Toxicity Of Cancer Therapy Research Articles

455 (PB443): Uncovering a molecular mechanism of radiation-induced, T cell toxicity in cancer therapy

455 (PB443): Uncovering a molecular mechanism of radiation-induced, T cell toxicity in cancer therapy

Chinese expert consensus on cardiac biomarkers for monitoring and management of cardiovascular toxicity in cancer therapy (2024 edition)

In recent years, the treatment of malignant tumors has continually advanced, significantly extending the survival period of cancer patients. Tumors are increasingly present as chronic diseases over the long term, and the cardiovascular toxicity associated with cancer treatment has become increasingly prominent, severely affecting the effective treatment and survival of cancer patients. As a result, cardio-oncology has gained considerable attention as an emerging discipline. However, cardiovascular diseases in cancer patients often have an insidious onset, and early identification and treatment are frequently overlooked. Throughout the course of cancer treatment, it is crucial to reasonably apply cardiac biomarkers for risk stratification, early identification, and screening of cardiovascular diseases in patients, as well as to improve the early diagnosis and treatment levels of cardiovascular diseases in cancer patients. To this end, Cardio-Oncology Group, Chinese Society of Cardiology in conjunction with Cardiovascular Expert Committee, China Medical Doctor Association of Laboratory Medicine, organized experts in relevant fields to compile this consensus. It aims to provide a basis for clinicians to standardize the screening and management of cardiovascular toxicity related to cancer treatment through the reasonable application of cardiac biomarkers.

Cardiovascular Toxicity in Cancer Therapy: Protecting the Heart while Combating Cancer.

This review explores the cardiovascular toxicity associated with cancer therapies, emphasizing the significance of the growing field of cardio-oncology. It aims to elucidate the mechanisms of cardiotoxicity due to radiotherapy, chemotherapy, and targeted therapies, and to discuss the advancements in human induced pluripotent stem cell technology (hiPSC) for predictive disease modeling. Recent studies have identified several chemotherapeutic agents, including anthracyclines and kinase inhibitors, that significantly increase cardiovascular risks. Advances in hiPSC technology have enabled the differentiation of these cells into cardiovascular lineages, facilitating more accurate modeling of drug-induced cardiotoxicity. Moreover, integrating hiPSCs into clinical trials holds promise for personalized cardiotoxicity assessments, potentially enhancing patient-specific therapeutic strategies. Cardio-oncology bridges oncology and cardiology to mitigate the cardiovascular side-effects of cancer treatments. Despite advancements in predictive models using hiPSCs, challenges persist in accurately replicating adult heart tissue and ensuring reproducibility. Ongoing research is essential for developing personalized therapies that balance effective cancer treatment with minimal cardiovascular harm.

Effect of time-of-day nivolumab and stereotactic body radiotherapy in metastatic head and neck squamous cell carcinoma: A secondary analysis of a prospective randomized trial.

Prior work documented circadian rhythm impacts on efficacy and toxicity of cancer therapies. Secondary analysis of prospective, phase II trial of metastatic HNSCC randomized to nivolumab+/-SBRT. Used cutoffs of 1100 and 1630. Timing classified by first infusion or majority of SBRT (e.g., PM SBRT defined by two or three fractions after 1630). Of 62 patients, there was no significant difference in median PFS between AM nivolumab (n = 7, 175 days), PM nivolumab (n = 21, 58 days), or Mid-Day nivolumab (n = 34, 67 days; p = 0.8). There was no significant difference in median PFS with AM SBRT (n = 4, 78 days), PM SBRT (n = 13, 111 days), or Mid-Day SBRT (n = 15, 63 days; p = 0.8). There was no significant difference in Grade 3-4 toxicity or ORR. Sensitivity analyses with other timepoints were negative. Further work may elucidate circadian impacts on select patients, tumors, and therapies; however, we found no significant effect in this study.

Gut microbiota: a potential target for improved cancer therapy.

Drug resistance and toxicity are major challenges observed during cancer treatment. In recent years, gut microbiota has been found to be strongly associated with the efficacy, toxicity, and side effects of chemotherapy, radiotherapy, and immunotherapy. Both preclinical studies and clinical trials have demonstrated the potential of microbiota modulation for cancer treatment. The human gut microbiota has exciting prospects for developing biomarkers to predict the outcome of cancer treatment. Moreover, multiple approaches can alter the gut microbiota composition, including faecal microbiota transplantation (FMT), probiotics, antibiotics (ATB), and diet. We describe the mechanisms by which the gut microbiota influences the efficacy and toxicity of cancer therapy, disease-related biomarkers, and methods to target the gut microbiota to improve outcomes. The purpose of this review is to provide new ideas for optimising cancer therapy by providing up-to-date information on the relationship between gut microbiota and cancer therapy, and hopes to find new targets for cancer treatment from human microbiota.

