The risk of treatment-related toxicities with PD-1/PD-L1 inhibitors in patients with lung cancer.

The risk of treatment-related toxicities with programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitors in patients with lung cancer is unclear and inconclusive. PubMed, EMBASE, and the Cochrane Library databases were systematically searched without language restrictions from inception to May 31, 2024 to identify Phase 3 randomized controlled trials of lung cancer comparing PD-1/PD-L1 inhibitors versus placebo/best supportive care (alone or in combination with nontargeted chemotherapy) that had available data regarding treatment-related adverse events (TRAEs) or incidence and sample size. Random-effect models were employed to study the pooled relative risk (RR) and 95% confidence intervals (CIs). Finally, 36 trials, involving 19,693 participants, fulfilled the inclusion criteria. PD-1/PD-L1 inhibitors significantly augmented the likelihood of developing all-grade (RR, 1.03; 95% CI, 1.01-1.04, p < .01) and grade ≥3 TRAEs (RR, 1.16; 95% CI, 1.10 to 1.23, p < .01). PD-1/PD-L1 inhibitors substantially augmented the odds of developing treatment-related serious adverse events (SAEs) (RR, 1.48; 95% CI, 1.27-1.71, p < .01) and fatal adverse events (FAEs) (RR, 1.42; 95% CI, 1.11-1.82, p < .01). Subgroup analyses indicated that the RR of SAEs and FAEs were generally consistent, regardless of treatment type, tumor type, treatment setting, PD-1/PD-L1 inhibitors type and study design. The most common causes of FAEs were respiratory failure/insufficiency (33.3%), cardiac events (16.1%), and hematological disorders (10.1%). We demonstrated that PD-1/PD-L1 inhibitors were significantly correlated with higher possibility of developing treatment-related toxicities, especially SAEs and FAEs, compared with placebo/best supportive care controls.

The potential impact of exercise upon symptom burden in adolescents and young adults undergoing cancer treatment.

PURPOSE: Adolescents and young adults (AYAs) experience vast symptom burden resulting from cancer treatment-related toxicities (TRTs). Evidence supports integrated exercise to mitigate several TRTs in other cohorts; however, evidence in AYAs is lacking. Conventional reporting of TRTs adopts a maximum grade approach failing to recognise the trajectory over time, of persistent, or lower grade toxicities. Alternatively, longitudinal analysis of toxicities over time (ToxT) may provide clinically meaningful summaries of this data. We evaluated the longitudinal impact of an exercise intervention on TRTs in AYAs undergoing cancer treatment. METHODS: A prospective, randomised trial allocated participants to a 10-week exercise intervention (EG) or control group (CG) undergoing usual care. Detailed information on TRTs was collected throughout the intervention. All TRTs were graded per the Common Terminology Criteria for Adverse Events (CTCAE v5.0). RESULTS: Forty-three (43) participants (63% male, mean age 21.1 years) were enrolled. When categorised to reflect the maximal worst grade experienced (Grade 0, Grade 1-2 and ≥ Grade 3), the CG reported an increased incidence of severe fatigue (≥ Grade 3) compared with the EG (p = 0.05). No other differences between groups were evident (p > 0.05). ToxT analysis of the four most common toxicities (fatigue, pain, nausea and mood disturbances) demonstrated no difference in the mean grade of each over time (p > 0.05). CONCLUSION: A 10-week exercise intervention reduces the severity of fatigue in AYAs undergoing treatment. While the ToxT approach provided insight into the toxicity profile, adequately powered studies are needed to better understand these differences within a homogenous sample. TRIAL REGISTRATION: (ACTRN12620000663954) 10th June 2020.

The patient perspective on dose optimization for anticancer treatments: A new era of cancer drug dosing-Challenging the "more is better" dogma.

