A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

Interventions to de-implement unnecessary antibiotic prescribing for ear infections (DISAPEAR Trial): protocol for a cluster-randomized trial.

BACKGROUND: Watchful waiting management for acute otitis media (AOM), where an antibiotic is used only if the child's symptoms worsen or do not improve over the subsequent 2-3 days, is an effective approach to reduce antibiotic exposure for children with AOM. However, studies to compare the effectiveness of interventions to promote watchful waiting are lacking. The objective of this study is to compare the effectiveness and implementation outcomes of two pragmatic, patient-centered interventions designed to facilitate use of watchful waiting in clinical practice. METHODS: This will be a cluster-randomized trial utilizing a hybrid implementation-effectiveness design. Thirty-three primary care or urgent care clinics will be randomized to one of two interventions: a health systems-level intervention alone or a health systems-level intervention combined with use of a shared decision-making aid. The health systems-level intervention will include engagement of a clinician champion at each clinic, changes to electronic health record antibiotic orders to facilitate delayed antibiotic prescriptions as part of a watchful waiting strategy, quarterly feedback reports detailing clinicians' use of watchful waiting individually and compared with peers, and virtual learning sessions for clinicians. The hybrid intervention will include the health systems-level intervention plus a shared decision-making aid designed to inform decision-making between parents and clinicians with best available evidence. The primary outcomes will be whether an antibiotic was ultimately taken by the child and parent satisfaction with their child's care. We will explore the differences in implementation effectiveness by patient population served, clinic type, clinical setting, and organization. The fidelity, acceptability, and perceived appropriateness of the interventions among different clinician types, patient populations, and clinical settings will be compared. We will also conduct formative qualitative interviews and surveys with clinicians and administrators, focus groups and surveys of parents of patients with AOM, and engagement of two stakeholder advisory councils to further inform the interventions. DISCUSSION: This study will compare the effectiveness of two pragmatic interventions to promote use of watchful waiting for children with AOM to reduce antibiotic exposure and increase parent satisfaction, thus informing national antibiotic stewardship policy development. CLINICAL TRIAL REGISTRATION: NCT06034080.

Comparative analysis of upfront stereotactic radiosurgery and watchful waiting in the management of newly diagnosed vestibular schwannomas: a systematic review and meta-analysis.

Vestibular schwannomas (VS) are benign intracranial tumors posing significant management challenges. This study aims to compare the outcomes of stereotactic radiosurgery (SRS) and watchful waiting (WW) in the management of newly diagnosed VS, integrating findings from both retrospective and the pioneering V-REX prospective trial. Adhering to PRISMA guidelines, a systematic review was conducted using MEDLINE, Embase, and Cochrane databases. Studies directly comparing SRS with WW for newly diagnosed VS were included. Primary outcomes focused on hearing preservation assessed through the AAO-HNS or Gardner-Robertson hearing classification scales and tumor progression, with secondary outcomes focusing on neurological symptoms, and the need for further treatment. Thirteen studies encompassing 1,635 patients (WW: 891; SRS: 744) were included.While no significant difference was found in serviceable hearing loss at last follow-up (RR = 1.51, [95%CI: 0.98, 2.32], p = 0.06), significant differences favoring WW were observed in pure tone audiometry (PTA) (MD = -13.51 [95%CI: -22.66, -4.37], p = 0.004) and word recognition score (WRS) (MD = 20.48 [95%CI: 9.72, 31.25], p = 0.0002). Analysis of tumor progression indicated no overall significant difference in risk between SRS and WW (RR = 0.40, [95%CI 0.07, 2.40], p = 0.32), but subgroup analysis suggested a lower risk with SRS in certain contexts. The need for further treatments favored SRS (RR = 0.24, [95%CI: 0.07, 0.74], p = 0.007). No significant differences were found in tinnitus and imbalance between the two groups. This comprehensive analysis suggests no marked difference in functional hearing preservation between SRS and WW in managing VS. However, untreated tumors commonly necessitate additional interventions. These findings highlight the need for individualized treatment decisions and underscore the importance of continued monitoring. The study advocates for further prospective trials to refine management strategies for VS.