Targeting the gut microbiota for cancer therapy.

Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The poor response to immunotherapy in patients treated with antibiotics supports this influential role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analysed the underlying mechanisms. A better understanding of the taxonomy of the species involved and of the mechanisms of action has since been achieved. Defined bacterial species have been shown to promote an improved response to immune-checkpoint inhibitors by producing different products or metabolites. However, a suppressive effect of Gram-negative bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on the microbiota composition of patients can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, interest in modulating the microbiota composition to improve patient responsiveness to therapy has been mounting. Clinical proof-of-concept studies have demonstrated that faecal microbiota transplantation or dietary interventions might be utilized clinically to improve the success rate of immunotherapy in patients with cancer. Here, we review recent advances and discuss emerging strategies for microbiota-based cancer therapies.

Myocardial Ischemia Related to Common Cancer Therapy-Prevention Insights.

Modern antineoplastic therapy improves survival and quality of life in cancer patients, but its indisputable benefits are accompanied by multiple and major side effects, such as cardiovascular ones. Endothelial dysfunction, arterial spasm, intravascular thrombosis, and accelerated atherosclerosis affect the coronary arteries, leading to acute and chronic coronary syndromes that negatively interfere with the oncologic treatment. The cardiac toxicity of antineoplastic agents may be mitigated by using adequate prophylactic measures. In the absence of dedicated guidelines, our work provides the most comprehensive, systematized, structured, and up-to-date analyses of the available literature focusing on measures aiming to protect the coronary arteries from the toxicity of cancer therapy. Our work facilitates the implementation of these measures in daily practice. The ultimate goal is to offer clinicians the necessary data for a personalized therapeutic approach for cancer patients receiving evidence-based oncology treatments with potential cardiovascular toxicity.

Communication about cost of cancer care: Attitudes and practices of oncologists.

e18826 Background: With the cost of cancer care rising, it is becoming ever so important for physicians to be mindful of financial toxicity to their patients. Patient-provider cost discussions are associated with lower out of pocket costs (Hong el al, Value in Health 2020), yet few patients report having this discussion with their physician. There are few reports on oncologist’s preparedness, current practice, and barriers in discussing costs with their patients. Methods: An online survey was administered to hematology/oncology faculty physicians and fellows at the IU Simon Comprehensive Cancer Center. The objectives were to assess attitudes on communication about cost of cancer care and awareness around financial toxicity of cancer therapy. The questions included physician perception on patient’s attitudes towards cost discussion in clinics, current state of cost discussion in their clinic and their preparedness on having this discussion in the future. Results: 27/48 (56%) fellows and faculty members completed the survey. All respondents believed cost communication is associated with improved patient outcomes and 82% believed cost communication is desired by most patients. 22/27 (81%) indicated cost of care were discussed in less than half of patient encounters. 22/27 (81%) believed clear communication about cost should be a part of the patient’s clinic visit. When asked to rate their preparedness level on a scale of 0-100 on discussing cost of cancer care in their clinics, the median preparedness level was 20. Median awareness level about patient’s insurance plan was 20 and median awareness level about patient out of pocket cost was 21. 26/27 (96%) believed knowing cost of therapy and out of pocket cost would change the way they practice. 20/27 (74%) reported that not knowing the cost of cancer care themselves was the greatest barrier behind not discussing costs. Conclusions: Despite believing cost of cancer care should be discussed in the clinic, most hematologists/oncologists surveyed did not do so. Physician education on cost of cancer care and patient out-of-pocket costs is greatly needed.

Cardio-oncology: a focus on cardiovascular toxicities of cancer therapies and on atrial fibrillation in cancer.

Cardio-oncology: a focus on cardiovascular toxicities of cancer therapies and on atrial fibrillation in cancer.

An overview of chemotoxicity and radiation toxicity in cancer therapy.

