Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study.

BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.

The Acceptance and Use of Digital Technologies for Self-Reporting Medication Safety Events After Care Transitions to Home in Patients With Cancer: Survey Study.

BACKGROUND: Actively engaging patients with cancer and their families in monitoring and reporting medication safety events during care transitions is indispensable for achieving optimal patient safety outcomes. However, existing patient self-reporting systems often cannot address patients' various experiences and concerns regarding medication safety over time. In addition, these systems are usually not designed for patients' just-in-time reporting. There is a significant knowledge gap in understanding the nature, scope, and causes of medication safety events after patients' transition back home because of a lack of patient engagement in self-monitoring and reporting of safety events. The challenges for patients with cancer in adopting digital technologies and engaging in self-reporting medication safety events during transitions of care have not been fully understood. OBJECTIVE: We aim to assess oncology patients' perceptions of medication and communication safety during care transitions and their willingness to use digital technologies for self-reporting medication safety events and to identify factors associated with their technology acceptance. METHODS: A cross-sectional survey study was conducted with adult patients with breast, prostate, lung, or colorectal cancer (N=204) who had experienced care transitions from hospitals or clinics to home in the past 1 year. Surveys were conducted via phone, the internet, or email between December 2021 and August 2022. Participants' perceptions of medication and communication safety and perceived usefulness, ease of use, attitude toward use, and intention to use a technology system to report their medication safety events from home were assessed as outcomes. Potential personal, clinical, and psychosocial factors were analyzed for their associations with participants' technology acceptance through bivariate correlation analyses and multiple logistic regressions. RESULTS: Participants reported strong perceptions of medication and communication safety, positively correlated with medication self-management ability and patient activation. Although most participants perceived a medication safety self-reporting system as useful (158/204, 77.5%) and easy to use (157/204, 77%), had a positive attitude toward use (162/204, 79.4%), and were willing to use such a system (129/204, 63.2%), their technology acceptance was associated with their activation levels (odds ratio [OR] 1.83, 95% CI 1.12-2.98), their perceptions of communication safety (OR 1.64, 95% CI 1.08-2.47), and whether they could receive feedback after self-reporting (OR 3.27, 95% CI 1.37-7.78). CONCLUSIONS: In general, oncology patients were willing to use digital technologies to report their medication events after care transitions back home because of their high concerns regarding medication safety. As informed and activated patients are more likely to have the knowledge and capability to initiate and engage in self-reporting, developing a patient-centered reporting system to empower patients and their families and facilitate safety health communications will help oncology patients in addressing their medication safety concerns, meeting their care needs, and holding promise to improve the quality of cancer care.

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors.

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Evaluation of biliary toxicity in patients with hepatic artery infusion pumps.

PURPOSE: Identify risk factors for biliary toxicity in patients with colorectal liver metastases who received floxuridine (FUDR) via a surgically implanted hepatic artery infusion pump (HAIP). Describe the incidence of biliary toxicity and evaluate relevant patterns in the biliary toxicity cohort. METHODS: A single center, retrospective, case-control study included adult colorectal cancer patients with liver metastases who received at least one cycle of FUDR via a surgically implanted HAIP from 1 January 2017, to 1 October 2021. Patients were excluded if they had incomplete records, cholangiocarcinoma diagnosis, or received concurrent mitomycin and FUDR. Biliary toxicity criteria derived from existing HAIP literature were utilized to determine whether patients experienced biliary toxicity. Multiple variables were compared by univariate statistical analysis between the biliary toxicity and non-biliary toxicity cohorts to identify potential risk factors for development of FUDR-induced biliary toxicity. RESULTS: Out of 50 patients who had a HAIP implanted, 39 met the inclusion criteria. Five of the 39 patients (12.7%) included in the analysis met the pre-specified biliary toxicity criteria. No risk factors for biliary toxicity were identified. All five patients who developed biliary toxicity demonstrated elevations in alkaline phosphatase (ALP) prior to meeting the toxicity criteria. CONCLUSION: Biliary toxicity remains a significant and therapy-limiting consequence of FUDR administration. Rising ALP may be an early indicator of subsequent biliary toxicity. Future studies with more patients may identify risk factors that can facilitate risk mitigation strategies.

Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.

BACKGROUND: Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. METHODS: In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. FINDINGS: On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). INTERPRETATION: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. FUNDING: Amgen.

Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.

BACKGROUND: Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. METHODS: An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001). FINDINGS: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. INTERPRETATION: Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. FUNDING: Ignyta/F Hoffmann-La Roche.

Patient Engagement With an Automated Telephone Symptom Management Intervention: Predictors and Outcomes.

BACKGROUND: Self-management of symptoms related to cancer and its treatment is important for maintaining treatment regimens and improving outcomes. PURPOSE: To determine factors associated with engagement in a symptom self-management intervention among patients initiating oral anticancer treatment. METHODS: This secondary analysis included 127 patients randomized to the medication adherence reminder and symptom management intervention in a recently completed trial. Patients were recruited from six Comprehensive Cancer Centers, interviewed at intake, and mailed a Symptom Management Toolkit (Toolkit) with self-care management strategies for 18 symptoms. During eight automated telephone weekly calls, patients were asked to use the Toolkit to manage elevated symptoms. Toolkit use and symptoms were tracked weekly, and generalized linear mixed-effects models were used to determine factors predictive of Toolkit use. General linear modeling was used to relate the Toolkit use during intervention to postintervention symptom severity. RESULTS: Better cognitive function at intake into the trial and higher symptom burden were predictive of the patients' initial decision to try the Toolkit during Week 1. In subsequent weeks, Toolkit use in the previous week and worsening of symptoms were associated with greater odds of Toolkit use. The extent of Toolkit use modified the relationship between intake and 8 week symptom severity: among patients with higher levels of severity at intake, use of the Toolkit conferred greater benefit at 8 weeks. CONCLUSIONS: Patients make realistic decisions regarding when to use a self-directed approach to self-management and are likely to use strategies when their symptoms are higher and to forego use once symptoms subside. CLINICAL TRIAL REGISTRATION: NCT02043184.

Effects of depressive symptomatology on cancer-related symptoms during oral oncolytic treatment.

OBJECTIVE: This manuscript assesses association between depressive symptoms and symptoms from cancer and its treatment during the first 12 weeks of a new oral oncolytic treatment. METHODS: This secondary analysis used data from a recently completed trial of an intervention to improve adherence to oral oncolytic treatment and manage symptoms. Following the initiation of the new oral oncolytic medication, 272 patients were interviewed at intake and weeks 4, 8, and 12 to assess depressive symptoms, and symptoms from cancer and its treatment. Depressive symptoms were measured using the Center for Epidemiologic Studies-Depression (CES-D20). The summed index of 18 cancer-related and treatment-related symptoms as well as the number of symptoms above threshold at intake, weeks 4, 8, and 12 were related to intake and time-varying CES-D20 using linear mixed effects models. RESULTS: Depressive symptomatology was a significant predictor of cancer-related and treatment-related symptoms at all-time points, but the strength of this relationship was greatest at the time of oral oncolytic agent initiation and at week 4. The strength of this relationship was the same for both summed symptom severity index and the number of symptoms above threshold, and using either intake or time-varying CES-D20. CONCLUSION: Introducing strategies to treat and manage symptoms of depression along with other symptoms might have added benefits among patients who start a new oral oncolytic treatment and report modest to higher levels of depressive symptoms. Assessments for the impact of strategies to lower depressive symptoms can be taken within the first 4 weeks.

Do treatment patterns alter beliefs cancer patients hold regarding oral oncolytic agents?

