Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study.

BACKGROUND: HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer. METHODS: HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment. FINDINGS: Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58-70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58-77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4-17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer. FUNDING: Zymeworks, Jazz, and BeiGene.

Using Tumor-Informed Circulating Tumor DNA (ctDNA)-Based Testing for Patients with Anal Squamous Cell Carcinoma.

BACKGROUND: Anal squamous cell carcinoma (SCCA) is an uncommon malignancy with a rising incidence that has a high cure rate in its early stages. There is an unmet need for a reliable method to monitor response to treatment and assist in surveillance. Circulating tumor DNA (ctDNA) testing has shown great promise in other solid tumors for monitoring disease progression and detecting relapse in real time. This study aimed to determine the feasibility and use of personalized and tumor-informed ctDNA testing in SCCA. PATIENTS AND METHODS: We analyzed real-world data from 251 patients (817 plasma samples) with stages I-IV SCCA, collected between 11/5/19 and 5/31/22. The tumor genomic landscape and feasibility of ctDNA testing was examined for all patients. The prognostic value of longitudinal ctDNA testing was assessed in patients with clinical follow-up (N = 37). RESULTS: Whole-exome sequencing analysis revealed PIK3CA as the most commonly mutated gene, and no associations between mutations and stage. Anytime ctDNA positivity and higher ctDNA levels (MTM/mL) were associated with metastatic disease (P = .004). For 37 patients with clinical follow-up, median follow-up time was 21.0 months (range: 4.1-67.3) post-diagnosis. For patients with stages I-III disease, anytime ctDNA-positivity after definitive treatment was associated with reduced DFS (HR: 28.0; P = .005). CONCLUSIONS: Our study demonstrates the feasibility of personalized and tumor-informed ctDNA testing as an adjunctive tool in patients with SCCA as well as potential use for detection of molecular/minuteimal residual disease, and relapse during surveillance. Prospective studies are needed to better evaluate the use of ctDNA testing in this indication.

A Phase Ib, Open-Label Study of Dalantercept, an Activin Receptor-Like Kinase 1 Ligand Trap, plus Sorafenib in Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor-like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted. BACKGROUND: Targeting the activin receptor-like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC). METHODS: In this phase Ib study, patients with advanced HCC were enrolled to dose-escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response. RESULTS: A total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de-escalated to 0.4 mg/kg in the second cohort (n = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort (n = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease. CONCLUSION: The addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.

The Influence of Patient Race and Activation on Pain Management in Advanced Lung Cancer: a Randomized Field Experiment.

BACKGROUND: Pain management racial disparities exist, yet it is unclear whether disparities exist in pain management in advanced cancer. OBJECTIVE: To examine the effect of race on physicians' pain assessment and treatment in advanced lung cancer and the moderating effect of patient activation. DESIGN: Randomized field experiment. Physicians consented to see two unannounced standardized patients (SPs) over 18 months. SPs portrayed 4 identical roles-a 62-year-old man with advanced lung cancer and uncontrolled pain-differing by race (black or white) and role (activated or typical). Activated SPs asked questions, interrupted when necessary, made requests, and expressed opinions. PARTICIPANTS: Ninety-six primary care physicians (PCPs) and oncologists from small cities, and suburban and rural areas of New York, Indiana, and Michigan. Physicians' mean age was 52 years (SD = 27.17), 59% male, and 64% white. MAIN MEASURES: Opioids prescribed (or not), total daily opioid doses (in oral morphine equivalents), guideline-concordant pain management, and pain assessment. KEY RESULTS: SPs completed 181 covertly audio-recorded visits that had complete data for the model covariates. Physicians detected SPs in 15% of visits. Physicians prescribed opioids in 71% of visits; 38% received guideline-concordant doses. Neither race nor activation was associated with total opioid dose or guideline-concordant pain management, and there were no interaction effects (p > 0.05). Activation, but not race, was associated with improved pain assessment (ẞ, 0.46, 95% CI 0.18, 0.74). In post hoc analyses, oncologists (but not PCPs) were less likely to prescribe opioids to black SPs (OR 0.24, 95% CI 0.07, 0.81). CONCLUSIONS: Neither race nor activation was associated with opioid prescribing; activation was associated with better pain assessment. In post hoc analyses, oncologists were less likely to prescribe opioids to black male SPs than white male SPs; PCPs had no racial disparities. In general, physicians may be under-prescribing opioids for cancer pain. TRIAL REGISTRATION: NCT01501006.