While immunotherapy and targeted therapies represent major advances against different types of malignancies, the mainstay of cancer therapy continues to be radiation and surgery for localized disease, and chemotherapy for systemic disease, with the preponderance of chemotherapeutic agents (such as anthracyclines, alkylating agents, and antimetabolites) having been developed decades ago. Combination chemotherapy regimens have changed the natural history of once deadly diseases such as breast and prostate cancer and led to curative regimens in advanced hematological malignancies and testicular cancer. However, while oncologists maintain their focus on disease suppression, and where feasible, disease eradication, obstacles to achieving cure remain, such as tumor dormancy and ultimately disease recurrence, as well as both intrinsic and acquired resistance. In this review, complications of current cancer therapies toward major organs (heart, lung, kidney, gastro-intestinal, neuromuscular, brain, and skin) are emphasized, and efforts to mitigate these complications are described. This is particularly relevant for patients treated with curative intent, where adherence to treatment plan, and avoidance of interruptions in treatment schedule are essential for optimal outcome. Consequently, these patients are treated with an "aggressive" approach, with high tolerance for side effects. However, a deeper understanding of normal tissue toxicity resulting from the different cancer therapies remains an area of unmet medical need that will ultimately lead to improved therapeutic index for current and future therapies, planning for treatment adverse effects, and ultimately improvement in patient satisfaction, compliance and outcome.

Efficacy of Nutrients in Reducing the Symptoms of Radiation Induced Oral Mucositis in a Hamster Model

Radiation-induced oral mucositis (RIOM) is a painful, dose-limiting toxicity in cancer therapy. RIOM was induced by radiation on the left buccal pouch mucosa of Golden Syrian hamsters (n = 8/group). Animals were treated topically with polyphenols (Curcumin or Quercetin) or amino acids/metabolite mixtures (Alanyl-Glutamine or Arginine + Glutamine + β-Hydroxy β-methylbutyric acid (Arg/Gln/HMB)) for over 20 day. Progression of RIOM was assessed using a standard visual scoring six-point scale, for differences in severity of mucositis (score ≥3) (Chi-square analysis) and in the daily group scores (Mann-Whitney rank sum test). Compared to the controls, there was a significant reduction in number of days with severe RIOM (score ≥3) in the treatment groups: Curcumin (50 μg/ml) = 17%; Control = 38.5%, p < 0.001; Quercetin (50 μg/ml) = 27.6% and Quercetin (100 μg/ml) = 25%; Control = 41.3%, p = 0.007 and p = 0.001, respectively; Arg/Gln/HMB (50 mg/ml) = 31.9%; Control = 50.0%, p = 0.040. In addition, Curcumin (50 μg/ml), Quercetin (100 μg/ml) and Arg/Gln/HMB (100 mg/ml) groups had lower mucositis scores (≥3) on at least two consecutive time points over the course of the study than their respective controls. There were no significant group differences in deaths or body weight. This study demonstrates the potential benefits of topical application of either plant polyphenols or amino acid/metabolite mixtures in addressing severity and progression of RIOM.

Negative impact of antibiotic administration on the clinical activity in patients with advanced gastric cancer

Antibiotics (ATBs) induce dysbiosis of the gut microbiota by altering the diversity and composition of the microbiota, which mediates the efficacy and toxicity of cancer therapy. The influence of dysbiosis induced by ATB administration on primary resistance to chemotherapy in patients with advanced gastric cancer (GC) has been rarely studied. We evaluated the effect of ATB administration on chemotherapy efficacy in patients with advanced GC. Patients with GC were divided into two groups according to the status of ATB administration: ATB-treated and control groups. Tumor responses, progression-free survival (PFS) and overall survival (OS) were assessed. We found that the incidence of progressive disease in the ATB-treated group was significantly higher when compared with that in the control group that received no ATB treatment (72.73% vs. 29.55%, p = 0.007). In addition, ATB administration was associated with shorter PFS [median PFS: 1.47 vs. 4.97 months, hazard ratio (HR): 2.296, 95% confidence interval (CI): 1.214 − 4.342, p = 0.011] and reduced OS (median OS: 9.97 vs. 13.3 months, HR: 2.101, 95% CI: 1.030 − 4.286, p = 0.041) based on univariate analysis. Subsequent multivariate analysis also indicated that ATB administration was an independent prognostic factor for PFS (HR: 3.361, 95% CI: 1.592 − 7.097, p = 0.001) and OS (HR: 2.280, 95% CI: 1.042 − 4.991, p = 0.039). ATB administration is associated with reduced chemotherapy efficacy and poor prognosis in patients with advanced GC. Modulations in ATB-related dysbiosis and gut microbiota composition improve the clinical outcomes of chemotherapy. Supplemental data for this article is available online at https://dx.doi.org/10.1080/13102818.2021.1953400 .

Relative Impact of Anticancer Therapy on Unplanned Hospital Care in Patients With Non-Small-Cell Lung Cancer.

