Treatment of Early Stage Prostate Cancer
▪ 11A Quality of Life after Treatment for Early-Stage Prostate Cancer
Mehrdad Alemozaffar
Martin G. Sanda
Contemporary approaches to prostate cancer detection and treatment have led to survivorship beyond 10 years for the vast majority of men diagnosed with early-stage prostate cancer. Consequently, the focus of medical decision making regarding primary treatment options has moved beyond considering only survival and toward a concurrent emphasis on the quality of survival (1,2,3).
Before the advent of patient-reported prostate cancer outcome measures, physician-reported methodology had served as a cornerstone of prospective studies that revolutionized primary prostate cancer treatment by aiming to reduce treatment side effects such as impotence, incontinence, and proctitis. Such methodology enabled benefits of pivotal innovations, such as nerve-sparing surgical technique and highly conformal radiation techniques, to be demonstrated and adopted (4,5,6,7,8,9). The patient-reported methodology of contemporary healthrelated quality of life (HRQOL) research does not diminish the value of the physician’s perspective exemplified by such groundbreaking technical developments, but rather provides a means to elevate physicians’ and patients’ perspectives to open new avenues for improving care.
An appreciation for differences between the perspectives of physicians and prostate cancer survivors regarding outcomes was first elicited through cross-sectional, retrospective surveys administered by Fowler and others after primary treatment (10,11,12,13). From the patient perspective, it was recognized that severity of therapy side effects was greater than appreciated by physician-reported methodology (14,15). Validated questionnaires developed by rigorous survey research methods are thus required to accurately measure HRQOL outcomes from the patient-reported perspective in a manner suitable for comparative analyses. This paradigm was introduced to early-stage prostate cancer by the UCLA Prostate Cancer Index (UCLA-PCI), whereby Litwin and others introduced the concept of distinct urinary, bowel, and sexual HRQOL domains as core components of HRQOL outcomes from the early-stage prostate cancer survivor’s perspective (16).
Initially, cross-sectional studies that used validated questionnaires to assess HRQOL after primary prostate cancer treatment elucidated the negative impact of surgery, radiotherapy, and brachytherapy on sexual and urinary HRQOL; of radiation on bowel HRQOL; and of adjuvant hormonal therapy on vitality (16,17,18). Such cross-sectional studies are limited in that they cannot take into account baseline (pretreatment) factors that are known to affect subsequent HRQOL outcomes (19). Prospective, single-institution studies began using validated questionnaires to measure HRQOL effects of primary treatment (20), and were followed by prospective, multicenter observational trials to provide more generalizable information. Information from such prospective studies can guide outcome expectations and facilitate individualized decision making, especially by elucidating effects of baseline patient and tumor characteristics (e.g., extent of urinary symptoms prior to treatment or extent of the primary tumor) on individual outcomes. However, as treatment choice in such nonrandomized, prospective studies is subject to selection bias, comparison between treatments in these studies is not as robust as in randomized clinical trials (RCTs). The measurement of HRQOL has therefore become commonplace in recent RCTs, and has provided conclusive evidence regarding HRQOL consequences of treatment.
This chapter describes validated questionnaires that are available to evaluate HRQOL effects of early-stage prostate cancer treatment, summarizes HRQOL outcomes from prospective nonrandomized and randomized trials, and illustrates how HRQOL outcomes data can be used to facilitate clinical decisions.
VALIDATED QUESTIONNAIRES TO MEASURE HRQOL IN EARLY-STAGE PROSTATE CANCER
The patient-reported perspective regarding health and well-being is based on extensive prior clinical use in psychology and psychiatry, where quantitative measures of patient-reported psychological health and illness had been first formulated and where such measures serve as focal points of diagnosis and evaluation of treatment efficacy. The quintessential instrument for measuring general HRQOL, the SF-36, was developed by the Medical Outcomes Study to measure general HRQOL and was later abridged to a shorter version, SF-12, for ease of administration (21,22). Questionnaires were then developed to specifically assess HRQOL concerns of cancer survivorship, including the Functional Assessment of Cancer Therapy (FACT) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (23,24).
The use of validated questionnaires to measure patient- reported outcomes has already transformed nononcologic urology clinical practice. In order to evaluate urinary symptoms in men with benign prostatic hyperplasia (BPH), the International Prostate Symptom Score (IPSS), also known as the AUA symptom index, was developed by Barry et al. (25). The IPSS contains eight questions, answered on a 1 to 5 Likert scale, and provides a summary score categorizing the severity of obstructive symptoms into mild, moderate, and severe categories with an additional measure of bother from these symptoms. It provided a core endpoint for approval of medical therapy for BPH, and is a mainstay of general urology clinical practice. The International Index of Erectile Function (IIEF) ensued, using 15 questions to evaluate sexual function, and led to approval of PDE-5 inhibitors (26). To facilitate its use, it was shortened to the IIEF-5, also known as the Sexual Health Inventory in Men (27). The IPSS and IIEF measure obstructive urinary symptoms from BPH, and erectile dysfunction, respectively, and they have been used to measure specific aspects
of urinary and sexual HRQOL after treatment for prostate cancer (Table 11A.1).
of urinary and sexual HRQOL after treatment for prostate cancer (Table 11A.1).
TABLE 11A.1 VALIDATED HEALTH RELATED QUALITY OF LIFE QUESTIONNAIRES USED FOR PATIENTS WITH PROSTATE CANCER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Several HRQOL instruments (questionnaires) were developed and validated for the purpose of measuring a more comprehensive range of prostate cancer treatment-related outcomes. Development and validation of such HRQOL instruments entail a multistep process that includes gathering information from focus groups or other patient and/or caregiver sources to identify the full breadth of symptoms and physical or emotional sequelae of the condition (prostate cancer) and its treatments; constructing questionnaires that include standard response options, each of which can be converted to a numerical score designating a range of possible outcomes relevant to that question; assembling questionnaires and administering them to moderate-size cohorts that represent/reflect the clinical setting whose outcomes the questionnaire is ultimately intended to measure; and conducting biometric analyses to determine how questions in a questionnaire should be grouped together to quantify outcomes in distinct HRQOL domains (e.g., urinary, sexual, bowel, hormonal, or other specific HRQOL domains relevant to the disease state of interest and side effects of its treatment) (28).
The UCLA-PCI was the first questionnaire validated to measure HRQOL after early-stage prostate cancer treatment (29). The UCLA-PCI used input regarding side effects and consequent problems reported by men who had undergone prostatectomy or external radiotherapy in the early 1990s. It has 20 questions regarding three HRQOL domains (urinary- incontinence, bowel, and sexual), and discerns function (i.e., symptom severity) from bother (impact of the symptom on well-being, or how much of a problem the symptoms causes). Limitations of the UCLA-PCI include that it measured neither urinary irritative symptoms common after brachytherapy or external radiotherapy nor symptoms of hormonal therapy. These limitations simply reflect that UCLA-PCI was developed before brachytherapy or hormonal therapy became standard components of early-stage prostate cancer care and underscore that HRQOL instruments are most informative and appropriate when used in a treatment setting similar to that in which the instrument was developed.
Other instruments were validated after the UCLA-PCI to measure HRQOL concerns of prostate cancer survivorship (Table 11A.1). The prostate module (PR25) for the EORTC QLQ-C30 consists of 12 questions measuring urinary, bowel, and sexual domains (30). Unlike the UCLA-PCI, the PR25 includes items that query urinary irritation/obstruction; however, in scoring of the PR25, urinary irritative items are combined with urinary incontinence items, providing only one overall measure for urinary function. The FACT-P contains 12 questions regarding a broad range of prostate cancer HRQOL concerns and was validated in patients with advanced prostate cancer (31). However, FACT-P provides only an overall summary score, without distinction between different HRQOL domains, limiting its sensitivity to discerning different treatment-related symptoms.
The Expanded Prostate Cancer Index Composite (EPIC) was developed with the goal of retaining the biometrically robust and clinically relevant focus of the UCLA-PCI on urinary, bowel/rectal, and sexual outcomes as distinct HRQOL domains, while adding concurrent measure of HRQOL consequences of androgen deprivation therapies, adding items to query urinary irritative symptoms (as distinct from urinary incontinence) and refining content of the original UCLA-PCI urinary incontinence, bowel, and sexual domains (Table 11A.1) (17,32). EPIC measures prostate cancer HRQOL in five domains: urinary incontinence, urinary irritation/obstruction, bowel/rectal, sexual, and vitality/hormonal. The initial EPIC contained 50 questions; later, to facilitate its use either in routine practice or in combination with other instruments as part of broader studies, item reduction was used to develop an abbreviated EPIC version having 26 questions (33,34). While the EPIC-50 allows differentiating function from bother in each domain, each of the five domains of EPIC-26 (urinary irritative, urinary incontinence, bowel/rectal, sexual, and vitality/hormonal) entails combining function and bother items in each domain. In order to facilitate cross-reference of studies using the UCLA-PCI to those using EPIC, the latter retained the original UCLA-PCI global urinary, sexual, and bowel bother items.
Other HRQOL questionnaires ensued with various attributes (Table 11A.1). The Prostate Cancer Symptoms Index (PCSI) adopted questions from prior surveys, yielding 29 questions measuring urinary incontinence, urinary irritation, bowel, and sexual domains, and was validated in patients treated by prostatectomy or radiotherapy (35). The Prostate Cancer Symptom Scale (PCSS) evolved from a Scandinavian questionnaire, QUFW94, that had been piloted in prostate cancer survivors treated with radiotherapy (36). The 43-item questionnaire provides only a single, global prostate HRQOL summary score, but answers to specific questions can be inspected to discern general urinary incontinence, urinary irritation, and intestinal and sexual symptoms.
The notion that cancer survivors experience illness uncertainty or anxiety that reduces HRQOL, brought forth by Mishel et al., is emerging as a focal point of prostate cancer HRQOL outcomes relevant to the renewed interest in conservative management, or active surveillance, for low-risk early-stage prostate cancer (37). Uncertainty regarding cancer control influences patients’ treatment decisions and was reported as a key reason why patients without evidence of progression on active surveillance elected to proceed to treatment for prostate cancer (38,39). The role of uncertainty and anxiety was further applied to prostate cancer patients with the development of the Memorial Anxiety Scale for Prostate Cancer, and expanded with additional HRQOL questions to form the validated Memorial Sloan-Kettering Prostate Cancer QOL questionnaire (PC-QoL) (40,41). The 52-question PC-QoL measures cancer worry as well as urinary, sexual, and bowel domains but does not distinguish between urinary incontinence and irritation/obstruction (Table 11A.1).
Consensus is lacking regarding how best to reconcile divergent effects on HRQOL across different domains to provide an overall measure of cancer care outcomes from the patient perspective. One approach incorporates surgical margin status, continence, and potency (deemed by the investigators as the dominant factors contributing to overall HRQOL or “trifecta” effect) to represent a potentially optimal outcome (42). However, a priori designation of these three specific endpoints as requisite and exclusive determinants of overall treatment efficacy is not applicable to nonsurgical treatment and, even when used only in surgical patients, does not accommodate differences in baseline cancer severity or baseline sexual function that are known to vary between individuals. More recently, a broader approach to resolving the differing effects of treatment among HRQOL domains has focused on evaluating patient satisfaction with overall cancer treatment outcome. This strategy is based on the paradigm proposed by Donabedian, founder of health care quality research, and others that satisfaction with health care outcome is the ultimate measure of overall health care quality (43,44). Toward this goal, questionnaires specifically measuring satisfaction with cancer care outcome have been developed—such as the Satisfaction Scale for Cancer Care (SCA)—that when applied in a multicenter, prospective study demonstrated that prostate cancer survivors valued urinary irritative/obstructive and hormonal/vitality HRQOL as having similar impact on their overall well-being as urinary incontinence or sexual concerns (33,45,46,47,48).