Conservative or surgical management of orbital schwannomas: a population-based case series.

INTRODUCTION: Orbital schwannomas (OS) are rare occurrences with no more than 500 cases reported in the literature. The tumor's potential to compromise the delicate neuro-ophthalmic structures within the orbit prompts surgical removal. Tumor removal is performed by ophthalmologists, often requiring a multidisciplinary surgical approach. The literature contains a very limited number of cases managed non-surgically. However, the inherent risks of orbital surgery warrant a comparison of the outcomes of conservative and surgical management strategies. AIMS: To review the national Swedish experience with the management of orbital schwannomas. METHODS: The study center is the primary Swedish referral center for the multidisciplinary management of orbital tumors, including schwannomas. During the period of 2005 to 2021, 16 patients with an OS diagnosis were managed at the center. RESULTS: Four patients initially underwent surgery where gross total resection (GTR) was achieved in three (75%) and subtotal resection (STR) in one (25%) case. The remaining 12 patients, who had a low risk of neuro-ophthalmic impairment, were managed conservatively with radiological and clinical examinations at regular intervals. After an average follow-up of 17 months, surgery was performed in three of these cases (25%). No recurrences or tumor growths were detected on radiological follow-ups (mean 50 months), and all patients experienced postoperative improvement at clinical follow-up (mean 65 months). The remainder of the conservatively treated patients (n=9) experienced no clinical progression (mean 30 months). A slight radiological tumor progression was detected in one patient after 17 months. CONCLUSION: There were no differences in long-term outcome between patients who had been managed with early surgery and those operated later after an initially conservative management. Conservatively treated patients had minimal to no symptoms and remained clinically stable throughout the follow-up period. Based on these findings, conservative management may successfully be adopted in cases with mild symptoms, no signs of compressive optic neuropathy and low risk of neuro-ophthalmic impairment. Conversion to surgical management is indicated upon clinical deterioration or tumor growth. Based on the findings of this study a decision tree for the management of orbital schwannomas is suggested.

Long-term Outcomes Following Active Surveillance of Low-grade Prostate Cancer: A Population-based Study Using a Landmark Approach.

PURPOSE: Active surveillance is widely used to manage low-risk prostate cancer, but population-level long-term outcomes are limited. Our objective was to determine long-term population-level oncological outcomes in active surveillance patients. A secondary objective examined the active surveillance discontinuation rate. MATERIALS AND METHODS: In this retrospective, population-based study using linked administrative databases from Ontario, Canada, we identified low-grade prostate cancer patients managed with active surveillance or initial treatment between 2002-2014. The 10- and 15-year metastasis-free survival, overall survival, and cancer-specific survival were compared between active surveillance and initial treatment. A landmark of 24 months was selected for the primary analysis. Long-term outcomes were examined using multivariable proportional hazards models and a propensity-based approach. RESULTS: The cohort consisted of 21,282 low-grade prostate cancer patients with a median follow-up of 9.8 years. At 10-year follow-up the survival rate of remaining on active surveillance was 39%, metastasis-free survival was 94.2%, overall survival 88.7%, and cancer-specific survival 98.1%. In adjusted models active surveillance was associated with higher risk of metastasis (HR 1.34, 95%CI 1.15-1.57), overall mortality (HR 1.12, 95%CI 1.01-1.24), and prostate cancer-specific mortality (HR 1.66, 95%CI 1.15-2.39) compared to initial treatment. Survival analysis using 7,525 propensity-matched pairs was consistent with the primary analysis for metastasis-free survival, overall survival and cancer-specific survival. CONCLUSIONS: In this large population-based study of long-term outcomes in men with low-grade prostate cancer, active surveillance is associated with excellent long-term metastasis-free survival and overall survival. However, long-term cancer-specific survival was slightly inferior (1% worse at 10 years with active surveillance), and this must be balanced against known harms of overtreatment.

