Edward M. Messing

Immediate Hormonal Therapy Compared with Observation after Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-Positive Prostate Cancer

BACKGROUND Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. METHODS Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually. RESULTS After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome. CONCLUSIONS Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.

Adjuvant Radiotherapy for Pathological T3N0M0 Prostate Cancer Significantly Reduces Risk of Metastases and Improves Survival: Long-Term Followup of a Randomized Clinical Trial

PURPOSE Extraprostatic disease will be manifest in a third of men after radical prostatectomy. We present the long-term followup of a randomized clinical trial of radiotherapy to reduce the risk of subsequent metastatic disease and death. MATERIALS AND METHODS A total of 431 men with pT3N0M0 prostate cancer were randomized to 60 to 64 Gy adjuvant radiotherapy or observation. The primary study end point was metastasis-free survival. RESULTS Of 425 eligible men 211 were randomized to observation and 214 to adjuvant radiation. Of those men under observation 70 ultimately received radiotherapy. Metastasis-free survival was significantly greater with radiotherapy (93 of 214 events on the radiotherapy arm vs 114 of 211 events on observation; HR 0.71; 95% CI 0.54, 0.94; p = 0.016). Survival improved significantly with adjuvant radiation (88 deaths of 214 on the radiotherapy arm vs 110 deaths of 211 on observation; HR 0.72; 95% CI 0.55, 0.96; p = 0.023). CONCLUSIONS Adjuvant radiotherapy after radical prostatectomy for a man with pT3N0M0 prostate cancer significantly reduces the risk of metastasis and increases survival.

Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy

BACKGROUND Appropriate timing of androgen deprivation treatment (ADT) for prostate cancer is controversial. Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed. METHODS Eligible patients from 36 institutes in the USA were randomly assigned in 1988-93 to receive immediate ADT (n=47) or to be observed (n=51), with ADT to be given on detection of distant metastases or symptomatic recurrences. Patients were followed up every 3 months for the first year and every 6 months thereafter. The primary endpoint was progression-free survival; secondary endpoints were overall and disease-specific survival. Analysis was by intention to treat. To ensure that the treatment groups were comparable, we did a retrospective central pathology review of slides and regraded the Gleason scores for available samples. This trial predates the requirement for clinical trial registration. FINDINGS At median follow-up of 11.9 years (range 9.7-14.5 for surviving patients), men assigned immediate ADT had a significant improvement in overall survival (hazard ratio 1.84 [95% CI 1.01-3.35], p=0.04), prostate-cancer-specific survival (4.09 [1.76-9.49], p=0.0004), and progression-free survival (3.42 [1.96-5.98], p<0.0001). Of 49 histopathology slides received (19 immediate ADT, 30 observation), 16 were downgraded from the original Gleason score (between groups < or = 6, 7, and > or = 8) and five were upgraded. We recorded similar proportions of score changes in each group (p=0.68), and no difference in score distribution by treatment (p=0.38). After adjustment for score, associations were still significant between treatment and survival (overall, p=0.02; disease-specific, p=0.002; progression-free survival, p<0.0001). INTERPRETATION Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy, compared with those who receive deferred treatment. The beneficial effects of early ADT, rather than an imbalance in risk factors, are likely to explain the differences in outcomes between treatments.

Interstitial cystitis early diagnosis, pathology, and treatment

In a retrospective review, 52 patients with interstitial cystitis have been studied. Patients with persistent lower tract irritative symptoms, repeatedly sterile urine, and negative urine cytology must be suspected of having interstitial cystitis, and a diagnosis of urethral syndrome in such patients is highly questionable until cystoscopy under anesthesia has been performed. We believe that the finding of multiple petechia-like hemorrhages (glomerulations) on the second distention of the bladder is the hallmark of interstitial cystitis, and that a reduced bladder capacity and a Hunners ulcer represent a different (classic) stage of this disease. In all stages, the characteristic histologic finidng is submucosal edema and vasodilation. The presence of eosinophils and mast cells is variable, and even in the classic disease the muscularis often appears to be normal. Immuno fluorescent studies and laboratory tests, including the fluorescent antinuclear antibody test (FANA), have not helped us to diagnose (or investigate) interstitial cystitis. Bladder instillations with a 0.4 per cent solution of oxychlorosene sodium (Clorpactin WCS-90) have provided remarkable relief for many patients with this disease, particulary those with the classic form.

