Toxicity Of Cancer Treatment Research Articles

Comparing the time toxicity of cancer treatments in the CCTG LY.12 trial.

12135 Background: When different cancer treatments have similar oncologic outcomes, their respective time-related burdens can aid patient-oncologist decision-making regarding which treatment approach to pursue. We have previously developed a pragmatic and patient-centered metric of these time burdens-- which we term ‘’time toxicity’’-- as any day with physical healthcare system contact. This includes outpatient (e.g., bloodwork, scans, clinician, etc.) and emergency room visits, and overnight stays in a healthcare facility. Herein we sought to assess time toxicity in a completed RCT. Methods: We conducted a secondary analysis of the Canadian Cancer Trials Group LY.12 RCT that evaluated 2-3 outpatient cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates, transplantation rates, event-free-survival, and overall survival across arms. We calculated patient-level time toxicity by analyzing RCT forms. The study period was the date of assignment to the date of progression or the day before stem cell transplant. We considered days without healthcare contact as ‘’home days’’. We compared time measures across arms. Results: The median study duration was longer in the GDP arm (50, vs. 47 days in the DHAP arms, p=0.007). Median time toxic days were comparable in both arms (18 vs 19 days, p=0.79), but median home days were higher in the GDP arm (33 vs 28 days, p<0.001). The proportion of time toxic days (time toxic days divided by study duration) was lower in the GDP arm (34%, vs. 38%, p=0.009). The GDP arm experienced more time toxicity related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more hospitalization days (median, 11 vs. 0 days) (Table). Conclusions: This study demonstrates that measures of time toxicity can be extracted from RCTs. These measures can add clinical insight into patient burdens. In LY.12, despite broadly comparable short- and long-term oncologic outcomes, the GDP arm experienced less time toxicity. Such information can guide decision-making for patients with aggressive hematological cancers, who already spend a significant portion of time with healthcare contact. Clinical trial information: NCT00078949 . [Table: see text]

Association of sarcopenia and treatment tolerability in older adults with advanced cancer: Secondary analysis of a nationwide NCI Community Oncology Research Program (NCORP) randomized clinical trial.

12038 Background: Sarcopenia (sarc) is defined by reduced muscle function paired with low muscle mass or quality. Sarc is common in older adults, but the relationship between sarc and treatment tolerability in older patients (pts) with cancer has not been established. This secondary analysis of our nationwide University of Rochester NCORP Research Base randomized trial examines whether pre-treatment sarc was associated with treatment toxicity and survival in older pts with advanced cancers. Methods: Pts aged 70 and older with incurable solid tumors and lymphoma initiating a new high-risk systemic treatment were enrolled in GAP70+ (NCT02054741). GAP70+ was a cluster randomized trial evaluating whether a geriatric assessment intervention can reduce cancer treatment toxicity. This secondary analysis included 161 pts with baseline computed tomography (CT) scans and physical function testing. Sarc was defined as low muscle strength (5-time Chair Stand Test > 16.7 seconds) with reduced muscle mass (BMI and sex-specific cutoffs, cm/m2) or low muscle quality (Hounsfield units [HU] average radiodensity thresholds) utilizing validated cross-sectional CT imaging metrics. Sarc was defined as severe in presence of reduced physical performance (Timed-Up-And-Go > 13.5 seconds). We evaluated if the proportion of pts experiencing any grade 3-5 toxicity in the first 3 months of treatment using Common Terminology Criteria for Adverse Events (CTCAE) V4.0 was higher in those with sarc than those without sarc. Multivariate logistic regression was used to further explore this relationship. Multivariate Cox regression analysis was performed to evaluate the association of sarc and severe sarc with 1-year survival. Results: Mean age of the 161 participants included in this cohort was 76.6 years and 60.9% of were male; over half had gastrointestinal (34.8%) or lung cancer (23.6%). Sarc was found in 91 of 161 (56.5%) pts; 54 had severe sarc. Pts with sarc did not experience significantly more grade 3-5 toxicity compared to those without sarc (79.1% vs. 71.4%, p = 0.26). However, pts with sarc experienced more grade 3-5 non-hematologic toxicity (63.7% vs. 44.3%, p = 0.01) on univariate and multivariate analysis (OR 2.2, CI 1.1-4.5, p = 0.02). The association between sarc and worse survival at 1-year was not statistically significant (OR 1.5, CI 0.9-2.4, p = 0.13). Those with severe sarc did demonstrate significantly worse 1-year survival on multivariate analysis (HR 1.8, CI 1.1-2.9, p = 0.02). Conclusions: Older pts with cancer and sarc were more likely to suffer serious non-hematologic toxicity from cancer treatment. Furthermore, those with severe sarc had significantly worse survival. Evaluation for sarc before initiating treatment in older adults could help oncologists identify pts at higher risk of toxicity and poor survival. Clinical trial information: NCT02054741 .