Wireless transcutaneous electrical nerve stimulation device for chemotherapy-induced peripheral neuropathy: an open-label feasibility study.

Chemotherapy-induced peripheral neuropathy (CIPN) occurs in approximately 68% of patients who receive neurotoxic chemotherapy and lasts at least 6 months post-chemotherapy in approximately 30% of individuals. CIPN is associated with decreased quality of life and functional impairments. Evidence suggests that CIPN symptoms are caused, in part, by enhanced excitability and impaired inhibition in the central nervous system. Transcutaneous electrical nerve stimulation (TENS) decreases pain by counteracting both of these mechanisms and is efficacious in other conditions associated with neuropathic pain. This single-arm study (n = 29) assessed the feasibility of investigating TENS for CIPN after chemotherapy completion using a wireless, home-based TENS device. Eighty-one percent of eligible patients who were approached enrolled, and 85% of participants who received the TENS device completed the primary (6-week) study term. Qualitative interview data suggest that use of the device on the continuous setting that automatically alternates between 1-h stimulation and rest periods for 5 h/day would be acceptable to most participants. Significant (i.e., p < 0.05) improvements were observed with the EORTC-CIPN20 (percent change from baseline: 13%), SF-MPQ-2 (52%), numeric rating scale of pain (38%), tingling (30%), numbness (20%), and cramping (53%), and UENS large fiber sensation subscore (48%). Preliminary data that support the reliability and construct validity of the UENS for CIPN in cancer survivors are also provided. Together these data suggest that it is feasible to evaluate TENS for CIPN using a wireless, home-based device and that further evaluation of TENS for CIPN in a randomized clinical trial is warranted.

Patterns of interactions among patients with advanced pancreatic cancer, their caregivers, and healthcare providers during symptom discussions.

PURPOSE: Effective symptom discussion is an essential step to enhance symptom management in patients with advanced pancreatic cancer (APC). However, little is known about how these patients communicate their symptoms during health encounters. The purpose of this study was to develop a typology to describe patterns of interactions between patients with APC, their caregivers, and healthcare providers as regards to symptoms and symptom management. METHODS: Thematic analysis was used to analyze 37 transcripts of audio-recorded, naturally occurring encounters among APC patients, caregivers, and healthcare providers. Transcripts were drawn from the Values and Options in Cancer Care study, a larger randomized controlled communication and decision-making intervention trial, which recruited advanced cancer patients and caregivers across the USA. All transcripts from APC patients that were pre-intervention were analyzed. RESULTS: Eight unique types of interaction patterns among patients, caregivers, and healthcare providers were identified as follows: collaborative interactions, explanatory interactions, agentic interactions, checklist interactions, cross-purpose interactions, empathic interactions, admonishing interactions, and diverging interactions. CONCLUSIONS: Our findings provide a systematic description of a variety of types of interaction patterns regarding symptom discussion among APC patients, caregivers, and healthcare providers. These typologies can be used to facilitate effective communication and symptom management.

Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. FINDINGS: Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6-12·0) for patients in the rilotumumab group and 9·4 months (5·3-13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7-10·2) in the rilotumumab group compared with 10·7 months (9·6-12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10-1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 [14%] vs 31 [10%]). In the rilotumumab group, 33 (11%) of 298 patients had fatal adverse events due to disease progression, and nine (3%) had fatal events not due to disease progression. In the placebo group, 23 (8%) of 299 patients had fatal adverse events due to disease progression, and eight (3%) had fatal events not due to disease progression. INTERPRETATION: Ligand-blocking inhibition of the MET pathway with rilotumumab is not effective in improving clinical outcomes in patients with MET-positive gastric or gastro-oesophageal adenocarcinoma. FUNDING: Amgen.

The impact of age on complications, survival, and cause of death following colon cancer surgery.

