Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Stereotactic MRI-guided radiation therapy for localized prostate cancer (SMILE): a prospective, multicentric phase-II-trial.

BACKGROUND: Normofractionated radiation regimes for definitive prostate cancer treatment usually extend over 7-8 weeks. Recently, moderate hypofractionation with doses per fraction between 2.2 and 4 Gy has been shown to be safe and feasible with oncologic non-inferiority compared to normofractionation. Radiobiologic considerations lead to the assumption that prostate cancer might benefit in particular from hypofractionation in terms of tumor control and toxicity. First data related to ultrahypofractionation demonstrate that the overall treatment time can be reduced to 5-7 fractions with single doses > 6 Gy safely, even with simultaneous focal boosting of macroscopic tumor(s). With MR-guided linear accelerators (MR-linacs) entering clinical routine, invasive fiducial implantations become unnecessary. The aim of the multicentric SMILE study is to evaluate the use of MRI-guided stereotactic radiotherapy for localized prostate cancer in 5 fractions regarding safety and feasibility. METHODS: The study is designed as a prospective, one-armed, two-stage, multi-center phase-II-trial with 68 patients planned. Low- and intermediate-risk localized prostate cancer patients will be eligible for the study as well as early high-risk patients (cT3a and/or Gleason Score ≤ 8 and/or PSA ≤ 20 ng/ml) according to d'Amico. All patients will receive definitive MRI-guided stereotactic radiation therapy with a total dose of 37.5 Gy in 5 fractions (single dose 7.5 Gy) on alternating days. A focal simultaneous integrated boost to MRI-defined tumor(s) up to 40 Gy can optionally be applied. The primary composite endpoint includes the assessment of urogenital or gastrointestinal toxicity ≥ grade 2 or treatment-related discontinuation of therapy. The use of MRI-guided radiotherapy enables online plan adaptation and intrafractional gating to ensure optimal target volume coverage and protection of organs at risk. DISCUSSION: With moderate hypofractionation being the standard in definitive radiation therapy for localized prostate cancer at many institutions, ultrahypofractionation could be the next step towards reducing treatment time without compromising oncologic outcomes and toxicities. MRI-guided radiotherapy could qualify as an advantageous tool as no invasive procedures have to precede in therapeutic workflows. Furthermore, MRI guidance combined with gating and plan adaptation might be essential in order to increase treatment effectivity and reduce toxicity at the same time.

Mathematical description of the effect of HIF inhibition on the radiobiological response of LNCaP cells.

According to the National Institute of Public Health, prostate cancer (PCa) is the leading cause of cancer death in Mexican men, highly associated with aggressiveness, resistance to treatment, and metastatic spread (Bharti et al., 2019) mediated by activation of the hypoxia-inducible factor 1 (HIF-1α). The objective of the present study was to evaluate the participation of HIF-1α activation in the radiobiological response of the human prostate adenocarcinoma cell line LNCaP, describing the phenomena with a mathematical model. Four groups were formed under different exposure conditions, including hypoxic cells treated with CoCl2 (300 µM for 22 h) with or without hypoxia-inducible factor inhibitor (150 nM chetomin for 4 h added after an incubation period of 18 h with CoCl2, just before completing the incubation period of 22 h). They were exposed to a source of 60Co in a dose range between 2 and 10 Gy to obtain survival curves that are fitted to a mathematical model. CoCl2 or chetomin treatments do not affect the viability of LNCaP cells that remained unchanged after irradiation. CoCl2 induced hypoxia reduces the survivability of LNCaP, and obstruction of HIF-1α signaling with chetomine produces a slight radioprotective effect. As others report, the genetic reprogramming induced by HIF-1α activation acts as an intrinsic agent that selects cells with more aggressive behavior (Pressley et al., 2017), while chetomin protects cells from death due to its scavenger properties. Interestingly, treatment with chetomin of cells induced to hypoxia (HIF-1 activation with CoCl2) produces a significant reduction in the radioresistance of LNCaP cells, demonstrating that the simultaneous use of chetomin and gamma radiation is an effective option for the treatment of hypoxic prostate cancer. At the molecular level, we suggest that the selective force exerted by HIF-1α depends on the production of free radicals by radiation. The proposed mathematical model showed that the rate of change in cell survival as a function of radiation dose is proportional to the product of two functions, one that describes cell death and the other that describes natural or artificial resistance to radiation.

Improvement in bladder volume reproducibility using A-mode portable ultrasound bladder scanner in moderate-hypofractionated volumetric modulated arc therapy for prostate cancer patients.