HRQOL OUTCOMES IN PROSPECTIVE, MULTICENTER STUDIES OF EARLY-STAGE PROSTATE CANCER
Cross-sectional surveys that elucidated HRQOL outcomes important to prostate cancer patients and led to development of validated questionnaires to measure these outcomes provided a foundation for subsequent prospective, multicenter, nonrandomized studies that characterized HRQOL consequences of treatment (Table 11A.2).
The Prostate Cancer Outcomes Study (PCOS) used the SF-36 and a modified version of the UCLA-PCI to study the outcomes of radical prostatectomy or external radiotherapy for prostate cancer, in a multiregional cohort of patients from Surveillance Epidemiology and End Results sites (49,50). Two years’ follow-up revealed an expectedly higher rate of urinary incontinence in patients undergoing prostatectomy (28% reporting pad use after prostatectomy; 14% after radiotherapy). However, urinary bother was problematic in 23% of radiotherapy and 12% of prostatectomy patients, suggesting that urinary concerns other than simply incontinence merit emphasis. Bowel symptoms were problematic for 8% of radiotherapy and 3% of prostatectomy patients. Erectile dysfunction occurred in 80% of prostatectomy and 62% of radiotherapy patients. Young age was associated with greater sexual bother, however, sexual function and bother were not closely related, perhaps because older men were impotent at baseline and therefore not as bothered by it. Reexamination at 5 years revealed convergence of HRQOL between prostatectomy and radiotherapy, as prostatectomy patients’ symptoms remained stable, while those after radiotherapy continued to decline (51). These findings were confirmed by a Dutch community-based cohort that evaluated HRQOL after prostatectomy or external radiotherapy (52,53). A limitation of both these studies is that they lacked evaluation of urinary irritative concerns, and hormonal therapy concerns, such as hot flashes, weight change, and loss of vitality; although PCOS did evaluate HRQOL effects of androgen deprivation, finding that 51% of men reported loss of interest in sex and 69% became impotent consequent to androgen deprivation (54). The PCOS study was further limited by relying on patient recall of baseline HRQOL after already undergoing treatment, compromising accuracy of baseline data.
The community-based CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) cohort, consisting of over 30 urology-based community practices, reported HRQOL outcomes for radical prostatectomy or brachytherapy compared to pretreatment baseline (Table 11A.2) (55). Urinary HRQOL was adversely affected by prostatectomy and brachytherapy alike; sexual HRQOL was worse after prostatectomy, and bowel function deteriorated after brachytherapy. CaPSURE also explored HRQOL consequences of watchful waiting, finding that those men, too, had deterioration in urinary function, urinary bother, and sexual function (56). These CaPSURE studies were limited in that <50% of patients returned questionnaires past 1 year, restricting the duration of follow-up analyses. Another study from CaPSURE examined HRQOL after multimodal therapy and found that addition of androgen deprivation to other treatments aggravated impotence, and that combining external radiation therapy with brachytherapy led to worsening of urinary function and bother than either therapy alone (57).
A recent study at nine US academic centers, the PROST-QA cohort evaluated HRQOL and satisfaction with care outcome in patients undergoing radical prostatectomy, external radiotherapy, and brachytherapy and their spouses (Table 11A.2) (33). Sexual function was found to be negatively affected across all three therapies (worst early after radical prostatectomy), and was adversely affected by older age, larger prostate size, and high pretreatment prostate-specific antigen (PSA). Nervesparing surgical technique mitigated sexual effects of prostatectomy, whereas adjuvant androgen deprivation was associated with worse sexual HRQOL effects of external radiotherapy. Urinary incontinence was worse for older men, African Americans, and those with higher pretreatment PSA. Urinary irritation/obstruction deteriorated after brachytherapy, but improved after prostatectomy, and these treatment consequences were magnified by larger prostates (the effect of prostate size on radiation was confirmed by another prospective, single-institution study) (58). Patient satisfaction with their overall outcome was determined to a similar extent by sexual function, vitality, urinary function, and bowel function. Spouses/partners verified the importance of hormonal/vitality and urinary irritative HRQOL domains as warranting similar emphasis as sexual dysfunction or urinary incontinence.
TABLE 11A.2 PROSPECTIVE, MULTICENTER, NONRANDOMIZED COHORTS REPORTING HRQOL OUTCOMES FOR PATIENTS TREATED FOR PROSTATE CANCER | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The effects of prostatectomy, radiotherapy, and brachytherapy on patients’ quality of life that had been observed in the PROST-QA cohort were corroborated in multicenter, prospective cohorts in Spain and Australia (Table 11A.2) (59,60). The Australian study also evaluated active surveillance or primary androgen deprivation as sole therapy. As expected, the worst rates of incontinence were seen after radical prostatectomy while the worst bowel effects were noted after external radiotherapy. High dose rate (HDR) brachytherapy was noted to have worse rates of incontinence, impotence, and bowel problems than low dose rate (LDR) brachytherapy. At 3 years, after controlling for baseline function, primary androgen deprivation therapy affected sexual function more so than any other primary treatment; moreover, it was the only treatment showing significant, durable deterioration of general HRQOL, specifically in the physical and mental components as measured by SF-36. Patients undergoing active surveillance had a 27% incidence of new impotence from baseline as compared to 56% after prostatectomy (less impotence with nerve-sparing), 56% with sole androgen deprivation therapy, 47% after HDR brachytherapy, 43% after external radiotherapy/androgen deprivation therapy, 38% after external radiotherapy alone, and 17% after LDR brachytherapy. The Australian study was limited by relying on patient recall of baseline data and by its single-region (albeit multicenter) setting restricted to New South Wales.
These prospective, multicenter center studies provide useful data to aid physicians in presenting prostate cancer patients appropriate expectations of treatment side effects. The most dependable information from such nonrandomized studies are conclusions regarding how nonrandomizable patient characteristics, such as age or prostate size, affect the changes in quality of life consequent to a specific therapy, and which patient or treatment factors merit consideration in decision making regarding treatment. These nonrandomized studies are less robust, however, in serving to provide direct comparison between different treatments due to selection bias. Controlling for baseline factors can help reduce such bias and can assist in comparison of treatments to which randomization is difficult (e.g., comparing prostatectomy to brachytherapy). However, formal measurement of HRQOL has become commonplace in contemporary RCTs, providing important insight regarding the relative efficacy of different treatments.
QUALITY OF LIFE OUTCOMES IN RANDOMIZED CLINICAL TRIALS
Randomization to different treatment options for early-stage prostate cancer is challenging, as patients in some cultures prefer to actively participate in treatment selection rather than accepting random assignment (61). Moreover, enrollment to all but the most recent early-stage prostate cancer RCTs predated availability of validated HRQOL questionnaires. Recently reported RCTs have nevertheless provided invaluable information regarding comparative quality of life outcomes (Table 11A.3).
The Scandinavian Prostate Cancer Group study number 4 (SPCG-4) that randomized men to no treatment or radical prostatectomy found a modest cancer-specific survival advantage for prostatectomy at 6 years’ follow-up (p = 0.02) (1). A questionnaire (similar to the PCSS) sent to patients 4 years after randomization detected impotence in 80% of prostatectomy versus 45% of untreated men (62). Urinary obstruction (defined as IPSS score of >8) was less common after prostatectomy (present in 35% vs. 49% of untreated men), whereas urinary incontinence (defined as requiring pads) was noted in 43% of men after prostatectomy versus 10% of untreated men. Longer-term follow-up 4 years later revealed no further HRQOL deterioration in the radical prostatectomy group, whereas men randomized to no surgery showed increase of impotence to 53%, incontinence to 25%, and lower general HRQOL (63). However, unlike cotemporary active surveillance protocols, men randomized to no treatment were not monitored by repeat biopsy and were restricted to radiotherapy or hormonal therapy for local progression.
A Japanese RCT that randomized patients with locally advanced prostate cancer (all of whom first underwent neoadjuvant androgen deprivation therapy) to radical prostatectomy versus external radiotherapy demonstrated a 12% cause-specific survival advantage for radical prostatectomy at 5 years (64). HRQOL data revealed similarly high rates of impotence after prostatectomy (90%) or radiotherapy (80%), presumably influenced by neoadjuvant androgen deprivation therapy (Table 11A.3). A follow-up to this Japanese RCT reported that 10% of external radiotherapy patients developed new incontinence and impotence from 5 to 10 years after treatment, while these outcomes in the prostatectomy group remained unchanged (65).
Several RCTs have explored strategies to mitigate adverse HRQOL effects of androgen deprivation (Table 11A.3). A comparison of continuous versus intermittent androgen suppression as a primary treatment for early-stage prostate cancer found no difference in progression-free survival. Both treatment arms showed improvement of urinary symptoms but worsening of sexual function (66). However, erectile dysfunction after interrupted androgen suppression was less common than after continuous androgen deprivation (18% and 50%, respectively). This finding was limited by small sample size and substandard HRQOL survey response rates of only 38%. Short-term adjuvant androgen deprivation (6 months) was compared to long-term androgen deprivation (3 years) after external radiotherapy in EORTC 22961 that demonstrated a 3.8% overall survival advantage for long-term androgen deprivation (67). At 1.5 years after start of treatment, longterm androgen deprivation patients experienced worse fatigue, insomnia, hot flashes, and sexual dysfunction as compared to men randomized to 6 months of androgen deprivation (Table 11A.3). The authors contended that these HRQOL effects were clinically inconsequential—however, they were statistically irrefutable and, based on the HRQOL scores, had major impact on the patients. Unfortunately, the adverse HRQOL outcomes observed with long-term androgen deprivation in EORTC 22961 were reported only as mean HRQOL scores for each arm, not allowing readers to determine how commonly these problems were encountered by patients. This omission exemplifies the need for HRQOL data to be reported not only as summary scores but also as frequency or prevalence of the most common manifestations that comprise the HRQOL deficiency—this aspect is pivotal for enabling HRQOL study data to be used to facilitate clinical decision making in routine practice.
Two RCTs compared the HRQOL effects of external radiotherapy to effects of other care options (Table 11A.3). A Swedish, single-institution RCT compared external radiotherapy to deferred therapy with a primary endpoint of late urinary and intestinal toxicities (68). In addition to expected rectal problems in the radiotherapy group, hematuria and incontinence (17%) were also bothersome after radiotherapy; unfortunately, this study did not evaluate sexual HRQOL. The Scandinavian Prostate Cancer Group study number 7 (SPCG-7) showed a survival benefit of 12% with the addition of external radiotherapy to androgen deprivation therapy compared to androgen deprivation therapy alone (69). HRQOL findings of this RCT showed worse urinary incontinence and bother among men randomized to radiotherapy: 11% of subjects in the radiotherapy arm versus 5% in the androgen deprivation therapy alone arm reported pad use, whereas some of those treated only with androgen deprivation therapy experienced improvements from baseline in urinary bother (70). An increase of bowel symptoms was noted after external radiotherapy (8% of patients limiting daily activity due to bowel problems with radiotherapy compared to 3% after androgen deprivation alone). Impotence developed in 85% of patients receiving external radiotherapy and in 72% of those receiving androgen deprivation therapy alone. Of note, many patients in this study had clinical stage ≥T3 cancer.
TABLE 11A.3 RANDOMIZED TRIALS REPORTING COMPARATIVE EARLY-STAGE PROSTATE CANCER HRQOL OUTCOMES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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An RCT from Italy comparing radical prostatectomy to brachytherapy was underpowered to detect difference in progression-free survival, but allowed comparison of HRQOL outcomes between these treatments (71). Urinary symptoms, evident in both groups at 6 months, subsequently improved in the prostatectomy group but persisted in the brachytherapy group at 1 year (Table 11A.3). The major urinary symptom in the prostatectomy group was incontinence, being reported in 18% of patients at 6 months, while the brachytherapy patients primarily complained of irritation/obstruction measured by IPSS. Erections sufficient for intercourse 1 year after treatment were reported by 58% of men after brachytherapy versus 40% after prostatectomy, but this difference resolved by 5 years after treatment.
