Cardio-oncology in advanced prostate cancer.

Treatment intensification with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPi) have led to improved survival in advanced prostate cancer. However, ADT is linked to significant cardiovascular toxicity, and ARPi also negatively impacts cardiovascular health. Together with a higher prevalence of baseline cardiovascular risk factors reported among prostate cancer survivors at diagnosis, there is a pressing need to prioritise and optimise cardiovascular health in this population. Firstly, While no dedicated cardiovascular toxicity risk calculators are available, other tools such as SCORE2 can be used for baseline cardiovascular risk assessment. Next, selected patients on combination therapy may benefit from de-escalation of ADT to minimise its toxicities while maintaining cancer control. These patients can be characterised by an exceptional PSA response to hormonal treatment, favourable disease characteristics and competing comorbidities that warrant a less aggressive treatment regime. In addition, emerging molecular and genomic biomarkers hold the potential to identify patients who are suited for a de-escalated treatment approach either with ADT or with ARPi. One such biomarker is AR-V7 splice variant that predicts resistance to ARPi. Lastly, optimization of modifiable cardiovascular risk factors for patients through a coherent framework (ABCDE) and exercise therapy is equally important. This article aims to comprehensively review the cardiovascular impact of hormonal manipulation in metastatic hormone-sensitive prostate cancer, propose overarching strategies to mitigate cardiovascular toxicity associated with hormonal treatment, and, most importantly, raise awareness about the detrimental cardiovascular effects inherent in our current management strategies involving hormonal agents.

Efficacy, toxicity, and quality-of-life outcomes of ultrahypofractionated radiotherapy in patients with localized prostate cancer: A single-arm phase 2 trial from Asia.

AIMS: Ultra-hypofractionated radiotherapy (UHF-RT) is widely utilized in men with localized prostate cancer (PCa). There are limited data in Asian cohorts. We report the outcomes of a single-arm, phase II trial of UHF-RT from an Asian center. METHODS: We recruited men with histologically confirmed, nonmetastatic localized PCa. UHF-RT regimens were 36.25 Gy (Cohort A) and 37.5 Gy (Cohort B) delivered in five fractions every other day over 1.5-2.5 weeks. Primary endpoint was physician-scored late genitourinary (GU) and gastrointestinal (GI) adverse events (AEs). Quality-of-life (QoL) was assessed by Expanded Prostate Cancer Index Composite (EPIC) at baseline, 1- and 2-year post-UHF-RT. RESULTS: Between March 2014 and August 2019, 105 men were recruited; four were subsequently excluded from analysis. Median age was 68.0 (Interquartile range (IQR): 63.8-73.0) years. 26 (24.8%) and 68 (64.8%) men had NCCN-defined low-and intermediate-risk PCa, respectively. No late ≥G3 GU or GI toxicities were reported in both cohorts. Peak incidence of acute ≥G2 GU AEs at 14 days post-UHF-RT was 23.6% (17/72) and 24.0% (6/25) in Cohorts A and B, respectively; ≥G2 GI AEs were observed in 9.7% (7/72) and 36.0% (9/25), respectively. Late ≥G2 GU and GI AEs occurred in 4.7% and 3.1% of Cohort A patients, and 5.0% in Cohort B at 12 months, with no AEs at 24 months. EPIC scores changed minimally across all domains. At a median follow-up of 44.9 months, we recorded one (1.3%) biochemical relapse by the Phoenix criteria (Cohort A). CONCLUSION: UHF-RT is well tolerated in Asian men and can be a recommended fractionation schema for localized PCa.

Validation of Modified Breast Graded Prognostic Assessment for breast cancer patients with brain metastases: extra-cranial disease progression is an independent risk factor.

BACKGROUND: Breast cancer (BC) patients with brain metastases (BM) are heterogeneous with markedly variable survival. The Breast Graded Prognostic Assessment (B-GPA) and Modified B-GPA (mB-GPA) have been proposed as useful tools for stratifying survival in this population. However, extra-cranial disease progression, a clinically important variable, is not incorporated into the final model. We undertook the validation of B-GPA and mB-GPA in an Asian cohort and further explore extra-cranial disease progression as a prognostic factor. METHODS: Data of BC patients with newly diagnosed BM between 2006 and 2017 was extracted retrospectively from a prospectively maintained institutional database. Patients were classified based on their B-GPA and mB-GPA scores. Univariate (UVA) and multivariate analysis (MVA) using the Cox proportional hazard model were performed to investigate the factors prognostic of overall survival (OS). The Kaplan-Meier method was used to estimate OS and log-rank test to compare survival between scores. The performances of B-GPA and mB-GPA were compared using Harrell's concordance index (C-index) and Akaike information criterion (AIC). RESULTS: In our cohort of 282 patients, the B-GPA and mB-GPA were validated as prognostic tools for OS, demonstrating excellent separation between survival curves (P <0.001). In MVA, we found all components of mB-GPA (age, performance status, number of BM, tumour subtype) to be independent predictors of survival. C-index was 0.64 and AIC was 2,483.39 for B-GPA. mB-GPA demonstrated marginally better discrimination with a C-index of 0.65 and AIC of 2,445.78. Extra-cranial progression was an independent predictor for survival in our population (P <0.001). CONCLUSIONS: The mB-GPA incorporates four simple clinical variables each of independent prognostic significance. Both B-GPA and mB-GPA demonstrate moderate discriminative capabilities for OS with mB-GPA performing marginally better. Inclusion of extra-cranial disease progression as a factor in future model development may further improve its prognostic value.