The Patient-Centered Dosing Initiative, a patient-led effort advocating for a paradigm shift in determining cancer drug dosing strategies, pioneers a departure from traditional oncology drug dosing practices. Historically, oncology drug dosing relies on identifying the maximum tolerated dose through phase 1 dose escalation methodology, favoring higher dosing for greater efficacy, often leading to higher toxicity. However, this approach is not universally applicable, especially for newer treatments like targeted therapies and immunotherapies. Patient-Centered Dosing Initiative challenges this "more is better" ethos, particularly as metastatic breast cancer patients themselves, as they not only seek longevity but also a high quality of life since most metastatic breast cancer patients stay on treatment for the rest of their lives. Surveying 1221 metastatic breast cancer patients and 119 oncologists revealed an evident need for flexible dosing strategies, advocating personalized care discussions based on patient attributes. The survey results also demonstrated an openness toward flexible dosing and a willingness from both patients and clinicians to discuss dosing as part of their care. Patient-centered dosing emphasizes dialogue between clinicians and patients, delving into treatment efficacy-toxicity trade-offs. Similarly, clinical trial advocacy for multiple dosing regimens encourages adaptive strategies, moving away from strict adherence to maximum tolerated dose, supported by recent research in optimizing drug dosages. Recognizing the efficacy-effectiveness gap between clinical trials and real-world practice, Patient-Centered Dosing Initiative underscores the necessity for patient-centered dosing strategies. A focus on individual patient attributes aligns with initiatives like Project Optimus and Project Renewal, aiming to optimize drug dosages for improved treatment outcomes at both the pre- and post-approval phases. Patient-Centered Dosing Initiative's efforts extend to patient education, providing tools to initiate dosage-related conversations with physicians. In addition, it emphasizes physician-patient dialogues and post-marketing studies as essential in determining optimal dosing and refining drug regimens. A dose-finding paradigm prioritizing drug safety, tolerability, and efficacy benefits all stakeholders, reducing emergency care needs and missed treatments for patients, aligning with oncologists' and patients' shared goals. Importantly, it represents a win-win scenario across healthcare sectors. In summary, the Patient-Centered Dosing Initiative drives transformative changes in cancer drug dosing, emphasizing patient well-being and personalized care, aiming to enhance treatment outcomes and optimize oncology drug delivery.

Efficacy and safety of hypofractionated radiotherapy versus conventional fractionated radiotherapy in diffuse intrinsic pontine glioma: A systematic review and meta-analysis.

Background: Diffuse intrinsic pontine glioma (DIPG) stands as the predominant type of brainstem glioma. It is characterized by a notably brief median survival period, with the majority of patients experiencing disease progression within six months following radiation therapy. This systematic review and meta-analysis aims to assess the efficacy and safety of hypofractionated radiotherapy (HFRT) compared to conventionally fractionated radiotherapy (CFRT) in DIPG treatment. Materials and methods: A systematic literature search was conducted in four databases, and relevant studies comparing HFRT and CFRT in DIPG were included. Data were extracted and analyzed for overall survival (OS), progression-free survival (PFS), and treatment-related toxicities. Statistical analysis was performed using random-effects models with heterogeneity assessment. Results: Five studies met the inclusion criteria, comprising 518 patients. No significant difference in one-year OS was observed between HFRT and CFRT (29% vs. 22%, p = 0.94). The median OS was similar in both treatment groups (9.7 vs. 9.3 months, p = 0.324). Similarly, no significant difference in one-year PFS was found between HFRT and CFRT (19.8% vs. 16.6%, p = 0.82), with comparable median PFS (9.3 vs. 9.4 months, p = 0.20). In meta-regression analysis, there was no association of chemotherapy (p > 0.05) or radiation biologically effective dose (BED) (p > 0.05) regarding OS or PFS outcomes. There were no significant differences in treatment-related toxicities. Conclusions: HFRT yields one-year OS and PFS rates similar to CFRT in DIPG, with no significant differences in treatment-related toxicities. Chemotherapy and BED did not affect OS or PFS.

Second-line treatment with axitinib plus toripalimab in metastatic renal cell carcinoma: a retrospective multicenter study.