In Southwest Oncology Group (SWOG), 8,794 patients with pT3 disease or positive margins after radical prostatectomy who were randomized to adjuvant external radiotherapy had better metastasis-free survival as compared to men randomized to no adjuvant (65% vs. 57% at 11 years) (72). However, this marginal benefit was counterbalanced by greater problems with bowel function (47% after radiotherapy vs. 5% after no adjuvant), and more common urinary frequency problems (25% after radiotherapy vs. 10% after no adjuvant) were reported after radiotherapy (Table 11A.3) (73). Impotence was ubiquitous in both arms of this RCT, possibly because patients had more advanced disease than in other studies.
Determining the appropriate dose of radiation for the treatment of prostate cancer requires finding a balance between cancer control and side effects, and several studies have evaluated the HRQOL effects of higher doses of radiation (Table 11A.3). One dose escalation trial randomized patients to 70 Gy of conventional versus 78 Gy of 3D conformal external radiotherapy, noting a 6% improvement in biochemical-free survival at the higher dose (74,75). Despite using a nonvalidated questionnaire, this RCT detected more problems from bowel urgency in the conventional radiotherapy group than in the 3D conformal radiotherapy at 2 years (31% vs. 21%, respectively). Multicenter assessment of external radiotherapy dose escalation was undertaken through MRC RT01, wherein subjects were randomized to 74 or 64 Gy, with adjuvant androgen deprivation in both arms (76). The escalated group realized an 11% improvement in biochemical progression-free survival and showed worse overall bowel function at the higher dose as measured by UCLA-PCI; unfortunately, prevalence of the bowel problems was not reported in MRC-RT01, making it difficult to discern clinical significance of this difference.
Quality of life consequences of more recent innovations such as HDR brachytherapy or external radiotherapy hypofractionation have been studied in RCTs that are informative albeit not definitive, due to being limited to a single institution, using nonvalidated questionnaires, or lacking a third party to measure HRQOL (Table 11A.3). Hypofractionation was compared to conventional external radiotherapy in an RCT using an ad hoc HRQOL questionnaire that showed worse rectal urgency in the hypofractionated group (77). A single-institution RCT from the United Kingdom that found 8 months’ longer biochemical-free survival after combination external radiotherapy and HDR brachytherapy compared to external radiotherapy alone showed an overall advantage for combination external radiotherapy and HDR brachytherapy at 3 months (as measured by FACT-P) that resolved by 6 months, with questionable clinical relevance (78).
Cryotherapy was compared to external radiotherapy in a recent RCT, wherein all patients received adjuvant androgen deprivation therapy, leading to similar rates of progression-free survival (Table 11A.3) (79). HRQOL measured by the UCLAPCI revealed that cryotherapy led to worse urinary problems than radiotherapy (7% vs. 3% reporting moderate or worse overall urinary problems at 6 months, and 5% vs. 3% at 18 months) and worse erectile dysfunction (78% of cryotherapy patients vs. 64% of men reporting impotence 3 years after radiotherapy) (80). In contrast, external radiotherapy patients experienced worse bowel/rectal bother that persisted for 3 years when compared to cryotherapy patients (16% vs. 7% at 6 months, and 10% vs. 7% at 36 months). An important omission from this RCT was the lack of any validated measure of urinary irritation/obstruction, a problem that is well recognized as being commonplace after cryotherapy—hence, this RCT was flawed by design bias favoring the cryotherapy arm. Nevertheless, this RCT corroborated the prospective, multicenter Cryo Online Data Registry study findings that had suggested infrequent urinary incontinence and commonplace new impotence after cryotherapy (81).
Despite the challenges to completing RCTs in earlystage prostate cancer, recent RCTs have provided invaluable HRQOL data to help guide treatment decision making. The use of validated instruments to measure HRQOL outcomes is now standard in ongoing RCTs such as RTOG 0232, Pro-COC, START, and ProtecT (82,83,84,85). HRQOL outcome differences in some case mitigate and in other case may magnify cancer survival benefits, or lack thereof, to facilitate decisions regarding treatment.
NEW FRONTIERS
New approaches for prostate cancer treatment whose outcomes have not yet been conclusively compared to existing treatments include surgical innovations such as laparoscopic or robot-assisted radical prostatectomy, radiotherapy innovations such as intensity-modulated radiation therapy (IMRT) or proton-beam radiotherapy, and technological innovations such as high-intensity focused ultrasound (HIFU). Some of these innovations have already become a mainstay of early-stage prostate cancer treatment, despite little to no published comparative HRQOL evidence from prospective, multicenter studies, nor evidence from definitive RCTs. In this context, nonrandomized studies of these innovations warrant comment.
Several single-institution, prospective studies have used validated questionnaires to evaluate HRQOL outcomes of IMRT for prostate cancer. A prospective study in Japan used the UCLA-PCI to demonstrate that IMRT had better bowel outcomes than conventional or 3D conformal external radiotherapy with no differences in the urinary and sexual domains, while another group demonstrated worse bowel function but better sexual function with IMRT (86,87,88). A study from the Netherlands using EORTC QLQ-PR25 demonstrated better early urinary function in patients receiving IMRT compared to a lower dose of conformal radiotherapy (89). In a further attempt to deliver greater amounts of radiation to the prostate while avoiding involvement of adjacent structures, newer technologies such as proton-beam and ultraconformal (e.g. CyberKnife) radiotherapy are also being applied to prostate cancer therapy. Preliminary studies of proton therapy
that used the PCSI instrument to measure HRQOL in a dose-escalation RCT did not detect HRQOL differences with dose escalation (90,91). HRQOL consequences of ultraconformal therapy are largely unknown, as side effect characterization of these modalities has been limited to physician-reported RTOG toxicity data (92,93).
that used the PCSI instrument to measure HRQOL in a dose-escalation RCT did not detect HRQOL differences with dose escalation (90,91). HRQOL consequences of ultraconformal therapy are largely unknown, as side effect characterization of these modalities has been limited to physician-reported RTOG toxicity data (92,93).
The introduction of laparoscopic and robot-assisted technical modifications of radical prostatectomy has prompted question as to whether these techniques alter prostatectomy outcomes. Despite many single-institution studies that are recognized as exhibiting unintended yet inevitable surgeonspecific bias (94), only one RCT has compared traditional open prostatectomy to its laparoscopic counterpart, and neither RCTs nor multicenter prospective studies have evaluated outcomes of the robot-assisted technique. The RCT that compared laparoscopic to open radical prostatectomy was conducted at a single site in Italy and demonstrated lower mean blood loss (by 600 mL), lower transfusion rate (13% vs. 45%), earlier catheter removal, and longer operative times with the laparoscopic technique; however, it did not evaluate HRQOL outcomes (95). Prospective, single-center studies comparing HRQOL outcomes of laparoscopic with open prostatectomy have yielded mixed results; some have demonstrated earlier return of potency and incontinence with laparoscopy, others have reported no difference in HRQOL outcomes, while others have depicted more rapid recovery of incontinence with the open technique (96,97,98,99). One multicenter, prospective trial from Japan using the UCLA-PCI found the open technique to have earlier recovery of urinary and sexual function in comparison to laparoscopy (100). However, after dividing the laparoscopic group into two sequential cohorts, no difference between the later laparoscopic and open prostatectomy groups could be elucidated, demonstrating the possible effects of a learning curve in these newer minimally invasive techniques. Analysis of diagnostic codes reported by physicians to Medicare suggested no benefit in urinary or sexual outcome for minimally invasive compared to traditional surgical techniques (101); however, use of claims-based diagnostic codes as measures of actual HRQOL outcome is inaccurate and unreliable. Robot-assisted radical prostatectomy, despite marketing claims of improved outcomes due to enhanced optics and increased range of motion, has not been shown to differ from standard laparoscopy in clinical outcomes (102,103), while direct HRQOL comparisons of robot-assisted to other prostatectomy techniques have not been reported using validated questionnaires. In one single-institution, prospective study of robot-assisted radical prostatectomy, the EPIC questionnaire was administered and reported return to baseline sexual and urinary domain summary scores at 1 year in 19%, and 77% of patients, respectively (104). Another prospective, singleinstitution study, using the UCLA-PCI, demonstrated that performing interfascial nerve sparing during robot-assisted radical prostatectomy resulted in higher rates of potency (42% at 3 months and 64% at 1 year) than when nerve sparing was performed in an “extrafascial manner” (22% at 3 months and 40% at 1 year) (105), corroborating the robotic/laparoscopic equivalent of lateral pelvic fascia release during open nervesparing surgery. Variance between surgeons in such outcomes is uncharacterized and warrants further multicenter, prospective study to elucidate surgeon effects on outcome.
HIFU represents another early-stage prostate cancer treatment innovation for which evidence regarding HRQOL outcomes is in its infancy. While HIFU is still being investigated for efficacy of cancer control, HRQOL effects have been evaluated by single institutions using IIEF, IPSS, and ad hoc questionnaires (106,107). Impotence developed in one third to half of patients, new urinary incontinence in about 10%, and short-term worsening of urinary irritation/obstruction was noted (12% of patients underwent transurethral resection of the prostate for obstructive symptoms in one study). To justify approval of HIFU as a prostate cancer treatment option, prospective, multicenter outcome studies using validated HRQOL questionnaires are needed, in addition to further information regarding oncologic efficacy.
Evaluating HRQOL outcomes of these treatment innovations for early-stage prostate cancer would be most informative if carried out through prospective, multicenter trials, in the context of active surveillance, especially for patients with low-risk disease. Better characterization of HRQOL outcomes for active surveillance itself is needed, as HRQOL consequences of active surveillance remain largely uncharacterized. If obstacles to randomization between active surveillance and definitive treatment prove insurmountable, then prospective, multicenter comparative studies that adjust for baseline covariates while comparing innovative treatments for low-risk disease to active surveillance may help elucidate comparative HRQOL outcomes and determine whether adoption of the proposed treatment is justified.
USING HRQOL OUTCOMES TO FACILITATE EARLYSTAGE PROSTATE CANCER TREATMENT DECISIONS
There is sufficient evidence regarding HRQOL consequences of the standard care options for early-stage prostate cancer to provide a foundation for facilitating medical decision making based on expected outcomes after prostatectomy (open and minimally invasive), external radiotherapy, brachytherapy, or active surveillance (Table 11A.4; based on reference 108)—notwithstanding a paucity of reliable data regarding whether HRQOL outcomes are mitigated by treatment innovations such as proton-beam radiotherapy, HIFU, or robotic assistance for prostatectomy. Using HRQOL data to guide treatment decisions requires not only an understanding of the data but also an appreciation for each patient’s unique concerns and consideration of baseline factors that impact outcomes.
Radical prostatectomy, whether performed via traditional open or contemporary minimally invasive techniques, is a major operation requiring hospitalization and brief urinary catheterization. The greatest HRQOL effects of prostatectomy include erectile dysfunction and incontinence that are commonplace in the first several months after surgery with variable improvement over the ensuing 2 years. Sexual function is affected less abruptly after radiotherapy or brachytherapy than after prostatectomy, deteriorating over 2 to 3 years following radiation to levels similar to those experienced by patients undergoing radical prostatectomy (unless androgen deprivation adjuvant is used, in which case sexuality deteriorates more precipitously) (33) (Table 11A.4). On the other hand, patients with urinary obstructive symptoms prior to treatment may see improvement in HRQOL following prostatectomy, and consideration of baseline lower urinary tract symptoms warrants greater emphasis in treatment decision making (33). Conventional clinical knowledge often steered older men toward radiation therapy as it was felt that the perioperative risks related to blood loss were overwhelming for elderly patients; however, this paradigm may need to be reconsidered with the advent of minimally invasive surgical techniques that have reduced surgical blood loss, in a setting wherein life expectations in the elderly have otherwise been extended.