Clinical Significance of Perineural Invasion in Men With Grade Group 1 Prostate Cancer on Active Surveillance.

PURPOSE: We aimed to evaluate the clinical significance of perineural invasion in men on active surveillance for Grade Group 1 prostate cancer. MATERIALS AND METHODS: We identified 1,969 men with Grade Group 1 prostate cancer and at least 1 follow-up biopsy. A time-dependent Cox model and a logistic regression model were used to assess the association between biopsy-detected perineural invasion and grade reclassification (defined as the detection of Grade Group ≥2 prostate cancer on a surveillance biopsy), and adverse pathology (defined as Grade Group ≥3 ± seminal vesicle invasion ± lymph node involvement) at radical prostatectomy, respectively. RESULTS: The 198 men with perineural invasion detected during active surveillance had lower rates of grade reclassification-free survival than those without perineural invasion (P < .001). On multivariable analysis perineural invasion was significantly associated with grade reclassification (HR 3.25, 95% CI 2.54-4.16, P < .001); an association that persisted in the multiparametric magnetic resonance imaging subset. At radical prostatectomy, men with biopsy-detected perineural invasion had more extraprostatic extension than men without perineural invasion (Relative Risk 1.71, 95% CI 1.15-2.56). However, on multivariable analysis biopsy-detected perineural invasion was not associated with adverse pathology (OR 0.68, 95% CI 0.27-1.68, P = .40) and these patients did not exhibit more biochemical recurrence at 5 years (P > .05). CONCLUSIONS: Perineural invasion during active surveillance was associated with grade reclassification. At radical prostatectomy biopsy-detected perineural invasion patients exhibited more extraprostatic extension but biopsy-detected perineural invasion was not independently associated with more adverse pathology. In addition, these patients did not have more biochemical recurrence during follow-up. Perineural invasion should not preclude Grade Group 1 patients from active surveillance but they may warrant more stringent monitoring.

Gleason Grade 1 Prostate Cancer Volume at Biopsy Is Associated With Upgrading but Not Adverse Pathology or Recurrence After Radical Prostatectomy: Results From a Large Institutional Cohort.

PURPOSE: Clinical guidelines suggest that for low-grade, clinically localized prostate cancer, patients with higher volume of disease at diagnosis may benefit from definitive therapy, although the data remain unclear. Our objective was to determine associations between low-grade prostate cancer volume and outcomes in men managed with primary radical prostatectomy. MATERIALS AND METHODS: Men with cT1-2N0/xM0/x prostate cancer, prostate specific antigen at diagnosis <10 ng/mL, and Gleason grade group 1 pathology on diagnostic biopsy managed with primary radical prostatectomy were included. Outcomes were pathological upgrade at radical prostatectomy (≥Gleason grade group 2), University of California, San Francisco adverse pathology at radical prostatectomy (≥Gleason grade group 3, pT3/4, or pN1), alternate adverse pathology at radical prostatectomy (≥Gleason grade group 3, ≥pT3b, or pN1), and recurrence (biochemical failure with 2 prostate specific antigen ≥0.2 ng/mL or salvage treatment). Multivariable logistic regression models were used to estimate associations between percentage of positive cores and risk of upgrade and adverse pathology at radical prostatectomy. Multivariable Cox proportional hazards regression models were used to estimate associations between percentage of positive cores and hazard of recurrence after radical prostatectomy. RESULTS: A total of 1,029 men met inclusion criteria. Multivariable logistic regression models demonstrated significant associations between percentage of positive cores and pathological upgrade (OR 1.31, 95% CI 1.1-1.57, P < .01), but not University of California, San Francisco adverse pathology at radical prostatectomy (P = .84); percentage of positive cores was negatively associated with alternate adverse pathology (OR 0.67, 95% CI 0.48-0.93, P = .02). Multivariable Cox regression models demonstrated no association between percentage of positive cores and hazard of recurrence after radical prostatectomy (P = .11). CONCLUSIONS: In men with Gleason grade group 1 prostate cancer, tumor volume may be associated with upgrading at radical prostatectomy, but not more clinically significant outcomes of adverse pathology or recurrence.