BACKGROUND: Given scarce data regarding the relationship among age, complications, and survival beyond the 30-day postoperative period for oncology patients in the United States, this study identified age-related differences in complications and the rate and cause of 1-year mortality following colon cancer surgery. METHODS: The NY State Cancer Registry and Statewide Planning and Research Cooperative System identified stage I-III colon cancer resections (2004-2011). Multivariable logistic regression and survival analyses assessed the relationship among age (<65, 65-74, ⩾75), complications, 1-year survival, and cause of death. RESULTS: Among 24 426 patients surviving >30 days, 1-year mortality was 8.5%. Older age groups had higher complication rates, and older age and complications were independently associated with 1-year mortality (P<0.0001). Increasing age was associated with a decrease in the proportion of deaths from colon cancer with a concomitant increase in the proportion of deaths from cardiovascular disease. Older age and sepsis were independently associated with higher risk of colon cancer-specific death (65-74: HR=1.59, 95% CI=1.26-2.00; ⩾75: HR=2.57, 95% CI=2.09-3.16; sepsis: HR=2.58, 95% CI=2.13-3.11) and cardiovascular disease-specific death (65-74: HR=3.72, 95% CI=2.29-6.05; ⩾75: HR=7.02, 95% CI=4.44-11.10; sepsis: HR=2.33, 95% CI=1.81-2.99). CONCLUSIONS: Older age and sepsis are associated with higher 1-year overall, cancer-specific, and cardiovascular-specific mortality, highlighting the importance of geriatric assessment, multidisciplinary care, and cardiovascular optimisation for older patients and those with infectious complications.

Variation in Delayed Time to Adjuvant Chemotherapy and Disease-Specific Survival in Stage III Colon Cancer Patients.

BACKGROUND: There is a paucity of literature quantifying the extent to which time to adjuvant chemotherapy for stage III colon cancer patients varies between individual surgeons, medical oncologists, and hospitals. METHODS: A retrospective cohort study was conducted by merging the New York State Cancer Registry with the Statewide Planning & Research Cooperative System and Medicare claims to identify stage III colon cancer patients from 2004 to 2009 who underwent resection and received adjuvant chemotherapy. Multilevel logistic regression models characterized variation in delayed time to adjuvant chemotherapy (>8 weeks vs. ≤8 weeks). Multilevel competing-risks Cox proportional hazards models assessed the effect of delayed time to adjuvant chemotherapy on disease-specific survival. RESULTS: The proportion of delayed time to adjuvant chemotherapy was 36 % in 1133 patients treated by 516 surgeons and 351 medical oncologists at 163 hospitals. After controlling for case-mix, the majority of the clustering variation (72 %) in delayed time to adjuvant chemotherapy is attributed to differences between medical oncologists. Risk-adjusted surgeon-specific, medical oncologist-specific, and hospital-specific probabilities of delayed time to adjuvant chemotherapy ranged from 30 to 38, 17 to 59, and 27 to 43 %, respectively. Delayed time to adjuvant chemotherapy was associated with disease-specific survival (hazard ratio [HR] 1.24, 95 % confidence interval [CI] 1.07-1.45). CONCLUSIONS: These findings suggest there is substantial variation in time to adjuvant chemotherapy among stage III colon cancer patients. Reasons for delays may be due to system factors that influence individual providers to make varying decisions on the time of initiation. Future research should identify what these factors may be and how to address them to promote better delivery of care.

The social and behavioral influences (SBI) study: study design and rationale for studying the effects of race and activation on cancer pain management.

BACKGROUND: Racial disparities exist in the care provided to advanced cancer patients. This article describes an investigation designed to advance the science of healthcare disparities by isolating the effects of patient race and patient activation on physician behavior using novel standardized patient (SP) methodology. METHODS/DESIGN: The Social and Behavioral Influences (SBI) Study is a National Cancer Institute sponsored trial conducted in Western New York State, Northern/Central Indiana, and lower Michigan. The trial uses an incomplete randomized block design, randomizing physicians to see patients who are either black or white and who are "typical" or "activated" (e.g., ask questions, express opinions, ask for clarification, etc.). The study will enroll 91 physicians. DISCUSSION: The SBI study addresses important gaps in our knowledge about racial disparities and methods to reduce them in patients with advanced cancer by using standardized patient methodology. This study is innovative in aims, design, and methodology and will point the way to interventions that can reduce racial disparities and discrimination and draw links between implicit attitudes and physician behaviors. TRIAL REGISTRATION: https://clinicaltrials.gov/ , #NCT01501006, November 30, 2011.

