Eric A. Klein

Management of local bacillus Calmette-Guerin failures in superficial bladder cancer

We attempt to define the treated natural history of patients with superficial bladder tumors (stages Ta, TIS and T1) managed with intravesical bacillus Calmette-Guerin (BCG) to determine the best form of treatment for locally recurrent tumors. The management and survival of 41 patients who failed BCG within the bladder or prostatic urethra and who subsequently were treated with a variety of secondary therapies are reviewed. Our aim was to assess the role of several independent clinical variables on the rate of death from bladder cancer. Of the 41 patients 6 (15%) died. Univariate statistical analysis identified early involvement of the prostatic urethra and the presence of superficially invasive (stage T1) tumor at initial treatment with BCG as factors having an adverse effect on survival. A multivariate statistical model revealed that patients with early prostatic urethral involvement and the presence of superficially invasive (stage T1) tumor at diagnosis had the highest risk of death from bladder cancer. The reason for change in therapy at failure of BCG, stage of the tumor at BCG failure, occurrence of upper tract tumors and early versus delayed radical cystectomy had no impact on survival. The results suggest that not all tumors that recur after BCG are destined to proceed to muscle invasion or metastases, and that some patients may be managed safely by repeated endoscopic resection and intravesical therapy with cystectomy delayed until objective progression is evident. Such an approach can yield survival equal to that in patients treated with early cystectomy and may result in longer intervals of bladder preservation in a select subset of patients who fail BCG locally.

Local BCG failures in superficial bladder cancer. A multivariate analysis of risk factors influencing survival

Of 221 patients with superficial bladder cancers treated with intravesical BCG, BCG therapy failed locally within the bladder or prostate in 41 patients. A multivariate analysis was done using data on these local failures to identify clinical variables influencing survival. Patients presenting with T1 tumors which relapsed initially in the prostate were at highest risk of dying of bladder cancer. Cystectomy is justified in such patients. Others with noninvasive local refractory disease can be managed by continued conservative therapy.

Selecting and Counseling Patients on Appropriate Treatment of Prostate Cancer

It has been estimated that in 1998, physicians will have diagnosed prostate cancer in approximately 200,000 American men, who will be offered a variety of treatments to cure or control the progression of their disease. The lack of data from large, randomized trials with long-term follow-up has caused considerable controversy and confusion regarding the treatment options of newly diagnosed localized prostate cancer. In the absence of such controlled trials, it becomes difficult to compare treatment outcomes because of differing pretreatment risk characteristics and different specific therapeutic techniques. Adding to the confusion are the various endpoints used to gauge the success or failure of a particular treatment. Many prostatectomy and radiation therapy series use prostate-specific antigen (PSA) recurrence-free survival, defined a variety of ways, as an outcome parameter that may not translate into overall and prostate-cancer specific survival within the lifetime of a patient. Also, because of the profound downward-stage migration to more organ-confined disease during the PSA-screened era, improved outcomes reported from recent prostatectomy, external-beam radiation therapy, and interstitial brachytherapy series may not be related only to improvements in specific therapeutic techniques.

Contemporary Technique of Radical Retropublic Prostatectomy

Radical retropubic prostatectomy remains a popular therapy for localized prostate caner and is frequently performed in most urological practices. We describe our current technique for this procedure developed from watching many experienced surgeons, studying other published descriptions, and our own surgical experience over the last decade. We recognize that there are many ways to accomplish the goals of any operation and describe what has worked best for us in terms of pathological and functional results.