External radiotherapy has been demonstrated to improve survival only with concurrent use of androgen deprivation therapy, yet androgen deprivation is associated with adverse HRQOL consequences (Table 11A.3), tempering enthusiasm for its use in low- or intermediate-risk disease. Radiotherapy
leads to worse bowel/rectal HRQOL problems than does prostatectomy and does not reduce or palliate preexisting urinary obstructive symptoms as effectively as does prostatectomy (Table 11A.4) (33). Newer radiotherapy techniques such as IMRT, ultraconformal radiotherapy, and proton therapy are focused on delivering greater levels of radiation to the prostate while avoiding exposure of adjacent tissues and consequent side effects; however, HRQOL outcomes have not yet been definitively compared to standard radiotherapy or brachytherapy.
leads to worse bowel/rectal HRQOL problems than does prostatectomy and does not reduce or palliate preexisting urinary obstructive symptoms as effectively as does prostatectomy (Table 11A.4) (33). Newer radiotherapy techniques such as IMRT, ultraconformal radiotherapy, and proton therapy are focused on delivering greater levels of radiation to the prostate while avoiding exposure of adjacent tissues and consequent side effects; however, HRQOL outcomes have not yet been definitively compared to standard radiotherapy or brachytherapy.
TABLE 11A.4 PREVALENCE OF MODERATE TO SEVERE PROBLEMS IN SPECIFIC HRQOL DOMAINS AFTER EARLY STAGE PROSTATE CANCER TREATMENT OR SURVEILLANCE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Androgen deprivation as primary treatment for early-stage prostate cancer is not advisable, as survival benefits of such therapy are questionable, whereas HRQOL consequences of androgen deprivation are arguably worse than after prostatectomy, radiotherapy, or brachytherapy (54,60). When used as an adjuvant to external radiation or brachytherapy, patients are also subjected to these adverse quality of life consequences (Table 11A.4). Studies that demonstrated minimal survival advantage of continuous, long-term androgen deprivation over short-term or intermittent therapy also demonstrated substantially greater detriments to HRQOL outcomes in the sexual and vitality domains (66,67). Side effects of hormone therapy also include an increased incidence of cardiac events, especially in patients with preexisting cardiac conditions (109); therefore, overall patient physical health needs to be taken into account prior to deciding on such treatments.
Brachytherapy offers patients optimal near-term convenience in the form of 1-day outpatient treatment of early-stage prostate cancer. However, brachytherapy is contraindicated in patients with larger prostates and can seriously exacerbate even modest obstructive urinary symptoms, which are commonplace in the aging male. Long-term after brachytherapy, patients can experience erectile dysfunction that can gradually deteriorate to levels near those of patients undergoing radical prostatectomy (Table 11A.4) (33,59,60). While efforts are made to minimize radiation to the rectum through treatment planning, patients experience long-term bowel symptoms similar to patients undergoing external radiotherapy. Moreover, unlike external radiotherapy or prostatectomy, brachytherapy has not been shown to confer a survival advantage over more conservative management strategies.
None of the preceding active therapies for patients with early-stage prostate cancer is clearly superior to the others in regard to HRQOL outcomes, and many patients elect to pursue active surveillance protocols in an attempt to avoid the side effects of active therapy (60). Although this option avoids therapy-related HRQOL effects on urinary, bowel, sexual, and vitality domains, it is associated with a greater degree of uncertainty or anxiety that can lead patients to elect for active therapy even though they have not demonstrated disease progression on active surveillance (38). Consideration for active surveillance needs to take into account the morbidity of multiple repeat prostate needle biopsies, higher levels of anxiety from patients feeling that they have “cancer that is not being treated,” and knowledge that many patients proceed to active therapy within a few years. However, even if patients progress to active therapy, active surveillance can extend freedom from the HRQOL effects of therapy (Table 11A.4), and has been found to maintain similar survival rates as immediate treatment in contemporary, community-based cohorts (110).
Effects on HRQOL outcomes following treatment of localized prostate are varied, and decisions regarding treatment choice pose difficult dilemmas for patients. Through a better understanding of HRQOL outcomes, patients can be more truthfully guided to choose a treatment based on accurate expectations of treatment outcome, resulting in the greatest degree of satisfaction with their cancer care. Efforts to further elucidate HRQOL consequences of established and evolving early-stage prostate cancer treatments alike will help ensure optimal treatment decisions and consummate quality of cancer care.
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99. Touijer K, Eastham JA, Secin FP, et al. Comprehensive prospective comparative analysis of outcomes between open and laparoscopic radical prostatectomy conducted in 2003 to 2005. J Urol 2008;179(5):1811-1817; discussion 1817.
100. Namiki S, Egawa S, Terachi T, et al. Changes in quality of life in first year after radical prostatectomy by retropubic, laparoscopic, and perineal approach: multi-institutional longitudinal study in Japan. Urology 2006;67(2):321-327.
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▪ 11B Active Surveillance for Prostate Cancer: Rationale, Methods, and Results
Laurence Klotz
INTRODUCTION
Rather bear those ills we have, Than fly to others we know not of William Shakespeare, Hamlet
The use of PSA to screen for prostate cancer has been demonstrated to reduce the mortality from the disease by 20% to 31% (1,2). However, this comes at the cost of a great deal of treatment of patients with indolent disease. In the European Randomized Trial of Screening for Prostate Cancer (ERSPC), the number needed to treat for each prostate cancer avoided was 48. It has become widely accepted that prostate cancer screening must be accompanied by a more selective approach to treating localized prostate cancer.
Active surveillance is a solution to this widely acknowledged problem. It uses the opportunity provided by the long natural history of favorable risk prostate cancer to incorporate a period of initial observation into patient management. The underlying motif is that microfoci of low-grade prostate cancer develop normally with age in most men. Hence, most men diagnosed with low-grade, small volume cancer are not destined to have any clinical manifestations of the condition during their lifetime. However, a subset of favorable risk patients are at risk, either due to the presence of unrecognized, higher risk cancers not apparent at the time of diagnosis, or progression to a more aggressive phenotype over time. These patients can be identified by close follow-up, including serial PSAs and biopsies, and treated effectively in most cases. The rationale, patient selection, method of follow-up, triggers for intervention, and recent results of this approach are reviewed. I address the issues of this controversial subject according to the following questions:
1. What is the rationale for surveillance?
2. What proportion of low-risk patients initially accept active surveillance?
3. What is the rate of reclassification to higher risk disease and the rate of definitive therapy?
4. Are there reliable criteria for detecting progression?
5. What are the psychological effects of surveillance, that is, living with untreated cancer? Can we measure and manage this?
6. What is the course of disease in patients managed this way?
7. What is the outcome of delayed treatment?
8. What are the major pitfalls of surveillance and how can they be avoided?
9. What is the role of 5ARIs and focal therapy in these patients?
Rationale: In the last 15 years, prostate cancer mortality has fallen about 25% in many regions, including the United States and Canada (3). The recently published ERSPC reported that in 180,000 men randomized between screening with PSA every 4 years and usual care, prostate cancer mortality was reduced by 20% (1). A subsequent analysis correcting for contamination calculated the “true” benefit as a 31% reduction (2). This study has proven for the first time that early detection of prostate cancer, notwithstanding the limitations of PSA and the problem of overdiagnosis, saves lives. However, PSA testing results in many men being diagnosed with clinically insignificant prostate cancer that may pose little or no threat to their life if left untreated. Prostate cancer is usually slow growing, and that prevented death would not in most cases have occurred until many years later, often near the end of an individual’s life span. The side effects of surgery and radiation have improved, due to better surgical technique and expertise and more precise radiation targeting. Nonetheless, many patients undergoing curative therapy for prostate cancer suffer long-term effects on quality of life. Among the 48 patients undergoing radiation or surgery to avoid one prostate cancer death, many will experience erectile dysfunction, decreased urinary control, or rectal problems. Furthermore, most patients dying of prostate cancer have intermediate- or high-grade disease. The number needed to treat with lowgrade, small volume prostate cancer for each death avoided is almost certainly higher—plausibly around 100. Most knowledgeable observers believe that this Number needed to treat (NNT) is too high, given the morbidity of treatment (4).
Unfortunately, the diagnosis of cancer often results, at least initially, in “cancer hysteria.” This refers to a reflexive fear, perfectly understandable by the uninformed, of an aggressive, life-threatening condition. Throughout history, a diagnosis of cancer was in most cases a death sentence. Even today the message that cancer is a dreadful disease, and must be caught early and treated aggressively to avoid what would otherwise be a horrible and premature death, is widely promulgated. This widely shared preconception often leads the patient to make a quick and early decision for aggressive treatment, regardless of the risks and benefits.
While for some cancers, there is truth to this view, the condition most men with favorable-risk disease have is far removed from a rampaging aggressive disease. The majority of men with favorable-risk prostate cancer are not destined to die of their disease, even in the absence of treatment.
Autopsy studies of men dying of other causes have documented the high prevalence of histologic prostate cancer; about 50% of men over age 50 (5). Since the introduction of PSA screening, the lifetime risk of being diagnosed with prostate cancer has doubled from around 8%, in the pre-PSA era, to 17% (5).
These studies have also demonstrated that prostate cancer typically begins in the third or fourth decade of life (5). Thirty percent of men in their 30s in Sakr’s autopsy series had foci of prostate cancer. This means that, in most patients, there is a period of slow subclinical tumor progression that lasts approximately 20 years, followed by a period of clinical progression (potentially to metastatic disease and death) lasting about 15 years. The implication is that most patients have a long window of curability. This is particularly true for patients with favorable-risk, low volume disease. It also implies that young age at diagnosis should not preclude a surveillance approach.
PSA screening has resulted in a consistent reduction in the volume and stage of cancer at the time of diagnosis (6). Factors contributing to this are the increasing use of PSA screening and more extensive biopsy strategies compared to the historical practice of six cores (7). Additionally, patients whose initial biopsies were negative often have these repeated if the PSA continues to rise. More biopsies means more prostate cancer diagnosed. Patients who have had several negative biopsies prior to a diagnosis are particularly likely to have small volume, clinically insignificant cancer.
Favorable-risk prostate cancer is characterized as a Gleason sum 6 or less (i.e., no pattern 4 or 5 disease), a PSA 10 ng/mL or less, and clinical stage T1c-T2a (8). As a result of stage migration due to PSA screening, the proportion of newly diagnosed patients who fall into the “favorable-risk” category has increased and now constitutes about 50% of patients (9).
The natural history of favorable-risk prostate cancer has been fairly well-defined. The Albertsen study reported a large group of patients treated with watchful waiting with 20-year follow-up (10). In that pre-PSA screening cohort, 23% of untreated Gleason 6 patients died of prostate cancer within 20 years. For Gleason 7 prostate cancer, about 65% died of prostate cancer within 20 years. In addition, there has been a shift in Gleason scoring (11) interpretation over the last 20 years. This is largely due to the current practice of calculating the Gleason sum based on the presence of any highgrade foci, even if these are scant. A pattern 3 + 3 cancer with 5% Gleason 4 would have been scored as Gleason 6, 10, or 20 years ago, but today would be scored as 7. Thus, the Connecticut results likely represent a “worst case” scenario for the expected mortality from untreated Gleason 6 cancer. Furthermore, lead time with PSA screening is about 10 years for men in their 60s, estimated from a variety of serum databases and modeling (12,13). A reasonable inference from the Albertsen series is that in a serially screened population the cancer mortality of Gleason 6 cancer may be as low as 10% at 25 or 30 years.
According to the Connecticut experience, the mortality rate, untreated, of Gleason 7 cancer is about three times greater than that of Gleason 6. This is the basis for restricting surveillance in men with more than a 10- to 15-year life expectancy to Gleason 6 or less cancers.
