Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable-risk prostate cancer undergoing active surveillance.

OBJECTIVES: To determine the frequency of disease reclassification and to identify clinicopathological variables associated with it in patients with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We assessed 191 men, selected by what may be the most stringent criteria used in AS studies yet conducted, who were enrolled in a prospective cohort AS trial. Clinicopathological characteristics were analysed in a multivariate Cox proportional hazards regression model. Key features were an extended biopsy with a single core positive for Gleason score (GS) 3 + 3 (<3 mm) or 3 + 4 (<2 mm) and a prostate-specific antigen (PSA) level <4 ng/mL (adjusted for prostate volume). Biopsies were repeated every 1-2 years and clinical evaluations every 6 months. Disease was reclassified when PSA level increased by 30% from baseline, or when biopsy tumour length increased beyond the enrolment criteria, more than one positive core was detected or any grade increased to a dominant 4 pattern or any 5 pattern. RESULTS: Disease was reclassified in 32 patients (16.8%) including upgrading to GS 4 + 3 in five patients (2.6%). The median (interquartile range) follow-up time among survivors was 3 (1.9-4.6) years. Overall, 13 of the 32 (40.6%) had incremental increases in GS. Tumour length (hazard ratio 2.95, 95% confidence interval [CI] 1.34-6.46; P = 0.007) and older age (hazard ratio 1.05, 95% CI 1.00-1.09; P = 0.05) were identified as significant and marginally significant predictors of disease reclassification, respectively. Disease remained stable in 83.2% of patients. CONCLUSION: The need persists for improvements in risk stratification and predictive indicators of cancer progression.

Robotic or open superficial inguinal lymph node dissection as staging procedures for clinically node negative high risk penile cancer.

OBJECTIVE: To evaluate perioperative and oncologic outcomes of a cohort of clinically node negative high-risk penile cancer patients undergoing robotic assisted inguinal lymph node dissection (RAIL) compared to patients undergoing open superficial inguinal lymph node dissection (OSILND). PATIENTS AND METHODS: We retrospectively reviewed the clinical characteristics and outcomes of clinically node negative high-risk penile cancer patients undergoing RAIL at MDACC from 2013-2019. We sought to compare this to a contemporary open cohort of clinically node negative patients treated from 1999 to 2019 at MDACC and Moffit Cancer Center (MCC) with an OSILND. Descriptive statistics were used to characterize the study cohorts. Comparison analysis between operative variables was performed using Fisher's exact test and Wilcoxon's rank-sum test. The Kaplan-Meier method was used to estimate survival endpoints. RESULTS: There were 24 patients in the RAIL cohort, and 35 in the OSILND cohort. Among the surgical variables, operative time (348.5 minutes vs. 239.0 minutes, P < 0.01) and the duration of operative drain (37 vs. 22 days P = 0.017) were both significantly longer in the RAIL cohort. Complication incidences were similar for both cohorts (34.3% for OSILND vs. 33.3% for RAIL), with wound complications making up 33% of all complications for RAIL and 31% of complications for OSILND. No inguinal recurrences were noted in either cohort. The median follow-up was 40 months for RAIL and 33 months for OSILND. CONCLUSIONS: We observed similar complication rates and surgical variable outcomes in our analysis apart from operative time and operative drain duration. Oncological outcomes were similar between the two cohorts. RAIL was a reliable staging and potentially therapeutic procedure among clinically node negative patients with penile squamous cell carcinoma with comparable outcomes to an OSILND cohort.

Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma.

Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%2. Here we report on the first pilot combination neoadjuvant trial ( NCT02812420 ) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease3-5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.

Neoadjuvant platelet derived growth factor receptor inhibitor therapy combined with docetaxel and androgen ablation for high risk localized prostate cancer.

PURPOSE: Platelet derived growth factor receptor inhibitor therapy improves the efficacy of taxane chemotherapy in preclinical models of prostate cancer. Men with high risk localized prostate cancer were treated with platelet derived growth factor receptor inhibitor therapy, docetaxel and hormone ablation in the preoperative setting, and clinicopathological outcomes were evaluated. MATERIALS AND METHODS: A total of 36 men with cT2 or greater disease, Gleason grade 8-10, serum prostate specific antigen more than 20 ng/ml or cT2b and prostate specific antigen more than 10 ng/ml and Gleason 7 disease, without radiological evidence of metastases, were scheduled to receive intramuscular leuprolide, 600 mg daily oral imatinib and 30 mg/m(2) weekly docetaxel x 4 every 42 days for 3 cycles before radical prostatectomy (beta [0.02, 1.98] prior on the possibility of pathological complete remission). Unresectable disease, postoperative prostate specific antigen 0.2 ng/ml or greater, or administration of postoperative radiation or hormones were defined as treatment failure. RESULTS: A total of 39 men were registered over 15 months. Median patient age was 57 years (range 44 to 71). Risk factors included T3 disease (22 of 39), Gleason 8-10 disease (31 of 39) and prostate specific antigen more than 20 ng/ml (12 of 39). Three men were ineligible or declined therapy, 29 of 36 (81%) received 3 cycles of therapy and 7 of 36 (19%) discontinued therapy related to toxicity. Grades 3-4 toxicity included rash (4), diarrhea (4), fatigue (6) and neutropenia (1). The surgical approach was feasible, without excessive or unusual complications such as wound dehiscence. No pathological complete remissions were defined. At a median followup of 39 months 53% were free from progression. CONCLUSIONS: Evidence for a favorable impact of platelet derived growth factor receptor inhibitor therapy on the efficacy of neoadjuvant docetaxel and hormonal ablation in high risk localized prostate cancer was not obtained.

Targeted antivascular therapy with the apolipoprotein(a) kringle V, rhLK8, inhibits the growth and metastasis of human prostate cancer in an orthotopic nude mouse model.

Antivascular therapy has emerged as a rational strategy to improve the treatment of androgen-independent prostate cancer owing to the necessity of establishing a vascular network for the growth and progression of the primary and metastatic tumor. We determined whether recombinant human apolipoprotein(a) kringle V, rhLK8, produces therapeutic efficacy in an orthotopic human prostate cancer animal model. Fifty thousand androgen-independent human prostate cancer cells (PC-3MM2) were injected into the prostate of nude mice. After 3 days, these mice were randomized to receive the vehicle solution (intraperitoneally [i.p.], daily), paclitaxel (8 mg/kg i.p., weekly), rhLK8 (50 mg/kg i.p., daily), or a combination of paclitaxel and rhLK8 for 4 weeks. Treatment with paclitaxel or rhLK8 alone did not show significant therapeutic effects on tumor incidence or on tumor size compared with the control group. The combination of rhLK8 and paclitaxel significantly reduced tumor size and incidence of lymph node metastasis. Significant reduction in microvessel density and cellular proliferation and induction of apoptosis of tumor cells, and tumor-associated endothelial cells, were also achieved. Similarly, PC-3MM2 tumors growing in the tibia showed significant suppression of tumor growth and lymph node metastasis by the combination treatment with rhLK8 and paclitaxel. The integrity of the bone was significantly preserved, and apoptosis of tumor cells and tumor-associated endothelial cells was increased. In conclusion, these results suggest that targeting the tumor microenvironment with the antivascular effect of rhLK8 combined with conventional cytotoxic chemotherapy could be a new and effective approach in the treatment of androgen-independent prostate cancer and their metastases.