013).
Latest developments in the tumor biology of prostate cancer
Index lesion as a driver of tumor progression
This understanding of PCa led to the exploration of small-volume disease in a way that potentially justifies an organ-sparing treatment approach with novel thermoablative technologies. Although a single focus of small-volume PCa may occur rarely (in general, in 13–33% of RP specimens), conversely the presence of multiple foci of PCa within the same gland is a common finding (Byar & Mostofi 1972; Mouraviev et al. 2011; Bostwick et al. 2007). Recently, the idea of cancer unilaterality has been developed as a reasonable compromise between uni- and multifocality as a concept for FT whereby a secondary satellite lesion(s) can be additionally destroyed along with the clinically significant index tumor when confined to one lobe (e.g. left or right side) of the prostate. The frequency of unilateral lesions is noted in range from 19% to 63%, for an average between 20 and 30% of cases (Mouraviev et al. 2011).
For the last few decades, in the urologic oncology community, the established concept has been heterogeneity of PCa, requiring mandatory whole gland therapy (Mouraviev et al. 2011). However, in 1972 Byar et al. hypothesized that an index (largest or dominant) lesion could be a driving force of tumor progression representing a more aggressive disease in its later stage than multiple bilateral tumors. This deserves to be marked as the ‘birth date’ of the FT concept.
The role of the index lesion in PCa may be three-fold:
- Driving force of tumor progression
- Contains more aggressive features
Figure 1.3: Typical tumor appearance of an index tumor on diffusion weighted MRI. (a) The green arrowheads show the index tumor on T2w image. (b) The same area appears dark on the apparent diffusion coefficient map. This indicates impaired diffusion, and may be a sign of cancer. (c) b2000 image superimposed upon T2w image. This colour overlay image shows the tumor with yellow color, highly suspicious of cancer (d) native b2000 image (courtesy of E. Rud et al. Oslo University Hospital).
Some survival studies have demonstrated a better survival rate for multifocal tumors suggesting clinical insignificance of secondary lesions. In a large series, the number of cancers increased slightly while the tumor volume decreased from the pre-PSA to contemporary PSA area (Ohori 2004). In this series of 947 RPs form Baylor performed by a single surgeon (P. Scardino), there were 22% unifocal tumors and 78% of tumors showing multifocal disease, with a mean number of cancer foci of 2.24. The mean volume of the index tumors was 2.42 mL, and the mean total volume of accessory tumors was 0.61 mL. Multifocal lesions increased from 71.5% in the period 1983–1988 to 77.9% in 1989–1993 and 80.8% in the period 1994-98. The occurrence of multifocal lesions was not dependent on age. A Kaplan-Meier plot of the bDFS at 12.7-year follow-up showed a significant difference between unifocal (73%) and multifocal disease (68%). Subanalysis according to the number of foci did not show any significant differences.
Rice et al. (2009) analyzed a series of 1,159 RP specimens and found multifocal disease in 1,056 patients (99.1%). Only 103 specimens (8.9%) harboured a single tumor lesion. The rates of positive surgical margins were significantly different between the two groups with 41% in the unifocal and 29.9% in the multifocal group, respectively. Grading also showed unifocal tumors to be more aggressive with Gleason score 8-10 disease in 18.7% versus 10.1% and the biochemical recurrence was 38.5% in the single focus group as compared to 24.2% in the multifocal group.
A significant limitation of the two studies mentioned above should be taken into consideration. The time frame for collecting these data included a long period from the early PSA-era to the current time and did not specifically address what happened in tumors stage migration a few years ago. In other words, it would be not fair to compare tumors in stage 3–4 development treated by RP in 1993 with small-sized tumors 12in stage T2a-b or T3a today. This mismatch of stages does not allow us to draw more robust conclusions from these studies.
The role of secondary satellite lesions
Wise et al. evaluated the behavior of small, independent cancers compared with the index tumor and its impact on bDFS in 486 men treated by RP (Wise 2003). The mean index tumor volume was 4.16 cm3 while smaller cancer volumes averaged 0.63 cm3. The bDFS rates were either higher or similar for the index tumor group compared to the group with the index plus satellite cancers, although this difference was only significant for tumors ≥ 12 mL. This data suggested the clinical importance of the measurement of the index lesion only (Figure 1.3).