Suprapubic Approach for Bilateral Orchiectomy and Placement of Testicular Prostheses

Bilateral orchiectomy frequently is performed in men with advanced prostatic carcinoma. We describe a suprapubic approach for simultaneous orchiectomy and placement of testicular prostheses for use in the occasional patient who desires cosmetic reconstitution of the scrotum. The described technique takes advantage of the proximity of the spermatic cords to the midline as they descend into the scrotum

Impact of the SPOP Mutant Subtype on the Interpretation of Clinical Parameters in Prostate Cancer

Purpose Molecular characterization of prostate cancer, including The Cancer Genome Atlas, has revealed distinct subtypes with underlying genomic alterations. One of these core subtypes, SPOP (speckle-type POZ protein) mutant prostate cancer, has previously only been identifiable via DNA sequencing, which has made the impact on prognosis and routinely used risk stratification parameters unclear. Methods We have developed a novel gene expression signature, classifier (Subclass Predictor Based on Transcriptional Data), and decision tree to predict the SPOP mutant subclass from RNA gene expression data and classify common prostate cancer molecular subtypes. We then validated and further interrogated the association of prostate cancer molecular subtypes with pathologic and clinical outcomes in retrospective and prospective cohorts of 8,158 patients. Results The subclass predictor based on transcriptional data model showed high sensitivity and specificity in multiple cohorts across both RNA sequencing and microarray gene expression platforms. We predicted approximately 8% to 9% of cases to be SPOP mutant from both retrospective and prospective cohorts. We found that the SPOP mutant subclass was associated with lower frequency of positive margins, extraprostatic extension, and seminal vesicle invasion at prostatectomy; however, SPOP mutant cancers were associated with higher pretreatment serum prostate-specific antigen (PSA). The association between SPOP mutant status and higher PSA level was validated in three independent cohorts. Despite high pretreatment PSA, the SPOP mutant subtype was associated with a favorable prognosis with improved metastasis-free survival, particularly in patients with high-risk preoperative PSA levels. Conclusion Using a novel gene expression model and a decision tree algorithm to define prostate cancer molecular subclasses, we found that the SPOP mutant subclass is associated with higher preoperative PSA, less adverse pathologic features, and favorable prognosis. These findings suggest a paradigm in which the interpretation of common risk stratification parameters, particularly PSA, may be influenced by the underlying molecular subtype of prostate cancer.

Counseling Patients With Localized Prostate Cancer

The treatment of localized prostate cancer remains controversial because of the lack of conclusive well-controlled or randomized studies comparing outcomes of radiotherapy (RT) and radical prostatectomy (RP). A randomized trial published in 1982 showing an advantage to RP was never widely accepted because of randomization artifacts and worse than previously reported RT results (1,2). The Southwest Oncology Group closed a randomized study comparing these two modalities in the mid-1980s owing to poor accrual. In 1993, Stamey et al. (3) reported a 20% 5-yr biochemical cure rate with RT and suggested that radiation accelerates prostate cancer growth. Subsequently, large RT series were published with outcome results stratified by biopsy grade, T stage, and serum PSA, demonstrating similar short-term outcomes for RT and RP (4–6). A close examination of the patients treated by RT in the series of Stamey et al. (3) suggests that the observation of a 20% “cure” rate with RT can largely be explained by patient selection factors—all patients had high-volume cancers diagnosed by palpable lesions, 35% had clinical stage C disease, 50% had Gleason sum ≥7, and 15% had positive lymph nodes (7). Furthermore, Liebman et al. (8) have subsequently demonstrated that prostate-specific antigen (PSA) velocity is similar in those who fail radiation or surgery. None of these studies clearly answers the question of which is the best local therapy for localized prostate cancer. The unsettled nature of this issue is further complicated by the marked polarization of radiation oncologists and urologists in their counseling of patients with newly diagnosed localized disease, with surgeons recommending surgery and radiation therapists recommending radiation in virtually all circumstances (9).

The Role of Prostate Specific Antigen and Its Variants in Prostate Cancer Screening

Prostate-specific antigen (PSA) is the most important marker for the detection and management of prostate cancer. PSA-based screening has been responsible for a profound downward stage migration in newly diagnosed prostate cancer compared to those detected in the pre-PSA era (1). This has been the result of the increased lead time for prostate cancer diagnosis that has resulted in the identification of prostate cancer earlier in the natural history of the disease (2). In addition, we have recently shown that rates of extracapsular extension in radical pro statectomy specimens have continued to decrease during the PSA era independent of preoperative serum PSA levels, T stage, and histological grade (3).