Aim: To evaluate the efficacy and safety of second-line treatment with axitinib plus toripalimab in patients with metastatic renal cell carcinoma and failure of VEGFR tyrosine kinase inhibitors. Methods: Data were collected restropectively. Kaplan-Meier analysis and Cox proportional hazards model determined the efficacy outcomes. Results: In 57 patients, objective response rate was 31.6% and median progression-free survival (PFS) was 11.7 months, while median overall survival was not reached. Median PFS was not reached in favorable-risk patients, whereas PFS of 11.0 and 7.8 months were observed in intermediate- and poor-risk patients, respectively (p = 0.011). The treatment-related toxicities were mild in nature. Conclusion: Second-line therapy with axitinib plus toripalimab provided durable response rate, longer PFS and a tolerable safety profile.

Renal cell carcinoma is the most common type of kidney cancer. In cases of metastatic RCC, the combination of axitinib (a VEGFR tyrosine kinase inhibitor) and toripalimab (a recombinant humanized anti-PD-L1 monoclonal antibody) may be beneficial. We investigated the efficacy and safety of second-line treatment with axitinib plus toripalimab in patients with metastatic renal cell carcinoma and anti-VEGFR tyrosine kinase inhibitor therapy failure. Data on patients treated with axitinib plus toripalimab were collected retrospectively and we evaluated the response rate, survival status and toxicities. In total, 31.6% of patients responded to the treatment, with a median progression-free survival of 11.7 months. The combination therapy was safe, with hypertension being the most common grade ≥3 adverse event.

Obstructive sleep apnea in head and neck cancer survivors.

IMPORTANCE: Chronic fatigue is present in 33.0% of all head and neck cancer (HNC) survivors; this impacts their quality of life negatively. A plausible cause is obstructive sleep apnea (OSA) after HNC treatment. However, studies regarding this topic are scarce. OBJECTIVE: To confirm if OSA is more prevalent after receiving radiotherapy for HNC. In addition, investigation of the risk factors for developing OSA in this population. DESIGN: A retrospective review of prospective data. METHODS: Treatment for HNC took place between 2016 and 2017 at the University Hospital of Leuven. One hundred sixty-four patients were eligible for participating in this study. Sixty-five responded (39.4%). Upon consulting their medical files, 15 patients were excluded based on the in- and exclusion criteria. Presence of OSA was estimated using standardized questionnaires, namely the Berlin Questionnaire, the Epworth Sleepiness Scale, and the CIS-20. This was compared to the proportion of OSA in the general population. RESULTS: Fifty patients (33 men, 17 women) with a mean age of 64.2 years (range 32-88) were included. Based on the questionnaires, OSA was suspected in twenty. The prevalence of suspected OSA in our study group (40.0%) was significantly greater (p < 0.0001) than our estimated prevalence of OSA in the general population (10.9%). No significant risk factors could be identified. CONCLUSION: Patients treated for HNC are at risk of developing OSA. When complaints of fatigue and sleeping problems persist, referral to a sleep clinic is suggested. Further investigation remains necessary to identify potential risk factors along with prevention and treatment strategies.

The Biological and Clinical Relevance of G Protein-Coupled Receptors to the Outcomes of Hematopoietic Stem Cell Transplantation: A Systematized Review.

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for several malignant and non-malignant diseases at the cost of serious treatment-related toxicities (TRTs). Recent research on extending the benefits of HSCT to more patients and indications has focused on limiting TRTs and improving immunological effects following proper mobilization and engraftment. Increasing numbers of studies report associations between HSCT outcomes and the expression or the manipulation of G protein-coupled receptors (GPCRs). This large family of cell surface receptors is involved in various human diseases. With ever-better knowledge of their crystal structures and signaling dynamics, GPCRs are already the targets for one third of the current therapeutic arsenal. The present paper assesses the current status of animal and human research on GPCRs in the context of selected HSCT outcomes via a systematized survey and analysis of the literature.

Potentially inappropriate medication use in elderly non-Hodgkin lymphoma patients is associated with reduced survival and increased toxicities.