In lung cancer, unplanned hospital care is a significant driver of costs. While toxicities of cancer therapies are well-known, there are little data on their relative contribution to unplanned care. This study aims to (1) determine the relative impact of tyrosine-kinase inhibitor (TKI) therapy, immune checkpoint inhibitor immunotherapy, and cytotoxic chemotherapy on unplanned hospital care and (2) identify potential strategies to prevent unplanned hospital encounters in patients with non-small-cell lung cancer (NSCLC). A research database search of the electronic health record was used to identify 97 patients with established NSCLC who were undergoing either TKI therapy, immunotherapy, or chemotherapy at our institution and visited our emergency department (ED) in 2018. The resulting 173 ED encounters were reviewed to determine (1) the cause (cancer, therapy, other, or rule-out) of each encounter and (2) whether the encounter was preventable. A small portion (9%) of all unplanned hospital encounters were therapy related (2% in the TKI therapy group, 12% in the immunotherapy group, and 21% in the chemotherapy group). Cancer itself was the leading cause (54%) of the encounters. Over 20% of all encounters were classified as preventable, and half of those encounters were deemed unnecessary. TKI therapy, immunotherapy, and, to a lesser extent, chemotherapy are relatively small drivers of unplanned acute hospital care for patients with NSCLC. A significant share of unplanned hospital encounters may be prevented through proactive evidence-based initiatives.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

BackgroundMucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis.MethodsThe literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible.ResultsThe guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions.ConclusionsThe updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting‐specific, evidence‐based tool to help with the management of mucositis in patients who have cancer.

Photoactivatable Protherapeutic Nanomedicine for Cancer

Therapeutic systems with site-specific pharmaceutical activation hold great promise to enhance therapeutic efficacy while reducing systemic toxicity in cancer therapy. With operational flexibility, noninvasiveness, and high spatiotemporal resolution, photoactivatable nanomedicines have drawn growing attention. Distinct from traditional controlled release systems relying on the difference of biomarker concentrations between disease and healthy tissues, photoactivatable nanomedicines capitalize on the interaction between nanotransducers and light to either trigger photochemical reactions or generate reactive oxygen species (ROS) or heat effect to remotely induce pharmaceutical actions in living subjects. Herein, the recent advances in the development of photoactivatable protherapeutic nanoagents for oncology are summarized. The design strategies and therapeutic applications of these nanoagents are described. Representative examples of each type are discussed in terms of structure, photoactivation mechanism, and preclinical models. Last, potential challenges and perspectives to further develop photoactivatable protherapeutic nanoagents in cancer nanomedicine are discussed.

Emerging role of microbiota in immunomodulation and cancer immunotherapy.

Gut microbiota is emerging as a key modulator of the immune system. Alteration of gut microbiota impacts functioning of the immune system and pathophysiology of several diseases, including cancer. Growing evidence indicates that gut microbiota is not only involved in carcinogenesis but also has an impact on the efficacy and toxicity of cancer therapy. Recently, several pre-clinical and clinical studies across diverse cancer types reported the influence of gut microbiota on the host immune response to immunotherapy. Advancement in our understanding of the mechanism behind microbiota-mediated modulation of immune response is paramount for their utilization as cancer therapeutics. These microbial therapies in combination with conventional immunotherapeutic methods have the potential to transform the pre-existing treatment strategies to personalized cancer therapy. In this review, we have summarized the current status of research in the field and discussed the role of microbiota as an immune system modulator in context of cancer and their impact on immunotherapy.

Simultaneous Delivery of antimiR-21 and Doxorubicin by Graphene Oxide for Reducing Toxicity in Cancer Therapy

Graphene oxide (GO) has been studied by many researchers for its potential drug-delivery value. In order to reduce the side effects of anticancer drugs by decreasing the dosage and maintain the therapeutic effects, a dual drug-delivery system that used GO as a carrier and simultaneously loaded with antitumor drugs and antimir-21 was rationally designed for the cooperative treatment of tumors. Results obtained from our studies have found that MDA-MB-231 cells were inhibited in low Dox dose. The outcomes of confocal microscopy indicated that Dox and antimiR-21 could be released rapidly in cancer cells, which is good for killing cancer cells. In addition, qRT-PCR further demonstrated that miR-21 was silenced by antimiR-21. Consequently, GO has a great potential to codeliver chemotherapeutic drugs and gene drugs in cancer combination therapy for reducing toxicity.

Antibiotics Modulate Chemotherapy Efficacy in Patients with Esophageal Cancer.

