Prostate-Specific Membrane Antigen (PSMA) Expression Predicts Need for Early Treatment in Prostate Cancer Patients Managed with Active Surveillance.

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate-glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83-13.94] and HR: 2.44, [CI 95%: 1.10-5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.

The Journey of Radiotherapy Dose Escalation in High Risk Prostate Cancer; Conventional Dose Escalation to Stereotactic Body Radiotherapy (SBRT) Boost Treatments.

High risk prostate cancer (HR-PrCa) is a subset of localized PrCa with significant potential for morbidity and mortality associated with disease recurrence and metastasis. Radiotherapy combined with Androgen Deprivation Therapy has been the standard of care for many years in HR-PrCa. In recent years, dose escalation, hypo-fractionation and high precision delivery with immobilization and image-guidance have substantially changed the face of modern PrCa radiotherapy, improving treatment convenience and outcomes. Ultra-hypo-fractionated radiotherapy delivered with high precision in the form of stereotactic body radiation therapy (SBRT) combines delivery of high biologically equivalent dose radiotherapy with the convenience of a shorter treatment schedule, as well as the promise of similar efficacy and reduced toxicity compared to conventional radiotherapy. However, rigorous investigation of SBRT in HR-PrCa remains limited. Here, we review the changes in HR-PrCa radiotherapy through dose escalation, hypo- and ultra-hypo-fractionated radiotherapy boost treatments, and the radiobiological basis of these treatments. We focus on completed and on-going trials in this disease utilizing SBRT as a sole radiation modality or as boost therapy following pelvic radiation.

Clinical integration of machine learning for curative-intent radiation treatment of patients with prostate cancer.

Machine learning (ML) holds great promise for impacting healthcare delivery; however, to date most methods are tested in 'simulated' environments that cannot recapitulate factors influencing real-world clinical practice. We prospectively deployed and evaluated a random forest algorithm for therapeutic curative-intent radiation therapy (RT) treatment planning for prostate cancer in a blinded, head-to-head study with full integration into the clinical workflow. ML- and human-generated RT treatment plans were directly compared in a retrospective simulation with retesting (n = 50) and a prospective clinical deployment (n = 50) phase. Consistently throughout the study phases, treating physicians assessed ML- and human-generated RT treatment plans in a blinded manner following a priori defined standardized criteria and peer review processes, with the selected RT plan in the prospective phase delivered for patient treatment. Overall, 89% of ML-generated RT plans were considered clinically acceptable and 72% were selected over human-generated RT plans in head-to-head comparisons. RT planning using ML reduced the median time required for the entire RT planning process by 60.1% (118 to 47 h). While ML RT plan acceptability remained stable between the simulation and deployment phases (92 versus 86%), the number of ML RT plans selected for treatment was significantly reduced (83 versus 61%, respectively). These findings highlight that retrospective or simulated evaluation of ML methods, even under expert blinded review, may not be representative of algorithm acceptance in a real-world clinical setting when patient care is at stake.

Rapid Adaptation of Breast Radiation Therapy Use During the Coronavirus Disease 2019 Pandemic at a Large Academic Cancer Center in Canada.

PURPOSE: Mitigation strategies to balance the risk of coronavirus disease 2019 (COVID-19) infection against oncologic risk in patients with breast cancer undergoing radiation therapy have been deployed. To this end, shorter hypofractionated regimens have been recommended where appropriate, with prioritization of radiation therapy by oncologic risk and omission or deferral of radiation therapy for lower risk cases. Timely adoption of these measures reduces COVID-19 risk to both patients and health care workers and preserves resources. Herein, we present our early response and adaptation of breast radiation therapy utilization during the COVID-19 pandemic at a large academic cancer center in Canada. METHODS AND MATERIALS: A state of emergency was announced in Ontario on March 17, 2020, owing to the COVID-19 pandemic. Emergency guidelines were instituted. To examine our response, the number of weekly breast radiation therapy starts, type of breast radiation therapy, and patient age were compared from March 1 to April 30, 2020 to the same period in 2019. RESULTS: After the declaration of emergency in Ontario, there was a decrease of 39% in radiation therapy starts in 2020 compared with 2019 (79 vs 129, P < .001). There was a relative increase in the proportion of patients receiving regional nodal irradiation (RNI) in 2020 compared with 2019 (46% vs 29%, respectively), with the introduction of hypofractionated RNI in 2020 (27 of 54 cases, 50%). A smaller proportion of patients starting radiation therapy were aged >50 years in 2020, 66% (78 of 118) versus 83% (132 of 160) in 2019, P = .0027. CONCLUSIONS: A significant reduction in breast radiation therapy starts was noted during the early response to the COVID-19 pandemic, with prioritization of radiation therapy to patients associated with higher oncologic risk requiring RNI. A quick response to a health care crisis is critical and is of particular importance for higher volume cancer sites where the potential effect on resources is greater.

A Randomized Phase II Trial of Prostate Boost Irradiation With Stereotactic Body Radiotherapy (SBRT) or Conventional Fractionation (CF) External Beam Radiotherapy (EBRT) in Locally Advanced Prostate Cancer: The PBS Trial (NCT03380806).

