Metabolic factors associated with the prognosis of oligometastatic patients treated with stereotactic body radiotherapy.

Over the past two decades, it has been established that cancer patients with oligometastases, i.e., only a few detectable metastases confined to one or a few organs, may benefit from an aggressive local treatment approach such as the application of high-precision stereotactic body radiotherapy (SBRT). Specifically, some studies have indicated that achieving long-term local tumor control of oligometastases is associated with prolonged overall survival. This motivates investigations into which factors may modify the dose-response relationship of SBRT by making metastases more or less radioresistant. One such factor relates to the uptake of the positron emission tomography tracer 2-deoxy-2-[18F]fluoro-D-glucose (FDG) which reflects the extent of tumor cell glycolysis or the Warburg effect, respectively. Here we review the biological mechanisms how the Warburg effect drives tumor cell radioresistance and metastasis and draw connections to clinical studies reporting associations between high FDG uptake and worse clinical outcomes after SBRT for oligometastases. We further review the evidence for distinct metabolic phenotypes of metastases preferentially seeding to specific organs and their possible translation into distinct radioresistance. Finally, evidence that obesity and hyperglycemia also affect outcomes after SBRT will be presented. While delivered dose is the main determinant of a high local tumor control probability, there might be clinical scenarios when metabolic targeting could make the difference between achieving local control or not, for example when doses have to be compromised in order to spare neighboring high-risk organs, or when tumors are expected to be highly therapy-resistant due to heavy pretreatment such as chemotherapy and/or radiotherapy.

Dose prescription for stereotactic body radiotherapy: general and organ-specific consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery.

PURPOSE AND OBJECTIVE: To develop expert consensus statements on multiparametric dose prescriptions for stereotactic body radiotherapy (SBRT) aligning with ICRU report 91. These statements serve as a foundational step towards harmonizing current SBRT practices and refining dose prescription and documentation requirements for clinical trial designs. MATERIALS AND METHODS: Based on the results of a literature review by the working group, a two-tier Delphi consensus process was conducted among 24 physicians and physics experts from three European countries. The degree of consensus was predefined for overarching (OA) and organ-specific (OS) statements (≥ 80%, 60-79%, < 60% for high, intermediate, and poor consensus, respectively). Post-first round statements were refined in a live discussion for the second round of the Delphi process. RESULTS: Experts consented on a total of 14 OA and 17 OS statements regarding SBRT of primary and secondary lung, liver, pancreatic, adrenal, and kidney tumors regarding dose prescription, target coverage, and organ at risk dose limitations. Degree of consent was ≥ 80% in 79% and 41% of OA and OS statements, respectively, with higher consensus for lung compared to the upper abdomen. In round 2, the degree of consent was ≥ 80 to 100% for OA and 88% in OS statements. No consensus was reached for dose escalation to liver metastases after chemotherapy (47%) or single-fraction SBRT for kidney primaries (13%). In round 2, no statement had 60-79% consensus. CONCLUSION: In 29 of 31 statements a high consensus was achieved after a two-tier Delphi process and one statement (kidney) was clearly refused. The Delphi process was able to achieve a high degree of consensus for SBRT dose prescription. In summary, clear recommendations for both OA and OS could be defined. This contributes significantly to harmonization of SBRT practice and facilitates dose prescription and reporting in clinical trials investigating SBRT.

Brooke-Spiegler syndrome: radiotherapy as the last resort?

PURPOSE: To describe the case of successful radiotherapeutic treatment of a woman suffering from Brooke-Spiegler syndrome who had multiple disfiguring cylindromas on the entire scalp and further tumors on the trunk. METHODS: After decades of treatment with conventional therapies including surgery and topically applied salicylic acid, the 73-year-old woman agreed to undergo radiotherapeutic treatment. She received 60 Gy to the scalp and 36 Gy to painful nodules in the lumbar spine region. RESULTS: Over a follow-up period of 14 and 11 years, respectively, the scalp nodules almost completely regressed, while the lumbar nodules became painless and considerably smaller. Apart from alopecia, no late adverse effects of treatment remain. CONCLUSION: This case should remind us of the potential role that radiotherapy could play in treating Brooke-Spiegler syndrome. The required dose for treatment of such extensive disease is still a matter of debate due to the scarcity of radiotherapeutic experience. This case demonstrates that for scalp tumors, 30â€¯× 2 Gy can result in long-term tumor control, while other dose prescriptions may be adequate for tumors in other locations.

