As new cancer therapies emerge and evolve, there is a need for a better understanding of their safety and tolerability. Safety and tolerability are distinct, albeit related, constructs; an unsafe treatment cannot be considered tolerable, whereas safe treatments may not be tolerable to some patients. Cancer treatment tolerability is a multidimensional construct, and is influenced both by the profile of adverse events and by whole‐person factors. This commentary provides definitions of safety, tolerability, adverse events, and toxicity by relating these constructs to the adverse event reporting paradigm. Measures, including summary indicators, that reflect the tolerability of cancer treatments are also identified. The commentary concludes with a discussion of how evaluations of tolerability may be meaningfully incorporated into the design and interpretation of future cancer treatment trials.

The authors comment on an article published in this issue of Cancer about emerging data for gemcitabine in clear cell ovarian cancer. In addition, current chemotherapeutic options for recurrent ovarian clear cell carcinoma are reviewed.

Tobacco use is the primary contributor to disease and death in the United States, and cigarette smoking is the leading risk factor for lung cancer. Safe and effective treatments for tobacco dependence exist; however, access to and use of tobacco treatment remains low. The most recent Centers for Medicare and Medicaid Services National Coverage Determination requires a shared decision-making visit for lung cancer screening that includes counseling on the importance of maintaining cigarette smoking abstinence if a person formerly smoked; or the importance of smoking cessation if a person currently smokes and, if appropriate, furnishing of information about tobacco-cessation interventions. The directive is not well defined and provides little guidance for delivering high-quality cessation services. Effective integration of best practices for tobacco treatment in the context of lung cancer screening must extend far beyond recommendations to quit, patient literature to reinforce quitting, and available evidence-based treatments. To optimize the provision of tobacco treatment and improve health outcomes in people being screened for lung cancer, the American Cancer Society National Lung Cancer Roundtable Tobacco Treatment in the Context of Lung Cancer Screening Task Group recommends: (1) specify quality indicators and document tobacco treatment delivery; (2) embed tobacco treatment in lung cancer screening; (3) advocate for increased access to tobacco treatment; (4) build and train lung cancer screening staff; (5) provide full coverage of treatment medications; (6) leverage electronic health records to improve the provision of cessation services to lung cancer screenees; and (7) identify and address contextual barriers to incorporating tobacco treatment guidelines in screening.

IntroductionTreatment intensification with androgen receptor signaling inhibitors and/or chemotherapy is guideline recommended for patients with de novo metastatic hormone‐sensitive prostate cancer (mHSPC). However, most patients only receive androgen deprivation therapy monotherapy. The aim was to identify physician‐, patient‐, and tumor‐related factors associated with the receipt of treatment intensification.MethodsA population‐based cohort study was conducted in Ontario, Canada, which included men ≥66 years newly diagnosed with de novo mHSPC between January 2014 and December 2022. Hierarchical regression modeling was used to examine the association of physician, patient, and tumor characteristics with the receipt of treatment intensification, defined as the initiation of an androgen receptor signaling inhibitor, docetaxel, or both within six months of diagnosis. Darlington’s method was used to assess predictor importance via standardized regression coefficients (SRC).ResultsAmong 6099 eligible older men newly diagnosed with de novo mHSPC, 1475 (24.2%) received treatment intensification. In multivariable modeling, patients initiated on androgen deprivation therapy by radiation oncologists were less likely to receive treatment intensification (odds ratio [OR]. 0.48; 95% CI, 0.37–0.61; p < .01; SRC: 19.46; p < .01) whereas those by medical oncologists were more likely to receive treatment intensification (OR, 1.64; 95% CI, 1.21–2.22; p < .01; SRC: 9.56; p < .01), each compared to urologists. Older patients were significantly less likely to receive treatment intensification (OR 0.94 per year over age 66; 95% CI, 0.93–0.95; p < .01; SRC: –36.21; p < .01).ConclusionPatient and physician characteristics significantly influence variation in the use of treatment intensification for de novo mHSPC. These findings inform targeted interventions and policies to enhance the delivery of life‐prolonging mHSPC care.

In this issue of Cancer , Schinke et al. report long‐term patient‐reported outcomes from the phase 1/2 MonumenTAL‐1 trial of talquetamab, which show durable improvements in quality of life despite early toxicities. Although these findings support the therapy’s tolerability, they also highlight the limitations of current patient‐reported outcome tools in capturing hallmark GPRC5D‐related adverse events and underscore the need for more targeted measures in future studies.

