Automated Radiation Therapy Patient Scheduling: A Case Study at a Belgian Hospital

The predicted increase in the number of patients receiving radiation therapy (RT) to treat cancer calls for an optimized use of resources. To manually schedule patients on the linear accelerators delivering RT is a time-consuming and challenging task. Operations research (OR), a discipline in applied mathematics, uses a variety of analytical methods to improve decision-making. In this paper, we study the implementation of an OR method that automatically generates RT patient schedules at an RT center with ten linear accelerators. The OR method is designed to produce schedules that mimic the objectives used in the clinical scheduling while following the medical and technical constraints. The resulting schedules are clinically validated and compared to manually constructed, historical schedules for a time period of one year. It is shown that the use of OR to generate schedules decreases the average patient waiting time by 80%, improves the consistency in treatment times between appointments by 80%, and increases the number of treatments scheduled the machine best suited for the treatment by more than 90% compared to the manually constructed clinical schedules, without loss of performance in other quality metrics. Furthermore, automatically creating patient schedules can save the clinic many hours of administrative work every week.Comment: 11 page

Comparing Optimization Methods for Radiation Therapy Patient Scheduling using Different Objectives

Radiation therapy (RT) is one of the most common technologies used to treat cancer. To better use resources in RT, optimization models can be used to automatically create patient schedules, a task that today is done manually in almost all clinics. This paper presents a comprehensive study of different optimization methods for modeling and solving the RT patient scheduling problem. The results can be used as decision support when implementing an automatic scheduling algorithm in practice. We introduce an Integer Linear Programming (IP) model, a column generation IP model (CG-IP), and a Constraint Programming model. Patients are scheduled on multiple machine types considering their priority for treatment, session duration and allowed machines, while taking expected future patient arrivals into account. Different cancer centers may have different scheduling objectives, and therefore each model is solved using multiple different objective functions, including minimizing waiting times, and maximizing the fulfillment of patients' preferences for treatment times. The test data is generated from historical data from Iridium Netwerk, a large cancer center in Belgium with 10 linear accelerators. The results demonstrate that the CG-IP model can solve all the different problem instances to a mean optimality gap of less than 1% within one hour. The proposed methodology provides a tool for automated scheduling of RT treatments and can be generally applied to RT centers.Comment: 20 pages, 4 figures, Submitted to Operations Research Foru

A phase III randomized-controlled, single-blind trial to improve quality of life with stereotactic body radiotherapy for patients with painful bone metastases (ROBOMET)

Background Bone metastases represent an important source of morbidity in cancer patients, mostly due to severe pain. Radiotherapy is an established symptomatic treatment for painful bone metastases, however, when conventional techniques are used, the effectiveness is moderate. Stereotactic body radiotherapy (SBRT), delivering very high doses in a limited number of fractions in a highly conformal manner, could potentially be more effective and less toxic. Methods This is a phase III, randomized-controlled, single-blind, multicenter study evaluating the response rate of antalgic radiotherapy for painful bone metastases and the acute toxicity associated with this treatment. A total of 126 patients will be randomly assigned to receive either the standard schedule of a single fraction of 8.0 Gy delivered through three-dimensional conformal radiotherapy or a single fraction of 20.0 Gy delivered through SBRT. Primary endpoint is pain response at the treated site at 1 month after radiotherapy. Secondary endpoints are pain flare at 24-48-72 h after radiotherapy, duration of pain response, re-irradiation need, acute toxicity, late toxicity, quality of life and subsequent serious skeletal events. In a supplementary analysis, patient-compliance for a paper-and-pencil questionnaire will be compared with an electronic mode. Discussion If a dose-escalated approach within the context of single fraction stereotactic body radiotherapy could improve the pain response to radiotherapy and minimize acute toxicity, this would have an immediate impact on the quality of life for a large number of patients with advanced cancer. Potential disadvantages of this technique include increased pain flare or a higher incidence of radiation-induced fractures. Trial registration: The Ethics committee of the GZA Hospitals (B099201732915) approved this study on September 4th 2018. Trial registered on Clinicaltrials. gov (NCT03831243) on February 5th 2019

GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients

International audienceGenetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46x10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16x10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors

Stereotactic Body and Conventional Radiotherapy for Painful Bone Metastases: A Systematic Review and Meta-Analysis