Imidazolyl Ethanamide Pentandioic Acid (IEPA) as Potential Radical Scavenger during Tumor Therapy in Human Hematopoietic Stem Cells.

Radiochemotherapy-associated leuco- or thrombocytopenia is a common complication, e.g., in head and neck cancer (HNSCC) and glioblastoma (GBM) patients, often compromising treatments and outcomes. Currently, no sufficient prophylaxis for hematological toxicities is available. The antiviral compound imidazolyl ethanamide pentandioic acid (IEPA) has been shown to induce maturation and differentiation of hematopoietic stem and progenitor cells (HSPCs), resulting in reduced chemotherapy-associated cytopenia. In order for it to be a potential prophylaxis for radiochemotherapy-related hematologic toxicity in cancer patients, the tumor-protective effects of IEPA should be precluded. In this study, we investigated the combinatorial effects of IEPA with radio- and/or chemotherapy in human HNSCC and GBM tumor cell lines and HSPCs. Treatment with IEPA was followed by irradiation (IR) or chemotherapy (ChT; cisplatin, CIS; lomustine, CCNU; temozolomide, TMZ). Metabolic activity, apoptosis, proliferation, reactive oxygen species (ROS) induction, long-term survival, differentiation capacity, cytokine release, and DNA double-strand breaks (DSBs) were measured. In tumor cells, IEPA dose-dependently diminished IR-induced ROS induction but did not affect the IR-induced changes in metabolic activity, proliferation, apoptosis, or cytokine release. In addition, IEPA showed no protective effect on the long-term survival of tumor cells after radio- or chemotherapy. In HSPCs, IEPA alone slightly enhanced CFU-GEMM and CFU-GM colony counts (2/2 donors). The IR- or ChT-induced decline of early progenitors could not be reversed by IEPA. Our data indicate that IEPA is a potential candidate for the prevention of hematologic toxicity in cancer treatment without affecting therapeutic benefits.

Monolayer LDH Nanosheets with Ultrahigh ICG Loading for Phototherapy and Ca2+-Induced Mitochondrial Membrane Potential Damage to Co-Enhance Cancer Immunotherapy.

Tumor recurrence and metastasis are the main causes of cancer mortality; traditional chemotherapeutic drugs have severe toxicity and side effects in cancer treatment. To overcome these issues, here, we present a pH-responsive, self-destructive intelligent nanoplatform for magnetic resonance/fluorescence dual-mode image-guided mitochondrial membrane potential damage (MMPD)/photodynamic (PDT)/photothermal (PTT)/immunotherapy for breast cancer treatment with external near infrared (NIR) light irradiation. To do so, we construct multifunctional monolayer-layered double hydroxide (LDH) nanosheets (MICaP), co-loading indocyanine green (ICG) with ultrahigh loading content realized via electrostatic interactions, and calcium phosphate (Ca3(PO4)2) coating via biomineralization. Such a combined therapy design is featured by the outstanding biocompatibility and provokes immunogenic cell death (ICD) of tumors toward cancer immunotherapy. The active transport of excess Ca2+ released from pH-sensitive Ca3(PO4)2 can induce MMPD of tumor cells to minimize oxygen consumption in the tumor microenvironment (TME). The presence of ICG not only generates singlet oxygen (1O2) to induce apoptosis by photodynamic therapy (PDT) but also initiates tumor cell necrosis by photothermal therapy (PTT) under near-infrared (NIR) light radiation. Eventually, the immune response generated by MMPD/PDT/PTT greatly promotes a cytotoxic T lymphocyte (CTL) response that can limit tumor growth and metastasis. Both in vitro and in vivo studies indeed illustrate outstanding antitumor efficiency and outcomes. We anticipate that such precisely designed nanoformulations can contribute in a useful and advantageous way that is conducive to explore novel nanomedicines with notable values in antitumor therapy.

Assessing the Acceptability of Home Blood Monitoring for Patients With Cancer Who Are Receiving Systemic Anticancer Therapy From a Patient, Caregiver, and Clinician Perspective: Focus Group and Interview Study.