The Scandinavian randomized trial of radical prostatectomy versus watchful waiting (14) also can be interpreted as providing support for surveillance. This study showed a 44% reduction in prostate cancer mortality with radical treatment. The trial population was mostly intermediate-risk and nonscreened. In addition, the survival benefit emerged within 5 years after treatment, a time course characteristic of patients with higher grade, high-risk disease. This means that the majority of the benefit seen in the Scandinavian trial likely represented mortality reduction in the high-risk group. Screening provides about a 10-year lead time. This study clearly shows that treatment in a screened population does not have to be early to be effective. Thus, patients initially managed with surveillance who are reclassified as higher risk and treated after several years of observation can likely be expected to derive the same substantial benefit from treatment as the Scandinavian prostatectomy cohort.
The challenge is to identify the subset who are at risk early enough that they are still amenable to curative therapy, thereby allowing the remainder to enjoy improved quality of life free from the side effects of treatment.
TABLE 11B.1 SUMMARY OF SIX ACTIVE SURVEILLANCE SERIES | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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WHAT PROPORTION OF LOW-RISK PATIENTS INITIALLY ACCEPT ACTIVE SURVEILLANCE?
To date, there are 6 published series of active surveillance, constituting a total of 2,130 patients (Table 11B.1) (15,16,17,18,19,20,21,22,23). None of these series report on the denominator, that is, the number of eligible patients offered this approach. One population based study (SEER) found that 10% of 3,300 newly diagnosed patients elected expectant management, but this included all grades and PSA levels, not just favorable risk (24). A New England Journal of Medicine case conference on a patient with favorable-risk prostate cancer polled readers internationally as to what they would advise patients (25). Remarkably, the breakdown between surgery, radiation, and expectant management was similar in every region of the world. Between 21% and 35% of responders indicated they would advise expectant management as the initial treatment of choice. In the United Kingdom, the NICE guidelines (26) state that the initial treatment of favorable-risk prostate cancer should be active surveillance. This kind of guideline has a significant effect on patient acceptance. Clearly, the proportion of patients accepting surveillance will reflect patient factors, including risk tolerance, age and comorbidity, extent of disease and PSA kinetics, and family attitudes; physician factors, including the way in which surveillance is presented and the local medical environment; and society factors, particularly the cancer “zeitgeist” in a community. What appears less critical is patient education and level of scientific literacy, socioeconomic status, or language and ethnicity. Most patients are capable of understanding the issues if they are clearly presented.
WHAT IS THE RATE OF RECLASSIFICATION TO HIGHER RISK DISEASE?
The published surveillance series report a rate of treatment of between 8% and 50%; the median is 33%. In the Toronto cohort, with the longest follow-up, the intervention rate was 38% at 10 years (15). Of these patients, 44% were treated for a short PSA DT; 24% for grade progression; and 11% due to patient preference. Of this latter group, most had an equivocal signal of some sort, that is, a PSA DT slightly longer than the 3-year threshold, or significant volume progression on repeat biopsy without grade progression.
Several authors have examined the pathology in radical prostatectomy specimens in patients who would have been candidates for active surveillance based on clinical stage and
biopsy grade. The frequency of upgrading and upstaging is considerable in some of these series (27,28). Catalona et al. reported that using three different criteria for active surveillance eligibility, 3% to 4% had a Gleason score of 8 to 10, 16% to 19% had positive surgical margins, 15% to 18% had extracapsular tumor extension, 3% to 5% had seminal vesicle invasion, and 0.4% to 1% had lymph node metastasis. These data underscore the importance of refining the assessment of extent of disease at baseline. However, the extremely favorable outcome of large cohorts of patients managed with active surveillance suggests that the downside risk of an initial approach of expectant management is low. Patients with more aggressive disease are, in most cases, identified in a timely fashion by repeat biopsy or PSA kinetics.
biopsy grade. The frequency of upgrading and upstaging is considerable in some of these series (27,28). Catalona et al. reported that using three different criteria for active surveillance eligibility, 3% to 4% had a Gleason score of 8 to 10, 16% to 19% had positive surgical margins, 15% to 18% had extracapsular tumor extension, 3% to 5% had seminal vesicle invasion, and 0.4% to 1% had lymph node metastasis. These data underscore the importance of refining the assessment of extent of disease at baseline. However, the extremely favorable outcome of large cohorts of patients managed with active surveillance suggests that the downside risk of an initial approach of expectant management is low. Patients with more aggressive disease are, in most cases, identified in a timely fashion by repeat biopsy or PSA kinetics.
A note about semantics. The term “progression” in oncology implies an increase in stage or grade of cancer and generally has ominous implications regarding curability. Patients on surveillance may be offered treatment based on a short PSA DT/rapid velocity, or an increase in tumor volume on biopsy. This is more accurately referred to as “reclassification to higher risk disease,” prompting a decision to intervene for disease that is most likely still curable. The term “progression” is misleading in this context.
ARE THERE RELIABLE CRITERIA FOR DETECTING PATIENTS AT HIGHER RISK FOR PROGRESSION?
The challenge in managing patients on surveillance is to avoid excessive delay in patients who appear to be at higher risk for progression over time, and to avoid overtreating patients based on a transient change in PSA or other biomarkers. All groups have used a combination of PSA kinetics and serial biopsy. The specific approach varies. The Toronto group uses a doubling time of 3 years or less, based on multiple determinations at 3-month intervals, calculated using a General Linear Mixed Model (GLMM), which corrects for baseline PSA, grade, and age (29). This model is available freely to all at http://Asure.ca. Others use a calculated or actual PSA velocity >2.0 ng/mL/year.
Most groups advise serial biopsies, at intervals varying from 1 to 4 years. The Toronto group recommends a confirmatory biopsy at 1 year to identify higher grade disease that was missed on the original biopsy; following this, biopsies are performed every 4 years to identify biological progression, a much more uncommon event. The Hopkins group performs biopsies annually or when a rise in PSA occurs (18).
In the Toronto series, patients with a PSA DT of 3 years or less constituted 22% of the cohort. This cut point for intervention remains empirical and speculative. However, the 20% to 25% of patients with a 3-year doubling time or less represent a rough approximation of the proportion of good-risk patients “at risk” for disease progression. For patients with a PSA in the 6 to 10 range, it also approximates an annual rise of 2 ng/mL, an adverse predictor of outcome as described by D’Amico (30).
A major controversy in this area is the interpretation and reliability of PSA kinetics.
PSA is an imperfect surrogate marker for disease volume and growth rate. It is a labile marker with significant limitations. However, numerous studies emphasize the adverse prognostic significance of a sustained rapid rise in PSA in prostate cancer patients. Several groups prefer PSA velocity to doubling time. Figure 11B.1 shows the distribution of PSA DT and velocity in surveillance cohorts. The wide distribution of doubling time is striking compared to the relatively narrow spread of velocity. In addition, doubling time reflects the Gompertzian growth curve of cancer.
 FIGURE 11B.1. Cumulative hazard ratio for nonprostate cancer to prostate cancer mortality. |
We have analyzed the use of different PSA triggers (31). The Toronto cohort constitutes 453 patients followed for a median of 7.5 years. Approximately 300 of these patients have remained untreated and completely stable. None of these 300 have metastasized or otherwise progressed. All of these patients have had a PSA DT >3 years using the GLMM method. Over time, 50% of these patients had a PSA velocity of >2.0/year at some point during their follow-up, reflecting the degree of PSA lability in untreated patients. This experience raises the concern that use of PSA velocity as a trigger may result in significant overtreatment.
Biopsy sampling error is a significant limitation of surveillance. This has been addressed, in part, by serial biopsies with particular attention to the anterolateral horn, a common site for disease missed on routine biopsies. Some have advocated saturation biopsies, consisting of 50 or more cores performed under GA, for patients contemplating surveillance (32). This approach, which may identify some patients with higher risk disease, has not been embraced by most advocates of active surveillance and does not appear necessary in the majority of patients. Dynamic contrast-enhanced magnetic resonance imaging (MRI) is emerging as a means to further assess extent of disease in patients, for example, with borderline PSA kinetics and minimal disease on biopsy (33).
WHAT ARE THE PSYCHOLOGICAL EFFECTS OF SURVEILLANCE, THAT IS, LIVING WITH UNTREATED CANCER? CAN WE MEASURE AND MANAGE THIS?
The psychological effects of living for many years with untreated cancer are a potential concern. Does the cumulative effect, year after year, of knowing that one is living with untreated cancer lead to depression or other adverse effects? The best data on this question come from a companion study to the Holmberg randomized trial of surgery versus
watchful waiting in Sweden. It found absolutely no significant psychological difference between the two groups after 5 years. Worry, anxiety, and depression all were equal between the two arms (34). The absence of any adverse psychological effect compared to patients treated radically has been reported by others (35). While surveillance may be stressful for some men, the reality is that most patients with prostate cancer, whether treated or not, are concerned about the risk of progression. Patients who have been treated curatively with surgery or radiation often remain focused on their PSA for many years, reflecting significant anxiety about recurrence. Patients who are educated to appreciate the very indolent natural history of most good-risk prostate cancers may avoid much of this anxiety. However, the long-term psychological effects of surveillance have not been studied in depth, and further studies in this area are a priority.
watchful waiting in Sweden. It found absolutely no significant psychological difference between the two groups after 5 years. Worry, anxiety, and depression all were equal between the two arms (34). The absence of any adverse psychological effect compared to patients treated radically has been reported by others (35). While surveillance may be stressful for some men, the reality is that most patients with prostate cancer, whether treated or not, are concerned about the risk of progression. Patients who have been treated curatively with surgery or radiation often remain focused on their PSA for many years, reflecting significant anxiety about recurrence. Patients who are educated to appreciate the very indolent natural history of most good-risk prostate cancers may avoid much of this anxiety. However, the long-term psychological effects of surveillance have not been studied in depth, and further studies in this area are a priority.
 FIGURE 11B.2. (A) Overall survival in Toronto cohort. (B) Cause-specific survival in Toronto cohort. |
WHAT IS THE COURSE OF DISEASE?
Table 11B.1 summarizes the seven published series to date, comprising more than 2,100 patients. These data show that in an intermediate time frame (5-10 years), the prostate mortality is exceptionally low. In part, this may reflect the modest duration of follow-up in some of the surveillance series. Collectively, approximately 200 patients have been followed from between 10 and 15 years. The prostate cancer mortality in this group is also low. The most mature cohort is the Toronto group. Among the 453 patients in this cohort, the actuarial 10-year prostate cancer survival is 97% (Fig. 11B.2).
Mortality from other causes is the cause of death in almost all men on surveillance. In the Toronto experience, the cumulative hazard ratio for nonprostate cancer to prostate cancer mortality was 19:1 (Fig. 11B.1). While prostate cancer mortality is likely to increase as the surveillance cohorts mature, so will nonprostate cancer mortality. It is very plausible that this ratio will remain relatively constant.
In the Toronto cohort, five men have died of prostate cancer. All five men had a PSA doubling time of 1.6 years or less. Three were treated within 6 to 12 months of diagnosis based on their PSA kinetics, progressed to metastatic disease within 1 year of treatment, and died 2 to 3 years later. These men undoubtedly harbored occult metastatic disease at diagnosis and would not have benefited from treatment a few months earlier. One patient refused treatment offered at 9 months, progressed to metastatic disease 5 years later, and died at 8 years. The fifth patient was treated 2 years after diagnosis, progressed to metastasis 3 years later, and died at 9 years. He is, arguably, the only patient in the cohort of 453 who might have had a better outcome with earlier treatment.