Standard therapy for high-risk (HR) prostate cancer (PrCa) involves androgen deprivation therapy (ADT) and pelvic conventional fractionation (CF) external beam radiotherapy (EBRT) followed by boost CF-EBRT treatment to prostate for a total of 78 to 80 Gy in 39 to 40 fractions. This is a long and inconvenient treatment for patients. Brachytherapy boost treatment studies indicate that escalation of biological dose of radiotherapy (RT) can improve outcomes in HR-PrCa. However, brachytherapy is an invasive treatment associated with increased toxicity and requires specialized resources. Stereotactic body radiotherapy (SBRT) is a promising, non-invasive alternative to brachytherapy. However, its impact on patient quality of life (QoL) and RT-associated toxicity has not been investigated in a randomized setting. In this study, we investigate SBRT as a boost treatment, following pelvic CF-EBRT, in patients with HR-PrCa treated with ADT. One hundred patients with locally advanced PrCa will be randomized to receive daily CF-EBRT of 45 to 46 Gy in 23 to 25 fractions followed by either daily CF-EBRT of 32 to 33 Gy in 15 to 16 fractions (control arm) or SBRT boost treatment of 19.5 to 21 Gy in 3 fractions (1 fraction per week) (experimental arm). The primary objective of the PBS trial is early bowel and urinary QoL (expanded prostate index composite [EPIC], up to 6 months after RT). This phase II randomized study (PBS) provides an appropriate setting to investigate effectively the impact of SBRT boost on QoL and toxicity in patients with HR-PrCa, before this modality can be compared against the current standard of care in larger phase III protocols.

Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer (NSCLC) to cytotoxic therapy: translational biology and rationale for current clinical trials.

Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept.

A Novel Neoadjuvant Therapy for Operable Locally Invasive Non-Small-Cell Lung Cancer. Phase I Study of Neoadjuvant Stereotactic Body Radiotherapy. LINNEARRE I (NCT02433574).

BACKGROUND: Despite improved staging and surgical techniques, the rate of incomplete resection (R1) of non-small-cell lung cancer (NSCLC) has not significantly decreased. Patients with R1 resection have worse survival compared with those with complete resection (R0). Stereotactic body radiotherapy (SBRT) is a rapid and convenient radiotherapy treatment that delivers high-dose radiotherapy to tumors with high precision while sparing normal organs. Although its efficacy in treating small lung tumors is documented, its use as neoadjuvant therapy for locally advanced (LA) NSCLC has not been examined. We hypothesized that a short course of preoperative SBRT is feasible and can be delivered safely as a neoadjuvant therapy in patients at risk for incomplete resection. METHODS: In this phase I study, 20 patients with cT3 to 4, N0 to 1, M0 NSCLC at risk for incomplete resection will be treated with neoadjuvant SBRT followed by surgery and adjuvant chemotherapy. Four groups of 5 patients will be treated with escalating doses (35, 40, 45, and 50 Gy) in 10 daily fractions. The primary outcome is feasibility (ie, the ability to complete SBRT and surgery as planned; within 7 weeks). Secondary outcomes include acute and late adverse events; R0, R1, and R2 rates; and secondary surrogates of feasibility and safety. RELEVANCE: This study is an important first step in introducing a new therapeutic modality to patients with LA NSCLC that could improve surgical outcomes in the future. If neoadjuvant SBRT is found to be feasible and safe for LA NSCLC, its effect in achieving R0 resection could be investigated in randomized trials.

Hypofractionation Is an Acceptable Alternative to Conventional Fractionation in the Treatment of Postlumpectomy Ductal Carcinoma In Situ With Radiotherapy.

PURPOSE: The standard dose of postlumpectomy radiotherapy (RT) for ductal carcinoma in situ (DCIS) is 50 Gy in 25 fractions using conventional fractionation (CF). However, in invasive carcinoma, hypofractionation (HF) with 40 to 42.6 Gy in 15 to 16 fractions has largely become a standard of care. The purpose of this study was to review the management of postlumpectomy DCIS in terms of RT dose-fractionation and its impact on local recurrence (LR), in one of the largest Canadian academic centers. METHODS AND MATERIALS: Between 2003 and 2008, a total of 348 women with DCIS were treated with postlumpectomy RT. Patient characteristics, histopathology, dose-fractionation, use of endocrine therapy, local, regional, contralateral breast recurrences, and cause of death were collected. Local recurrence-free survival was determined. Univariate and multivariate analyses were performed to identify risk factors for LR. RESULTS: The median age of the cohort was 59 years. Two hundred two (58%) patients received CF and 146 (42%) HF. Initially, the yearly proportion of HF was 34%, but increased up to 68% since 2007. Estrogen receptor was positive in 195 patients, and 43% of those received endocrine therapy. With a median follow-up of 64.8 months, 36 LRs were detected. The 5-year local recurrence-free survival rate was 94% for the HF group versus 91% for the CF group (P = .80). On multivariate analysis, only the use of endocrine therapy showed a trend towards decreasing LR (hazard ratio, 0.44; 95% confidence interval, 0.18-1.08; P = .07). CONCLUSIONS: The utilization of HF for DCIS postlumpectomy has increased over time and is a valid option as it results in similar rates of local control.