Regular blood testing is an integral part of systemic anticancer therapy delivery. Blood tests are required before every administration of treatment to ensure that a patient is sufficiently well to receive it. Blood testing is burdensome for patients as they require either an extra visit within 48 hours of planned administration of treatment or a significantly long visit if performed on the day of treatment. The additional time for appointments can have a significant impact on the quality of life of someone who is living with cancer. In the United Kingdom, the COVID-19 pandemic created unprecedented disruption to the delivery of cancer care. Face-to-face hospital visits were reduced, resulting in the need to develop more innovative ways of working to minimize treatment interruptions. This led to significant uptake of digital technologies, with new models of care rapidly deployed across the UK health service to meet these challenges. This study aimed to explore the acceptability of a point-of-care home blood monitoring device for people with cancer who are receiving systemic anticancer therapy, which is being developed in response to the increased need for remote care for patients with cancer. Qualitative focus groups and semistructured interviews were conducted with patients (23/47, 49%), caregivers (6/47, 13%), and health care professionals (18/47, 38%) over a 19-month time frame from May 2019 to December 2020. Data were analyzed using framework analysis guided by the Unified Theory of Acceptance and Use of Technology model. Analysis identified 4 overarching themes: performance expectancy, effort expectancy, social influence, and facilitating conditions. This study found that patients with cancer, their caregivers, and health care professionals had positive perceptions about home blood monitoring. Although they are often considered synonymously, self-testing and self-management are not mutually exclusive, and this study illustrated some disparity in opinions regarding patient self-management. Home blood monitoring has the potential to provide patients with cancer with a convenient option for blood monitoring. It would minimize hospital attendances, decrease late treatment deferrals, and provide prompt recognition of cancer treatment toxicities, thus enhancing the existing nurse-led protocols and clinical pathways. Home blood monitoring would create a long-term sustainable transformation for the delivery of cancer care, using digital health to act as a facilitator to address a pertinent issue regarding improving the efficiency of hospital resources and increasing the delivery of personalized patient care. Further studies are needed to determine how and where home blood monitoring would fit within clinical pathways, in a way that is robust and equitable.

The Synergistic Effect of Cold Atmospheric Plasma Mediated Gold Nanoparticles Conjugated with Indocyanine Green as An Innovative Approach to Cooperation with Radiotherapy.

The multimodality treatment of cancer provides a secure and effective approach to improve the outcome of treatments. Cold atmospheric plasma (CAP) has got attention because of selectively target and kills cancer cells. Likewise, gold nanoparticles (GNP) have been introduced as a radiosensitizer and drug delivery with high efficacy and low toxicity in cancer treatment. Conjugating GNP with indocyanine green (ICG) can develop a multifunctional drug to enhance radio and photosensitivity. The purpose of this study is to evaluate the anticancer effects of GNP@ICG in radiotherapy (RT) and CAP on DFW melanoma cancer and HFF fibroblast normal cell lines. In this experimental study, the cells were irradiated to RT and CAP, alone and in combination with or without GNP@ICG at various time sequences between RT and CAP. Apoptosis Annexin V/PI, MTT, and colony formation assays evaluated the therapeutic effect. Finally, the index of synergism was calculated to compare the results. Most crucially, the cell viability assay showed that RT was less toxic to tumors and normal cells, but CAP showed a significant anti-tumor effect on melanoma cells with selective toxicity. In addition, cold plasma sensitized melanoma cells to radiotherapy so increasing treatment efficiency. This effect is enhanced with GNP@ICG. In comparison to RT alone, the data showed that combination treatment greatly decreased monolayer cell colonization and boosted apoptotic induction. The results provide new insights into the development of better approaches in radiotherapy of melanoma cells assisted plasma and nanomedicine.

Self-assembling nanoarchitectonics of size-controllable celastrol nanoparticles for efficient cancer chemotherapy with reduced systemic toxicity

Celastrol, extracted from Tripterygium wilfordii Hook F, is one of the most promising natural extract for cancer treatment. Nevertheless, insufficient tumor retention and severe systemic toxicity still hinder its application. Herein, we report for the first time that Celastrol can directly self-assemble into size-controllable nanoparticles through the anti-solvent method by using different good solvent or by the variation of Celastrol concentrations. In vitro anti-cancer experiment revealed that the as-prepared nanoparticles can kill MCF-7 cells more effectively. Moreover, the nanoparticles can efficiently accumulate in tumors of the tumor bearing mice after tail vein injection. Under the administration of lethal dosage of Celastrol, the tumors are greatly suppressed and the mice maintain the activity. These results demonstrate that anti-solvent method may be a promising strategy to fabricate Celastrol nano-drugs with controllable size and less systemic toxicity for further clinical cancer treatment.

Static Magnetic Fields Protect against Cisplatin-Induced Kidney Toxicity.