Noguchi et al. investigate the role of satellite lesions in tumor biology of multifocal localized disease validated by final pathology assessment of post radical prostatectomy specimen in 222 patients with T1c clinical stage (Noguchi 2003). They distributed a whole population into 3 groups, those with:
- a single (index) lesion in 54 (24%) men
- an index tumor and secondary satellite lesions less than 0.5 mL in 86 (39%) cases;
- an index tumor and secondary cancers greater than 0.5 mL in 82 (37%) cases.
This pathology distribution did not reveal any correlation with preoperative clinical data such as baseline PSA, number of positive cores, percentage of Gleason grade 4/5 cancer in the needle biopsy, and was based on results of multivariate analysis. Surprisingly, after analyzing a rate of biochemical failure in all groups, the second group with multifocal lesions and smaller secondary cancers were found to have a better prognosis than the group with a single tumor.
More recently, a study by Haffner et al. suggested a smaller size of secondary lesions (in an evaluation of 108 RP specimens) demonstrated that secondary cancers are rarely large in size (Haffner et al. 2013). Based on sample size of 108 post-radical prostatectomy specimens, they demonstrated a low frequency of secondary lesions with more than 0.5 mL (only 7% of cases, i.e. 11 of 152).
Unilaterality as a prerequisite for hemiablation
A multidisciplinary report from two institutions recently analyzed 1000 radical prostatectomy specimens from early stage PCa patients (Ohori et al. 2006). Only 18% of cancers were unilateral, which is in concert with the data of Mouraviev et al (Mouraviev et al. 2007). Of all foci 377 (16%) had extracapsular extension (ECE), and of these 86% were originated from the largest focus and 14% from smaller foci (Ohori et al. 2006). Thus, the largest focus of cancer represented a mean of 80% of the volume of all cancer present and in over 90% of these patients ECE, if present, arose from the largest focus. In other words, if the largest focus of cancer could be eradicated by FT, the tumor burden would be reduced by 80% and the focus giving rise to ECE would be controlled in > 90% of patients.13
Cheng et al. found that the majority of small volume prostate cancers (< 0.5 cm) are multifocal (69%), although in almost 2/3 of all cases (63%) involving only one side of the prostate (Cheng et al. 2005). Tumors were located predominantly in the peripheral zone (79%) and the posterior aspect (84%) of the prostate. These data suggested that prostatic carcinogenesis may be attributed to a field effect, supported by recent molecular evidence that multiple prostate cancers arise independently. The finding of frequent multifocality in small volume PCa is extremely important when considering focal ablative treatment strategies. These data support the concept of heterogeneity of prostate cancer when any small lesions could be potentially life-threatening. Most importantly, the authors demonstrated that 16% of these small tumors had high Gleason grades and were considered as clinically significant and potentially life-threatening if left untreated. Therefore, using a new armamentarium of molecular biomarkers we can potentially define more aggressive tumor(s) to be ablated first. Furthermore, it will be possible to follow the progress of other lesion(s) so ablation can be performed in order of urgency, and with a view to preserving quality of life issues, such as potency and incontinence (Cheng et al. 2005).
The concept of unilaterality, especially in the early stage of disease, means a cancer field effect could be limited to one lobe, giving a rationale for performing a hemiablation for complete eradication of the tumor (Cheng et al. 2005). Mouraviev et al. evaluated biochemical outcomes of unilateral versus bilateral lesions within the prostate and concluded that there was not a significant difference between the two groups in PSA recurrence rate after RP (Mouraviev 2007). In other words, unilateral cancers have the same risk of biochemical failure as bilateral cancers. Therefore, the radicalism of whole gland therapy may not be the right option for unilateral lesions diagnosed preoperatively.
