A randomized comparison of two-stage versus traditional one-stage consent for a low-stakes randomized trial.

BACKGROUND/AIMS: It has been proposed that informed consent for randomized trials should be split into two stages, with the purported advantage of decreased information overload and patient anxiety. We compared patient understanding, anxiety and decisional quality between two-stage and traditional one-stage consent. METHODS: We approached patients at an academic cancer center for a low-stakes trial of a mind-body intervention for procedural distress during prostate biopsy. Patients were randomized to hear about the trial by either one- or two-stage consent (n = 66 vs n = 59). Patient-reported outcomes included Quality of Informed Consent (0-100); general and consent-specific anxiety and decisional conflict, burden, and regret. RESULTS: Quality of Informed Consent scores were non-significantly superior for two-stage consent, by 0.9 points (95% confidence interval = -2.3, 4.2, p = 0.6) for objective and 1.1 points (95% CI = -4.8, 7.0, p = 0.7) for subjective understanding. Differences between groups for anxiety and decisional outcomes were similarly small. In a post hoc analysis, consent-related anxiety was lower among two-stage control patients, likely because scores were measured close to the time of biopsy in the two-stage patients receiving the experimental intervention. CONCLUSION: Two-stage consent maintains patient understanding of randomized trials, with some evidence of lowered patient anxiety. Further research is warranted on two-stage consent in higher-stakes settings.

Have urinary function outcomes after radical prostatectomy improved over the past decade?

BACKGROUND: Changes in surgical technique and postoperative care that target improvements in functional outcomes are widespread in the literature. Radical prostatectomy (RP) is one such procedure that has seen multiple advances over the past decade. The objective of this study was to leverage RP as an index case to determine whether practice changes over time produced observable improvements in patient-reported outcomes. METHODS: This study analyzed patients undergoing RP by experienced surgeons at a tertiary care center with prospectively maintained patient-reported outcome data from 2008 to 2019. Four patient-reported urinary function outcomes at 6 and 12 months after RP were defined with a validated instrument: good urinary function (domain score ≥ 17), no incontinence (0 pads per day), social continence (≤1 pad per day), and severe incontinence (≥3 pads per day). Multivariable logistic regressions evaluated changes in outcomes based on the surgical date. RESULTS: Among 3945 patients meeting the inclusion criteria, excellent urinary outcomes were reported throughout the decade but without consistent observable improvements over time. Specifically, there were no improvements in good urinary function at 12 months (P = .087) based on the surgical date, and there were countervailing effects on no incontinence (worsening; P = .005) versus severe incontinence (improving; P = .003). Neither approach (open, laparoscopic, or robotic), nor nerve sparing, nor membranous urethral length mediated changes in outcomes. CONCLUSIONS: In a decade with multiple advances in surgical and postoperative care, there was evidence of improvements in severe incontinence, but no measurable improvements across 3 other urinary outcomes. Although worsening disease factors could contribute to the stable observed outcomes, a more systematic approach to evaluating techniques and implementing patient selection and postoperative care advances is needed. LAY SUMMARY: Although there have been advances in radical prostatectomy over the past decade, consistent observable improvements in postoperative incontinence were not reported by patients. To improve urinary function outcomes beyond the current high standard, the approach to studying innovations in surgical technique needs to be changed, and further development of other aspects of prostatectomy care is needed.

Association of Family History of Cancer with Clinical and Pathological Outcomes for Prostate Cancer Patients on Active Surveillance.

PURPOSE: The impact of germline mutations associated with hereditary cancer syndromes in patients on active surveillance (AS) for prostate cancer is poorly defined. We examined the association between family history of prostate cancer (FHP) or family history of cancer (FHC) and risk of progression or adverse pathology at radical prostatectomy (RP) in patients on AS. MATERIALS AND METHODS: Patients on AS at a single tertiary-care center between 2000-2019 were categorized by family history. Disease progression was defined as an increase in Gleason grade on biopsy. Adverse pathology was defined as upgrading/upstaging at RP. Multivariable Cox and logistic regression models were used to assess association between family history and time to progression or adverse pathology, respectively. RESULTS: Among 3,211 evaluable patients, 669 (21%) had FHP, 34 (1%) had FHC and 95 (3%) had both; 753 progressed on AS and 481 underwent RP. FHP was associated with increased risk of progression (HR 1.31; 95% CI, 1.11-1.55; p=0.002) but FHC (HR 0.67; 95% CI, 0.30-1.50; p=0.3) or family history of both (HR 1.22; 95% CI, 0.81-1.85; p=0.3) were not. FHP, FHC or both were not associated with adverse pathology at RP (p >0.4). CONCLUSIONS: While FHP was associated with an increased risk of progression on AS, wide confidence intervals render this outcome of unclear clinical significance. FHC was not associated with risk of progression on AS. In the absence of known genetically defined hereditary cancer syndrome, we suggest FHP and/or FHC should not be used as a sole trigger to preclude patients from enrolling on AS.