Cisplatin is one of the most widely used anti-cancer drugs that can effectively inhibit the growth of multiple types of cancer. However, its clinical application is limited by its severe side effects, especially kidney toxicity, caused by cisplatin-induced oxidative stress, inflammation and kidney cell apoptosis. Here, we found that moderate (a few hundred mT) quasi-uniform static magnetic fields (SMFs) could inhibit cisplatin-induced renal proximal tubular cell death, especially the vertically downward direction SMF. RNA-seq experiments demonstrate that SMFs induced differential gene expressions that are closely associated with oxidative stress, apoptosis, cytokine production, transmembrane transport and DNA repair. In vivo experiments show that SMFs can reduce cisplatin-induced kidney injury in cisplatin-administrated tumor-bearing mice by reducing oxidative stress, inflammation and cell apoptosis. Furthermore, high-dose cisplatin-induced acute nephrotoxicity can be effectively alleviated by SMF treatment of as little as one day, which significantly reduced the reactive oxygen species levels in kidneys and prolonged the mice's survival. Moreover, the concentration of cisplatin in the kidney was significantly attenuated in SMF-treated mice. Therefore, our study demonstrates the effects of moderate SMFs as a novel physical method to reduce oxidative stress, and revealed their future potential to be used against cisplatin-induced kidney toxicity in cancer treatment.

RGD_PLGA Nanoparticles with Docetaxel: A Route for Improving Drug Efficiency and Reducing Toxicity in Breast Cancer Treatment

Breast cancer is the leading cause of cancer-related death in women. Although many therapeutic approaches are available, systemic chemotherapy remains the primary choice, especially for triple-negative and advanced breast cancers. Unfortunately, systemic chemotherapy causes serious side effects and requires high doses to achieve an effective concentration in the tumor. Thus, the use of nanosystems for drug delivery may overcome these limitations. Herein, we formulated Poly (lactic-co-glycolic acid) nanoparticles (PLGA-NPs) containing Docetaxel, a fluorescent probe, and a magnetic resonance imaging (MRI) probe. The cyclic RGD tripeptide was linked to the PLGA surface to actively target αvβ3 integrins, which are overexpressed in breast cancer. PLGA-NPs were characterized using dynamic light scattering, fast field-cycling 1H-relaxometry, and 1H-nuclear magnetic resonance. Their therapeutic effects were assessed both in vitro in triple-negative and HER2+ breast cancer cells, and in vivo in murine models. In vivo MRI and inductively coupled plasma mass spectrometry of excised tumors revealed a stronger accumulation of PLGA-NPs in the RGD_PLGA group. Targeted PLGAs have improved therapeutic efficacy and strongly reduced cardiac side effects compared to free Docetaxel. In conclusion, RGD-PLGA is a promising system for breast cancer treatment, with positive outcome in terms of therapeutic efficiency and reduction in side effects.

The Bacterial Chaperone High-Temperature Protein G (HtpG) Decreases in Abundance with Induction Therapy in Children with Acute Lymphoblastic Leukemia

Introduction: Heat shock proteins (HSPs) are ancient and highly conserved genes that participate in protein quality control in eukaryotes and bacteria. These proteins are produced in large quantities when cells are exposed to stress that causes denaturation of essential proteins. HSPs help maintain cellular homeostasis, and act as molecular chaperones, assisting with protein folding and stability, multi-protein assembly, intracellular protein trafficking and degrading damaged proteins. The Hsp90 family of proteins includes 4 genes, with 1 (HtpG) being a bacterial form. Members of the Hsp90 family interact with a diverse set of client proteins, some involved in cell signalling and proliferation. Many of these client proteins are involved in growth, survival and adaptation of cancer cells. Eukaryotic Hsp90 plays an important role in tumorigenesis and there has been much research into the use of Hsp90 inhibitors to inhibit growth of cancer cells, but little has been done to examine what role the other paralogues have in stabilizing cancer cells. In addition, no work to date has looked at whether bacterial HtpG paralogues might interact with cancer cells. While it is anticipated that bacterial stress and the behaviour of HtpG would correlate to the host response to stress, this has not been examined. The first step is to examine bacterial HtpG gene levels before and during induction to determine if there are changes in HtpG gene abundance. Methods: Forty-eight stool samples were collected from 29 pediatric patients with Acute Lymphoblastic Leukemia (ALL) being treated at the IWK health centre, Nova Scotia, Canada after informed consent. DNA was extracted and whole shotgun metagenome sequencing (Illumina, Nextera XT) was performed. Low quality and contaminated sequences (human and PhiX174) were removed using the kneaddata pipeline (Trimmomatic and Bowtie2). Paired cleaned sequences were concatenated and HUMAnN3 was used to assign gene families to reads using the Uniref90 database. Genes assigned to HtpG or "Hsp90-like" gene families were included and summed from each sample and corrected for sequencing depth. Samples were grouped by phase of treatment (13 pre-treatment samples from 13 patients and 35 induction samples from 23 patients) for analysis. Comparisons between pre-treatment (PT) and induction (IN) samples were performed using Wilcoxon-Mann-Whitney U. Fisher's exact test was used to compare age group and sex between PT and IN samples. The study was approved by the IWK ethics board. Results: Neither sex nor age category differed between PT and IN (p=1). HtpG gene counts among the 48 stool samples from 29 patients ranged from 0 to 329 (mean 119). The mean counts of HtpG genes were significantly decreased in samples during induction therapy compared to pre-treatment (p=0.002). Shannon diversity, a measure of microbial diversity, did not differ between PT and IN samples (p=0.2793), nor did counts of bacteria (Chao-1 p=0.47). Discussion: Studies have found that Hsp90 is generally over expressed in cancer patients with elevated levels, suggesting poorer overall survival. They have been proposed as a potential biomarker of poor prognosis. We had anticipated increased stress and protein damage to occur in the gut environment as a result of chemotherapy, rather than as a result of the underlying cancer. The anticipated increase in HtpG during induction did not occur but rather declined with cancer remission. One possibility is that the decline in HtpG genes was a result of a loss of bacterial diversity due to treatment. However, we did not see significant differences in diversity between PT and IN. The increase in HtpG genes during PT and reduction during induction therapy seems to follow a similar pattern to Hsp90 expression in host cells, suggesting that bacterial HtpG might also serve as a marker of disease remission. It also highlights that a better understanding of bacterial HtpG, a protein known to be present in outer membrane vesicles, which are crucial for host communication and have been implicated in contributing to carcinogenic potential is warranted. Conclusion: This study suggests that the bacterial chaperone HtpG is possibly related to degree of inflammation caused by leukemic cells rather than leukemia treatment. A larger study is needed to verify the potential of HtpG as a marker of cancer remission or treatment toxicity or cancer immune response.