Survival outcomes for elderly lymphoma patients are disproportionally inferior to those of younger patients. We examined medication usage at diagnosis for 171 elderly patients (median age 70 years) with aggressive non-Hodgkin lymphoma treated between 2009 and 2014. At least one potentially inappropriate medication was used in 47% of patients according to the Beers Criteria, 59% experienced treatment delays and/or dose reduction and 65% experienced ≥ grade 3 treatment-related toxicities. We report here for the first time that potentially inappropriate medication use was associated with reduced progression-free survival and overall survival, and increased ≥ grade 3 treatment-related toxicities in multivariate analysis.

Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma.

Management of patients with glioblastoma (GBM) often includes radiation (RT) and temozolomide (TMZ). The association between severe treatment-related lymphopenia (TRL) after the standard chemoradiation and reduced survival has been reported in GBM patients with the median age of 57. Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancers. This retrospective study is designed to evaluate whether elderly GBM patients (age ≥65) develop similar TRL after RT/TMZ and whether such TRL is associated with decreased survival. Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients (age ≥65) with newly diagnosed GBM undergoing RT/TMZ and associated with treatment outcomes. Seventy-two patients were eligible: median KPS 70, median age 71 years (range 65-86) with 56 % of patients >70 years, 53% female, 31% received RT ≤45 Gy. Baseline median TLC was 1100 cells/mm(3) which fell by 41% to 650 cells/mm(3) 2 months after initiating RT/TMZ (p < 0.0001). Patients with TLC <500 cells/mm(3) at 2 months had a shorter survival than those with higher TLCs with a median overall survival of 4.6 versus 11.6 months, respectively. Multivariate analysis revealed a significant association between TRL and survival (HR 2.76, 95% CI 1.30-5.86, p = 0.008). Treatment-related lymphopenia is frequent, severe, and an independent predictor for survival in elderly patients with GBM. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes. Prospective studies are needed to confirm these findings suggesting that immune preservation is important in this cancer.

R-CSS: A clinically applicable score to classify cachexia stages in patients with cancer undergoing intensity-modulated radiation therapy.

Objective: Accurate cachexia staging is the key to its management. However, there is currently a lack of tools to distinguish the staging of cachexia in patients with cancer undergoing radiotherapy. The Radiotherapy Cachexia Staging Scale (R-CSS) was developed for the stratification of cachexia in patients undergoing cancer radiotherapy. Methods: Patients with cancer undergoing radiotherapy were divided into four stages - noncachexia, precachexia, cachexia, and refractory cachexia - by the R-CSS scale, and the clinical outcomes of the four groups were compared. Results: A total of 270 patients with cancer undergoing radiation therapy were included in the study. All participants were classified into four stages of cachexia: stage 0, I, II, and III. Patients with a higher cachexia stage had a higher prevalence of sarcopenia (P â€‹= â€‹0.015). Scores on the 16-item M. D. Anderson Symptom Inventory were higher in patients with higher cachexia stages (P â€‹< â€‹0.05), but levels of forgetfulness, numbness, and shortness of breath were not higher in these patients (P â€‹> â€‹0.05). Patients with higher cachexia stages exhibited better scores on the QLQ-C30 scale (P â€‹< â€‹0.05), except for in the domains of cognitive functioning, diarrhea, and dyspnea (P â€‹> â€‹0.05). The incidence of treatment-related events (any grade III or higher grade of [non-]hematologic adverse events, the need for hospitalization, emergency room admission) was higher in patients with higher cachexia stages. Conclusions: The R-CSS scale is a screening tool that can simultaneously distinguish different stages of cachexia.

Identification of Key Elements in Prostate Cancer for Ontology Building via a Multidisciplinary Consensus Agreement.