OBJECTIVE: Cancer patients, particularly those prescribed with oral oncolytic medications, face treatment side effects and temporary and permanent stoppages of treatment. This research examines how events during treatment affect patients' beliefs regarding oral oncolytic medications. METHODS: A total of 272 cancer patients initiating 1 of 28 oral oncolytic agents were followed for 12 weeks. Assessments of Beliefs About Medications Questionnaire, symptoms, physical function, and depression measures were performed during telephone interviews at intake (medication start) and 4, 8, and 12 weeks. Electronic medical record audits identified dates of temporary and permanent medication stoppages. Linear mixed-effects models were used for longitudinal analyses of the Beliefs About Medications Questionnaire scores in relation to patient characteristics, symptom severity, and medication stoppages. RESULTS: Over the initial 12 weeks, beliefs about the necessity of oral medications have increased, concerns have decreased, and interference of medications with daily lives has increased. Permanent stoppage of a medication predicted significant declines in beliefs about its necessity over time. Male patients, those less educated, those reporting higher symptom severity, and those experiencing temporary stoppages had greater concerns. Interference of medications with daily life was higher for males, increased with higher symptom severity, and differed by drug category. CONCLUSIONS: Patients' beliefs in the necessity of their oral medication were affected only by a permanent drug stoppage. Symptom severity, education, and patient sex affected patients' beliefs about their concerns with their medications and the interference medications posed for their daily lives. Interventions may need to target the distinct dimensions of beliefs during treatment with oral oncolytic agents.

Challenges to the design and testing supportive interventions for cancer patients treated with oral oncolytic agents.

Conducting research into supportive care for patients as they initiate treatment with oral oncolytic agents poses numerous new challenges. Some of these medications have very complex dosing schedules and produce symptoms that patients need to manage at home with less reliance on oncology clinicians. We describe lessons learned from a multi-site trial designed to improve adherence to these medications and self-management of symptoms among patients newly prescribed oral oncolytic agents. Identifying these challenges can assist researchers to improve the integrity of their future supportive care trials.

Potential mediators of improvement in painful chemotherapy-induced peripheral neuropathy via a web-based cognitive behavioural intervention.

PURPOSE: Preliminary evidence suggests that a self-guided cognitive and behaviourally-based pain management intervention (PROSPECT) is effective for chronic painful chemotherapy-induced peripheral neuropathy (CIPN), but its mechanism of action is unknown. The purpose of this secondary analysis was to explore if changes in anxiety, depression, sleep-related impairment, or fatigue mediated improvements in worst pain following PROSPECT in individuals with chronic painful CIPN. METHODS: Sixty participants were randomized to receive self-guided cognitive behavioural pain management (access for eight weeks) or treatment as usual. A seven-day worst CIPN pain diary and the PROMIS measures of anxiety, depression, fatigue, and sleep-related impairment were administered pre/posttest (eight-weeks). Causal mediation analysis was used to quantify mediators of worst pain improvement. RESULTS: None of the hypothesized mediators had a statistically significant effect on worst pain (n=38). IMPLICATIONS: Further research is needed to identify potential mediators of pain intensity that can be targeted by specific cognitive behavioural strategies to improve painful CIPN severity.

Emerging Systemic Therapies for Colorectal Cancer.

Despite advances over the past 20 years in colorectal cancer (CRC) screening, diagnosis, and treatment, survival outcomes remain suboptimal. Five-year survival for patients with locally advanced CRC is 69%; 5-year survival drops to 12% for patients with metastatic disease. Novel, effective systemic therapies are needed to improve long-term outcomes. In this review, we describe currently available systemic therapies for the treatment of locally advanced and metastatic CRC and discuss emerging therapies, including encouraging advances in identifying novel targeted agents and exciting responses to immunotherapeutic agents.

Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402.

The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub-study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B-cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31-49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR.

Exploring Chemotherapy-Induced Peripheral Neuropathy Management Practice Patterns Among Oncology Clinicians.