Outcomes show a reduction in treatment failure associated with doseescalated, hypofractionated radiation therapy for localized prostate cancer

The response to ruxolitinib after 6 months (RR6) model allows early identification of ruxolitinib-treated myelofibrosis (MF) patients with poorer overall survival (OS); however, it is less applicable to lower-risk patients. To further explore this, the authors performed a subanalysis of the "RUX-MF" study (NCT06516406) with an aim to validate the RR6 and to develop a score specific for intermediate-1 DIPSS/MYSEC-PM risk patients. Among the 776 evaluable patients, 34.4%, 47.8%, and 17.8% were at low, intermediate, and high RR6 risk, with 5-year OS of 64.1%, 51.8%, and 44.5%, respectively (p<.001). In the 428 intermediate-1 patients, the RR6 model did not discriminate between intermediate and low-risk patients (5-year OS: 74.4% vs. 72.0%, p=.24). The intermediate-1 specific RR6 (iRR6) model was therefore developed by incorporating new variables: underdosed ruxolitinib with respect to platelet count at one or more time points (hazard ratio [HR], 3.91; p<.001), absence of palpable spleen reduction by≥50% at 6 months (HR, 1.45; p=.02), and red blood cell transfusion requirement at all time points (HR, 1.85; p=.01). The iRR6 model stratified patients into three risk categories: low (score 0, 20.3%), intermediate (score 1-2, 45.8%), and high-risk (score >2, 33.9%), with 5-year OS of 84.8%, 76.4%, and 56.6%, respectively (p<.0001). The iRR6 model was validated in a cohort of 95 intermediate-1 risk patients from the Moffitt Cancer Center, yielding stratification into the same three risk categories, with 5-year OS of 83.3% (low-risk), 71.7% (intermediate-risk), and 54.5% (high-risk) (p=.01). The iRR6 model provides a more refined tool for the identification of intermediate-1 MF patients who may benefit from early therapy shift.

Identifying disease burden among childhood cancer survivors (CCS) can guide tailored care. Physical fitness predicts health and mortality and may help reduce disease burden in CCS. This study aimed to 1) describe the burden of clinically ascertained adverse health outcomes in long-term CCS, and 2) investigate the association between physical fitness and adverse health outcomes. This study used baseline data of the SURfit study, a randomized controlled physical activity trial. The authors included 163 CCS, diagnosed <16 years, ≥16 years at enrollment, and ≥5 years since last cancer diagnosis. Clinically assessed health outcomes were categorized using the Common Terminology Criteria for Adverse Events. Physical fitness was assessed by cardiopulmonary-exercise-test (CPET), hand-grip strength, and the 1-minute sit-to-stand test (STS). Using multivariable Poisson regression models, this study investigated the association between physical fitness and adverse health outcomes. Participants (30.5±8.6 years old, time since diagnosis 22.9±9 years) had 1170 adverse health outcomes, with 99% CCS having at least one. Musculoskeletal disorders were most common (130 of 163 [80%]). Higher levels of physical fitness were associated with fewer adverse health outcomes of any grade (CPET: prevalence rate ratio [PRR], 0.71 per watt/kg bodyweight, 95% confidence Interval [CI], 0.63-0.81, p<.001; hand-grip: PRR, 0.60 kg/kg bodyweight; 95% CI, 0.35-1.03, p=.063; STS: PRR, 0.95 per five repetitions; 95% CI, 0.93-0.97, p<.001). CCS participating in an exercise intervention trial experienced a high burden of adverse health outcomes. Increased physical fitness was associated with reduced disease burden for all survivors, emphasizing the importance of encouraging fitness improvements, regardless of cancer history.

Chordomas are rare ectodermal bone malignancies derived from transformed notochordal remnants. Histologic variants include conventional (80%-90%), chondroid (5%-15%), and dedifferentiated (2%-8%). Because chordomas are relatively resistant to chemotherapy and radiotherapy, novel targeted agents are needed to expand treatment approaches and improve outcomes. This study analyzes the genomic landscape of chordoma and identifies potential pathogenic and druggable targets. Eighty-six tumor samples derived from chordoma patients treated at Massachusetts General Hospital, University of California, Los Angeles, and the University of Miami were included. Tumor specimens were sent for comprehensive molecular profiling using next-generation sequencing. The most frequently mutated genes were identified and categorized by subtype, and microsatellite instability and programmed death ligand-1 (PD-L1) staining were assessed. Histologic subtypes included 70 conventional (81.4%), nine chondroid (10.5%), and seven dedifferentiated chordomas (8.1%). The most common mutations were cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) (28 of 86, 33%), low-density lipoprotein receptor-related protein 1B (10 of 86, 12%), polybromo-1 (9 of 86, 11%), and epidermal growth factor receptor (EGFR) (8 of 86, 9%). By subtype, CDKN2A/B mutation was most common in conventional chordoma (24 of 70, 34%), and chondroid chordoma (3 of 9, 33%). CDKN2A/B and EGFR mutations were most common in dedifferentiated chordoma (2/7, 29%). Microsatellite instability was not detected in seven of 69 (10.1%) samples. PD-L1 staining of tumor and immune cells was scarce, with scores <1 in 38 of 41 (92.7%) and 22 of 25 (88%) patients, respectively. This study provides a robust, high-dimensional sequencing assessment from 86 chordoma tissue samples and a descriptive overview of the genomic landscape of this rare, difficult to treat malignancy. Future studies should include in vitro assessment of gain and loss of function of frequently altered pathways to validate these findings.