Initial Management of Indeterminate Renal Lesions in a Statewide Collaborative: A MUSIC-KIDNEY Analysis.

PURPOSE: Renal masses can be characterized as "indeterminate" due to lack of differentiating imaging characteristics. Optimal management of indeterminate renal lesions remains nebulous and poorly defined. We assess management of indeterminate renal lesions within the MUSIC-KIDNEY (Michigan Urological Surgery Improvement Collaborative-Kidney mass: Identifying and Defining Necessary Evaluation and therapY) collaborative. MATERIALS AND METHODS: Each renal mass is classified as suspicious, benign, or indeterminate based on radiologist and urologist assessment. Objectives were to assess initial management of indeterminate renal lesions and the impact of additional imaging and biopsy on characterization prior to treatment. RESULTS: Of 2,109 patients, 444 (21.1%) had indeterminate renal lesions on their initial imaging, which included CT without contrast (36.2%), CT with contrast (54.1%), and MRI (9.7%). Eighty-nine patients (20.0%) underwent additional imaging within 90 days, 8.3% (37/444) underwent renal mass biopsy, and 3.6% (16/444) had reimaging and renal mass biopsy. Additional imaging reclassified 58.1% (61/105) of indeterminate renal lesions as suspicious and 21.0% (22/105) as benign, with only 20.9% (22/105) remaining indeterminate. Renal mass biopsy yielded a definitive diagnosis for 87%. Treatment was performed for 149 indeterminate renal lesions (33.6%), including 117 without reimaging and 123 without renal mass biopsy. At surgery for indeterminate renal lesions, benign pathology was more common in patients who did not have repeat imaging (9.9%) than in those who did (6.7%); for ≤4 cm indeterminate renal lesions, these rates were 11.8% and 4.3%. CONCLUSIONS: About 33% of patients diagnosed with an indeterminate renal lesion underwent immediate treatment without subsequent imaging or renal mass biopsy, with a 10% rate of nonmalignant pathology. This highlights a quality improvement opportunity for patients with cT1 renal masses: confirmation that the lesion is suspicious for renal cell carcinoma based on high-quality, multiphase, cross-sectional imaging and/or histopathological features prior to surgery, even if obtaining subsequent follow-up imaging and/or renal mass biopsy is necessary. When performed, these steps lead to reclassification in 79% and 87% of indeterminate renal lesions, respectively.

Use of Monitoring Tests Among Patients With Localized Prostate Cancer Managed With Observation.

PURPOSE: It is unknown whether compliance with recommended monitoring tests during observation of localized prostate cancer has changed over time. MATERIALS AND METHODS: We performed a retrospective cohort study of Medicare beneficiaries diagnosed with low- or intermediate-risk prostate cancer in 2004-2016 who were initially managed with observation for a minimum of 12 months. The primary objective was to examine rates of PSA testing, prostate biopsy, and prostate MRI. We used multivariable mixed effects Poisson regression to determine whether rates of PSA testing and prostate biopsy increased over time. In addition, we identified clinical, sociodemographic, and provider factors associated with the frequency of monitoring tests during observation. RESULTS: We identified 10,639 patients diagnosed at a median age of 73 (IQR 69-77) years. The median follow-up time was 4.3 (IQR 2.7-6.6) years after diagnosis. Among patients managed without treatment for 5 years, 98% received at ≥1 PSA test, 48.0% ≥1 additional prostate biopsy, and 31.0% ≥1 prostate MRI. Among patients managed with observation for ≥12 months, mixed effects Poisson regression revealed that rates of PSA testing and biopsy increased over time (per calendar year: RR 1.02, 95% CI: 1.02-1.03 and RR 1.10, 95% CI: 1.08-1.11, respectively). Clinical and sociodemographic factors including age, clinical risk, race/ethnicity, census tract poverty, and region were associated with rates of biopsy and PSA testing. CONCLUSIONS: Use of recommended monitoring tests including repeat prostate biopsy remains low among Medicare beneficiaries undergoing observation for low- and intermediate-risk prostate cancer.

Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer.

PURPOSE: Men on active surveillance with Grade Group 1 prostate cancer who reclassify to Grade Group 2 on surveillance biopsy often leave active surveillance. We aimed to identify subgroups of men who can safely remain on active surveillance despite preoperative reclassification to Grade Group 2. MATERIALS AND METHODS: We studied 249 active surveillance patients with surveillance biopsies classified as Grade Group 1 or Grade Group 2 who underwent radical prostatectomy. Perineural invasion, cancer volume, linear length and maximum percentage of Gleason pattern 4, and prostate-specific antigen density were evaluated. Radical prostatectomy adverse pathology was defined by any of: pN1; ≥pT3; ≥Grade Group 2 with ≥20% Gleason pattern 4; intraductal carcinoma; large cribriform glands. RESULTS: A multivariable logistic regression model incorporating prostate-specific antigen density and perineural invasion stratified radical prostatectomy adverse pathology risk among Grade Group 1 and Grade Group 2 active surveillance patients. 57% (39/68) of Grade Group 1 men reclassified to Grade Group 2 while on active surveillance had favorable radical prostatectomy pathology. Those without biopsy perineural invasion and with low prostate-specific antigen density were more likely to have favorable radical prostatectomy pathology. CONCLUSIONS: Most Grade Group 1 men who enter active surveillance and subsequently reclassify to Grade Group 2 have favorable findings at radical prostatectomy and can remain on active surveillance. Among patients reclassified to Grade Group 2, those with low prostate-specific antigen density and without perineural invasion had the lowest risk of radical prostatectomy adverse pathology, comparable to (or below) that of Grade Group 1 patients who were not reclassified to Grade Group 2 preoperatively. Prostate-specific antigen density and perineural invasion stratify risk in active surveillance patients reclassified to Grade Group 2 and, if concordant with other clinicopathological and radiographic findings, can enable more patients to remain on active surveillance. Reclassification to Grade Group 2 alone should not disqualify men from remaining on active surveillance.

Renal Mass Biopsy Mandate Is Associated With Change in Treatment Decisions.

PURPOSE: To prevent avoidable treatment and make more informed care decisions about small renal masses, the use of renal mass biopsies has increased since the early 2000s. In April 2017, Atrium Health Carolinas Medical Center began requiring biopsies before all percutaneous thermal ablation procedures for renal masses. We aim to determine the effect of this preablation biopsy mandate on small renal mass treatment decisions. MATERIALS AND METHODS: Our study is a retrospective analysis of a prospectively managed database designed to track patients with small renal masses presented at the Kidney Tumor Program from 2000-2020. We separated patients into 2 cohorts (pre- and postmandate) based on the initial encounter date, excluding those from April 2017-April 2018 to allow for implementation of the mandate. We also excluded patients with masses >4 cm. RESULTS: Overall, we found no significant difference between the pre- and postmandate cohorts, with race as an exception. Implementation of the mandate coincided with an increase in biopsies for both ablation and nonablation treatment pathways (P < .001, P = .01). Renal mass biopsy rates increased in all socioeconomic groups except the lowest quartile. Additionally, Black/Hispanic patients had the highest biopsy rate. We found significant changes in treatment decisions between our cohorts: surgery decreased 24% (P < .001), active surveillance increased 28% (P < .001), and patients with no follow-up decreased 8% (P = .03). CONCLUSIONS: Our data indicate that a preablation renal mass biopsy mandate is associated with the wider use of biopsies for all small renal mass patients, fewer surgical interventions, and an increase in active surveillance.