The relative risk of prostate cancer to other cause mortality is directly correlated to the age of the patient at diagnosis, insofar as the risk of other cause mortality is a function of age. In men over 70, the cumulative hazard ratio of nonprostate to prostate cancer mortality was 33:1, approximating the ratio of the lifetime risk of nonprostate to prostate cancer mortality in all men. In men under 70, it was 9:1.
In addition to these case series, a population study recently reported the results of delaying treatment in 343 men placed on initial surveillance compared to 3,000 treated at the time of diagnosis (24). Fifty percent of the surveillance patients were eventually treated. With a median follow-up of about 8 years, there was absolutely no difference in mortality rate or metastasis rate.
The limitation of these studies is the duration of follow-up. It will require another 5 to 7 years before even the most mature of these studies will have a median 15 years follow-up. Nonetheless, the results are extremely encouraging to date.
WHAT IS THE OUTCOME OF DELAYED TREATMENT?
Only the Toronto group has reported the outcome of the subset of patients treated radically. Of 453 patients, 137 were treated radically; two thirds with radiation and one third with surgery. The time to PSA failure (nadir + 2 for the radiation group, and >0.2 in the surgery group) is shown in Figure 11B.3. In the treated group, the PSA recurrence rate was 50%.
This high rate of failure in the treated patients is sobering. However, it should be interpreted in the following context. Among the “stable” cohort of untreated patients, none have progressed clinically, either to metastatic or locally advanced disease. Thus, the appropriate denominator for PSA failure is the 453 patients in the total cohort. Using the entire cohort as the denominator, the PSA failure rate is 59/453 or 13%. This is comparable to PSA failure rates for radical prostatectomy or radiation for favorable-risk patients. Clearly, a PSA DT <3 years and Gleason upgrading identify a group of high-risk patients, in spite of favorable prognostic criteria at diagnosis.
Furthermore, PSA failure does not mean death from prostate cancer. In the Hopkins radical prostatectomy cohort, the 15-year prostate cancer mortality in men with Gleason sum 6 to 7 with PSA recurrence before 3 years was 19% (36). Extrapolating this to the current cohort gives an overall cancer
mortality of 3% at 15 years postrecurrence (19% × 13%). These patients were not offered salvage radiation therapy. In this case, the prostatectomy patients have been managed with early salvage radiation therapy, and the expectation is that half or more will have a complete response. Thus, the PSA failure rate in the treated patients, although high, is consistent with a prostate cancer mortality of about 2% in the 15-year time frame. Longer follow-up will be required to determine the true impact of the PSA failure rate in this cohort.
mortality of 3% at 15 years postrecurrence (19% × 13%). These patients were not offered salvage radiation therapy. In this case, the prostatectomy patients have been managed with early salvage radiation therapy, and the expectation is that half or more will have a complete response. Thus, the PSA failure rate in the treated patients, although high, is consistent with a prostate cancer mortality of about 2% in the 15-year time frame. Longer follow-up will be required to determine the true impact of the PSA failure rate in this cohort.
 FIGURE 11B.3. PSA failure in 117 patients treated with surgery or radiation after a period of surveillance. |
ALTERNATIVES: 5ARIs AND FOCAL THERAPY
The surveillance approach is driven, in part, by the morbidity and cost of currently available therapy. An effective treatment that produced minimal or no side effects and was reasonably inexpensive would likely replace surveillance. Two large trials (PCPT and REDUCE) (37,38) have reported that the rate of prostate cancer diagnosis is decreased by 30% with 5ARIs. Many men in these studies harbored undiagnosed prostate cancer at entry. It is a reasonable inference that these drugs act to stabilize and/or reduce the volume of existing prostate cancer; indeed, that may be their main mode of action as prevention agents. One study testing this hypothesis in surveillance patients, the REDEEM study, has been completed but has not yet reported. It is possible that for many men with favorable-risk prostate cancer, a 5ARI represents a low cost, minimal intervention that is sufficient to reduce their risk of progression to exceedingly low levels. At this point, however, there is no direct evidence to support this hypothesis. A study demonstrating a reduced rate of positive biopsies and/or reclassification to higher risk disease in surveillance patients on 5ARIs would be a major contribution. While 5ARIs are appealing in this setting, particularly if they have other indications for the drug (i.e., BPH symptoms), it should not be considered a definitive therapy. Such patients still require close monitoring and periodic biopsies. If 5ARIs are used in men on surveillance, the PSA kinetics are simply recalibrated from the new baseline once a nadir is reached.
Advocates of focal therapy claim that the index lesion, which is the clinically relevant one, can be identified and treated with minimal morbidity (39). The limitations of focal therapy are similar to those of surveillance; namely, that some patients with favorable clinical parameters will harbor higher risk disease and be inadequately treated. Focal therapy risks being a treatment that is only effective in patients who do not require treatment and is ineffective in those who do. It may have a role in selected patients. However, the appeal of active surveillance is the ability to use the observed natural history of the patient’s disease over time to identify those who harbor more aggressive disease. Focal therapy may contaminate these observations. Focal therapy may have a role in treating patients who are candidates for surveillance but are unable to accept the notion of no treatment, or those on surveillance who have an increase in cancer volume on biopsy without grade progression. Since patients treated with focal therapy are still at risk for untreated disease, they will require follow-up very similar to that of surveillance patients, that is, serial PSA and repeat biopsy. Given the low mortality rate of favorable-risk prostate cancer managed with active surveillance, advocates for focal therapy face a major challenge in demonstrating that the natural history of this condition is improved by their approach.
WHAT ARE THE MAJOR PITFALLS OF SURVEILLANCE AND HOW CAN THEY BE AVOIDED?
The critical components of active surveillance are rigorous patient selection, provision of clear information and reassurance tailored to the patient’s educational level, appropriate and timely identification of the patients with higher risk disease, and appropriate treatment for them.
Patient selection: Young age is not a contraindication. Rather, the longer the patient’s life expectancy, the more stringent the criteria should be. Men under 60, for example, are better candidates if they fulfill the Epstein criteria for insignificant prostate cancer (no more than one third of all cores positive, no more than half of any one core involved, and a PSA density <0.15). Men over 70, particularly with comorbidity, may have a PSA >10 or minor elements of Gleason 4 pattern and still be appropriate candidates. Patient choice is a key component of the decision making. Men under 70 with substantial Gleason 4 pattern (some would argue, any Gleason 4 pattern) (40) are not good candidates for surveillance.
A clear unmet need is more accurate prediction of an individual patient’s likely risk of disease progression at baseline. Advances in this field have already occurred in MR imaging of prostate cancer, and this will have an increasing role. Major progress is also being made in the molecular characterization of higher risk disease based on multiplex analysis of biopsy specimens and/or somatic single nucleotide polymorphism (SNPs) (41). All hold the promise of more accurate characterization of disease aggressivity in the near future. This remains an active area of research.
Education: The patient who is told he has prostate cancer often interprets this as meaning he has an aggressive lethal disease. This point is often reinforced by wellmeaning family and friends. Correcting this misconception is a major communication challenge. The key facts that should be provided to dispel this include the high prevalence of histologic prostate cancer (roughly equal to the patient’s age as a percentage), the high incidence to mortality ratio, the long natural history of favorable-risk disease (30-40 years from inception to lethal disease, when it occurs), and the side effects of therapy. Phrases like “part of the normal aging process” are convincing. The NNT in the ERSPC trial (2) and the nonprostate-to-prostate cancer mortality ratio of 19:1 in the Toronto cohort are useful facts for more sophisticated patients.
TABLE 11B.2 ACTIVE SURVEILLANCE: SUGGESTED CALENDAR FOR FOLLOW-UP
Follow-up schedule:
PSA, DRE q3mo × 2 yr, then q6mo assuming PSA is stable.
Confirmatory 10-12 core biopsy within first year, including anterolateral horn.
Repeat biopsy every 3-5 yr until age 80.
Intervention: For PSA doubling time <3 yr (in most cases, based on at least eight determinations) (about 20% of patients). Consider multiparametric MRI in uncertain cases, with targeted biopsy.
For grade progression to Gleason 7 with substantial proportion of 4 pattern (5% of patients).
These are guidelines and should be modified according to patient age and comorbidity.
(c) Follow-up: Table 11B.2 contains a suggested schedule for follow-up. It is the responsibility of the physician and the patient to maintain regular follow-up on surveillance, to monitor PSA kinetics, and have periodic repeat biopsies. A key task is to reassure the patient as to the indolent course of the disease.
Biopsy Strategy
A major limitation in patient selection is pathological miss of higher grade or higher volume disease on biopsy. The Hopkins group has reviewed the pathologic results of radical prostatectomy in 48 patients of the 470 patients on surveillance (28). Twenty-seven percent fulfilled the Epstein criteria for clinically insignificant disease. Importantly, 20% of patients had a dominant nodule >1.0 cm; these were all located anteriorly. This emphasizes the importance of modifying the biopsy strategy in men on surveillance to evaluate the anterior prostate.
Various biopsy schedules have been employed in follow-up. We perform a second set of biopsies within 1 year of diagnosis, including the anterior zone and lateral horn. This is intended as a confirmatory biopsy, to identify higher grade disease missed on the initial biopsy. In patients in whom no higher grade cancer is found, we then biopsy patients every 3 to 4 years, stopping at age 80. The Hopkins group has subjected patients to annual biopsies. While this has the advantage of more precise evaluation of disease, patient compliance may diminish after a few years of annual biopsies. They have reported an increase in erectile dysfunction in patients subjected to three or more sets of annual biopsies (42). We are also concerned about the risk of overly frequent prostate biopsy. A recent population-based study reported that the postbiopsy urosepsis rate requiring hospitalization doubled between 1999 and 2009, from 2% to 4% (43).
Trigger for Intervention
The challenge is to intervene appropriately in those who warrant it and avoid overtreatment in those who do not. To date, clinicians have relied on the combination of PSA kinetics and serial prostate biopsy. The criteria consist of a PSA doubling time <3 years, a PSA velocity of >2.0/year, or the presence of significant amounts of Gleason 4 pattern on follow-up biopsy. This requires clinical judgment; the criteria for intervention in a 55-year-old and an 80-year-old are clearly different. In borderline cases, MRI may be helpful in elucidating the presence or absence of a large volume of cancer. A negative MRI in the presence of a PSA DT of 3 years, for example, is reassuring; a large nodule of unequivocal cancer in this patient would facilitate a decision to intervene.
Clinical Trials
The NCI (Canada), in conjunction with four US-based cooperative oncology trials groups, and the United Kingdom have opened a trial entitled Surveillance Therapy Against Radical Treatment (START). This trial, which opened to accrual in September 2007, will randomize 2,100 patients between the active surveillance approach described above and the patient’s choice of radical treatment (surgery or radiation). The primary end point is prostate cancer survival. The trial has a major correlative science component. Successful accrual to this trial will demonstrate conclusively whether active surveillance is equivalent to radical treatment in the favorable-risk patient.
SUMMARY
PSA screening identifies patients with life-threatening prostate cancer at a time when they are more curable but diagnoses many patients with non-life-threatening cancer who are susceptible to overtreatment. In a population subjected to regular screening, the latter group is far more prevalent. PSA testing results in hundreds of thousands of patients subjected to the side effects of unnecessary therapy. However, conservative management has been resisted in many constituencies due to legitimate concern about the inaccuracies of clinical staging and grading.
A rational approach is to offer definitive treatment to the intermediate- and high-risk group, and little or no treatment to the low-risk group. The limitation is that some apparently favorable-risk patients harbor more aggressive disease and would benefit from curative treatment. Expectant monitoring with selective intervention for those whose cancers exhibit characteristics of higher risk disease over time is an appealing way to deal with this. Intervention is offered for grade progression, or adverse PSA kinetics (a PSA doubling time <3 years or PSA velocity >2.0/year), tempered with clinical judgment of the patient’s life expectancy. This approach is currently being evaluated in a large-scale phase 3 study, which is open in Canada, the United States, and Britain. Ongoing studies of multiplex biomarkers to better identify patients at higher risk for progression, MR-based imaging to more accurately identify patients with larger volume of disease unappreciated at baseline or during follow-up, and studies of the benefit of 5ARIs and other secondary prevention strategies in surveillance patients are ongoing and likely to have a favorable impact on this approach.