Abstract 15439: Longitudinal Assessment of Racial Differences in Exercise Capacity After Breast Cancer Treatment: WF-97415

Introduction: Breast cancer (BC) treatment toxicity contributes to elevated rates of cardiovascular morbidities, such as reduced exercise capacity, a risk factor for long-term cardiovascular disease (CVD) and mortality. Past studies have shown that Black women experience greater cardiotoxicity after BC treatment than white women. No studies have investigated racial differences in exercise capacity. The lack of longitudinal data leaves uncertainty as to whether greater declines in exercise capacity are experienced by Black BC survivors. Methods: This cohort was comprised of 236 women with stage I-III BC (80% white; 20% Black) and 130 cancer-free controls in the UPBEAT (NCT02791581) and DETECT (NCT01719562) studies. Submaximal exercise capacity was obtained via 6-Minute Walk Distance (6MWD, meters [m]) at baseline (pre-treatment) and 3 months. Linear regression was used to examine associations of race with baseline 6MWD and changes in 6MWD. Results: Mean age [SD] of BC survivors was 55.7 [10.9] years. Mean [SD] total meters walked pre-treatment was lower in Black women with BC (423 m [81.0]) than white women with BC (475 m [87.7]; p=0.01), and lower than Black women without BC (471 m [76.9]; p=0.07). Black BC survivors experienced a greater mean decline from baseline to 3-months in 6MWD (30 m [68.5]) than white BC survivors (21.7 m [86.6]; Table 1; p=0.02) or Black women without BC (9.2 m [67.3]; p=0.001), translating to a mean difference of 60 m between Black and white BC survivors during BC treatment. Conclusions: This is the first study to suggest racial differences in submaximal exercise capacity during BC treatment. Black BC survivors experienced a greater reduction in exercise capacity than white BC survivors after cancer treatment as early as 3-months post-diagnosis. This clinically-meaningful difference in exercise capacity warrants further investigation, particularly to determine interventions to reverse the loss of exercise capacity.

Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review.

Simple SummaryChemotherapy and radiotherapy are essential components to the management of most solid malignancies. These modalities exert their effects primarily by mediating the DNA damage of malignant cells; however, healthy cells are also damaged by the same mechanisms and can incur acute and late side effects resulting in both morbidity and mortality. Dietary interventions have been shown to reduce cancer growth, progression, and metastasis in many different solid tumor models and they show promise for improving cancer outcomes in early phase clinical studies. Here, we review preclinical and clinical studies that examine how dietary interventions can impact cancer treatment toxicity and efficacy in patients who were undergoing chemotherapy and/or radiotherapy. This information can help clinicians tailor the dietary regimens to patients based on their treatment methods and promote larger clinical trials to test the dietary effects on cancer treatment safety and efficacy.Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy.

Quantification of promoting efficiency and reducing toxicity of Traditional Chinese Medicine: A case study of the combination of Tripterygium wilfordii hook. f. and Lysimachia christinae hance in the treatment of lung cancer.