Evaluating the Prognostic Role of Elevated Preoperative Carcinoembryonic Antigen Levels in Colon Cancer Patients: Results from the National Cancer Database.

OBJECTIVES: Carcinoembryonic antigen (CEA) is a reliable tumor marker for the management and surveillance of colon cancer. However, limitations in previous studies have made it difficult to elucidate whether CEA should be established as a prognostic indicator. This study examines the association between elevated preoperative CEA levels and overall survival in colon cancer patients using a national population-based registry. METHODS: Stage I-III colon cancer patients were identified from the 2004-2006 National Cancer Database. A multivariable Cox proportional hazards model was used to estimate the association between elevated CEA levels and overall survival after controlling for important patient, hospital, and tumor characteristics. A Monte Carlo Markov Chain was used to impute the large degree of missing CEA data. All models controlled for the propensity score in order to account for selection bias. RESULTS: A total of 137,381 patients met the inclusion criteria. Overall, 34 % of patients had an elevated CEA level and 66 % had a normal CEA level, with a median survival of 70 and 100 months, respectively. Patients with an elevated CEA level had a 62 % increase in the hazard of death (HR 1.62, 95 % CI 1.53-1.74) compared with patients with a normal CEA level. CONCLUSIONS: Preoperative CEA was an independent predictor of overall survival across all stages. The results support recommendations to include CEA levels as another high-risk feature that clinicians can use to counsel patients on adjuvant chemotherapy, especially for stage II patients.

Variation in Hospital-Specific Rates of Suboptimal Lymphadenectomy and Survival in Colon Cancer: Evidence from the National Cancer Data Base.

BACKGROUND: Little is known about between-hospital differences in the rate of suboptimal lymphadenectomy. This study characterizes variation in hospital-specific rates of suboptimal lymphadenectomy and its effect on overall survival in a national hospital-based registry. METHODS: Stage I-III colon cancer patients were identified from the 2003-2012 National Cancer Data Base. Bayesian multilevel logistic regression models were used to assess the impact of patient- and hospital-level factors on hospital-specific rates of suboptimal lymphadenectomy (<12 lymph nodes), and multilevel Cox models were used to estimate the effect of suboptimal lymphadenectomy at the patient (yes vs. no) and hospital level (quartiles of hospital-specific rates) on overall survival. RESULTS: A total of 360,846 patients across 1345 hospitals in the US met the inclusion criteria, of which 25 % had a suboptimal lymphadenectomy. Wide variation was observed in hospital-specific rates of suboptimal lymphadenectomy (range 0-82 %, median 44 %). Older age, male sex, comorbidity score, no insurance, positive margins, lower tumor grade, lower T and N stage, and sigmoid and left colectomy were associated with higher odds of suboptimal lymphadenectomy. Patients treated at lower-volume and non-academic hospitals had higher odds of suboptimal lymphadenectomy. Patient- and hospital-level factors explained 5 % of the between-hospital variability in suboptimal lymphadenectomy, leaving 95 % unexplained. Higher suboptimal lymphadenectomy rates were associated with worse survival (quartile 4 vs. quartile 1: hazard ratio 1.19, 95 % confidence interval 1.16-1.22). CONCLUSION: Large differences in hospital-specific rates of suboptimal lymphadenectomy were observed, and this variation was associated with survival. Quality improvement initiatives targeting hospital-level adherence to the national standard may improve overall survival among resected colon cancer patients.

Systemic therapy for advanced appendiceal adenocarcinoma: an analysis from the NCCN Oncology Outcomes Database for colorectal cancer.

