Oligometastasis in Prostate Cancer: Can We Learn from Those “Excluded” from a Phase 2 Trial?

We conducted and previously published a phase 2 trial of metastasis-directed therapy (MDT) in men with recurrence of prostate cancer at a low prostate-specific antigen level following radical prostatectomy and postoperative radiotherapy. All patients had negative conventional imaging and underwent prostate-specific membrane antigen (PSMA) positron emission tomography (PET). Patients without visible disease (n = 16) or with metastatic disease not amenable to MDT (n = 19) were excluded from the interventional study. The remaining patients with disease visible on PSMA-PET received MDT (n = 37). We analyzed all three groups to identify distinct phenotypes in the era of molecular imaging–based characterization of recurrent disease. Median follow up was 37 mo (interquartile range 27.5–43.0). There was no significant difference in time to the development of metastasis on conventional imaging among the groups; however, castrate-resistant prostate cancer-free survival was significantly shorter for patients with PSMA-avid disease not amenable to MDT (p = 0.047). Our findings suggest that PSMA-PET findings can help in discriminating diverging clinical phenotypes among men with disease recurrence and negative conventional imaging after local therapies with curative intent. There is a pressing need for better characterization of this rapidly growing population of patients with recurrent disease defined by PSMA-PET to derive robust selection criteria and outcome definitions for ongoing and future studies. Patient summary: In men with prostate cancer with rising PSA levels following surgery and radiation, a newer type of scan called PSMA-PET (prostate-specific membrane antigen positron emission tomography) can be used to characterize and differentiate the patterns of recurrence, and inform future cancer outcomes

The predictive value of nadir neutrophil count during treatment of cervical cancer: Interactions with tumor hypoxia and interstitial fluid pressure (IFP)

Background and purpose: Hypoxia, high interstitial fluid pressure (IFP) and immune effects have individually been shown to modulate radiotherapy (RT) response in cervical cancer. The aim of this study was to investigate the interplay between hypoxia or IFP and circulating neutrophil levels, and their combined effect on survival following RT. Material and methods: A total of 287 FIGO stage IB to IIIB cervical cancer patients treated with RT or RT and cisplatin (RTCT) were included. Tumor hypoxia and IFP were measured at baseline prior to treatment. Absolute neutrophil count (ANC) was measured at baseline and weekly during treatment. Median follow up was 7.1 years. Results: High nadir ANC at the point of maximal myelosuppression was a stronger predictor of inferior survival than high baseline ANC after adjusting for clinical prognostic factors and treatment (RT vs. RTCT). The predictive effect of nadir ANC was most evident in patients with well-oxygenated tumors or tumors with high IFP at diagnosis. Conclusions: This study provides new information about the combined influence of the tumor microenvironment and myeloid cells on the survival of cervical cancer patients treated with RT/RTCT to motivate the development of new treatments based on molecular targeting of immune–based radioresistance pathways

Practice-based training strategy for therapist-driven prostate MR-Linac adaptive radiotherapy

Purpose: To develop a practice-based training strategy to transition from radiation oncologist to therapist-driven prostate MR-Linac adaptive radiotherapy. Methods and materials: In phase 1, 7 therapists independently contoured the prostate and organs-at-risk on T2-weighted MR images from 11 previously treated MR-Linac prostate patients. Contours were evaluated quantitatively (i.e. Dice similarity coefficient [DSC] calculated against oncologist generated online contours) and qualitatively (i.e. oncologist using a 5-point Likert scale; a score ≥ 4 was deemed a pass, a 90% pass rate was required to proceed to the next phase). Phase 2 consisted of supervised online workflow with therapists required no intervention from the oncologist on 10 total cases to advance. Phase 3 involved unsupervised therapist-driven workflow, with offline support from oncologists prior to the next fraction. Results: In phase 1, the mean DSC was 0.92 (range 0.85–0.97), and mean Likert score was 3.7 for the prostate. Five therapists did not attain a pass rate (3–5 cases with prostate contour score < 4), underwent follow-up one-on-one review, and performed contours on a further training set (n = 5). Each participant completed a median of 12 (range 10–13) cases in phase 2; of 82 cases, minor direction were required from the oncologist on 5 regarding target contouring. Radiation oncologists reviewed 179 treatment fractions in phase 3, and deemed 5 cases acceptable but with suggestions for next fraction; all other cases were accepted without suggestions. Conclusion: A training stepwise program was developed and successfully implemented to enable a therapist-driven workflow for online prostate MR-Linac adaptive radiotherapy

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

Abstract Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation. Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan–Meier method. Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106). Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio. Clin Cancer Res; 19(24); 6741–50. ©2013 AACR.</jats:p

European Association of Urology (EAU) Testicular Cancer Guidelines Panel: A new prognostic factor risk group classification for patients with clinical stage 1 seminoma in active surveillance.

...American Society of Clinical Oncolog