Combinatorial strategies of radiotherapy and immunotherapy in nasopharyngeal carcinoma.

Immunotherapy and radiation therapy (RT) have each demonstrated clinical success in the treatment of nasopharyngeal carcinoma (NPC) when utilized independently. Several characteristics of NPC make it particularly well suited for immunotherapeutic strategies, such as the association with viral infections like EBV and human papilloma virus (HPV), upregulation of PD-L1 expression, and the high number of tumor infiltrating lymphocytes. Immune checkpoint blockade is one such immunotherapeutic strategy that is gaining popularity rapidly. However, clinical benefit of immunotherapy using immune checkpoint inhibitors has been limited to only a small subset of patients with existing T cell responses. Additionally, they are frequently associated with dose-limiting immune-related toxicities. On the other hand, RT is a conventional strategy for NPC treatment, which has demonstrated high efficacy in local tumor control and has also been reported to exhibit immune modulatory effects. However, the abscopal effect of RT alone, i.e., the regression of distant metastases outside of the irradiation field, remains a rare phenomenon. Furthermore, RT treatment efficacy is also limited by radioresistance and radiation-related toxicities. Hence, the combination of RT and immunotherapy has the potential to improve treatment efficacy over either individual therapies alone. Here, we reviewed the clinical problem in locally advanced and recurrent/metastatic NPC, and discussed how combinatorial RT and immunotherapeutic strategies can be relevant to NPC treatment in each clinical scenario by examining the underlying mechanisms involved in the different strategies.

"Cor Occidere": a novel strategy of targeting the tumor core by radiosurgery in a radio- and chemo-resistant intracranial hemangiopericytoma.

Intracranial hemangiopericytomas (HPC) are chemotherapy- and radiotherapy (RT)-resistant. Here, we report on a novel stereotactic radiosurgery (SRS) technique-"Cor Occidere" (Latin), as a potential strategy of overcoming radioresistance of HPC. A 36-year old female presented to our clinic for consideration of a 3rd-course of RT for her recurrent cavernous sinus HPC, following previous cranial RT at 13 and 5 years prior, and a failed 9 months trial of bevacizumab/temozolomide. The tumor-adjacent brain stem and carotid artery risked substantial damage given the cumulative RT doses to these organs. We therefore designed an SRS plan targeting only the tumor core with 16 Gy single-fraction. Despite underdosing the tumor margin, we achieved stable disease over 25 months, contrasting her responses to systemic therapies. Achieving tumor control despite a suboptimal treatment that utilized high dose ablation of the tumor core suggests novel biological mechanisms to overcome radioresistance of HPC.

Prognostic Model for Stratification of Radioresistant Nasopharynx Carcinoma to Curative Salvage Radiotherapy.

Purpose To investigate for a prognostic index (PI) to personalize recommendations for salvage intensity-modulated radiotherapy (IMRT) in patients with locally recurrent nasopharyngeal carcinoma (lrNPC). Methods Patients with lrNPC from two academic institutions (Sun Yat-Sen University Cancer Center [SYSUCC-A; n = 251 (training cohort)] and National Cancer Centre Singapore [NCCS; n = 114] and SYSUCC-B [n = 193 (validation cohorts)]) underwent salvage treatment with IMRT from 2001 to 2015. Primary and secondary clinical end points were overall survival (OS) and grade 5 toxicity-free rate (G5-TFR), respectively. Covariate inclusion to the PIs was qualified by a multivariable two-sided P < .05. Discrimination and calibration of the PIs were assessed. Results The primary PI comprised covariates that were adversely associated with OS in the training cohort (gross tumor volumerecurrence hazard ratio [HR], 1.01/mL increase [ P < .001], agerecurrence HR, 1.02/year increase [ P = .008]; repeat IMRT equivalent dose in 2-Gy fractions [EQD2] ≥ 68 Gy HR, 1.42 [ P = .03]; prior radiotherapy-induced grade ≥ 3 toxicities HR, 1.90 [ P = .001]; recurrent tumor [rT]-category 3 to 4 HR, 1.96 [ P = .005]), in ascending order of weight. Discrimination of the PI for OS was comparable between training and both validation cohorts (Harrell's C = 0.71 [SYSUCC-A], 0.72 [NCCS], and 0.69 [SYSUCC-B]); discretization by using a fixed PI score cutoff of 252 determined from the training data set yielded low- and high-risk subgroups with disparate OS in the validation cohorts (NCCS HR, 3.09 [95% CI, 1.95 to 4.89]; SYSUCC-B HR, 3.80 [95% CI, 2.55 to 5.66]). Our five-factor PI predicted OS and G5-TFR (predicted v observed 36-month OS and G5-TFR, 22% v 15% and 38% v 44% for high-risk NCCS and 26% v 31% and 45% v 46% for high-risk SYSUCC-B). Conclusion We present a validated PI for robust clinical stratification of radioresistant NPC. Low-risk patients represent ideal candidates for curative repeat IMRT, whereas novel clinical trials are needed in the unfavorable high-risk subgroup.