Traditional Chinese medicine (TCM) usually acts in the form of compound prescriptions in the treatment of complex diseases. The herbs contained in each prescription have the dual nature of efficiency and toxicity due to their complex chemical component, and the principle of prescription is usually to increase efficiency and reduce toxicity. At present, the studies on prescriptions have mainly focused on the consideration of the material basis and possible mechanism of the action mode, but the quantitative research on the compatibility rule of increasing efficiency and reducing toxicity is still the tip of the iceberg. With the extensive application of computational pharmacology technology in the research of TCM prescriptions, it is possible to quantify the mechanism of synergism and toxicity reduction of the TCM formula. Currently, there are some classic drug pairs commonly used to treat complex diseases, such as Tripterygium wilfordii Hook. f. with Lysimachia christinae Hance for lung cancer, Aconitum carmichaelii Debeaux with Glycyrrhiza uralensis Fisch. in the treatment of coronary heart disease, but there is a lack of systematic quantitative analysis model and strategy to quantitatively study the compatibility rule and potential mechanism of synergism and toxicity reduction. To address this issue, we designed an integrated model which integrates matrix decomposition and shortest path propagation, taking into account both the crosstalk of the effective network and the propagation characteristics. With the integrated model strategy, we can quantitatively detect the possible mechanisms of synergism and attenuation of Tripterygium wilfordii Hook. f. and Lysimachia christinae Hance in the treatment of lung cancer. The results showed the compatibility of Tripterygium wilfordii Hook. f. and Lysimachia christinae Hance could increase the efficacy and decrease the toxicity of lung cancer treatment through MAPK pathway and PD-1 checkpoint pathway in lung cancer.

Gut Microbiota-Derived Short-Chain Fatty Acids: Impact on Cancer Treatment Response and Toxicities.

The gut microbiota has emerged as a key modulator of cancer treatment responses in terms of both efficacy and toxicity. This effect is clearly mediated by processes impacting the activation and modulation of immune responses. More recently, the ability to regulate chemotherapeutic drug metabolism has also emerged as a key driver of response, although the direct mechanisms have yet to be fully elucidated. Through fermentation, the gut microbiota can produce several types of metabolites, including short-chain fatty acids (SCFAs). SCFAs play an important role in maintaining epithelial barrier functions and intestinal homeostasis, with recent work suggesting that SCFAs can modulate response to cancer treatments and influence both anti-tumor immune response and inflammatory-related side effects. In this review, we will discuss the importance of SCFAs and their implications for cancer treatment response and toxicities.

A novel PA-led urgent care model for medical oncology patients at a large academic cancer center.

37 Background: Oncology patients are high users of the emergency department (ED), which often results in hospital admissions for management of cancer symptoms or cancer treatment toxicities. Interventions such as urgent care (UC) models can decrease such visits, and help improve patient management, health care utilization, and patient experience. Sunnybrook Health Sciences Centre, a large tertiary care hospital in Toronto, Canada has a high volume of medical oncology ED visits (average 4 per day) with about 50% admitted for management. Methods: A novel physician-assistant (PA) led and physician supervised UC model was developed to assist in medical oncology patient phone triage, assessment, and management of cancer or treatment related issues that would otherwise have been sent to the ED by the oncology team. There were two phases: 1) due to COVID, the patients were managed in a dedicated stream primarily using space and nursing in the ED, 2) a dedicated UC clinic with nursing support was opened for these patients. Results: In phase 1, there were 424 referrals over 24 months; 84% would have otherwise been sent through the usual ED process. 26% of patients were managed with PA navigation outside the UC program in other hospital settings. Of the 204 patients formally treated in the UC stream, 67.7% were discharged home. At 48 hours, 89% of discharged patients were stable or improved; this was 80% at 14 days, and 17.3% came back to the ED or were admitted within 14 days of the UC visit. In phase 2, there have so far been 214 referrals over 5 months; 83.6% would have otherwise been sent to the ED. Of the patients who were assessed, 77.9% were discharged home. Outcomes of these patients are being collected. The top 3 patient issues managed during both phases were: fever, pain, and dyspnea. Fifteen patient telephone surveys were completed, and 93.3% were either satisfied or highly satisfied with their UC experience. Conclusions: A novel PA-led triage and management model for urgent medical oncology patient issues was found in initial phase to be feasible and effective with streamlined care through the ED. Once a dedicated UC clinic was opened, referral volumes increased, and a high rate of ED diversion, patient discharge, and effective care was continued. Patients were also highly satisfied. Several ongoing process and outcome measures are being evaluated to help expand the scope and impact of this resource.

Enrollment patterns and site-level predictors of Black participant recruitment to a multisite randomized clinical trial (RCT) of endocrine therapy adherence support.

