A Century of Fractionated Radiotherapy: How Mathematical Oncology Can Break the Rules.

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the past century and does not account for the development of radioresistance during treatment. Even if under-optimized, deviating from a century of successful therapy delivered in FED can be difficult. One way of exploring the infinite space of fraction size and scheduling to identify optimal fractionation schedules is through mathematical oncology simulations that allow for in silico evaluation. This review article explores the evidence that current fractionation promotes the development of radioresistance, summarizes mathematical solutions to account for radioresistance, both in the curative and non-curative setting, and reviews current clinical data investigating non-FED fractionated radiotherapy.

Clinically validated model predicts the effect of intratumoral heterogeneity on overall survival for non-small cell lung cancer (NSCLC) patients.

BACKGROUND AND OBJECTIVE: Radiation therapy is used in nearly 50% of cancer treatments in the developed world. Currently, radiation treatments are homogenous and fail to take into consideration intratumoral heterogeneity. We demonstrate the importance of considering intratumoral heterogeneity and the development of resistance during fractionated radiotherapy when the same dose of radiation is delivered for all fractions (Fractional Equivalent Dosing FED). METHODS: A mathematical model was developed with the following parameters: a starting population of 1011 non-small cell lung cancer (NSCLC) tumor cells, 48 h doubling time, and cell death per the linear-quadratic (LQ) model with α and ß values derived from RSIα/ß, in a previously described gene expression based model that estimates α and ß. To incorporate both inter- and intratumor radiation sensitivity, RSIα/ß output for each patient sample is assumed to represent an average value in a gamma distribution with the bounds set to -50% and +50% of RSIα/b. Therefore, we assume that within a given tumor there are subpopulations that have varying radiation sensitivity parameters that are distinct from other tumor samples with a different mean RSIα/ß. A simulation cohort (SC) comprised of 100 lung cancer patients with available RSIα/ß (patient specific α and ß values) was used to investigate 60 Gy in 30 fractions with fractionally equivalent dosing (FED). A separate validation cohort (VC) of 57 lung cancer patients treated with radiation with available local control (LC), overall survival (OS), and tumor gene expression was used to clinically validate the model. Cox regression was used to test for significance to predict clinical outcomes as a continuous variable in multivariate analysis (MVA). Finally, the VC was used to compare FED schedules with various altered fractionation schema utilizing a Kruskal-Wallis test. This was examined using the end points of end of treatment log cell count (LCC) and by a parameter described as mean log kill efficiency (LKE) defined as: LCC  = â€…log10(tumorcellcount) [Formula: see text] RESULTS: Cox regression analysis on LCC for the VC demonstrates that, after incorporation of intratumoral heterogeneity, LCC has a linear correlation with local control (p = 0.002) and overall survival (p = < 0.001). Other suggested treatment schedules labeled as High Intensity Treatment (HIT) with a total 60 Gy delivered over 6 weeks have a lower mean LCC and an increased LKE compared to standard of care 60 Gy delivered in FED in the VC. CONCLUSION: We find that LCC is a clinically relevant metric that is correlated with local control and overall survival in NSCLC. We conclude that 60 Gy delivered over 6 weeks with altered HIT fractionation leads to an enhancement in tumor control compared to FED when intratumoral heterogeneity is considered.

Intermittent radiotherapy as alternative treatment for recurrent high grade glioma: a modeling study based on longitudinal tumor measurements.

Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, [Formula: see text] Gy [Formula: see text] 5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering high dose intermittent radiation treatment (iRT, [Formula: see text] Gy [Formula: see text] 1 every 6 weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost ([Formula: see text] Gy [Formula: see text] 3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumor growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/- boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modeling results demonstrated that iRT + boost(- boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients for prospective clinical evaluation.

A Proof-of-Concept Study on the Use of Prostate Artery Embolization Before Definitive Radiation Therapy in Prostate Cancer.