Clinical Performance of Technetium-99m-Sestamibi SPECT/CT Imaging in Differentiating Oncocytic Tumors From Renal Cell Carcinoma in Routine Clinical Practice.

PURPOSE: Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses. MATERIALS AND METHODS: Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed. RESULTS: A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma. CONCLUSIONS: Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.

International Bladder Cancer Group Intermediate-risk Nonmuscle-invasive Bladder Cancer Scoring System Predicts Outcomes of Patients on Active Surveillance.

PURPOSE: We sought to determine if the International Bladder Cancer Group IR-NMIBC (Intermediate-risk Nonmuscle-invasive Bladder Cancer) scoring system can predict the requirement of delayed transurethral resection of bladder tumor in low-grade nonmuscle-invasive bladder cancer managed by active surveillance. MATERIALS AND METHODS: We prospectively studied recurrent low-grade Ta/T1 nonmuscle-invasive bladder cancer patients managed with active surveillance with the following characteristics: low-grade papillary nonmuscle-invasive bladder cancer, ≤5 apparent low-grade nonmuscle-invasive bladder tumors, tumor diameter ≤1 cm, absence of gross hematuria, and negative urinary cytology. Subsequent transurethral resection of bladder tumor was offered to patients who no longer met the inclusion criteria or patient choice. The ability of the International Bladder Cancer Group IR-NMIBC scoring system to predict receipt of subsequent transurethral resection of bladder tumor was determined. Multivariable Cox proportional hazards analysis was used to determine factors associated with subsequent transurethral resection of bladder tumor. RESULTS: A total of 163 patients with low-grade Ta/T1 nonmuscle-invasive bladder cancer were included for analysis. After a median follow-up of 33 months (IQR: 21-46), transurethral resection of bladder tumor was performed on 109 patients. At landmark time point of 24 months, patients with 0 risk factors were over 2-fold more likely to continue active surveillance compared to patients with ≥3 risk factors (59% vs 24%). Multivariable Cox regression suggested that the International Bladder Cancer Group IR-NMIBC scoring system was associated with subsequent transurethral resection of bladder tumor (1-2 risk factors [HR: 1.66, 95% CI: 0.96-2.90, P = .072], ≥3 risk factors [HR: 3.21, 95% CI: 1.70-6.09, P < .001]) after adjusting for age, T stage, and sex. CONCLUSIONS: The International Bladder Cancer Group IR-NMIBC scoring system can predict the risk of subsequent transurethral resection of bladder tumor in patients with low-grade nonmuscle-invasive bladder cancer on active surveillance.

Pathological Effects of Apalutamide in Lower-risk Prostate Cancer: Results From a Phase II Clinical Trial.

PURPOSE: Active surveillance is a safe and effective strategy for men with lower-risk prostate cancer who want to avoid local therapy; however, many patients on active surveillance progress to active treatment (eg, prostatectomy or radiation). We hypothesized that apalutamide would decrease active surveillance attrition rates through downstaging low-grade tumors. MATERIALS AND METHODS: This was an open-label, single-arm, phase II study testing 90 days of oral apalutamide 240 mg daily in men with low- to intermediate-risk prostate cancer on active surveillance. The primary objective was to determine the percentage of patients with a negative biopsy immediately following treatment. Secondary objectives were to assess long-term clinical outcomes, quality of life, safety, and biomarkers of response/resistance. RESULTS: Twenty-three patients enrolled and 22 completed 90 days of apalutamide with post-treatment biopsy. Fifteen (65%) had Grade Group 1 disease, and all others had Grade Group 2 disease. Seven (30%) had favorable- to intermediate-risk disease. Of 22 evaluable patients, 13 (59%) had no residual cancer on post-treatment biopsy. The median time to first positive biopsy was 364 days (95% CI: 91-742 days). The impact of apalutamide on quality of life was minimal and transient. Decipher risk classifier revealed a greater number of negative post-treatment biopsies in those with higher baseline genomic risk score (P = .01). CONCLUSIONS: The negative repeat biopsy rate following 90 days of apalutamide was high in men with prostate cancer followed on active surveillance. Apalutamide was safe, well tolerated, and had minimal impact on quality of life. Randomized studies evaluating the effects of apalutamide in men enrolled on active surveillance are warranted.