Pathological and oncological outcomes in patients with sarcomatoid differentiation undergoing cystectomy.

OBJECTIVE: To evaluate whether urothelial carcinoma (UC) with sarcomatoid differentiation is associated with a lower pathological response rate to neoadjuvant chemotherapy (NAC) and worse oncological outcomes compared to UC without variant histology among patients undergoing radical cystectomy. PATIENTS AND METHODS: Patients with UC undergoing cystectomy from 1995 to 2018 at the Memorial Sloan Kettering Cancer Centre were identified. Patients with sarcomatoid differentiation at transurethral resection (TUR) or cystectomy, and patients without variant histology were selected. Downstaging from ≥cT2 to ≤pT1N0 defined partial response and pT0N0 defined complete response. Recurrence-free, cancer-specific and overall survival were modelled. RESULTS: We identified 131 patients with sarcomatoid differentiation and 1722 patients without variant histology, of whom 25 with sarcomatoid histology on biopsy and 313 without variant histology received NAC. Those with sarcomatoid differentiation presented with higher consensus tumour stage (94% ≥T2 vs 62%; P < 0.001) and were, therefore, more likely to receive NAC (29% vs 18%; P = 0.003). We found no evidence to support a difference in partial (24% vs 31%) or complete (20% vs 24%) response between patients with sarcomatoid histology and those with pure UC at TUR (P = 0.6). Among patients with sarcomatoid differentiation, 5-year recurrence-free survival was 55% (95% confidence interval [CI] 41-74) among patients receiving NAC and 40% (95% CI 31-52) among patients undergoing cystectomy alone (P = 0.1). Adjusting for stage, nodal involvement, margin status and receipt of NAC, sarcomatoid differentiation was associated with worse recurrence-free (hazard ratio [HR] 1.82, 95% CI 1.39-2.39), disease-specific (HR 1.66, 95% CI 1.23-2.22), and overall survival (HR 1.37, 95% CI 1.06-1.78). CONCLUSIONS: Sarcomatoid differentiation was associated with higher stage at presentation and independently associated with worse survival. Given similar pathological response rates if sarcomatoid differentiation is detected at initial resection, and greater survival among patients receiving NAC, treatment with NAC appears warranted. Other drivers of the poor outcomes of this histology must be investigated.

Clinical utility of subclassifying positive surgical margins at radical prostatectomy.

OBJECTIVE: To determine whether subclassification of positive surgical margins (PSMs) increases predictive ability for biochemical recurrence (BCR) and aids clinical decision-making in patients undergoing radical prostatectomy. PATIENTS AND METHODS: We studied 2147 patients with pT2 and pT3a prostate cancer with detailed surgical margin parameters and BCR status. We compared a base model, a linear predictor calculated from the Memorial Sloan Kettering Cancer Center postoperative nomogram (prostate-specific antigen, pathological tumour grade and stage), with the addition of surgical margin status to five additional models (base model plus surgical margin subclassifications) to evaluate enhancement in predictive accuracy. Decision curve analysis (DCA) was performed to determine the clinical utility of parameters that enhanced predictive accuracy. RESULTS: Among 2147 men, 205 had PSMs, and 231 developed BCR. Discrimination for the base model with addition of surgical margin status was high (c-index = 0.801) and not meaningfully improved by adding surgical margin subclassification in the full cohort. In analyses considering only men with PSMs (N = 55 with BCR), adding surgical margin subclassification to the base model increased discrimination for total length of all PSMs - alone or with maximum Gleason grade at the margin (c-index improvement = 0.717 to 0.752 and 0.753, respectively). DCA demonstrated a modest benefit to clinical utility with the addition of these parameters. CONCLUSIONS: Specific subclassification parameters add predictive accuracy for BCR and may aid clinical utility in decision-making for patients with PSMs. These findings may be useful for patient counselling and future adjuvant therapy trial design.