BACKGROUND: Clinical data collection related to prostate cancer (PCa) care is often unstructured or heterogeneous among providers, resulting in a high risk for ambiguity in its meaning when sharing or analyzing data. Ontologies, which are shareable formal (i.e., computable) representations of knowledge, can address these challenges by enabling machine-readable semantic interoperability. The purpose of this study was to identify PCa-specific key data elements (KDEs) for standardization in clinic and research. METHODS: A modified Delphi method using iterative online surveys was performed to report a consensus agreement on KDEs by a multidisciplinary panel of 39 PCa specialists. Data elements were divided into three themes in PCa and included (1) treatment-related toxicities (TRT), (2) patient-reported outcome measures (PROM), and (3) disease control metrics (DCM). RESULTS: The panel reached consensus on a thirty-item, two-tiered list of KDEs focusing mainly on urinary and rectal symptoms. The Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire was considered most robust for PROM multi-domain monitoring, and granular KDEs were defined for DCM. CONCLUSIONS: This expert consensus on PCa-specific KDEs has served as a foundation for a professional society-endorsed, publicly available operational ontology developed by the American Association of Physicists in Medicine (AAPM) Big Data Sub Committee (BDSC).

Title: Obesogenic microbial signatures and the development of obesity in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer with survival exceeding 90% for standard-risk groups. A debilitating side-effect of treatment is the development of overweight/obesity (OW/OB), which develops in approximately 40% of children by the end of treatment. The microbiome has been associated with the development of OW/OB. We examined fluctuations in the microbiome with the development of OW/OB during the first six months of treatment at diagnosis, and two subsequent timepoints (N = 62). Shotgun metagenomic sequencing was performed on Illumina Nextseq system, and taxa and functional pathways were extracted from sequences using kraken2 and humann2, respectively. An association of increased presence of several species (e.g., Klebsiella pneumoniae, Escherichia coli) was observed in children with OW/OB, while lean-promoting species (Veillonella, Haemophilus, and Akkermansia) were increased in children who maintained a normal weight. Pathway analysis revealed purine nucleotide biosynthesis, sugar nucleotide biosynthesis, and enzyme cofactor biosynthesis were positively correlated with Bacteroides spp. among children with OW/OB. We identified several taxa and functional pathways that may confer increased risk for the development of OW/OB. The associations observed in this pilot are preliminary and warrant further research in the microbiome and the development of OW/OB in childhood ALL.

Treatment-related toxicities associated with hospitalization in children, adolescents, and young adults with acute lymphoblastic leukemia: population level analysis.

Treatment-related toxicities (TRTs) are a potential cause of survival disparities in patients with acute lymphoblastic leukemia (ALL). We aimed to identify the most frequent TRTs associated with hospitalizations at a population level in children, adolescents and young adults (AYAs). We used the California Cancer Registry linked to a statewide hospital discharge database to identify children and AYAs with TRTs within 3 years of diagnosis. We assessed the frequency of TRTs, length of stay (LOS), admission rates associated with TRTs and TRTs impact on survival. Febrile neutropenia, hypertension, and thrombocytopenia were the most common TRTs for both children and AYAs. AYAs had longer median LOS compared to children for most toxicities. AYAs at non-specialized cancer centers (SCCs) had higher frequency of admissions associated with TRTs compared to non-SCC. Cardiovascular, respiratory, gastrointestinal, renal, and infectious TRTs were associated with worse survival. This study demonstrates the burden of TRTs in patients with ALL.

Association of MDR1 C1236T Polymorphisms and B Cell Non-Hodgkin Lymphoma.

Background: Multidrug resistance gene 1 (MDR-1) encodes for P-glycoprotein (P-gp) recognized for removing cytostatic drugs from tumor cells. MDR1 gene polymorphisms change function of P-gp. In this study, we are interested in investigating whether MDR1 C1236T single nucleotide polymorphisms (SNPs) affect the susceptibility and treatment-related toxicities in B-cell non-Hodgkin lymphoma (B-NHL) in the population of eastern China. Materials and methods: A group of 107 B-NHL patients and 150 healthy donors, unrelated ethnic Han Chinese and residents of eastern China, were included in this study. The MDR1 C1236T polymorphisms were determined using polymerase chain reaction-allele specific primers after extraction of genomic DNA. Analyses were performed using SPSS and Arlequin software. Results: MDR1 C1236T polymorphisms were not significantly related to the risk and treatment-related toxicities of B-NHL. A significant association between extranodal sites and C1236T allele was observed (C vs T: P=0.01). Conclusion: Our findings could expand our understanding of MDR1 in B-NHL and provide references for further research in multidrug resistance.