Effect of Ketogenic Diets on Cardio-Metabolic Outcomes in Cancer Patients: A Systematic Review and Meta-Analysis of Controlled Clinical Trials.

In this systematic review and meta-analysis of clinical controlled trials (CCTs) we aimed to investigate the efficacy of KDs as an adjuvant therapy on cardiometabolic outcomes in patient with cancer compared to conventional non-ketogenic diets. Only CCTs involving cancer patients that were assigned to either a KD or a standard diet control group were selected. Two reviewers independently extracted the data, and a meta-analysis was performed using a random effects model to estimate weighted mean differences (WMDs) and confidence intervals (CIs) in body composition, metabolite, lipid profile, liver and kidney function parameters and quality of life. This meta-analysis showed a significant reduction in body weight (WMD= -2.99 kg; 95% CI: -4.67, -1.31; and P < 0.001), BMI (WMD= -1.08 kg/m2; 95% CI: -1.81, -0.34; P ≤ 0.002) and fat mass (WMD= -1.48 kg; 95% CI: -2.56, -0.40; and P = 0.007) by a KD. KDs significantly decreased glucose (WMD= -5.22 mg/dl; 95% CI: -9.0, -1.44; and P = 0.007), IGF-1 (WMD= -17.52 ng/ml; 95% CI: -20.24, -14.8; and P ˂0.001) and triglyceride (WMD= -24.46 mg/dl; 95% CI: -43.96, -4.95; and P = 0.014) levels. Furthermore, KDs induced ketosis by increasing ß-hydroxybutyrate (WMD= 0.56 mmol/l; 95% CI: 0.37, 0.75; and P < 0.001). There were non-significant pooled effects of KDs on improving insulin, C-reactive protein and cholesterol levels and kidney and liver function. Emotional functioning was even increased significantly in the KD compared to the SD groups. In summary we found that KDs result in a greater reduction in glucose, IGF-1, triglycerides, body weight, BMI, and fat mass in cancer patients compared to traditional non-ketogenic diets and improved emotional functioning. The quality of evidence in the meta-analysis was moderate according to the Nutrigrade assessment.

Impact of a ketogenic diet intervention during radiotherapy on body composition: V. Final results of the KETOCOMP study for head and neck cancer patients.

PURPOSE: Patients with head and neck cancer (HNC) are at risk of malnutrition, especially during radiochemotherapy. We aimed to study the impact of a ketogenic diet (KD) versus an unspecified standard diet (SD) on body composition and survival in HNC patients undergoing radio(chemo)therapy. METHODS: As part of a controlled clinical trial, non-metastasized HNC patients were enrolled into either a KD (N = 11) or an SD (N = 21) group between May 2015 and May 2021. Body composition was measured weekly by bioimpedance analysis and analyzed using linear mixed effects models. Overall and progression-free survival was assessed during regular follow-up. RESULTS: A total of 7 KD and 21 SD patients completed the study and were eligible for comparative analysis. Chemotherapy was significantly associated with declines in all body composition parameters, while the KD had opposing, yet nonsignificant effects. In patients receiving chemotherapy, average weekly reductions of body mass (BM) and skeletal muscle mass (SMM) were 0.9 kg and 0.31 kg in the KD group versus 1.2 kg and 0.57 kg in the SD group, respectively. Patients in the KD group receiving no chemotherapy achieved an average increase of 0.04 kg BM and 0.12 kg SMM per week. After a median follow-up of 42 months (range 6.7-78 months) there were no significant differences in progression-free or overall survival between the groups. CONCLUSION: The KD may partially counteract the detrimental effects of radiochemotherapy on body composition in HNC patients. This should encourage further research into KDs in frail cancer patient populations and motivate their implementation as complementary therapy for selected patients.

Accelerated hyper-versus normofractionated radiochemotherapy with temozolomide in patients with glioblastoma: a multicenter retrospective analysis.

BACKGROUND AND PURPOSE: The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis. MATERIALS AND METHODS: A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset. RESULTS: After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis. CONCLUSIONS: Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.

Ketogenic diets consumed during radio-chemotherapy have beneficial effects on quality of life and metabolic health in patients with rectal cancer.