68 Background: Accrual of racial and ethnic minority patients (pts) to clinical trials has been an ongoing challenge in research. Barriers exist at many levels of engagement including trial availability, screening biases, strict enrollment criteria, and structural racism. Lack of trial diversity has led to less generalizable medical evidence, suboptimal data for toxicity and efficacy of cancer treatments, poorer outcomes and continued mistrust by communities of color in research processes that exclude or marginalize them. Site factors and study design strategies associated with successful recruitment of diverse study populations are understudied. Methods: Alliance A191901 is an RCT testing combinations of text and telephone support to promote endocrine therapy adherence among breast cancer survivors. It oversamples Black participants and those < 50 years at thresholds of 30% each. Administrative enrollment data was used to track and describe monthly accrual trajectory by race among the initial 50% of participants (n = 590) and to examine associations between % Black participants accrued and accruing site characteristics, including site type, geographic region, % Black population in the site’s zip code and volume of pts by race accrued to recent (2018-2019) Alliance trials, using χ2 tests. We also examined patterns of Black participant accrual before and after closure of the A191901 study to non-Black participants. Results: At 50% accrual, 124 sites had enrolled at least 1 participant. Among 590 participants, 9.7% were Black and 22.5% were < 50 years. Neither site type nor volume was associated with % Black participants recruited. Sites in the South recruited higher proportions of Blacks (19.0% vs 5.6% for Midwest, the lowest region, p < 0.001). Neighborhood racial composition was positively associated with accrual of Black participants (17.2% at sites from highest Black composition vs. 2.3% in lowest, p < 0.001). Recruitment trajectories of Black participants consistently lagged those of non-Black participants in the first half of the study; however, Black participants recruited per month numerically increased after the study reached target accrual of non-Blacks and closed to non-Black participants. Conclusions: Sites in neighborhoods and geographic regions with larger Black populations recruited higher proportions of Black participants, but site type and volume were not associated with recruitment of Black participants. Closure of non-Black study strata based on predetermined accrual targets may positively impact recruitment trajectories of Black participants, but further study is needed. Site selection based on neighborhood composition and geography may be an appropriate tool for increasing trial diversity. Support: UG1CA189823. Clinical trial information: NCT04379570.

Evaluating the time toxicity of cancer treatment in the CCTG CO.17 randomized clinical trial (RCT).

248 Background: Most individual treatments for advanced cancer are associated with modest survival benefits. The time spent in pursuing these treatments can be substantial. We have previously developed a pragmatic and patient-centered metric of these time costs, which we term ‘’time toxicity’’, as any day with physical healthcare system contact. This includes outpatient visits (e.g., for bloodwork, scans, infusions, urgent care), emergency room visits, and overnight stays in a healthcare facility. Herein we sought to assess time toxicity in a completed RCT. Methods: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions vs supportive care alone in 572 patients with advanced colorectal cancer. CO.17 recruited participants in Canada, Australia and New Zealand. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 vs 4.6 months, p = 0.005). Subsequent analyses reported that OS benefit was restricted to and significantly more in patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing treatment, follow-up, and resource utilization forms. We considered a day without physical healthcare contact as a ‘’home day’’. Thus, for a patient, OS was time toxic days + home days. We compared medians of time measures across arms, and stratified results by K-ras status. Results: In the overall population, median time toxic days were higher in the cetuximab arm (28, vs 10, p < 0.001), although median home days were not statistically different (140, vs 121, p = 0.09). The proportion of time toxic days (time toxic days/OS) were significantly more with cetuximab (18%, vs 6%, p < 0.001). Of the 28 time toxic days in the overall cetuximab arm, 14 (50%) were protocol-related (e.g., scheduled infusions etc). Stratified results are in the table. Conclusions: Time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS-benefit with cetuximab, home days were statistically similar across arms. In the K-ras-mutated group, cetuximab was associated with numerically similar OS but more time toxic days. In the K-ras-wild type group, cetuximab was associated with higher home days. Thus, time toxicity data need not always be sobering. Time toxicity measures can supplement traditional survival endpoints in RCTs to guide patient-oncologist decision-making. Cooperative group RCTs are well positioned for such analyses. Clinical trial information: NCT00079066. [Table: see text]

New Advances in Supportive Care: Chemoprotective Agents as Novel Opportunities in Geriatric Oncology.