PURPOSE: Prostatic artery embolization (PAE) is an effective therapy for alleviating lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia; however, is not well studied in patients with concurrent prostate cancer (PCa). We demonstrate a proof of concept for PAE before definitive radiation therapy (RT) in patients with PCa. METHODS AND MATERIALS: From December 2017 to July 2019, 9 patients with PCa underwent PAE for the indication of LUTS from benign prostatic hyperplasia with concurrent PCa. Five received radiation and all follow-ups at our institution and were therefore included in the analysis. Median follow-up was 18 months from the time of PAE. Side effects during radiation were quantified using the Common Terminology Criteria for Adverse Events scoring system. Pre- and post-PAE plans were compared in the 5 patients by performing an isovolumetric expansion of the post-PAE plan (treated plan) equivalent to the measured volume reduction after PAE. Patient 1 (PT-01) and PT-02 had prostate RT alone whereas PT-03, PT-04, and PT-05 had prostate with elective nodal coverage RT. Mean doses to organs at risk were compared between the 2 plans. RESULTS: The mean International Prostate Symptom Score reduction after PAE was 13.8 (5.0-30.0; P = .02). The mean prostatic volume reduction after PAE was 23.1% (7.2%-47.7%). There were no Common Terminology Criteria for Adverse Events grade 3 (severe) or higher during radiation. Post-PAE plans in PT-01 and PT-02 had on average 23.2%, 39.8%, and 22.9% decrease in mean dose across the bladder, rectum, and penile bulb, respectively, compared with the pre-PAE plans. There were no appreciable differences in dosimetry in PT03, PT-04, and PT-05 who had nodal coverage. There was no biochemical failure in any of the patients. CONCLUSIONS: We demonstrate a proof of concept that PAE is a clinically significant adjunctive therapy for alleviating LUTS and achieving significant volume reduction before RT, resulting in decreased radiation-related toxicity from RT for PCa.

Personalizing Radiotherapy Prescription Dose Using Genomic Markers of Radiosensitivity and Normal Tissue Toxicity in NSCLC.

INTRODUCTION: Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation. METHODS: We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics. RESULTS: Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit. CONCLUSIONS: Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT.

Harnessing COVID-Driven Technical Innovations for Improved Multi-Disciplinary Cancer Care in the Post-COVID Era: The Virtual Patient Room.

Emergence of the COVID-19 crisis has catalyzed rapid paradigm shifts throughout medicine. Even after the initial wave of the virus subsides, a wholesale return to the prior status quo is not prudent. As a specialty that values the proper application of new technology, radiation oncology should strive to be at the forefront of harnessing telehealth as an important tool to further optimize patient care. We remain cognizant that telehealth cannot and should not be a comprehensive replacement for in-person patient visits because it is not a one for one replacement, dependent on the intention of the visit and patient preference. However, we envision the opportunity for the virtual patient "room" where multidisciplinary care may take place from every specialty. How we adapt is not an inevitability, but instead, an opportunity to shape the ideal image of our new normal through the choices that we make. We have made great strides toward genuine multidisciplinary patient-centered care, but the continued use of telehealth and virtual visits can bring us closer to optimally arranging the spokes of the provider team members around the central hub of the patient as we progress down the road through treatment.

Using the Radiosensitivity Index (RSI) to Predict Pelvic Failure in Endometrial Cancer Treated With Adjuvant Radiation Therapy.

PURPOSE: Variability exists in the adjuvant treatment for endometrial cancer (EC) based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multigene expression index that estimates tumor radiosensitivity. We evaluate RSI as a genomic predictor for pelvic failure (PF) in EC patients treated with adjuvant radiation therapy (RT). METHODS AND MATERIALS: Using our institutional tissue biorepository, we identified EC patients treated between January 1999 and April 2011 with primarily endometrioid histology (n = 176; 86%) who received various adjuvant therapies. The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined using the previously identified cutpoint where RSI ≥ 0.375 denotes radioresistance (RR) and RSI < 0.375 describes radiosensitivity. RESULTS: A total of 204 patients were identified, of which 83 (41%) were treated with adjuvant RT. Median follow-up was 38.5 months. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n = 181; 88%). In patients treated with radiation, RR tumors were more likely to experience PF (3-year pelvic control 84% vs 100%; P = .02) with worse PF-free survival (PFFS) (3-year PFFS 65% vs 89%; P = .04). Furthermore, in the patients who did not receive RT, there was no difference in PF (P = .87) or PFFS (P = .57) between the RR/radiosensitive tumors. On multivariable analysis, factors that continued to predict for PF included the RR phenotype (hazard ratio [HR], 12.2; P = .003), lymph node involvement (HR, 4.4; P = .02), and serosal or adnexal involvement (HR, 5.3; P = .01). CONCLUSIONS: On multivariable analysis, RSI was found to be a significant predictor of PF in patients treated with adjuvant RT. We propose using RSI to predict which patients are at higher risk for failing in the pelvis and may be candidates for treatment escalation in the adjuvant setting.

Fibroblasts and alectinib switch the evolutionary games played by non-small cell lung cancer.

Heterogeneity in strategies for survival and proliferation among the cells that constitute a tumour is a driving force behind the evolution of resistance to cancer therapy. The rules mapping the tumour's strategy distribution to the fitness of individual strategies can be represented as an evolutionary game. We develop a game assay to measure effective evolutionary games in co-cultures of non-small cell lung cancer cells that are sensitive and resistant to the anaplastic lymphoma kinase inhibitor alectinib. The games are not only quantitatively different between different environments, but targeted therapy and cancer-associated fibroblasts qualitatively switch the type of game being played by the in vitro population from Leader to Deadlock. This observation provides empirical confirmation of a central theoretical postulate of evolutionary game theory in oncology: we can treat not only the player, but also the game. Although we concentrate on measuring games played by cancer cells, the measurement methodology we develop can be used to advance the study of games in other microscopic systems by providing a quantitative description of non-cell-autonomous effects.