References
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▪ 11C PLND: Indications for and Technique of Pelvic Lymph Node Dissection
Fiona C. Burkhard
Urs E. Studer
INTRODUCTION
Pelvic lymph node dissection (PLND) in prostate cancer has remained a controversial topic over the last decade. Although it represents the most reliable and exact procedure for lymph node staging (number of metastatic nodes, tumor volume, extranodular extension), a consensus has not been reached as to what extent and in which patients PLND should be performed. The reasons for this may include stage migration, expertise, economics, and a lack of Level 1 evidence concerning the effect of PLND on outcome. A multitude of nomograms have been designed to identify patients who may not need a PLND (1,2,3). These are based on routinely available preoperative parameters; however, although well designed, these nomograms have inherent problems, and it is questionable if this approach is acceptable from an oncological standpoint. Imaging procedures such as computed tomography (CT) or magnetic resonance imaging (MRI) are of limited value to detect minimal lymph node metastasis (4,5,6). Positron emission tomography combined with computerized tomography has not proven to be useful for lymph node staging in prostate cancer (7,8). Newer sophisticated radiologic techniques are under development; however, these tend to be time consuming, examiner dependent, costly, and not all are freely available (9,10,11,12). The use of radio isotopes for intraoperative detection of a sentinel node or diseased nodes is time consuming, remains to be standardized, and may have a relatively high false-negative rate (13,14). Until reliable detection of micrometastatic disease is possible, templates with defined boundaries for PLND must be used. This improves staging and allows for identification and removal of minimal metastatic disease. However, controversy persists on the exact definition of these templates. Whether an additional therapeutic effect of a more extended PLND (distal common iliac vessels, external iliac vein, obturator fossa, and internal iliac vessels) with removal of all diseased nodes can be expected is still not fully determined. This is at least in part due to the relatively benign course of disease in the majority of patients with prostate cancer, where a follow-up of 15 to 20 years is a prerequisite to be able to identify a survival benefit. This benefit may not necessarily compromise cure but a delayed progression of the disease. There is some evidence
suggesting that patients with high-risk prostate cancer may be the ones most likely to profit from extended PLND, especially those with micrometastatic disease. In the case of more extensive lymph node metastases, androgen deprivation therapy (ADT) may be of additional benefit (15). This chapter critically analyzes past and more contemporary literature pertaining to anatomic extent, indications, as well as the diagnostic and therapeutic benefit of PLND.
suggesting that patients with high-risk prostate cancer may be the ones most likely to profit from extended PLND, especially those with micrometastatic disease. In the case of more extensive lymph node metastases, androgen deprivation therapy (ADT) may be of additional benefit (15). This chapter critically analyzes past and more contemporary literature pertaining to anatomic extent, indications, as well as the diagnostic and therapeutic benefit of PLND.
EXTENT OF PELVIC LYMPH NODE DISSECTION
In the current literature, a standardized universal definition of PLND in prostate cancer is still lacking. While the minimal template, which is most commonly used in the United States, is restrained to lymphatic tissue from the distal two thirds of the external iliac vein down to the level of the obturator nerve only, a limited PLND template extends proximally from the bifurcation of the common iliac vessels to the circumflex iliac vein distally and laterally to the medial border of the external iliac artery. There is now substantial evidence that a dissection to this extent is inadequate for correct staging in prostate cancer.
General agreement has been reached that if PLND is considered necessary, dissection should include the nodes around the bifurcation of the common iliac vessels as well as those along the internal iliac vessels, which in both a minimal and limited PLND are not included. The importance of completely excising all tissue around the internal iliac vessels was shown in a study by Bader et al., where over half (58%) of the positive lymph nodes identified were found along the internal iliac artery and 19% were exclusively at this location (16). In confirmation of this finding, Wawroschek et al., by extending the standard PLND template to include tissue along the internal iliac vessels as well as the paravesical, presacral, and pararectal tissue, detected an additional 35% of lymph node-positive patients (17). In a study comparing different templates for PLND by Heidenreich et al., lymph node metastases were diagnosed in 27% of patients with extended PLND compared to only 12% with standard PLND (18). In addition, nodal metastases were identified in the internal iliac and presacral regions even in patients with negative obturator nodes. Overall, 42% of all lymph node metastases were detected outside the standard template.
Recent data using intraprostatic technetium injections and fused single-photon emission computed tomography (SPECT) combined with either CT or MRI to map lymphatic drainage from the prostate have shown that the prostate has multiple primary lymphatic landing sites (Fig. 11C.1) (19). Theoretically, to achieve an accurate staging, all primary lymphatic draining sites should be included and the field of LND extended up to the origin of the inferior mesenteric artery. However, the extent of PLND must be a balance between the advantages of removing all primary landing sites with the disadvantages of possible increased morbidity, longer surgery, and associated costs. The authors defined a new template termed superextended PLND including the lymphatic tissue along the common iliac artery up to where it is crossed by the ureter. This extended template should allow removal of approximately 75% of all nodes potentially harboring metastases. The borders of the proposed template are cranial border, the mid-common iliac region where the ureter crosses the iliac vessels; lateral border, the medial border of the external iliac artery; caudal border, the deep circumflex iliac vein and femoral canal; medial border, the bladder and rectal wall; and posterior border, the presacral area together with the tissue lateral and medial to the internal iliac vessels, particularly distal to the superior vesical artery (presacral nodes) and down to the endopelvic fascia covering the sciatic nerve (Fig. 11C.2). Using this template approximately 20 nodes are removed per patient, which is in line with an adequate pelvic lymph node staging as described by Weingartner et al. (20) The minimum number of lymph nodes required for optimal staging is difficult to define, due to the interindividual variation in lymph node count. In addition, the number of nodes identified is dependent on the examining pathologist and how the tissue is submitted (number of separate packages). There is clear evidence in bladder cancer that submitting separate packages results in significantly higher lymph node counts (21). Adhering to a defined adequate template (extended PLND) is probably more important than to focus only on the number of lymph nodes retrieved.
 FIGURE 11C.1. Anatomic localization of primary lymphatic landing sites (sentinel nodes) by fusion of SPECT and CT or MRI in a 3D reconstruction model and confirmed by surgical removal. |
Therefore, based on the current evidence, a standardized bilateral extended PLND should be performed in patients undergoing radical prostatectomy for prostate cancer, extending cranially to where the ureter crosses the common iliac artery, laterally to the medial border of the external iliac artery and posteriorly to include tissue on both sides of the internal iliac vessels.
PLND AS A STAGING PROCEDURE
The main indication for PLND is accurate staging, as until now it remains the only reliable method for lymph node staging in the pelvis. In continued efforts to tailor treatment options to individual patient circumstances and minimize morbidity, nomograms have been developed (1,2). By assigning points for specific risk factors (e.g., prostate-specific antigen [PSA] level, clinical tumor stage, and biopsy Gleason score), these nomograms attempt to estimate the likelihood of lymph node metastasis in each individual patient diagnosed with prostate cancer. The majority of these tools, however, base the risk of lymph node metastases on the findings derived from a limited PLND (2,3). Therefore, despite the high accuracy described, they may underestimate the true prevalence of lymph node metastases. Briganti et al. developed the first nomogram based on an extended PLND at a single high volume center, which showed an accuracy of 76% in their hands, but is still awaiting external validation (1).
Despite continuing advances, imaging techniques still cannot match the reliability of PLND for the detection of lymph node metastasis. CT scan sensitivity for detecting lymph node metastasis is around 35%, which can be attributed to the fact that a lymph node diameter >1 cm is required for this diagnosis (6). No advantage could be shown for MRI studies (4,5,22). The use of lymphotropic paramagnetic iron
oxide nanoparticles as a contrast agent at MRI (LNMRI), however, may improve the detection of lymph node metastasis (9,11). Reported rates of sensitivity are 90% to 100% and of specificity 80% to 90% for LNMRI. However, the limitations of these studies are that most patients underwent a limited PLND, primarily removing the suspicious nodes. This falsely increases the sensitivity because other nodes potentially harboring small metastases were not removed and consequently not recognized. In addition the interpretation of LNMRI studies, for which a high interobserver variability has been reported, requires considerable experience and time. A recently proposed technique of MRI enhanced with ultrasmall superparamagnetic particles of iron oxide combined with diffusion-weighted MRI was found to be a fast and accurate method for detecting lymph node metastasis in prostate and bladder cancer, but needs to be confirmed in larger patient groups by other authors (12).
oxide nanoparticles as a contrast agent at MRI (LNMRI), however, may improve the detection of lymph node metastasis (9,11). Reported rates of sensitivity are 90% to 100% and of specificity 80% to 90% for LNMRI. However, the limitations of these studies are that most patients underwent a limited PLND, primarily removing the suspicious nodes. This falsely increases the sensitivity because other nodes potentially harboring small metastases were not removed and consequently not recognized. In addition the interpretation of LNMRI studies, for which a high interobserver variability has been reported, requires considerable experience and time. A recently proposed technique of MRI enhanced with ultrasmall superparamagnetic particles of iron oxide combined with diffusion-weighted MRI was found to be a fast and accurate method for detecting lymph node metastasis in prostate and bladder cancer, but needs to be confirmed in larger patient groups by other authors (12).
 FIGURE 11C.2. Anatomical extent for our recommended extended PLND during radical prostatectomy where in addition to lymphatic tissue removed from the obturator fossa and the external iliac vein, the template also encompasses tissue on the medial and lateral aspects of the internal iliac vessels as well as along the common iliac vessels up to the ureteric crossing. |
The sentinel lymph node concept in prostate cancer was first introduced by Wawroshek and co-workers (23). One of the first applications of this concept was described by Cabanas for penile cancer and based on the idea that lymphogenic spread of cancer cells is a gradual process and that the first node to be affected is the first node reached by the lymphatic outflow from the diseased organ (24). This implies that if the first node with technetium (99mTc) uptake is without metastases, an LND is unnecessary. However, this technique has some limitations. First, the prostate does not only have one or two, but multiple primary landing sites. Second, the collimator has to be in direct contact with the Tc-uptaking nodes to be able to detect them. Nodes that are difficult to access or in areas not routinely examined, such as lymphatic tissue along the internal iliac vessels, the common iliac vessels, the aorta, and in the presacral area, may be missed. Third, lymph nodes with extensive metastasis blocking the technetium uptake are not identified (14).
In summary, available preoperative imaging studies are unreliable. In the future, innovative imaging studies may allow reliable staging, but until then, an extended PLND at least up to where the ureter crosses the common iliac vessels remains the only reliable method for staging in prostate cancer.