Prospective validation of microseminoprotein-ß added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort.

OBJECTIVES: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-ß (MSP) adds predictive value. PATIENTS AND METHODS: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. RESULTS: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014-0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. CONCLUSION: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.

Patient accrual and understanding of informed consent in a two-stage consent design.

BACKGROUND: We previously introduced the concept of "two-stage" (or "just-in-time") informed consent for randomized trials with usual care control. We argued that conducting consent in two stages-splitting information about research procedures from information about the experimental intervention-would reduce the decisional anxiety, confusion, and information overload commonly associated with informed consent. We implemented two-stage consent in a low-stakes randomized trial of a mindfulness meditation intervention for procedural distress in patients undergoing prostate biopsy. Here, we report accrual rates and patient understanding of the consent process. METHODS: Patients approached for consent for the biopsy trial were asked to complete the standard "Quality of Informed Consent" questionnaire to assess their knowledge and understanding of the trial. RESULTS: Accrual was excellent with 108 of 110 (98%) patients approached for consent signing first-stage consent. All 51 patients randomized to the experimental arm and who later presented for biopsy signed second-stage consent and received the mindfulness intervention. Quality of Informed Consent data were available for 48 patients assigned to the mindfulness treatment arm and 44 controls. The mean Quality of Informed Consent score was similar in the meditation and control arms with and overall mean of 75 (95% confidence interval = 74-76) for the knowledge section and 86 (95% confidence interval = 81-90) for understanding, comparable to the normative scores of 80 and 88. On further analysis and patient interview, two of the Quality of Informed Consent questions were found to be misleading in the context of a two-stage consent study for a mindfulness intervention. Excluding these questions increased knowledge scores to 88 (95% confidence interval = 87-90). CONCLUSION: We found promising data that two-stage consent facilitated accrual without compromising patient understanding of randomized trials or compliance with allocated treatment. Further research is needed incorporating randomized comparison of two-stage consent to standard consent approaches, measuring patient anxiety and distress as an outcome, using suitable modifications to the Quality of Informed Consent questionnaire and trials with higher stakes.

Prespecified 4-Kallikrein Marker Model at Age 50 or 60 for Early Detection of Lethal Prostate Cancer in a Large Population Based Cohort of Asymptomatic Men Followed for 20 Years.

PURPOSE: A prespecified statistical model based on 4 kallikrein markers in blood, commercially available as the 4Kscore®, has been shown to accurately detect high grade (greater than Grade Group 2) prostate cancer in men with moderately elevated prostate specific antigen. We assessed whether the model predicted prostate cancer metastasis or death in men not subject to prostate specific antigen screening. MATERIALS AND METHODS: The cohort includes 43,692 unscreened prostate cancer-free men from a Swedish population based cohort with low rates of prostate specific antigen screening (Västerbotten Intervention Project). Using cryopreserved blood collected at ages 50 and 60 years from men in this cohort we analyzed the association between prostate specific antigen and other kallikrein marker levels in blood and risk of prostate cancer metastasis or death. RESULTS: There were 308 with metastases and 172 prostate cancer deaths. Baseline prostate specific antigen was strongly associated with 20-year risk of prostate cancer death (c-index at age 50, 0.859, 95% CI 0.799-0.916; age 60, 0.840, 95% CI 0.799-0.878). Men 60 years old with prostate specific antigen below median (less than 1.2 ng/ml) had 0.4% risk of prostate cancer death at 20 years. Among men with moderately elevated prostate specific antigen (2.0 ng/ml or greater) the 4Kscore markedly improved discrimination (c-index 0.767 vs 0.828 and 0.774 vs 0.862 in men age 50 and 60, respectively). Long-term risk of prostate cancer death or metastasis in men with low 4Kscores was very low. CONCLUSIONS: Screening should focus on men in top prostate specific antigen quartile at age 60 years. Men with elevated prostate specific antigen but a low 4Kscore can safely be monitored with repeated blood markers in place of immediate biopsy.

Late Recurrences Following Radical Cystectomy Have Distinct Prognostic and Management Considerations.