PURPOSE: Interest in ketogenic diets (KDs) as complementary nutritional treatments for cancer patients is rising, although some skepticism about their safety exists. We, therefore, studied the effects of KDs on quality of life and blood parameters in rectal cancer patients undergoing radio-chemotherapy. METHODS: EORTC-QLQ30 questionnaire scores and different metabolic and hormonal blood parameters were obtained prior to, in the middle of and at the end of radiotherapy within the KETOCOMP study (ClinicalTrials.gov Identifier: NCT02516501). A total of 18 patients consuming a KD were compared to 23 patients consuming their standard diet (SD). Baseline-end differences were measured using Wilcoxon tests, and repeated measures analysis was performed using linear mixed effects models. RESULTS: Eighty-nine percent of patients on the KD reported subjectively feeling good or very good, but roughly half of them rated the daily routine implementation as difficult. Only the SD group experienced significant declines in physical and role functioning, while the KD group improved in role (p = 0.045), emotional (p = 0.018) and social functioning (p = 0.009).Urinary frequency, buttock pain and fatigue significantly increased in the SD group, but to a much lesser extent in the KD group. Several biomarkers of metabolic health (gamma-glutamyl-transpeptidase, triglyceride-glucose index, HDL cholesterol/triglyceride ratio, and free T3) improved in the KD, but not the SD group. CONCLUSIONS: Despite being perceived as difficult to implement by ≈50% of patients, KDs are feasible as complementary therapies alongside radio-chemotherapy and associated with subjective well-being. The hypothesis that they exert beneficial effects on quality of life and metabolic health in rectal cancer patients is supported by our data. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02516501, registered Aug 6th 2015.

Stereotactic or conformal radiotherapy for adrenal metastases: Patient characteristics and outcomes in a multicenter analysis.

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway.

Impact of a ketogenic diet intervention during radiotherapy on body composition: III-final results of the KETOCOMP study for breast cancer patients.

BACKGROUND: Obesity and low muscle mass are associated with worse outcomes of breast cancer patients. We conducted a controlled trial to study the impact of a ketogenic diet (KD) based on natural foods versus an unspecified standard diet (SD) on body composition in breast cancer patients undergoing radiotherapy. METHODS: Patients with non-metastasized breast cancer were allocated to either the KD (N = 32) or the SD (N = 31) during radiotherapy. Body composition was measured weekly by bioimpedance analysis. Blood parameters and quality of life were assessed before, during, and at the end of radiotherapy. RESULTS: A total of 29 KD and 30 SD patients completed the study. During radiotherapy, mean and median fasting BHB concentrations in the KD group were 0.72 and 0.49 mmol/l (range 0.06-4.9) which was significantly higher than those in the SD group (p < 2.2 × 10-16). There was a very small and insignificant increase in body weight and fat mass in the SD group, as well as a decrease of fat free mass. In contrast, patients in the KD group lost body weight and fat free and skeletal muscle mass quickly after diet onset, which for the most part was related to water losses. The KD did not cause further substantial changes in fat free or skeletal muscle mass, but was associated with a gradual decrease of 0.4 kg body weight and fat mass per week (p < 0.0001). The KD significantly decreased free T3 levels by 0.06 pg/ml/week (p = 6.3 × 10-5). Global quality of life remained stable in the SD group but increased in the KD group from a score of 66.7 to 75.0 (p = 0.20). CONCLUSIONS: In breast cancer patients undergoing curative radiotherapy, a KD based on natural foods is feasible. After initial water losses, the KD tends to reduce body weight and fat mass while preserving fat free and skeletal muscle mass. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02516501 , registered on August 06, 2015.

The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases.

BACKGROUND: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. METHODS: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. RESULTS: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. CONCLUSION: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

Impact of Different Types of Diet on Gut Microbiota Profiles and Cancer Prevention and Treatment.

: Diet is frequently considered as a food regimen focused on weight loss, while it is actually the sum of food consumed by the organism. Western diets, modern lifestyle, sedentary behaviors, smoking habits, and drug consumption have led to a significant reduction of gut microbial diversity, which is linked to many non-communicable diseases (NCDs). The latter kill 40 million people each year, equivalent to more than 70% of all deaths globally. Among NCDs, tumors play a major role, being responsible for 29% of deaths from NCDs. A link between diet, microbiota, and cancer prevention and treatment has recently been unveiled, underlining the importance of a new food culture based on limiting dietary surplus and on preferring healthier foods. Here, we review the effects of some of the most popular "cancer-specific" diets on microbiota composition and their potential impact on cancer prevention and treatment.

Application of Bayesian evidence synthesis to modelling the effect of ketogenic therapy on survival of high grade glioma patients.