PurposeAccumulating evidence suggests that microbiota dysbiosis induced by antibiotic administration plays a crucial role in regulating the efficacy and toxicity of cancer therapy. We explored the influence of antibiotic administration on the efficacy of chemotherapy in patients with esophageal cancer (EC).Patients and MethodsEC patients were stratified into two groups: antibiotic-treated group and control group. The antibiotic-treated group included patients who received antibiotics within 60 days before or after chemotherapy initiation, and the control group included patients who did not receive antibiotics within 60 days before or after chemotherapy initiation. Progression-free survival (PFS) and overall survival (OS) curves were constructed using the Kaplan–Meier method. The Cox proportional hazards model was used for univariate and multivariate analyses.ResultsThe rate of primary progressive disease in the antibiotic-treated group was significantly higher than that in the control group (36.58% vs 10.45%, p = 0.002) as calculated using the chi-square test. Further, antibiotic administration was associated with shorter PFS (6.7 vs 14.6 months, hazard ratio (HR): 2.545, 95% confidence interval (CI): 1.554–4.168, p < 0.001) and reduced OS (15.0 vs 21.0 months, HR: 2.007, 95% CI: 1.213–3.319, p = 0.007) in univariate analysis. Subsequent multivariate analysis indicated that antibiotic administration was a significant independent prognostic factor for PFS (HR: 2.350, 95% CI: 1.423–3.882, p = 0.001) and OS (HR: 1.900, 95% CI: 1.140–3.167, p = 0.014).ConclusionAntibiotic administration was associated with reduced chemotherapy efficacy and poor prognosis in patients with EC.

Economic analysis of alternative pembrolizumab and nivolumab dosing strategies at an academic cancer center.

6504 Background: Pembrolizumab (P) and nivolumab (N) were initially investigated and FDA-approved with weight-based dosing strategies, but later the approval label was amended to a fixed dose administration. Given increasing concerns about financial toxicity of cancer therapies, we hypothesize that weight-based dosing of P and N and allowing vial sharing among patients will result in substantial cost savings. Methods: We obtained IRB approval to retrospectively examine all outpatient doses of P and N given at three Stanford Medicine infusion centers between July 1, 2018 and Oct 31, 2018 using the Stanford Medicine Research Data Repository (STARR) database. We performed cost-minimization analysis modeling the impact of dosing strategies based upon patient weight versus fixed dosing (2 mg/kg vs 200 mg q3wks for P; 3 mg/kg vs 240 mg q2wks or 6 mg/kg vs 480 q4wks for N). “Dose-minimization” (DM) was defined as whichever dose was lower (weight-based or fixed dose). The impact of allowing vial sharing (considering commercially available vial sizes) between patients treated at the same site and on the same date was assessed. Average sales price (ASP) from Center for Medicare and Medicaid Services for Part B drugs was used for cost estimates. Results: A total of 1,029 doses of P or N were administered across a variety of cancer types. For most doses (N = 789, 77%), the calculated weight-based dose was less than the fixed dose. DM resulted in decreased usage and expenditures of both P and N, and a further decrease was observed with vial sharing. Total savings estimated with DM and vial sharing strategy were &gt; $1.4 million (Table). This amounted to savings of &gt; 22,000 mg of P (112 fixed doses) and &gt; 11000 mg of N (47 fixed doses). Savings were greatest at the highest volume infusion center. Conclusions: Alternative dosing strategies of P and N would result in significantly less drug utilization and pharmaceutical expenditure without anticipated impact on efficacy. Potential barriers to this approach include existing policies regarding vial sharing and drug vial sizes. [Table: see text]

Cancer Survivorship and Subclinical Myocardial Damage.

Cancer survivors might have an excess risk of cardiovascular disease (CVD) resulting from toxicities of cancer therapies and a high burden of CVD risk factors. We sought to evaluate the association of cancer survivorship with subclinical myocardial damage, as assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT) test results. We included 3,512 participants of the Atherosclerosis Risk in Communities Study who attended visit 5 (2011-2013) and were free of CVD (coronary heart disease, heart failure, or stroke). We used multivariate logistic regression to evaluate the cross-sectional associations of survivorship from any, non-sex-related, and sex-related cancers (e.g., breast, prostate) with elevated hs-cTnT (≥14 ng/L). Of 3,512 participants (mean age, 76 years; 62% women; 21% black), 19% were cancer survivors. Cancer survivors had significantly higher odds of elevated hs-cTnT (OR = 1.26, 95% CI: 1.03, 1.53). Results were similar for survivors of non-sex-related and colorectal cancers, but there was no association between survivorship from breast and prostate cancers and elevated hs-cTnT. Results were similar after additional adjustments for CVD risk factors. Survivors of some cancers might be more likely to have elevated hs-cTnT than persons without prior cancer. The excess burden of subclinical myocardial damage in this population might not be fully explained by traditional CVD risk factors.