Phase I Study to Determine MTD of Docetaxel and Cisplatin with Concurrent Radiation Therapy for Stage III Non-Small Cell Lung Cancer.

OBJECTIVE: To evaluate the maximum tolerated dose (MTD) of docetaxel (DCT) and cisplatin (DDP) concurrently with three dimensional (3D) conformal radiotherapy or IMRT for patients with locally advanced non-small cell lung cancer (stage IIIa and IIIb) after 2-4 cycles of induction chemotherapy. METHODS: Fourteen patients with histological/cytological proven stage III non-small-cell lung cancer were eligible. 3D or IMRT radiotherapy (60-70Gy in 30-35 fractions, 6-7weeks, 2 Gy/fraction) was delivered concurrently with cisplatin and docetaxel, 2 cycles during concurrent chemoradiotherapy (CCRT). The level I dosage was composed of 56 mg/m(2) DCT, on day 1 and 28mg/m(2) DDP, on day 1 and day 2. The level II was composed of 60 mg/m(2) DCT, on day 1 and 30 mg/ m(2) DDP, on day 1 and day 2. The level III was composed of 64 mg/m(2) DCT, on day 1 and 32 mg/ m(2) DDP, on day 1 and day 2. RESULTS: Fourteen patients were allocated and finished concurrent chemoradiotherapy. The dose-limiting neutropenia was at the dose Level III (64 mg/m(2)) and occurred in 2 of 5 patients. No dose limiting non-hematologic or hematologic toxicity occurred in the other patients. CONCLUSIONS: Patients with locally advanced non-small cell lung cancer may tolerate 60mg/m(2) docetaxel and 60mg/m(2) cisplatin for 2 cycles during concurrent radiotherapy after 2-3 cycles of induction chemotherapy.

Medicinal mushroom extracts inhibit ras-induced cell transformation and the inhibitory effect requires the presence of normal cells.

Previously, we developed a simple Rat 6 (R6) cell system by which the inhibitory effects of non-cytotoxic chemicals can be assessed by focus formation assay upon transfection of ras oncogene to the host cells. Using this system, two well studied medicinal mushrooms Ganoderma lucidum and Tricholoma lobayense with anticancer potential were examined for their possible advert effects on cell transformation induced by ras oncogene. Results indicated that both species of mushrooms yielded strong inhibitory effects on ras-induced cell transformation. Further study on T.lobayense indicated that the DEAE-column-bound, polysaccharides (PS)-peptide enriched, but not the unbound fraction, showed strong inhibition in a dosage-dependent manner. Subsequent time course study revealed that the continued presence of the extract in the transfected cultures was required for a maximum inhibitory effect. At the same time, we also observed that significant levels of inhibition occurred even when the application of the extract was delayed until day 12 after transfection. Using a stable transformed cell line, R6/GFP-Ras expressing green fluorescent protein-ras fusion protein in a co-culture assay with normal R6 cells, we demonstrated that R6/GFP-Ras cells grew into green fluorescent foci with striking transforming morphology in the absence of extracts. However, in the presence of extracts, R6/GFP-Ras cells, in most cases, remained as small colonies compiled with only a few green fluorescent cells. Moreover, the inhibitory effect requires the presence of R6 cells. In our study, mushroom extracts have no effect on the growth of individually cultured normal and transformed R6 cells. It is noteworthy that the extracts do not affect the level, or the subcellular localization of the Ras protein. Collectively, the data strongly suggest that the inhibitory effect of the mushroom extracts is not due to a direct killing of the transformed cells, rather, it may be mediated through the surrounding normal R6. While the general understanding of the antitumor effect of PS and PSPC is mediated through the cytokines released by activated macrophages and T-lymphocytes, our data may provide a novel alternative mechanism that the mushroom PS peptides may exert anticancer effect by targeting the ras-mediated signaling pathway.