BACKGROUND: Ketogenic therapy in the form of ketogenic diets or calorie restriction has been proposed as a metabolic treatment of high grade glioma (HGG) brain tumors based on mechanistic reasoning obtained mainly from animal experiments. Given the paucity of clinical studies of this relatively new approach, our goal is to extrapolate evidence from the greater number of animal studies and synthesize it with the available human data in order to estimate the expected effects of ketogenic therapy on survival in HGG patients. At the same time we are using this analysis as an example for demonstrating how Bayesianism can be applied in the spirit of a circular view of evidence. RESULTS: A Bayesian hierarchical model was developed. Data from three human cohort studies and 17 animal experiments were included to estimate the effects of four ketogenic interventions (calorie restriction/ketogenic diets as monotherapy/combination therapy) on the restricted mean survival time ratio in humans using various assumptions for the relationships between humans, rats and mice. The impact of different biological assumptions about the relevance of animal data for humans as well as external information based on mechanistic reasoning or case studies was evaluated by specifying appropriate priors. We provide statistical and philosophical arguments for why our approach is an improvement over existing (frequentist) methods for evidence synthesis as it is able to utilize evidence from a variety of sources. Depending on the prior assumptions, a 30-70% restricted mean survival time prolongation in HGG patients was predicted by the models. The highest probability of a benefit (> 90%) for all four ketogenic interventions was obtained when adopting an enthusiastic prior based on previous case reports together with assuming synergism between ketogenic therapies with other forms of treatment. Combinations with other treatments were generally found more effective than ketogenic monotherapy. CONCLUSIONS: Combining evidence from both human and animal studies is statistically possible using a Bayesian approach. We found an overall survival-prolonging effect of ketogenic therapy in HGG patients. Our approach is best compatible with a circular instead of hierarchical view of evidence and easy to update once more data become available.

Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation.

Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R's of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K-Akt-mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K-Akt-mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.

Anti-tumor effects of ketogenic diets and their synergism with other treatments in mice: Bayesian evidence synthesis of 1755 individual mouse survival data.

BACKGROUND: Ketogenic diets (KDs) are high-fat diets with putative anti-tumor effects. The aim of this study was to synthesize the evidence for the anti-tumor effects of KDs in mice, with a focus on their possible synergism with chemotherapy (CT), radiotherapy (RT), or targeted therapies (TT). METHODS: Relevant studies were retrieved from a literature search. A total of 43 articles reporting on 65 mouse experiments fulfilled the inclusion criteria, and 1755 individual mouse survival times were collated from the study authors or the publications. The restricted mean survival time ratio (RMSTR) between the KD and control groups served as the effect size. Bayesian evidence synthesis models were used to estimate pooled effect sizes and to assess the impact of putative confounders and synergism between KD and other therapies. RESULTS: Overall, there was a significant survival-prolonging effect of KD monotherapy (RMSTR = 1.161 ± 0.040), which was confirmed in meta-regression accounting for syngeneic versus xenogeneic models, early versus late KD start and subcutaneous versus other organ growth. Combining the KD with RT or TT, but not CT, was associated with a further 30% (RT) or 21% (TT) prolongation of survival. An analysis accounting for 15 individual tumor entities showed that KDs exerted significant survival-prolonging effects in pancreatic cancer (all treatment combinations), gliomas (KD + RT and KD + TT), head and neck cancer (KD + RT), and stomach cancer (KD+RT and KD + TT). CONCLUSIONS: This analytical study confirmed the overall anti-tumor effects of KDs in a large number of mouse experiments and provides evidence for synergistic effects with RT and TT.

SEIR models in the light of Critical Realism - A critique of exaggerated claims about the effectiveness of Covid 19 vaccinations.

In a recent modeling study Watson et al. (Lancet Infect Dis 2022;3099:1-10) claim that Covid-19 vaccinations have helped to prevent roughly 14-20 million deaths in 2021. This conclusion is based on an epidemiological susceptible-exposed-infectious-recovered (SEIR) model trained on partially simulated data and yielding a reproduction number distribution which was then applied to a counterfactual scenario in which the efficacy of vaccinations was removed. Drawing on the meta-theory of Critical Realism, we point out several caveats of this model and caution against believing in its predictions. We argue that the absence of vaccinations would have significantly changed the causal tendencies of the system being modelled, yielding a different reproduction number than obtained from training the model on actually observed data. Furthermore, the model omits many important causal factors. Therefore this model, similar to many previous SEIR models, has oversimplified the complex interplay between biomedical, social and cultural dimensions of health and should not be used to guide public health policy. In order to predict the future in epidemic situations more accurately, continuously optimized dynamic causal models which can include the not directly tangible, yet real causal mechanisms affecting public health appear to be a promising alternative to SEIR-type models.