From index lesion ablation to lethal clone ablation
Recent tumor biology data reveals support for the role of a single aggressive lesion in the mortality of patients with advanced PCa. Recent literature demonstrates a monoclonal origin of lethal metastatic cells. This statement is supported by findings made by means of new genomics and molecular techniques such as high-resolution genome-wide single nucleotide polymorphism and copy numbers. For instance, Liu et al. published results of a multi-institutional study of 94 anatomically separate cancer sites in 30 men who died from metastatic PCa (Liu et al. 2009). All the patients had a monoclonal origin caused and maintained by a unique genetic signature copy number pattern. In parallel, another single-locus genetic study of the TMPRSS2-ETS gene showed that most metastatic cancers arose from a single precursor cancer cell (Chan et al. 2013; Rubin & Chinnaiyan 2006). Therefore, identification of these primary cancer lesions is a top-priority for early focal ablation.14
In addition, the role of tumor volume (TV) remains unknown and needs to be elucidated further. Renshaw et al. in their series of 434 patients demonstrated that 15% of patients with a maximal tumor diameter less than 1 cm have had biochemical failure, compared to 73% of patients with tumor size greater than 2 cm (Renshaw et al. 1999). Finally, it appears to be that in carefully selected patients, the estimated TV might provide additional prognostic information for risk stratification, disease progression and biochemical failure. As a clinical implication, the index lesion mostly contributes to the total tumor volume and clinical aggressiveness of the disease and eradication of this lesion can even control local spread such as ECE.
Until now, the FT community has embraced the statement that, in general, the majority of satellite lesions do not appear to be life-threatening to the patient. However, the recent breakthrough investigation using whole-genome sequencing and molecular pathological analyses of PCa showed contradictory data based on the molecular features associated with progression to lethal metastatic disease in a patient who died of PCa. Haffner et al. tracked the evolution of the lethal cell clone from primary cancer to metastases through samples collected during disease progression and at the time of death over a 17-year treatment course following primary RP (Haffner et al. 2013). Despite being limited to one case, this analysis demonstrated that the lethal clone arose from a small, relatively low-grade cancer focus with Gleason score of 6 in the primary tumor, and not from the bulky, higher-grade primary cancer of Gleason score 7 or from a lymph node metastasis resected at prostatectomy. It has become clear that the additional data provided by next-generation sequencing of PCa may shed light on temporal delineation of genomic events within individual tumors, determining which lesions occurred early and which developed later in the lifetime of the PCa. Such a case along with other recent studies defined SPOP mutation as an early event in the natural history of PCa, while PTEN and TP53 lesions mainly occur later (Barbieri 2014). As a take-home message from these new data and integrating further tumor genomics into longitudinal treatment of PCa, the FT community should take the following considerations into account:
- These data suggest the concept that only a single clone in the primary tumor might have metastatic and thus life-threatening potential and should be ablated or eradicated at an early stage
- We should potentially redefine the index moving from index tumor lesion ablation to driver focus (containing a lethal gene) ablation in every single patient
- Document tumor mutations at diagnosis and, subsequently, during periodic clinical visits
- This approach may not totally eliminate disease recurrence; however, it will be associated with prolonged survival while maintaining a decent quality of life
Conclusion
It is important to emphasize that, while the FT concept is a very attractive treatment approach driven by both sides (patients and physicians), much work needs to be done to prove both feasibility and efficacy using different ablation techniques in large randomized clinical trials with sufficient mid- and long-term follow-up results to coin its place in the treatment armamentarium of PCa. The main achievement in developing the concept of FT is the obligation of an interdisciplinary scientific community to steadily implement advances in imaging and ablative technologies into clinical practice. Although impediments to the widespread adoption of FT exist primarily due to the multifocal nature of PCa and the current lack of precise imaging, research into clinical predictors of PCa unifocality or unilaterality is necessary to further develop and prove the hemiabalation concept. A major research goal is the identification and development of reliable pretreatment prognostic indicators that can accurately predict the natural history of a patient's tumor. Significant advances in tumor biology and the introduction of novel minimally-invasive therapies may further facilitate the inclusion of minimally-invasive treatment options for select candidates in contrast to radical whole gland treatment as we move toward a more individually tailored therapy program. However, only long-term results of prospective multi-institutional clinical trials will determine outcomes among patients with small-volume PCa and increase our understanding of tumor biology.
The future of FT for PCa seems very promising. To concur or deny the idea of an organ-sparing image-guided ablation of localized PCa does not seem to be in parallel with breast and kidney oncology where it took one to two decades to introduce and prove it in wide clinical practice. A new era of needle or extracorporeal ablation is arriving and we need to be ready to utilize these innovations in our clinical activity on a daily basis.
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