INFLUENCE OF PLND ON OUTCOME IN PATIENTS WITH LOW-RISK PROSTATE CANCER
As a result of the stage migration seen over the last decade, the number of men with low-risk disease has increased profoundly, also reducing the risk of lymph node metastases, and many question the need for PLND in these low-risk patients. Although there is a variability in the definition of low risk, after extended PLND, the risk of lymph node metastases in patients with low-risk parameters (clinical stage T1/T2, PSA <10 ng/mL and Gleason score <7) has been shown to vary between approximately 3% and 11% (25,26,27,28,29). Schumacher et al. found that in patients with a PSA <10 ng/mL, a 25% incidence of lymph node metastases was seen in those with a specimen Gleason score ≥7, but only in 3% of patients with a specimen Gleason score ≤628. Using the extended template, Weckermann et al. similarly found the nodal metastases risk to be approximately 7% in their series of patients with a PSA ≤10 ng/mL and biopsy Gleason score ≤6, while Heidenreich and co-workers reported a 2.4% incidence of lymph node metastases in their patients with a PSA <10.5 ng/mL and biopsy Gleason score ≤618,29. Thus, it would seem reasonable to omit PLND in low-risk patients. The inaccuracy of preoperative staging, however, is the main limitation of this approach. Grossfeld et al. found 30% undergrading and understaging in patients with a preoperative biopsy Gleason score ≤6, while Bhatta-Dhar et al. found in their study that 40% of the biopsy Gleason scores ≤6 had to be upgraded to Gleason score >6 in the pathological specimen (30,31). Therefore, although it is generally considered permissible to refrain from performing a PLND in the low-risk patients with a PSA <10 ng/mL and a biopsy Gleason score ≤6, the inherent risk of biopsy-based understaging remains. Despite the general recommendation to omit PLND in low-risk patients, evidence is lacking to support an equal outcome with or without PLND in these patients. In a retrospective study, Bhatta-Dhar and colleagues compared biochemical recurrence (BCR)-free survival of low-risk patients who underwent no PLND or limited PLND (30). After a mean
follow-up of 5 years, there was no significant difference in BCR-free survival rates (86% and 88%). After reevaluation at a later time point, they again found no significant difference in the 10-year BCR-free survival rates (84% and 88%) (32). In a multicenter study comparing survival rates after no or limited PLND, again no difference in BCR-free survival rates was found (33). These studies, however, are limited by the fact that patients underwent a limited PLND only, the patients included were at low risk of dying of prostate cancer, and the number of patients included was too small for a statistically valid equivalence study. These data are not strong enough to rule out that a more extensive PLND may have been of benefit in some of these patients.
follow-up of 5 years, there was no significant difference in BCR-free survival rates (86% and 88%). After reevaluation at a later time point, they again found no significant difference in the 10-year BCR-free survival rates (84% and 88%) (32). In a multicenter study comparing survival rates after no or limited PLND, again no difference in BCR-free survival rates was found (33). These studies, however, are limited by the fact that patients underwent a limited PLND only, the patients included were at low risk of dying of prostate cancer, and the number of patients included was too small for a statistically valid equivalence study. These data are not strong enough to rule out that a more extensive PLND may have been of benefit in some of these patients.
Other authors have shown that there is an inverse correlation between the number of nodes removed and BCR-free survival in node-negative patients (34). Based on the analysis of the SEER program database in 1,923 patients, Josyln and colleagues also concluded that an extended PLND (>10 lymph nodes) reduces the long-term risk of prostate cancer-related death, even in patients with negative nodes compared to those who had no PLND (27). The observed benefit of removing negative nodes may be related to the possible presence of occult lymph node metastasis. Studies addressing the presence of molecular markers to identify micrometastases by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunostaining have demonstrated that the presence as well as the load of these markers was significantly associated with worse cancer-specific outcome (35,36,37). Contradictory to these findings, Di Marco and co-workers found that in node-negative patients, the number of nodes removed was not associated with survival (38). The limitations of this single institution study over a 13-year time period are that patients who underwent surgery at the beginning of the study had more nodes removed and had a similar outcome to the more recent group. If the stage migration is taken into consideration, patients operated on in the earlier period should have had worse outcomes. This was not so and therefore a beneficial role of PLND cannot be excluded.
These studies support a potential benefit of removing occult disease, which if left behind after no or an inadequate PLND would deprive patients of a potentially curative surgery. If a PLND is indicated, then an extended PLND should be performed. If PLND can be omitted, then in patients with a PSA <10 and a Gleason score ≤6, however, the risk of understaging in prostate biopsies must be taken into account.
INFLUENCE OF PLND ON OUTCOME IN PATIENTS WITH POSITIVE NODES
In 1987, Golimbu and co-workers found that patients with a low tumor bulk and single lymph node metastasis had survival rates comparable to their matched control counterparts after a mean follow-up of 5 years (39). In 1988, Catalona showed that 75% of men with lymph node-positive disease remained recurrence-free at 5 years and 58% at 7 years without adjuvant treatment (40). Pound et al. found a 68% 10-year metastasis-free survival in patients with lymph node micrometastasis without adjuvant therapy (41). In a more recent series, Schumacher et al. reported a 60% cancer-specific survival rate after a 10-year follow-up (42). Recently, Boorjian and colleagues retrospectively reviewed a large series of patients from the Mayo Clinic with positive lymph nodes with (˜90%) or without adjuvant hormonal therapy, where 56% and 86% of the lymph node-positive patients had a 10-year biochemical progression-free survival and cancer-specific survival, respectively (43). In the same study, they showed that not all patients with lymph node metastases have the same prognosis. Patients after radical prostatectomy and PLND with a single nodal metastasis were at a threefold increased risk of systemic progression and fourfold increased risk of prostate cancer death compared to those with negative nodes. But in comparison to those with one positive node, those with two or more lymph node metastases were twice as likely to experience systemic progression as well as prostate cancer death. Joslyn et al. showed that the presence of two or more lymph node metastases conferred a greater risk of prostate cancer-related death than a solitary metastasis (27). Similarly, Skinner’s group confirmed 10-year recurrence-free survival following a radical prostatectomy to be 70% to 73% in patients with one to two lymph node metastases but reduced to 49% in those with five or more involved nodes (44). In terms of lymph node density status, an advantage in PSA progression-free survival has been reported in men with <15% compared to those with ≥15% involved nodes (25). In addition, a <15% density in patients conferred a 5-year PSA progression-free survival of 43% following an extended PLND compared to only 10% after a limited PLND. In Daneshmand’s series, patients with a lymph node density ≤20% had a 72% 10-year recurrence-free survival, compared with 47% for those with >20% density44.
There are proponents of the idea that lymph node-positive prostate cancer may already be a systemic disease, and therefore removal of positive nodes will not cure men with highrisk disease. However, certain patients with nodal metastasis show good long-term survival without ADT (Table 11C.1). Although the majority of the node-positive patients in the study by Boorjian et al. received ADT, patients with a single positive node were not at increased risk for local recurrence compared to node-negative patients43. Furthermore, in Schumacher’s series of 122 lymph node-positive patients who underwent an extended PLND, two thirds of patients with a solitary positive lymph node and half of those with two positive nodes experienced no evident tumor progression and therefore did not require ADT during a follow-up period of 10 years (42). There are reports suggesting that progression-free survival may be prolonged when radical surgery and adjuvant therapy are combined (45). Messing et al. demonstrated in their study that early adjuvant ADT following radical prostatectomy in men with node-positive disease is associated with improvement in survival (46). However, this trial was based on patients with mostly gross nodal disease, the majority of which also had positive margins and seminal vesicle infiltration. Points of criticism are the lack of a standardized template for the PLND, the initiation of ADT at the time of clinical, not biochemical recurrence in the deferred treatment group and the small sample size. Its results therefore may not necessarily apply to patients with micrometastatic lymph nodes detected by RT-PCR or immunostaining, nor to patients with minimal metastatic disease. The available data suggest that ADT is of benefit in patients with gross nodal disease, but not in those with minimal metastatic disease unless their PSA doubling time is <12 months. These patients may well be the group who are most likely to benefit from immediate ADT (47).
To summarize, PLND with an extended template will remove more nodes and improve the accuracy of staging, although even the extended template reaching up to where the ureter crosses the common iliac artery may be inadequate in some patients, as approximately 25% of the primary lymphatic landing sites of the prostate lie outside this template (19). However, this approach is an attempt to optimize the risk-benefit ratio. Increasing evidence points to the potential benefit of removing occult molecular lymph node metastases with an extended PLND. Patients with minimal nodal metastases may also profit from removal of diseased nodes.
In patients with palpable and multiple nodal disease, however, it still remains to be seen if PLND, whether extended or not, represents more than just tumor mass reduction. Patients with gross nodal disease or with a PSA doubling time <12 months may profit from ADT.
In patients with palpable and multiple nodal disease, however, it still remains to be seen if PLND, whether extended or not, represents more than just tumor mass reduction. Patients with gross nodal disease or with a PSA doubling time <12 months may profit from ADT.
TABLE 11C.1 SURVIVAL RATES IN PATIENT WITH PROSTATE CANCER AND LYMPH NODE METASTASIS WITHOUT IMMEDIATE HORMONAL THERAPY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TECHNIQUE OF EXTENDED PELVIC LYMPH NODE DISSECTION
Following a lower midline incision, the peritoneum is bluntly swept away from the abdominal wall. The vasa deferentia are usually identified during this maneuver and can be transected. The lymphadenectomy is then begun on the tumor-bearing side. Following identification of the external iliac vein, the lymphatic tissue surrounding the vein is removed; small vessels are coagulated with the bipolar coagulation forceps. Care is taken to ligate all lymphatic vessels coming from the leg at the level of the femoral canal to avoid lymphocele formation. The external iliac vein is then gently retracted with a swab and the pelvic side wall is identified; thereafter, the tissue is dissected off the side wall and the vessels are coagulated. The obturator nerve is identified. A clamp is then placed encompassing the tissue between the external iliac vein and the obturator nerve; the tissue is then divided and ligated. The obturator nerve is freed of the surrounding tissue, and the obturator vessels are identified and left intact. The proximal external iliac artery and vein are then bluntly separated from the iliopsoas muscle, and the tissue along the proximal part of the obturator nerve in the fossa of Marcille is removed. This tissue package is sent separately for pathological examination (external iliac/obturator). The tissue on both sides of the common iliac vessels up to where the ureter crosses is then removed. Medial to the internal iliac artery, additional lymphatic tissue is dissected, but care is taken to spare the hypogastric nerves where they cross the medial aspects of the common iliac artery and run adjacent to the rectosigmoid. The tissue along the internal iliac artery, both on its medial and lateral side is removed. Particular attention is paid on removing the nodes distal to the superior vesical artery between the internal iliac artery and the rectal wall. This tissue is sent as the third package (internal iliac).
COMPLICATIONS OF PLND
A common argument against ePLND is the purported increased time of surgery and high complication rate. Although completing an extended PLND may add on average 30 to 45 minutes to the total operating time, as yet there are still no reports on the cost-benefit analysis for PLND in prostate cancer. Previous reports have shown complication rates for limited/standard PLND ranging from 2% up to 9.8%, while extended PLND complication rates varied from 2% to 51% (16,18,48,49,50). When assessing individual complication rates, only the rate of lymphoceles was significantly higher after ePLND (51).
To reduce or to prevent PLND-associated morbidity, several authors have provided advice regarding a meticulous surgical technique. First, instead of using clips, which are often rubbed off during subsequent surgery, all the lymphatic vessels coming from the lower extremities are tied using ligatures. Second, all lymphatics lateral to the external artery are saved to prevent lymphedema of the legs. Third, two drains are placed in each side of the pelvis and are not removed until the total amount of fluid is <30 mL/24 h. Fourth, low molecular heparin is injected into the upper arm to avoid damaging lower extremity lymphatics (52).
SUMMARY
There is clear evidence that a more extended PLND removes more nodes and achieves a more accurate staging. Extended PLND up to where the ureter crosses the common iliac artery removes the majority of the prostates primary landing sites and represents an attempt to optimize the benefit-risk ratio. If a PLND is considered necessary, then an extended PLND at the minimum up to where the ureter crosses the common iliac artery should be performed. To which extent there may be a survival benefit after radical retropubic prostatectomy (RRP) and extended PLND remains to be determined. Patients with negative nodes often seem to have a better probability of disease-specific survival if more nodes are removed. Metastatic disease limited to one or two nodes portends in general good outcome, and these patients may be the ones to benefit most from a PLND without additional treatment. In the case of more extensive nodal disease, PLND combined with ADT may improve outcome.
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▪ 11D Radical Prostatectomy for Clinical Stage T1 and T2 Prostate Cancer
James A. Eastham
Peter T. Scardino
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