The Significance of Asymptomatic Microhematuria in Men 50 or More Years Old: Findings of a Home Screening Study Using Urinary Dipsticks

In an ongoing home screening study 231 men 50 or more years old without known causes of hematuria have tested their urine each week with a chemical reagent strip for the presence of blood. After 3 months of testing 23 patients have had hematuria at least once. Of these men 5 have had urinary cancers and 5 have had other serious underlying diseases requiring immediate treatment. In only 3 of these 10 men (only 1 with cancer) did hematuria occur in more than a third of the testings or on subsequent microscopic urinalysis. The degree of hematuria was unrelated to the seriousness of its cause. We conclude that in this population hematuria occurs so intermittently that when found on routine urinalysis, regardless of quantity, serious underlying pathological conditions must be ruled out aggressively. Furthermore, regular hematuria home testing appears to offer promise as an economical means to detect urinary cancers and other serious diseases in asymptomatic men 50 or more years old.

Use of a New Tumor Marker, Urinary NMP22, in the Detection of Occult or Rapidly Recurring Transitional Cell Carcinoma of the Urinary Tract Following Surgical Treatment

PURPOSE We evaluated the ability of an immunoassay for nuclear matrix protein 22 (NMP22 test kit) to predict the subsequent disease status of patients with transitional cell carcinoma of the urinary tract at approximately 10 days after transurethral resection of bladder tumor. MATERIALS AND METHODS A total of 90 patients with transitional cell carcinoma provided voided urine samples at least 5 days postoperatively. NMP22 was determined using a commercial test kit. At initial cystoscopic examination 3 to 6 months later the disease status was recorded, and the NMP22 values before and after transurethral resection of bladder tumor were compared. RESULTS Of 125 followup cystoscopic examinations (60 patients had 1, 26 had 2, 3 had 3 and 1 had 4 recurrences) transitional cell carcinoma was pathologically confirmed in 33. No malignancy was present at 79 examinations (if tumor was seen endoscopically, pathological evaluation indicated atypia, dysplasia or no abnormality). NMP22 values in these 2 populations were significantly different (malignancy median 20.81 units per ml. and no malignancy median 5.72 units per ml., Mann-Whitney U test for differences between 2 medians p = 0.00005). Of the 33 recurrences 23 (70%) had NMP22 values greater than the reference range (10 units per ml.). Additionally, NMP22 identified all 6 subjects (100%) who had invasive disease 3 to 6 months later. Of 72 patients with NMP22 less than 10 units per ml. 62 (86%) had no malignancy at subsequent cystoscopy. CONCLUSIONS NMP22 was highly predictive of tumor status at followup cystoscopy. This quantitative, noninvasive assay, with high negative predictive value (86%) and sensitivity to detect malignancy (100% for invasive disease and 70% overall), may be a helpful adjunct to cytology and endoscopy for monitoring disease status after endoscopic tumor resection.

Phase III Study of Interferon Alfa-NL as Adjuvant Treatment for Resectable Renal Cell Carcinoma: An Eastern Cooperative Oncology Group/Intergroup Trial

PURPOSE To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma. PATIENTS AND METHODS A total of 283 eligible patients with pT3-4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate. RESULTS At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P =.09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P =.33). Performance status (P =.003), nodal status (N2 v N0, P <.0001), and tumor stage (P =.0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P =.009) and shorter time to recurrence (P <.0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment. CONCLUSION Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.