Efficacy of hospital germicides against adenovirus 8, a common cause of epidemic keratoconjunctivitis in health care facilities.

The inactivation of virus-contaminated nonporous inanimate surfaces was investigated using adenovirus type 8, a common cause of epidemic keratoconjunctivitis. A 10-microl inoculum of adenovirus was placed onto each stainless steel disk (1-cm diameter), and the inoculum was allowed to air dry for 40 min. Twenty-one different germicides (including disinfectants and antiseptics) were selected for this study based on their current uses in health care. After a 1- or 5-minute exposure to 50 microl of the germicide, the virus-germicide test mixture was neutralized and assayed for infectivity. Using an efficacy criterion of a 3-log10 reduction in the titer of virus infectivity and regardless of the virus suspending medium (i.e., hard water, sterile water, and hard water with 5% fetal calf serum), only five disinfectants proved to be effective against the test virus at 1 min: 0.55% ortho-phthalaldehyde, 2.4% glutaraldehyde, 2.65% glutaraldehyde, approximately 6,000 ppm chlorine, and approximately 1,900 ppm chlorine. Four other disinfectants showed effectiveness under four of the five testing conditions: 70% ethanol, 65% ethanol with 0.63% quaternary ammonium compound, 79.6% ethanol with 0.1% quaternary ammonium compound, and 0.2% peracetic acid. Of the germicides suitable for use as an antiseptic, 70% ethanol achieved a 3-log10 reduction under four of the five test conditions. These results emphasize the need for proper selection of germicides for use in disinfecting noncritical surfaces and semicritical medical devices, such as applanation tonometers, in order to prevent outbreaks of epidemic keratoconjunctivitis.

The seroprevalence of Helicobacter pylori in a referral population of children in the United States.

OBJECTIVES: The purpose of this study was to determine the prevalence of serum antibodies directed against Helicobacter pylori (H. pylori) in children referred to children's hospitals or medical centers throughout the United States. METHODS: This multisite cross-sectional prospective study involved 992 children from 12 states using a validated anti-H. pylori IgG enzyme immunoassay. The children were recruited into two groups: those without any GI complaints (non-GI referral, n = 619) and those who were referred for endoscopy because of abdominal pain (GI referral, n = 373). RESULTS: GI referral children had a higher rate of seropositivity (22.5%) than non-GI referral children (14.1%) from the same geographic regions. In both groups, older children were more likely to be seropositive for H. pylori, as were nonwhite children and those with lower socioeconomic status. H. pylori seropositivity rates were higher in GI referral children with four or more household members (relative risk [RR] = 1.47; CI 1.01-2.14). Multivariate analysis controlling for age, ethnicity, and household income, showed that presence of GI symptoms were associated with a nearly 2-fold risk for H. pylori seropositivity (odds ratio = 1.77, CI 1.27-2.47). Epigastric pain (RR = 2.21; CI = 1.33-3.66) and having three or more episodes of abdominal pain in the last 3 months (RR = 0.59, CI = 0.35-0.99) were the only specific symptoms significantly associated with H. pylori seropositivity. CONCLUSIONS: The H. pylori seropositivity rate of GI referral children with symptoms of abdominal pain was significantly higher. H. pylori infection in early childhood was found to be associated primarily with the child's household size and socioeconomic status.

Evaluation of the effects of strain-specific antigen variation on the accuracy of serologic diagnosis of Helicobacter pylori infection.

It has been suggested that enzyme immunoassay (EIA) kits validated in one region may yield variable diagnostic performance results in different regions, possibly due to strain-specific differences in antibody responses in different populations. We tested (13)C-urea breath test-characterized serum samples from 109 U.S. patients and 288 Japanese patients using enzyme immunoassay with different preparations of high-molecular-weight cell-associated (HM-CAP) antigens that are conserved across Helicobacter pylori strains. Replicate antigens were prepared from five H. pylori clinical isolates. Eight antigen preparations were evaluated: two of U.S. origin and six of Japanese origin. The accuracies achieved with the eight antigen preparations ranged from 94.4 to 96.3% with the U.S. samples. With the Japanese samples the accuracies achieved ranged from 92.3 to 97.2%. Use of a pool of HM-CAP antigens prepared from isolates from Japan resulted in a higher median enzyme immunoassay value and slightly fewer samples with indeterminate results compared to the results obtained by use of the U.S. standard HM-CAP antigen for H. pylori-positive patients (accuracies, 97.2 and 92.3%, respectively), suggesting that variations in performance between both antigen source and patient population might be reduced by using antigens pooled from several strains.