The Use and Short-term Outcomes of Active Surveillance in Men With National Comprehensive Cancer Network Favorable Intermediate-risk Prostate Cancer: The Initial Michigan Urological Surgery Improvement Collaborative Experience.

PURPOSE: National Comprehensive Cancer Network favorable intermediate-risk prostate cancer is a heterogeneous disease with varied oncologic and survival outcomes. We describe the Michigan Urological Surgery Improvement Collaborative's experience with the use of active surveillance and the short-term oncologic outcomes for men with favorable intermediate-risk prostate cancer.Materials and Methods:We reviewed the Michigan Urological Surgery Improvement Collaborative registry for men diagnosed with favorable intermediate-risk prostate cancer from 2012-2020. The proportion of men with favorable intermediate-risk prostate cancer managed with active surveillance was calculated by year of diagnosis. For men selecting active surveillance, the Kaplan-Meier method was used to estimate treatment-free survival. To assess for the oncologic safety of active surveillance, we compared the proportion of patients with adverse pathology and biochemical recurrence-free survival between men undergoing delayed radical prostatectomy after a period of active surveillance with men undergoing immediate radical prostatectomy. RESULTS: Of the 4,275 men with favorable intermediate-risk prostate cancer, 1,321 (31%) were managed with active surveillance, increasing from 13% in 2012 to 45% in 2020. The 5-year treatment-free probability for men with favorable intermediate-risk prostate cancer on active surveillance was 73% for Gleason Grade Group 1 and 57% for Grade Group 2 disease. More men undergoing a delayed radical prostatectomy had adverse pathology (46%) compared with immediate radical prostatectomy (32%, P < .001), yet short-term biochemical recurrence was similar between groups (log-rank test, P = .131). CONCLUSIONS: The use of active surveillance for men with favorable intermediate-risk prostate cancer has increased markedly. Over half of men with favorable intermediate-risk prostate cancer on active surveillance remained free of treatment 5 years after diagnosis. Most men on active surveillance will not lose their window of cure and have similar short-term oncologic outcomes as men undergoing up-front treatment. Active surveillance is an oncologically safe option for appropriately selected men with favorable intermediate-risk prostate cancer.

Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Prognostic Factors for Survival in Patients Undergoing Surveillance After Cytoreductive Nephrectomy.

PURPOSE: The clinical course of patients being placed on surveillance in a cohort of systemic therapy-naïve patients who undergo cytoreductive nephrectomy is not well documented. Thus, we evaluated the clinical course of patients placed on surveillance following cytoreductive nephrectomy and identified predictors of survival. MATERIALS AND METHODS: In this large single-institution study, we retrospectively analyzed metastatic renal cell carcinoma patients who underwent cytoreductive nephrectomy followed by surveillance. Predictors of survival were evaluated using the Kaplan-Meier method with a log-rank test. Patients were risk stratified based on IMDC (International mRCC Database Consortium) and number of metastatic sites (Rini score), with IMDC score ≤1 and ≤2 metastatic organ sites considered favorable risk. Primary end point was systemic therapy-free survival. Secondary end points included intervention-free survival, cancer-specific survival, and overall survival. RESULTS: Median systemic therapy-free survival was 23.6 months (95% CI: 15.1-40.6), intervention-free survival was 11.8 months (95% CI: 8.0-18.4), cancer-specific survival was 54.2 months (95% CI: 46.2-71.4), and overall survival 52.4 months (95% CI: 40.3-66.8). Favorable-risk patients compared to unfavorable-risk patients had longer systemic therapy-free survival (50.6 vs 11.1 months, P < .01), survival (25.2 vs 7.3, P < .01), and cancer-specific survival (71.4 vs 46.2 months, P = .02). CONCLUSIONS: Using risk stratification based on IMDC and number of metastatic sites, surveillance in favorable-risk patients can be utilized for a period without the initiation of systemic therapy. This approach can delay patients' exposure to the side effects of systemic therapy.