PURPOSE: Disease recurrence after radical cystectomy generally occurs within 2 years and has a poor prognosis. Less well defined are the outcomes in patients who experience a late recurrence (more than 3 years after radical cystectomy). We report our institutional experience with late recurrences and describe the relationships between time to recurrence, management strategies and survival. MATERIALS AND METHODS: The study cohort comprised 2,315 patients who underwent radical cystectomy for urothelial carcinoma at our center between 2000 and 2014, of whom 617 had a recurrence. Median followup for survivors was 2.6 years after recurrence (IQR 0.95-4.5). For the study we considered disease recurrence as recurrences outside the urinary tract. We compared baseline characteristics and post-recurrence management between those with recurrence 3 or less and more than 3 years after radical cystectomy. RESULTS: A total of 58 patients with late recurrence had significantly lower consensus T stage and lower frequency of nodal involvement. The average 1-year bladder cancer death rate from the time of recurrence declined from 66% to 50% to 33% for patients with recurrence times of 6 months, 2 years, and 5 years after radical cystectomy, respectively. For patients who survived at least 1 year after recurrence, the estimated survival at 5 years after recurrence was 45% for those with late recurrence and 21% for patients who had an early recurrence. Local consolidative therapy (metastasectomy or radiation) was more common in patients with late recurrence (19% vs 3.6%, p <0.0001). Cancer specific survival in early recurring cases was significantly worse than in late recurring cases in the subset receiving local consolidation (p=0.02). CONCLUSIONS: The prolonged lifespan of patients experiencing a late recurrence after radical cystectomy can be leveraged to individualize management. There is strong rationale for investigating the role of metastasectomy in the management of late recurrences.

Trends in Management and Outcomes among Patients with Urothelial Carcinoma Undergoing Radical Cystectomy from 1995 to 2015: The Memorial Sloan Kettering Experience.

PURPOSE: We evaluated trends in oncologic characteristics and outcomes as well as perioperative management among patients undergoing radical cystectomy at Memorial Sloan Kettering from 1995 to 2015. MATERIALS AND METHODS: We retrospectively reviewed our institutional database to analyze changes in disease recurrence probability, cancer specific and all cause mortality, incidence of muscle invasive bladder cancer, use of perioperative chemotherapy, rate of positive soft tissue surgical margins and lymph node yield. RESULTS: In 2,740 patients with nonmetastatic urothelial carcinoma undergoing radical cystectomy from 1995 to 2015 the 5-year probability of disease recurrence decreased from a peak of 42% in 1997 to 34% in 2013 (p=0.045), while the 5-year probability of cancer specific mortality likewise declined from 36% in 1997 to 24% in 2013 (p=0.009). The incidence of nonmuscle invasive disease before radical cystectomy did not change, comprising 30% to 35% of patients across the study period. Use of neoadjuvant chemotherapy rose significantly as 57% of patients with muscle invasive bladder cancer from 2010 to 2015 received it. We observed a corresponding rise in complete pathological response (pT0) at radical cystectomy, as well as decreasing positive soft tissue surgical margins (10% to 2.5%) and rising lymph node yield (7 to 24) from 1995 to 2015. CONCLUSIONS: During a 21-year period outcomes after radical cystectomy at our institution improved significantly, as the probability of recurrence and cancer specific mortality decreased. Increasing use of neoadjuvant chemotherapy, rising pT0 rates, decreased positive soft tissue surgical margins and increasing lymph node yields likely contributed, suggesting that optimized surgical and perioperative care led to improved cancer outcomes in patients undergoing radical cystectomy.

Primary urethral cancer: treatment patterns and associated outcomes.