Predominant Treatment Failure in Postprostatectomy Patients Is Local: Analysis of Patterns of Treatment Failure in SWOG 8794

PURPOSE Southwest Oncology Group (SWOG) trial 8794 demonstrated that adjuvant radiation reduces the risk of biochemical (prostate-specific antigen [PSA]) treatment failure by 50% over radical prostatectomy alone. In this analysis, we stratified patients as to their preradiation PSA levels and correlated it with outcomes such as PSA treatment failure, local recurrence, and distant failure, to serve as guidelines for future research. PATIENTS AND METHODS Four hundred thirty-one subjects with pathologically advanced prostate cancer (extraprostatic extension, positive surgical margins, or seminal vesicle invasion) were randomly assigned to adjuvant radiotherapy or observation. RESULTS Three hundred seventy-four eligible patients had immediate postprostatectomy and follow-up PSA data. Median follow-up was 10.2 years. For patients with a postsurgical PSA of 0.2 ng/mL, radiation was associated with reductions in the 10-year risk of biochemical treatment failure (72% to 42%), local failures (20% to 7%), and distant failures (12% to 4%). For patients with a postsurgical PSA between higher than 0.2 and <or = 1.0 ng/mL, reductions in the 10-year risk of biochemical failure (80% to 73%), local failures (25% to 9%), and distant failures (16% to 12%) were realized. In patients with postsurgical PSA higher than 1.0, the respective findings were 94% versus 100%, 28% versus 9%, and 44% versus 18%. CONCLUSION The pattern of treatment failure in high-risk patients is predominantly local with a surprisingly low incidence of metastatic failure. Adjuvant radiation to the prostate bed reduces the risk of metastatic disease and biochemical failure at all postsurgical PSA levels. Further improvement in reducing local treatment failure is likely to have the greatest impact on outcome in high-risk patients after prostatectomy.

Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904.

BACKGROUND In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI], 1.03-2.16). OBJECTIVE To examine the impact of NSS relative to RN on kidney function in EORTC 30904. DESIGN, SETTING, AND PARTICIPANTS This phase 3 international randomized trial was conducted in patients with a small (≤5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003. INTERVENTION Patients were randomized to RN (n=273) or NSS (n=268). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m(2)) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis). RESULTS AND LIMITATIONS With a median follow-up of 6.7 yr, eGFR <60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8-28.3); eGFR <30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, -1.0 to 8.5); and eGFR <15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of -0.1% (95% CI, -2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses. CONCLUSIONS Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although with available follow-up the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population. REGISTRATION EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473.

Prostate-specific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer.

PURPOSE A study of preradiation and postradiation, serial serum prostate-specific antigen (PSA) levels was performed in patients who had clinically localized prostate cancer. The prognostic value of the PSA in pretreatment evaluation and posttreatment follow-up was assessed. PATIENTS AND METHODS Sixty-three patients who presented with clinically localized prostate cancer and who were treated with external-beam radiation therapy were followed-up for a median of 25 months. A serum PSA and physical examination were performed at 3-month intervals, and a bone scan was done yearly. An increase in PSA triggered an additional metastatic workup. Prostate rebiopsy was performed for new, palpable nodules or for a serial increase in PSA in the context of a negative metastatic workup. RESULTS Forty-one patients remained recurrence-free and 22 recurred clinically, 15 distantly and seven locally. The PSA was the strongest, independent, pretreatment prognostic indicator (P = .019) among pretreatment PSA, stage, and grade, but lost significance when the serum prostatic acid phosphatase (PAP) status was included. The initial rate of the PSA decrease after radiation (median half-life, 2.6 months) failed to predict outcome. Recurrence-free patients reached postradiation PSA levels that were equivalent to those reported in disease-free male populations; failure of the PSA to reach such normal levels was a multivariate predictor of subsequent failure (P less than .037). All clinicopathologic documentations of failure were preceded by an increase in PSA levels during follow-up. Delayed versus early PSA increase was associated with clinically localized versus metastatic first recurrence. CONCLUSIONS The serum PSA is an independent pretreatment and posttreatment predictor of outcome. Additionally, for a median follow-up of 25 months, delayed PSA failure is associated with clinically localized rather than metastatic recurrence, a relationship that may help in selection for local salvage therapy.