Risk Stratification of Low-risk Prostate Cancer: Individualizing Care in the Era of Active Surveillance.

PURPOSE: While active surveillance is the preferred management for most men with low-risk prostate cancer, a subset may harbor more aggressive disease. In this review we examine the evidence underlying an accurate and nuanced assessment of oncologic risk in these men. MATERIALS AND METHODS: We performed a nonsystematic literature review current to January 2023 on PubMed for articles relating to clinical, pathological, molecular, and imaging-based modalities available for risk assessment in men with low-risk prostate cancer. Relevant articles were reviewed by the authors and evidence was summarized. RESULTS: Many tools are available to personalize clinical decision-making for men with low-risk prostate cancer. Total volume of cancer, PSA density, and presence of ductal components have been consistently and strongly associated with current or future evidence of higher-grade disease. PSA kinetics, Prostate Imaging Reporting & Data System 4/5 lesions on MRI, perineural invasion, germline mutations, and genomic classifiers all appear to be associated with an increased risk, although are not as extensively validated. Race, percent free PSA, and other serum biomarkers such as Prostate Health Index and 4Kscore do not appear to be associated with long-term elevated risk. CONCLUSIONS: Long-term prognosis for men diagnosed with low-risk prostate cancer is excellent. There are many factors which should be routinely integrated into the initial management decision as well as determining intensity and frequency of active surveillance. Development of comprehensive multivariable instruments to guide clinical decisions is encouraged.

Impact of an Expanded Definition of Family History on Outcomes of Active Surveillance for Prostate Cancer.

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes. MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression. RESULTS: Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence. CONCLUSIONS: An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.

Split scar sign to predict complete response in rectal cancer after neoadjuvant chemoradiotherapy: systematic review and meta-analysis.

OBJECTIVES: Magnetic resonance imaging (MRI) is the modality of choice for rectal cancer initial staging and restaging after neoadjuvant chemoradiation. Our objective was to perform a meta-analysis of the diagnostic performance of the split scar sign (SSS) on rectal MRI in predicting complete response after neoadjuvant therapy. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched for relevant published studies through June 2023. Primary studies met eligibility criteria if they evaluated the diagnostic performance of the SSS to predict complete response on pathology or clinical follow-up in patients undergoing neoadjuvant chemoradiation. A meta-analysis with a random-effects model was used to estimate pooled sensitivity and specificity, area under the curve (AUC), and diagnostic odds ratio (DOR) of the SSS. RESULTS: A total of 4 studies comprising 377 patients met the inclusion criteria. The prevalence of complete response in the studies was 21.7-52.5%. The pooled sensitivity and specificity of the SSS to predict complete response were 62.0% (95% CI, 43.5-78.5%) and 91.9% (95% CI, 78.9-97.2%), respectively. The estimated AUC for SSS was 0.83 (95% CI, 0.56-0.94) with a DOR of 18.8 (95% CI, 3.65-96.5). CONCLUSION: The presence of SSS on rectal MRI demonstrated high specificity for complete response in patients with rectal cancer after neoadjuvant chemoradiation. This imaging pattern can be a valuable tool to identify potential candidates for organ-sparing treatment and surveillance. CLINICAL RELEVANCE STATEMENT: SSS presents high specificity for complete response post-neoadjuvant. This MRI finding enhances rectal cancer treatment assessment and aids clinicians and patients in choosing watch-and-wait over immediate surgery, which can potentially reduce costs and associated morbidity. KEY POINTS: •Fifteen to 50% of rectal cancer patients achieve complete response after neoadjuvant chemoradiation and may be eligible for a watch-and-wait strategy. •The split scar sign has high specificity for a complete response. •This imaging finding is valuable to select candidates for organ-sparing management.