PURPOSE: This study introduced an A-mode portable ultrasound bladder scanner, the Lilium® α-200 (here after Lilium; Lilium Otsuka, Kanagawa, Japan), for the treatment of prostate cancer patients with hypofractionated volumetric modulated arc therapy to improve the reproducibility of bladder volume (BV). MATERIALS AND METHODS: Thirty patients were advised to maintain full BV prior to computed tomography (CT) simulation and daily treatment. Among these, the BV of 15 patients was measured using Lilium until a BV of 80% in the simulation was achieved (with the Lilium group). Daily cone-beam CT (CBCT) was performed for treatment. The correlation between BV measured by CBCT and Lilium was assessed. The differences in the BV and dosimetric parameters of the bladder in the CBCT versus planning CT were compared between the groups with and without Lilium. RESULTS: There was a significantly strong relationship (r = 0.796, p < 0.05) between the BVs measured using CBCT and Lilium. The relative BV ratios to simulation CT < 0.5 and > 2 were observed in 10.3% and 12.7%, respectively, of treatment sessions without Lilium group, while these ratios were 1% and 2.8%, respectively, in the Lilium group. The mean absolute difference in the range of V30Gy to V40Gy without Lilium sessions was significantly larger (p < 0.05) than that in the Lilium group. CONCLUSION: The use of the A-mode portable ultrasound bladder scanner significantly improved the reproducibility of the BV, resulting in few variations in the dosimetric parameters for the bladder.

Radiotherapy or Surgery? Comparative, Qualitative Assessment of Online Patient Education Materials on Prostate Cancer.

As multiple different treatment options are available for prostate cancer (PCa) and YouTube is commonly used as a source for medical information, we performed a systematic and comparative assessment of available videos guiding patients on their choice for the optimal treatment. An independent search for surgical therapy or radiotherapy of PCa on YouTube was performed and the 40 most viewed videos of both groups were analyzed. The validated DISCERN questionnaire and PEMAT were utilized to evaluate their quality and misinformation. The median overall quality of the videos was found to be low for surgery videos, while radiotherapy videos results reached a moderate quality. The median PEMAT understandability score was 60% (range 0-100%) for radiotherapy and 75% (range 40-100) for surgery videos. The radiotherapy videos contained less misinformation and were judged to be of higher quality. Summarized, the majority of the provided videos offer insufficient quality of content and are potentially subject to commercial bias without reports on possible conflict of interest. Thus, most of available videos on YouTube informing PCa patients about possible treatment methods are not suited for a balanced patient education or as a basis for the patient's decision.

Frequency and Risk Factors of Sleep Disturbances in Patients With Prostate Cancer Assigned to Local or Loco-regional Radiotherapy.

BACKGROUND/AIM: Many patients with prostate cancer receive definitive or adjuvant radiotherapy. This study aimed to identify the frequency of sleep disturbances and corresponding risk factors prior to radiation treatment. PATIENTS AND METHODS: Data of 48 patients assigned to local or loco-regional irradiation for prostate cancer were retrospectively analyzed for pre-radiotherapy sleep disturbances. Fifteen characteristics were analyzed including age, performance status, comorbidity, history of previous malignancy, distress score, (emotional, physical or practical) problems, prostate-specific antigen, primary tumor stage, Gleason-score, upfront androgen deprivation therapy (ADT), treatment volume, brachytherapy, and COVID-19 pandemic. RESULTS: Pre-radiotherapy sleep disturbances were reported by 20.8% of patients and significantly associated with distress scores ≥4 (p<0.0001) and ≥3 physical problems (p=0.0001). Trends were found for Karnofsky performance score ≤80 (p=0.095), Gleason score 7b-9 (p=0.079), and ADT (p=0.067). CONCLUSION: Pre-radiotherapy sleep disturbances were less common in prostate cancer patients than in other cancer patients. Risk factors were identified that can help identify patients requiring psychological support prior to radiotherapy.

Assessment of Simulated SARS-CoV-2 Infection and Mortality Risk Associated With Radiation Therapy Among Patients in 8 Randomized Clinical Trials.

Importance: During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown. Objective: To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT). Design, Setting, and Participants: This comparative effectiveness study used estimated individual patient-level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020. Exposures: COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs). Main Outcomes and Measures: Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios. Results: Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%). Conclusions and Relevance: In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19-risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.

COVID-19 and radiotherapy: potential new strategies for patients management with hypofractionation and telemedicine.