OBJECTIVES: To evaluate treatment patterns and associated outcomes of patients with urethral cancer. PATIENTS AND METHODS: After obtaining institutional review board approval we identified 165 patients treated for primary urethral cancer between 1956 and 2017. Treatment included monotherapy (surgery or radiation), dual therapy (surgery+radiation, surgery+chemotherapy, or chemotherapy+radiation) or triple therapy (surgery+radiation+chemotherapy). Rates of different treatments were described by treatment year. The association between treatment type and outcomes was evaluated with multivariable Cox regression models, adjusting for disease characteristics. RESULTS: The study cohort included 74 men and 91 women, with a median age of 61 years. Common histologies were squamous cell (36%), urothelial (27%) and adenocarcinoma (25%). At presentation, 72% of patients had invasive disease, 24% had nodal involvement, and 5% had metastases. Treatment included monotherapy (57%), dual therapy (21%), and triple therapy (10%). The use of monotherapy decreased over time, while rates of dual therapy remained consistent, and rates of triple therapy increased. The median follow-up was 4.7 years. Estimated 5-year local recurrence-free, disease-specific and overall survival were 51%, 48% and 41%, respectively. Monotherapy was associated with decreased local recurrence-free survival after adjusting for stage, histology, sex and year of treatment (P = 0.017). There was no evidence that treatment type was associated with distant recurrence, cancer-specific or overall survival. CONCLUSIONS: We found preliminary evidence that multimodal therapy, more commonly used in recent years, was of benefit in patients with primary urethral cancer. This finding should be confirmed in further studies involving multiple centres because of the low incidence of the disease.

Clinical Usefulness of Prostate and Tumor Volume Related Parameters following Radical Prostatectomy for Localized Prostate Cancer.

PURPOSE: We evaluated whether the prediction of biochemical recurrence after radical prostatectomy is enhanced by any of 6 parameters, including prostate volume, total tumor volume, high grade total tumor volume, the ratio of high grade total tumor volume to total tumor volume, the ratio of total tumor volume to prostate volume and/or the ratio of high grade total tumor volume to prostate volume. MATERIALS AND METHODS: A total of 1,261 patients who underwent radical prostatectomy during a 3-year period had tumor maps constructed with the Gleason pattern denoted as low-3 or high-4 or 5 and volumetric data generated using commercially available software. Univariate Cox regression models were used to assess whether each volume related parameter was associated with biochemical recurrence after radical prostatectomy. A multivariable Cox regression base model (age, prostate specific antigen, Gleason score/grade group, pathological stage and margin status) was compared with 6 additional models (base model plus each volume related parameter) to evaluate enhancement in predictive accuracy. Decision curve analysis was performed to determine the clinical utility of parameters that enhanced predictive accuracy. RESULTS: On univariate analysis each parameter was significantly associated with biochemical recurrence except prostate volume. Predictive accuracy of the multivariable base model was high (c-index = 0.861). Adding volume related parameters marginally enhanced discrimination. Decision curve analysis failed to show added benefit even for high grade total tumor volume/total tumor volume, which was the parameter with the highest discriminative improvement. CONCLUSIONS: Tumor volume related parameters are significantly associated with radical prostatectomy but do not add important discrimination to standard clinicopathological variables for radical prostatectomy prediction or provide benefit across a range of clinically relevant decision thresholds. Volume related measurement is not warranted in routine pathological evaluation and reporting.

Outcomes and Safety Among Patients With Obstructive Sleep Apnea Undergoing Cancer Surgery Procedures in a Freestanding Ambulatory Surgical Facility.