OBJECTIVES: Approximately 60% of cancer survivors receiving neurotoxic chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN) (eg, hand and foot numbness, tingling, or pain). There is only one recommended pharmacological treatment (duloxetine) and one modestly beneficial nonpharmacological treatment (exercise) for CIPN. However, data suggest national guideline recommendations are not routinely practiced. Further, less is known about nurses' CIPN management practices. The purpose of this convergent mixed methods study was to explore oncology clinicians' self-reported practices and perceptions regarding CIPN prevention and management. METHODS: Oncology clinicians at three cancer centers completed a survey about their recommendations for CIPN prevention and management in practice. A subset of clinicians also participated in a semi-structured interview to explore their perspectives of and motivations for implementing CIPN assessment, prevention, and management in practice. Quantitative data were described (eg, frequency or median) and qualitative data were analyzed using inductive content analysis. RESULTS: This study (N = 44 survey responses; n = 9 interviews) resulted in four themes: (1) clinicians primarily recommend gabapentin for CIPN management and often observe cryotherapy used for CIPN prevention, but these interventions are complicated by discomfort, intolerable side effects, and efficacy concerns; (2) clinicians perceive CIPN as troublesome and desire additional information and resources regarding CIPN prevention and management; (3) CIPN-related education provided by clinicians may be limited by patient retention of the amount of education received about cancer treatment and other factors; (4) clinicians use subjective CIPN assessment to screen at each visit for common CIPN symptoms (eg, numbness or tingling) and the impact of symptoms on day-to-day activities. CONCLUSIONS: Discrepancies persist between evidence-based guidelines on CIPN management and current oncology clinician practices. IMPLICATIONS FOR NURSING PRACTICE: Clinician involvement is needed when developing education and resources to help oncology clinicians provide the most evidence-based care to potentially prevent and manage their patients' CIPN.

Treatment of Locally Recurrent Rectal Cancer: A Review.

ABSTRACT: Up to 10% of patients with locally advanced rectal cancer will experience locoregional recurrence. In the setting of prior surgery and often radiation and chemotherapy, these represent uniquely challenging cases. When feasible, surgical resection offers the best chance for oncologic control yet risks significant morbidity. Studies have consistently indicated that a negative surgical resection margin is the strongest predictor of oncologic outcomes. Chemoradiation is often recommended to increase the chance of an R0 resection, and in cases of close/positive margins, intraoperative radiation/brachytherapy can be utilized. In patients who are not surgical candidates, radiation can provide symptomatic relief. Ongoing phase III trials are aiming to address questions regarding the role of reirradiation and induction multiagent chemotherapy regimens in this population.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

Home-based aerobic exercise feasibility in oxaliplatin-receiving newly-diagnosed cancer survivors.

PURPOSE: Physical activity (PA) is beneficial but difficult to maintain during chemotherapy. This pilot RCT explored the feasibility of the MI-Walk intervention-an 8-week motivational enhancement therapy- and home-based brisk walking intervention-among gastrointestinal (GI) cancer survivors receiving chemotherapy. METHODS: Sixty stage II-IV GI cancer survivors were recruited from 5 sites at their second infusion visit. Participants were randomized to receive PA education alone or the MI-Walk intervention: motivational enhancement therapy consisting of 3 motivational interviewing and self-efficacy-enhancing counseling sessions, a Fitbit Charge 2, exercise diaries, telephone follow-up, scripted motivational email messages, and optional weekly walking groups. RESULTS: The enrollment and completion rates were 62% and 90%, respectively. The MI-Walk participants (n = 29; mean age = 56.79, SD = 11.72; 97% white; 79% male) reported a baseline moderate-vigorous PA duration of 250.93 (SD = 636.52) min/wk. The mean MI-Walk Intervention acceptability score was 50.32 (SD = 12.02) on a scale of 14-70. Mean Fitbit and counseling helpfulness scores on a 5-point scale were 3.67 (SD = 1.43) and 3.44 (SD = 1.36), respectively. Participants' Fitbit moderate-vigorous PA 8-week averages ranged from 0 to 716.88 min/wk; 64% of participants adhered to ≥127 min/wk. Several characteristics (e.g., age, comorbidity, PA level, employment status, BMI, education level, gender, symptoms) were associated with enrollment, attrition, and intervention acceptability and adherence (p < 0.05). CONCLUSION: Enrollment and retention were adequate. The Fitbit and counseling were the most helpful. Acceptability and adherence varied based on participant characteristics; therefore, intervention tailoring and further research among cancer survivors less physically active at baseline and most in need of complex exercise intervention are needed. CLINICALTRIALS: gov NCT03515356.