IMPORTANCE: Conventional external beam radiotherapy (cEBRT) and stereotactic body radiotherapy (SBRT) are commonly used treatment options for relieving metastatic bone pain. The effectiveness of SBRT compared with cEBRT in pain relief has been a subject of debate, and conflicting results have been reported. OBJECTIVE: To compare the effectiveness associated with SBRT vs cEBRT for relieving metastatic bone pain. DATA SOURCES: A structured search was performed in the PubMed, Embase, and Cochrane databases on June 5, 2023. Additionally, results were added from a new randomized clinical trial (RCT) and additional unpublished data from an already published RCT. STUDY SELECTION: Comparative studies reporting pain response after SBRT vs cEBRT in patients with painful bone metastases. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data from eligible studies. Data were extracted for the intention-to-treat (ITT) and per-protocol (PP) populations. The study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. MAIN OUTCOMES AND MEASURES: Overall and complete pain response at 1, 3, and 6 months after radiotherapy, according to the study's definition. Relative risk ratios (RRs) with 95% CIs were calculated for each study. A random-effects model using a restricted maximum likelihood estimator was applied for meta-analysis. RESULTS: There were 18 studies with 1685 patients included in the systematic review and 8 RCTs with 1090 patients were included in the meta-analysis. In 7 RCTs, overall pain response was defined according to the International Consensus on Palliative Radiotherapy Endpoints in clinical trials (ICPRE). The complete pain response was reported in 6 RCTs, all defined according to the ICPRE. The ITT meta-analyses showed that the overall pain response rates did not differ between cEBRT and SBRT at 1 (RR, 1.14; 95% CI, 0.99-1.30), 3 (RR, 1.19; 95% CI, 0.96-1.47), or 6 (RR, 1.22; 95% CI, 0.96-1.54) months. However, SBRT was associated with a higher complete pain response at 1 (RR, 1.43; 95% CI, 1.02-2.01), 3 (RR, 1.80; 95% CI, 1.16-2.78), and 6 (RR, 2.47; 95% CI, 1.24-4.91) months after radiotherapy. The PP meta-analyses showed comparable results. CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, patients with painful bone metastases experienced similar overall pain response after SBRT compared with cEBRT. More patients had complete pain alleviation after SBRT, suggesting that selected subgroups will benefit from SBRT

Differential Modulation of TNF-α–Induced Apoptosis by Neisseria meningitidis

Infections by Neisseria meningitidis show duality between frequent asymptomatic carriage and occasional life-threatening disease. Bacterial and host factors involved in this balance are not fully understood. Cytopathic effects and cell damage may prelude to pathogenesis of isolates belonging to hyper-invasive lineages. We aimed to analyze cell–bacteria interactions using both pathogenic and carriage meningococcal isolates. Several pathogenic isolates of the ST-11 clonal complex and carriage isolates were used to infect human epithelial cells. Cytopathic effect was determined and apoptosis was scored using several methods (FITC-Annexin V staining followed by FACS analysis, caspase assays and DNA fragmentation). Only pathogenic isolates were able to induce apoptosis in human epithelial cells, mainly by lipooligosaccharide (endotoxin). Bioactive TNF-α is only detected when cells were infected by pathogenic isolates. At the opposite, carriage isolates seem to provoke shedding of the TNF-α receptor I (TNF-RI) from the surface that protect cells from apoptosis by chelating TNF-α. Ability to induce apoptosis and inflammation may represent major traits in the pathogenesis of N. meningitidis. However, our data strongly suggest that carriage isolates of meningococci reduce inflammatory response and apoptosis induction, resulting in the protection of their ecological niche at the human nasopharynx

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Escalation of stereotactic ablative radiotherapy as metastasis-directed therapy

Abstract: Stereotactic ablative body radiotherapy (SABR or SBRT) is a precise radiation therapy used for extracranial tumors, delivering high doses in one or a few sessions for effective tumor eradication. Its focused approach minimizes damage to surrounding tissues, making it ideal for metastatic cancer management. SBRT serves as a non-invasive Metastasis-Directed Therapy (MDT) for oligometastatic disease, achieving long-term control, and for palliative care in conditions like bone metastases. This research explores SBRT applications, evaluating its efficacy in disease control and patient outcomes. The first part of the thesis focuses on SABR for oligometastases. The DESTROY trial tested three fractionation schedules for non-spine bone and lymph node metastases. No grade 653 toxicity occurred among 90 patients, and despite lower PTV coverage in the 5-fraction cohort, local control was comparable. After a median follow-up of 50 months, grade 2 toxicity was comparable between the three arms, and local control rate was 93% at 4 years. Overall, all three schedules were feasible, effective, with low toxicity, highlighting the convenience of the single-fraction approach. Additionally, as SABR is commonly used for oligometastatic prostate cancer, which typically follows a relatively indolent disease progression with frequent relapses in the regional pelvic lymph nodes and predominantly metastasizes to the skeleton, we investigated the outcomes of SABR for both bone and nodal metastases in a real-life cohort of prostate cancer patients at our centre, finding a median disease-free survival of 22 months for hormone-sensitive prostate cancer (HSPC). Combining SABR with short-term androgen-deprivation therapy improved progression-free survival in specific HSPC cases. At 18 months, 2 in 5 patients remained free from relapse, identifying true oligometastatic cases. In the second part of the thesis, we explore SBRT's impact on pain palliation for bone metastases, known for causing severe pain. The ROBOMET trial compared a single SBRT fraction of 20 Gy with a single conventional fraction of 8 Gy. While SBRT didn't significantly improve pain response after one month, it outperformed conventional radiotherapy after three months. Dose-escalated SBRT achieved over 50% complete pain response compared to 31% with conventional radiotherapy, particularly benefiting patients with better prognoses. While not advantageous for patients with short life expectancy, SBRT demonstrated improved pain response durability for those with more favorable prognoses. This comprehensive exploration underscores SBRT's versatility in managing oligometastases and mitigating metastatic bone pain, shedding light on its efficacy and impact on patient well-being