BACKGROUND: Patients with obstructive sleep apnea (OSA) may be at increased risk for serious perioperative complications. The suitability of ambulatory surgery for patients with OSA remains controversial, and several national guidelines call for more evidence that assesses clinically significant outcomes. In this study, we investigate the association between OSA status (STOP-BANG risk, or previously diagnosed) and short-term outcomes and safety for patients undergoing cancer surgery at a freestanding ambulatory surgery facility. METHODS: We conducted a retrospective analysis of all patients having surgery at the Josie Robertson Surgery Center, a freestanding ambulatory surgery facility of the Memorial Sloan Kettering Cancer Center. Surgeries included more complex ambulatory extended recovery procedures for which patients typically stay overnight, such as mastectomy, thyroidectomy, and minimally invasive hysterectomy, prostatectomy, and nephrectomy, as well as typical outpatient surgeries. Both univariate and multivariable analyses were used to assess the association between OSA risk and transfer to the main hospital, urgent care center visit, and hospital readmission within 30 days postoperatively (primary outcomes) and length of stay and discharge time (secondary outcomes). Multivariable models were adjusted for age, American Society of Anesthesiologists score, robotic surgery, and type of anesthesia (general or monitored anesthesia care) and also adjusted for surgery start time for length of stay and discharge time outcomes. χ tests were used to assess the association between OSA risk and respiratory events and device use. RESULTS: Of the 5721 patients included in the analysis, 526 (9.2%) were diagnosed or at moderate or high risk for OSA. We found no evidence of a difference in length of stay when comparing high-risk or diagnosed patients with OSA to low- or moderate-risk patients whether they underwent outpatient (P = .2) or ambulatory extended recovery procedures (P = .3). Though a greater frequency of postoperative respiratory events were reported in high-risk or diagnosed patients with OSA compared to moderate risk (P = .004), the rate of hospital transfer was not significantly different between the groups (risk difference, 0.78%; 95% CI, -0.43% to 2%; P = .2). On multivariable analysis, there was no evidence of increased rate of urgent care center visits (adjusted risk difference, 1.4%; 95% CI, -0.68% to 3.4%; P = .15) or readmissions within 30 days (adjusted risk difference, 1.2%; 95% CI, -0.40% to 2.8%; P = .077) when comparing high-risk or diagnosed OSA to low- or moderate-risk patients. Based on the upper bounds of the CIs, a clinically relevant increase in transfers, readmissions, and urgent care center visits is unlikely. CONCLUSIONS: Our results contribute to the body of evidence supporting that patients with moderate-risk, high-risk, or diagnosed OSA can safely undergo outpatient and advanced ambulatory oncology surgery without increased health care burden of extended stay or hospital admission and avoiding adverse postoperative outcomes. Our results support the adoption of several national OSA guidelines focusing on preoperative identification of patients with OSA and clinical pathways for perioperative management and postoperative monitoring.

Acupuncture for breast cancer-related lymphedema: a randomized controlled trial.

PURPOSE: Approximately 20% of breast cancer survivors develop breast cancer-related lymphedema (BCRL), and current therapies are limited. We compared acupuncture (AC) to usual care wait-list control (WL) for treatment of persistent BCRL. METHODS: Women with moderate BCRL lasting greater than six months were randomized to AC or WL. AC included twice weekly manual acupuncture over six weeks. We evaluated the difference in circumference and bioimpedance between affected and unaffected arms. Responders were defined as having a decrease in arm circumference difference greater than 30% from baseline. We used analysis of covariance for circumference and bioimpedance measurements and Fisher's exact to determine the proportion of responders. RESULTS: Among 82 patients, 73 (89%) were evaluable for the primary endpoint (36 in AC, 37 in WL). 79 (96%) patients received lymphedema treatment before enrolling in our study; 67 (82%) underwent ongoing treatment during the trial. We found no significant difference between groups for arm circumference difference (0.38 cm greater reduction in AC vs. WL, 95% CI - 0.12 to 0.89, p = 0.14) or bioimpedance difference (1.06 greater reduction in AC vs. WL, 95% CI - 5.72 to 7.85, p = 0.8). There was also no difference in the proportion of responders: 17% AC versus 11% WL (6% difference, 95% CI - 10 to 22%, p = 0.5). No severe adverse events were reported. CONCLUSIONS: Our acupuncture protocol appeared to be safe and well tolerated. However, it did not significantly reduce BCRL in pretreated patients receiving concurrent lymphedema treatment. This regimen does not improve upon conventional lymphedema treatment for breast cancer survivors with persistent BCRL.

Risk Based Surveillance after Surgical Treatment of Renal Cell Carcinoma.

PURPOSE: We assessed the accuracy of the UISS (UCLA Integrated Staging System) to predict the postoperative recurrence of renal cell carcinoma. We also evaluated whether including patient age and tumor histology would improve clinical decision making. MATERIALS AND METHODS: We analyzed the records of 1,630 patients treated with nephrectomy at a single academic center. The accuracy of the UISS model to predict early (12 months or less) and late (more than 60 months) recurrence after surgery was compared with a new model including patient age and disease histology. RESULTS: The new model and the UISS model showed high accuracy to predict early recurrence after surgery (AUC 0.84, 95% CI 0.81-0.88 and 0.83, 95% CI 0.80-0.87, respectively). In patients diagnosed with low risk tumor types (eg papillary type 1 and chromophobe lesions) the average risk of early recurrence significantly decreased in each UISS risk category when tumor histology was added to the predictive model (low risk 1.6% vs 0.6%, intermediate risk 5.5% vs 1.9% and high risk 45% vs 22%). Kaplan-Meier analysis showed no difference in the risk of late recurrence among the UISS risk categories. CONCLUSIONS: The UISS model should be applied to tailor the early followup protocol after nephrectomy. Patients with low risk histology deserve less stringent followup regardless of the UISS risk category. Our results do not support a risk stratification model to design a surveillance protocol after 5 years postoperatively.