Longitudinal comparisons of a whole-mouth taste test to clinician-rated and patient-reported outcomes of dysgeusia postradiotherapy in patients with head and neck cancer and associations with oral intake.

BACKGROUND: After head and neck cancer (HNC) treatment, dysgeusia may be a barrier to oral intake. In this exploratory study, we prospectively examined taste perception, clinician-rated (CRO) and patient-reported (PRO) taste changes and their effect on oral intake postradiotherapy. METHODS: Twenty-eight patients were assessed at baseline, treatment weeks 2 and 4, and 1, 3, and 6 months post-treatment using a whole-mouth taste test and associated CRO and subjective PRO measures. RESULTS: Greater taste impairment was reflected by subjective than by a whole-mouth taste test. The most significant and consistent decline occurred mid-treatment. The Chemotherapy-Induced Taste Alteration Scale (PRO) discomfort subscale correlated significantly with maintaining an oral diet, percent of oral intake, and appetite level from mid-treatment to 6 months post-treatment. CONCLUSIONS: PRO results indicated ongoing oral intake issues. Whole-mouth taste tests may fail to fully reflect functional taste-loss. Dysgeusia prevention and treatment methods are needed to improve patient outcomes.

Obstructive sleep apnea in the irradiated head and neck cancer patient.

OBJECTIVES/HYPOTHESIS: To assess the prevalence of obstructive sleep apnea (OSA) in head and neck cancer (HNSCC) patients treated with radiation therapy. STUDY DESIGN: Prospective case series without comparison group. METHODS: Patients who underwent radiation therapy for oropharyngeal or laryngeal squamous cell carcinoma completed a 3-night home sleep test (HST), Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and University of Washington Quality of Life questionnaire. Exclusion criteria included oncologic surgical procedures, active disease, history of tracheotomy, history of OSA, or completion of radiation therapy within the last 3 months. RESULTS: Sixteen HNSCC patients completed the HST, with 50% (8) demonstrating objective evidence of OSA ranging from mild to severe (range 5.6-38.8, median 13.9). Median age was 61.6 years, with a median body mass index (BMI) of 29.8, and 13 of the subjects were male. There were no differences in age, BMI, median radiation dose, tumor primary site or stage, human papilloma virus status, or comorbidity status between the OSA and non-OSA groups. Self-reported questionnaire scores were no different between the two groups. OSA patients had a nonsignificant shorter time interval between the completion of radiation and the HST date (1.8 vs. 3.4 years, P = 0.065) and higher rate of gastrostomy tube placement during radiation (62.5% vs. 12.5%, P = 0.059). CONCLUSION: The results of this preliminary study suggest that the prevalence of OSA is increased in the head and neck irradiated patient when compared to the general population. Self-report of sleep symptoms alone may be unreliable to determine risk of OSA in the HNSCC population. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2673-2677, 2017.

Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.

BACKGROUND: Severe treatment-related lymphopenia occurs commonly in many cancers and is associated with early tumor progression. Data are lacking as to whether this occurs in squamous cell head and neck cancer. METHODS: Serial total lymphocyte counts were retrospectively reviewed in patients with newly diagnosed squamous head and neck cancer undergoing chemoradiation and associated with treatment outcomes. RESULTS: The median baseline total lymphocyte count in 56 patients was 1660 cells/mm(3) , which fell by 73% to 445 cells/mm(3) 2 months after initiating chemoradiation (p < .0001). Human papillomavirus negative (HPV-) patients with a total lymphocyte count <500 cells/mm(3) at 2 months had significantly earlier disease progression than those with higher total lymphocyte counts (hazard ratio [HR], 5.75; p = .045). CONCLUSION: Baseline total lymphocyte counts were normal, but at 2 months approximately 60% of patients had severe treatment-related lymphopenia regardless of HPV status. Severe treatment-related lymphopenia in HPV- patients is independently associated with earlier disease progression. Prospective studies are needed to confirm these findings, which suggest that immune preservation is important in this cancer.