To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. New chemoprotective agents are necessary because age is the main risk factor for chemotherapy complications that account largely for the poorer outcome of cancer in the elderly. Trilaciclib and ALRN-6924 cause a reversible block of the proliferation of normal cells through cell cycle arrest (CCA). With this mechanism, they may prevent the toxicity of cycle-active cancer treatment including neutropenia, anemia, thrombocytopenia, lymphopenia, mucositis, and alopecia. Myelopoietic growth factors may prevent neutropenia in the aged, but they may cause severe bone pain, may aggravate thrombocytopenia and anemia, and may cause myelodysplasia and acute leukemia as a late complication. The prevention of thrombocytopenia, anemia, mucositis, and alopecia is unsatisfactory at present. These complications may jeopardize the treatment outcome as they require a reduction of treatment dose/intensity and because many patients find the resulting symptoms intolerable. In three studies of patients with extensive disease small cell lung cancer (ES-SCLC), trilaciclib reduced the severity and duration of neutropenia and thrombocytopenia as well as the need for blood transfusions. In addition, it produced a significant expansion of T-cell clones. Trilaciclib received FDA approval for the prevention of chemotherapy-induced myelosuppression in patients with ES-SCLC. ALRN-6924 is currently studied in phase II study of ES-SCLC. In a phase IB of 38 patients, ALRN-6924 prevented myelosuppression to an extent comparable with trilaciclib. Both drugs proved as effective in patients 65 and older as they were in the younger ones. In an "ex vivo" study, ALRN-6924 protected the epithelial stem cells of hair follicles from taxanes and promised to prevent alopecia. The possibility that CCA of tumor cells may reduce the effectiveness of cycle-active chemotherapy is a major concern. For this reason, the use of trilaciclib, an inhibitor of CDK 4/6, should be limited to tumors with inactivated RB1, and the use of ALRN-6924, an inhibitor of P53, should be limited to tumors with inactivated P53. Chemotherapy-related toxicities limit dose intensity and contribute to significant morbidity and mortality in elderly cancer patients. Trilaciclib and ALRN-6924 are of particular interest to geriatric oncologists because of their novel mechanism of action. Ameliorating chemotherapy-induced toxicities holds the promise of transforming the practice of geriatric oncology by enabling chemotherapeutic regimens that are currently not feasible for this patient population. Specifically, these agents may prevent chemotherapy-induced neutropenia and thrombocytopenia, perhaps the most life-threatening complications of cytotoxic chemotherapy, thereby obviating the need for the use of rescue strategies such as hematopoietic growth factors. In addition, these agents offer the potential for broad tissue protection from other chemotherapy-related toxicities, including mucositis, diarrhea, and alopecia, which historically have been poorly managed. Importantly, by preventing a spectrum of chemotherapy-related toxicities, these agents may permit the administration of chemotherapy at full-dose intensity, prevent functional decline, and grant maintenance of resilience to older cancer patients. As a result, the successful prevention of chemotherapy-induced side effects may not only mitigate the costs of care but also improve patient outcomes and quality of life. Finally, chemoprotective strategies offer the opportunity to apply geriatric principles to clinical trials of cancer treatment. In particular, they may allow the testing of prolongation of "active life expectancy" as a major goal of clinical trials in elderly patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.

O15-3 Prophylactic strategies for chemotherapy-induced hand foot syndrome: A meta-analysis of randomized controlled trials

Hand-foot syndrome (HFS) is a common toxicity of several systemic cancer treatments. Trials have investigated the use of preventive strategies such as COX-inhibitors, pyridoxine and urea cream, however, no consensus has been made. This meta-analysis evaluated the efficacy of these strategies using randomized trials to provide strong evidence in forming recommendations to prevent chemotherapy-related HFS.

Homeopathy effects in patients during oncological treatment: a systematic review

PurposeIn this systematic review we included clinical studies from 1800 until 2020 to evaluate evidence of the effectiveness of homeopathy on physical and mental conditions in patients during oncological treatment.MethodIn February 2021 a systematic search was conducted searching five electronic databases (Embase, Cochrane, PsychInfo, CINAHL and Medline) to find studies concerning use, effectiveness and potential harm of homeopathy in cancer patients.ResultsFrom all 1352 search results, 18 studies with 2016 patients were included in this SR. The patients treated with homeopathy were mainly diagnosed with breast cancer. The therapy concepts include single and combination homeopathic remedies (used systemically or as mouth rinses) of various dilutions. Outcomes assessed were the influence on toxicity of cancer treatment (mostly hot flashes and menopausal symptoms), time to drain removal in breast cancer patients after mastectomy, survival, quality of life, global health and subjective well-being, anxiety and depression as well as safety and tolerance. The included studies reported heterogeneous results: some studies described significant differences in quality of life or toxicity of cancer treatment favouring homeopathy, whereas others did not find an effect or reported significant differences to the disadvantage of homeopathy or side effects caused by homeopathy. The majority of the studies have a low methodological quality.ConclusionsFor homeopathy, there is neither a scientifically based hypothesis of its mode of action nor conclusive evidence from clinical studies in cancer care.