Value of Intact Prostate Specific Antigen and Human Kallikrein 2 in the 4 Kallikrein Predictive Model: An Individual Patient Data Meta-Analysis.

PURPOSE: The 4 kallikrein panel, commercially available as the 4Kscore®, is a statistical model that has been shown to accurately predict Gleason Grade Group 2 or greater (high grade) cancer on biopsy and the long-term risk of distant prostate cancer metastases. The panel includes 2 novel markers, namely intact prostate specific antigen and hK2. It has been questioned whether these 2 additional markers add discrimination to the clinical predictors of patient age, digital rectal examination and prior biopsy, and the established molecular markers total and free prostate specific antigen. MATERIALS AND METHODS: We performed an individual patient data meta-analysis of published studies in which the 4 kallikrein panel was measured in men undergoing prostate biopsy. We assess the improvement in discrimination associated with including intact prostate specific antigen and hK2 along with total and free prostate specific antigen in the statistical model. RESULTS: Included in analysis were 14,510 men from a total of 10 studies. The fixed effects meta-analytical estimate of the discrimination of the model without intact prostate specific antigen and hK2 was 0.742 (95% CI 0.727-0.756) compared to 0.813 (95% CI 0.801-0.825) for the full kallikrein model. The 95% CIs did not overlap and the difference in discrimination was highly statistically significant (0.069, 95% CI 0.057-0.080, p <0.0001). Intact prostate specific antigen (increase in discrimination 0.059, 95% CI 0.050-0.069) and hK2 (increase in discrimination 0.024, 95% CI 0.020-0.029, each p <0.0001) added independently to the model. CONCLUSIONS: The clinical value of the panel could not be replicated using data readily available to urologists without measuring intact prostate specific antigen and hK2.

Biopsy Core Features are Poor Predictors of Adverse Pathology in Men with Grade Group 1 Prostate Cancer.

PURPOSE: Active surveillance is often restricted to patients with low risk prostate cancer who have 3 or fewer positive cores. We aimed to identify predictors of adverse pathology results for low risk prostate cancer treated with radical prostatectomy and determine whether a threshold number of positive cores could help the decision process for active surveillance. MATERIALS AND METHODS: A total of 3,359 men with low risk prostate cancer underwent radical prostatectomy between January 2000 and August 2016. We analyzed the relationship between biopsy core features and adverse pathology at radical prostatectomy, defined as Grade Group 3 or greater, seminal vesicle invasion or lymph node involvement. RESULTS: Of the 171 cases (5.1%) with adverse pathology findings at radical prostatectomy 144 (4.3%) were upgraded to Grade Group 3 or greater, 31 (0.9%) had seminal vesicle invasion and 15 (0.4%) had lymph node involvement. Prostate specific antigen and patient age were the only predictors of adverse pathology results. There was no significant association with the number of positive cores, the total mm of cancer or the maximum percent of cancer in any core. When we expanded the definition of adverse pathology to include Grade Group 2 and extraprostatic extension, the association between core features and outcome was statistically significant but clinically weak, and with no evidence of threshold effects. CONCLUSIONS: There is little basis for excluding patients with otherwise low risk prostate cancer on biopsy from active surveillance based on criteria such as the number of positive cores or the maximum cancer involvement of biopsy cores.

Does Subclassification of Pathologically Organ Confined (pT2) Prostate Cancer Provide Prognostic Discrimination of Outcomes after Radical Prostatectomy?