Understanding the Mechanosensitivity of the Median Nerve in Pre-Surgical Carpal Tunnel Syndrome Patients: A Correlational Study.

(1) Background: Neurodynamic tests are recommended for the diagnosis of entrapment neuropathies such as carpal tunnel syndrome (CTS). However, their association with clinical variables in severe patients or patients with associated comorbidities is poorly documented. This study aims to analyze the association between the mechanosensitivity of the median nerve and symptoms, function and psycho-social variables in moderate and severe carpal tunnel syndrome patients with comorbidities; (2) Methods: Correlational study. In total, 42 pre-surgical patients (24 females; 59.1 ± 12.7 years) included in the Spanish Public Healthcare System with an electrodiagnostic of CTS were selected. Sociodemographic variables and clinical features (symptoms, function, sensitivity and quality of life evaluated with the 36-item Short Form Survey (SF-36) and the Medical Outcomes Study Sleep Scale (MOS-sleep) were recorded. Upper Limb Neurodynamic Test 1 was used to evaluate neural mechanosensitivity; (3) Results: The 81% had a severe CTS and 78.6% had some comorbidity. The average time from the first medical visit to the surgeon's visit was 365.5 days. Median nerve mechanosensitivity correlated weakly with the SF-36 subscale, General Health, (Spearman's rho = 0.367) and MOS sleep scale, Awaken Short of Breath or with headache dimension (Spearman's rho = -0.353) and moderately with SF-36 subscale, Social Functioning (Spearman's rho = 0.553); (4) Conclusions: No associations were observed for median nerve mechanosensitivity, except for quality of life and sleep. Both social determinants and clinical variables should be considered when examining and treating these patients.

Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial.

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg-1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

ctDNA transiting into urine is ultrashort and facilitates noninvasive liquid biopsy of HPV+ oropharyngeal cancer.

BACKGROUNDTransrenal cell-free tumor DNA (TR-ctDNA), which transits from the bloodstream into urine, has the potential to enable noninvasive cancer detection for a wide variety of nonurologic cancer types.MethodsUsing whole-genome sequencing, we discovered that urine TR-ctDNA fragments across multiple cancer types are predominantly ultrashort (<50 bp) and, therefore, likely to be missed by conventional ctDNA assays. We developed an ultrashort droplet digital PCR assay to detect TR-ctDNA originating from HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC) and confirmed that assaying ultrashort DNA is critical for sensitive cancer detection from urine samples.ResultsTR-ctDNA was concordant with plasma ctDNA for cancer detection in patients with HPV+ OPSCC. As proof of concept for using urine TR-ctDNA for posttreatment surveillance, in a small longitudinal case series, TR-ctDNA showed promise for noninvasive detection of recurrence of HPV+ OPSCC.ConclusionOur data indicate that focusing on ultrashort fragments of TR-ctDNA will be important for realizing the full potential of urine-based cancer diagnostics. This has implications for urine-based detection of a wide variety of cancer types and for facilitating access to care through at-home specimen collections.FundingNIH grants R33 CA229023, R21 CA225493; NIH/National Cancer Institute grants U01 CA183848, R01 CA184153, and P30CA046592; American Cancer Society RSG-18-062-01-TBG; American Cancer Society Mission Boost grant MBGI-22-056-01-MBG; and the A. Alfred Taubman Medical Research Institute.