COVID-19 disease is one of the biggest public health challenges in Italy and global healthcare facilities, including radiotherapy departments, faced an unprecedented emergency. Cancer patients are at higher risk of COVID-19 infection because of their immunosuppressive state caused by both tumor itself and anticancer therapy adopted. In this setting, the radiation therapy clinical decision-making process has been partly reconsidered; thus, to reduce treatment duration and minimize infection risk during a pandemic, hypofractionated regimens have been revised. Moreover, telemedicine shows its helpfulness in the radiotherapy field, and patients get the supportive care they need minimizing their access to hospitals. This review aims to point out the importance of hypofractionated RT and telemedicine in cancer patient management in the COVID-19 era.

A plan template-based automation solution using a commercial treatment planning system.

PURPOSE: The purpose of this study was to develop an auto-planning platform to be interfaced with a commercial treatment planning system (TPS). The main goal was to obtain robust and high-quality plans for different anatomic sites and various dosimetric requirements. METHODS: Monaco (Elekta, St. Louis, US) was the TPS in this work. All input parameters for inverse planning could be defined in a plan template inside Monaco. A software tool called Robot Framework was used to launch auto-planning trials with updated plan templates. The template modifier external to Monaco was the major component of our auto-planning platform. For current implementation, it was a rule-based system that mimics the trial-and-error process of an experienced planner. A template was automatically updated by changing the optimization constraints based on dosimetric evaluation of the plan obtained in the previous trial, along with the data of the iterative optimization extracted from Monaco. Treatment plans generated by Monaco with all plan evaluation criteria satisfied were considered acceptable, and such plans would be saved for further evaluation by clinicians. The auto-planning platform was validated for 10 prostate and 10 head-and-neck cases in comparison with clinical plans generated by experienced planners. RESULTS: The performance and robustness of our auto-planning platform was tested with clinical cases of prostate and head and neck treatment. For prostate cases, automatically generated plans had very similar plan quality with the clinical plans, and the bladder volume receiving 62.5 Gy, 50 Gy, and 40 Gy in auto-plans was reduced by 1%, 3%, and 5%, respectively. For head and neck cases, auto-plans had better conformity with reduced dose to the normal structures but slightly higher dose inhomogeneity in the target volume. Remarkably, the maximum dose in the spinal cord and brain stem was reduced by more than 3.5 Gy in auto-plans. Fluence map optimization only with less than 30 trials was adequate to generate acceptable plans, and subsequent optimization for final plans was completed by Monaco without further intervention. The plan quality was weakly dependent on the parameter selection in the initial template and the choices of the step sizes for changing the constraint values. CONCLUSION: An automated planning platform to interface with Monaco was developed, and our reported tests showed preliminary results for prostate and head and neck cases.

COVID-19 impact on timing of brachytherapy treatment and strategies for risk mitigation.

PURPOSE: The purpose of this study was to highlight the importance of timely brachytherapy treatment for patients with gynecologic, breast, and prostate malignancies, and provide a framework for brachytherapy clinical practice and management in response to the COVID-19 pandemic. METHODS AND MATERIALS: We review amassing evidence to help guide the management and timing of brachytherapy for gynecologic, breast, and prostate cancers. Where concrete data could not be found, peer-reviewed expert opinion is provided. RESULTS: There may be a significant negative impact on oncologic outcomes for patients with gynecologic malignancies who have a delay in the timely completion of therapy. Delay of prostate or breast cancer treatment may also impact oncologic outcomes. If a treatment delay is expected, endocrine therapy may be an appropriate temporizing measure before delivery of radiation therapy. The use of shorter brachytherapy fractionation schedules will help minimize patient exposure and conserve resources. CONCLUSIONS: Brachytherapy remains a critical treatment for patients and may shorten treatment time and exposure for some. Reduced patient exposure and resource utilization is important during COVID-19. Every effort should be made to ensure timely brachytherapy delivery for patients with gynecologic malignancies, and endocrine therapy may help temporize treatment delays for breast and prostate cancer patients. Physicians should continue to follow developing institutional, state, and federal guidelines/recommendations as challenges in delivering care during COVID-19 will continue to evolve.

[Practical update of total dose compensation in case of temporary interruption of external radiotherapy in the COVID-19 pandemic context]. / Compensation de la dose totale en cas d'interruption temporaire de radiothérapie externe dans le contexte de la pandémie de COVID-19 : mise au point pratique.

Overall treatment time is an important factor of local recurrence and indirectly of distant evolution, namely in case of protracted treatments. The current pandemic impacts on the duration of radiotherapy if patients under treatments and synchronously suffering from COVID-19. The models used to compensate the total dose in case of temporary treatment interruption are well known but it is of importance in that pandemic context to update and homogenize clinical practice in order to improve local control without increasing normal tissue complications.