PURPOSE: We tested the latest update in the prostate cancer staging system by assessing the prognostic association of pT2 subclassification with the probability of survival related outcomes in patients who underwent radical prostatectomy. MATERIALS AND METHODS: We retrospectively analyzed the records of a total of 15,305 patients who underwent radical prostatectomy at 2 referral centers between 1985 and 2016, and had pT2 disease at the final pathological evaluation. Descriptive statistics were used to compare baseline data stratified by pT2 substages (pT2a/b vs pT2c). Cox regression models were adjusted for institution analyzed differences in the rate of biochemical recurrence, metastasis, cancer specific death and overall mortality. Multivariable Cox regression models were used to evaluate the predictive value of pT2 subclassification for survival, including the linear predictor from the Stephenson nomogram. RESULTS: Prostate specific antigen levels and Gleason score differed significantly between the pT2 substages (each p <0.0001). At a median followup of 6.0 years (IQR 3.3-10.1) 2,083 patients had biochemical recurrence, 161 had metastases, 43 had died of prostate cancer and 1,032 had died of another cause. On univariate analysis the pT2 subclassification was significantly associated with biochemical recurrence (p = 0.001) and distant metastasis (p = 0.033) but not with cancer specific death (p = 0.6) or overall mortality (p = 0.3). Multivariable analysis showed no evidence of a significant association between the pT2 subclassification and biochemical recurrence (p = 0.4) or distant metastasis (p = 0.6). Multivariable analysis of cancer specific death and overall mortality was omitted due to lack of significance on univariate analysis. CONCLUSIONS: Subclassification of pT2 prostate cancer is not a prognostic indicator of survival related outcomes after radical prostatectomy. Our results validate the elimination of pT2 substages in the updated staging system.

Effects of pathological upstaging or upgrading on metastasis and cancer-specific mortality in men with clinical low-risk prostate cancer.

OBJECTIVES: To determine if the presence of adverse pathological features in patients eligible for active surveillance (AS) are prognostic of poor oncological outcomes, independent of pretreatment risk. PATIENTS AND METHODS: A retrospective analysis was performed on patients who underwent radical prostatectomy (RP) at two institutions (Cleveland Clinic Foundation and Memorial Sloan Kettering Cancer Center) between 1987 and 2008, and who had subsequent follow-up. Rates of biochemical recurrence, metastasis and death from prostate cancer were compared amongst patients with adverse pathological features (Gleason score ≥7, ≥pT3, or lymph node invasion) based on D'Amico clinical risk (low vs intermediate/high). We also compared survival outcomes between patients with and without pathological upgrading/upstaging amongst D'Amico low-risk patients. Univariate and multivariable Cox regression models were used to assess the association between clinical risk, pathological reclassification, and oncological outcomes. RESULTS: We identified 16 341 patients who underwent RP, of whom 6 371 were clinically low-risk. Adverse outcomes in men with adverse pathological features were significantly lower in those with low clinical risk, with an ~50% and ~70% reduction in the risk of metastasis and death, respectively. Only pathological upgrading/upstaging to Gleason score ≥8, seminal vesicle invasion, and lymph node invasion from clinical low-risk disease, were associated with adverse outcomes. However, these types of reclassification were rare. CONCLUSION: Clinical low-risk patients with pathological upgrading/upstaging have substantially lower rates of important oncological outcomes compared to those with higher pretreatment risk and not substantially different than low-risk patients without pathological upgrading/upstaging. These results call into question the use of this endpoint to counsel patients about the merits and risks of AS.

Importance of wide re-resection in adult spermatic cord sarcomas: Report on oncologic outcomes at a single institution.

BACKGROUND AND OBJECTIVES: We evaluated the effect of re-resection with wide margins (undertaken because initial resection performed elsewhere was incomplete) on survival in patients with spermatic cord sarcoma (SCS). METHODS: After excluding those with metastatic disease and those not undergoing surgical intervention, the records of 72 consecutive patients treated for SCS between 1981 and 2011 at Memorial Sloan Kettering Cancer Center were reviewed. Recurrence-free survival (RFS) and cancer-specific survival were calculated using the Kaplan-Meier method for comparing between the 48 patients who underwent wide re-resection (WRR) within 5 months of diagnosis and the 24 who did not. The relationship of age, tumor size, tumor histology, adjuvant radiation, and wide re-resection with recurrence and death was assessed by univariate Cox regression. RESULTS: WRR significantly improved RFS (hazard ratio [HR] 0.16, 95%CI 0.07-0.37; P < 0.0001), despite the fact that patients receiving WRR had higher-grade disease. Tumor-positive margins upon WRR were strongly associated with both disease recurrence (HR 5.56; 95%CI 1.14-27.11, P = 0.034) and death from cancer (HR 6.16, 95%CI 1.25-30.29; P = 0.025). CONCLUSIONS: A WRR with negative margins is effective in the management of patients with SCS and leads to improved RFS.