Appendiceal malignancies are rare and represent 1% of intestinal tumors in the United States. The role and efficacy of modern systemic therapy in advanced appendiceal adenocarcinoma has not been established. This study analyzed patients with recurrent or metastatic appendiceal adenocarcinoma in the database for Colorectal Cancer (CRC; 2005-2012). This database tracks longitudinal care for patients treated at 8 specialty centers across the Unites States. Study objectives were to describe and evaluate the efficacy of systemic therapy and investigate relationships with clinicopathologic features. Cox regression analysis was performed to identify predictors of progression-free survival (PFS) and overall survival (OS). Of 248 patients with advanced appendiceal carcinoma, 112 (45%) received systemic therapy for measurable disease and are the focus of this report. The most common chemotherapy regimens included FOLFOX with or without bevacizumab (n=39 and n=37, respectively), FOLFIRI (n=15), and single-agent fluoro-pyrimidine (n=10). Among 99 patients evaluable for best response, 39 experienced a response (response rate [RR], 39%) and 36 (36%) had stable disease. The median PFS was 1.2 years (95% CI, 1.0-1.8) and median OS was 2.1 years (95% CI, 1.6-2.3). Patients with non-mucinous histology or high-grade tumors and those who underwent nondebulking surgery had worse PFS and OS. Treatment of advanced appendiceal adenocarcinoma at NCCN Member Institutions commonly incorporates agents used for CRC. RR, PFS, and OS are comparable to those achieved in the treatment of metastatic CRC. Poor prognostic factors include nonmucinous histology or high-grade tumors and history of nondebulking surgery.

Practice Patterns for Organ Preservation in US Patients With Rectal Cancer, 2006-2020.

Importance: In March 2023, the National Comprehensive Cancer Network endorsed watch and wait for those with complete clinical response to total neoadjuvant therapy. Neoadjuvant therapy is highly efficacious, so this recommendation may have broad implications, but the current trends in organ preservation in the US are unknown. Objective: To describe organ preservation trends among patients with rectal cancer in the US from 2006 to 2020. Design, Setting, and Participants: This retrospective, observational case series included adults (aged ≥18 years) with rectal adenocarcinoma managed with curative intent from 2006 to 2020 in the National Cancer Database. Exposure: The year of treatment was the primary exposure. The type of therapy was chemotherapy, radiation, or surgery (proctectomy, transanal local excision, no tumor resection). The timing of therapy was classified as neoadjuvant or adjuvant. Main Outcomes and Measures: The primary outcome was the absolute annual proportion of organ preservation after radical treatment, defined as chemotherapy and/or radiation without tumor resection, proctectomy, or transanal local excision. A secondary analysis examined complete pathologic responses among eligible patients. Results: Of the 175 545 patients included, the mean (SD) age was 63 (13) years, 39.7% were female, 17.4% had clinical stage I disease, 24.7% had stage IIA to IIC disease, 32.1% had stage IIIA to IIIC disease, and 25.7% had unknown stage. The absolute annual proportion of organ preservation increased by 9.8 percentage points (from 18.4% in 2006 to 28.2% in 2020; P < .001). From 2006 to 2020, the absolute rate of organ preservation increased by 13.0 percentage points for patients with stage IIA to IIC disease (19.5% to 32.5%), 12.9 percentage points for patients with stage IIIA to IIC disease (16.2% to 29.1%), and 10.1 percentage points for unknown stages (16.5% to 26.6%; all P < .001). Conversely, patients with stage I disease experienced a 6.1-percentage point absolute decline in organ preservation (from 26.4% in 2006 to 20.3% in 2020; P < .001). The annual rate of transanal local excisions decreased for all stages. In the subgroup of 80 607 eligible patients, the proportion of complete pathologic responses increased from 6.5% in 2006 to 18.8% in 2020 (P < .001). Conclusions and Relevance: This case series shows that rectal cancer is increasingly being managed medically, especially among patients whose treatment historically relied on proctectomy. Given the National Comprehensive Cancer Network endorsement of watch and wait, the increasing trends in organ preservation, and the nearly 3-fold increase in complete pathologic responses, international professional societies should urgently develop multidisciplinary core outcome sets and care quality indicators to ensure high-quality rectal cancer research and care delivery accounting for organ preservation.

Multi-modality therapy for cancer of the esophagus and GE junction.

Cancers of the esophagus and gastroesophageal junction (GEJ) are associated with a high mortality rate. In the United States, the incidence of adenocarcinoma of the distal esophagus and GEJ is rising at an alarming rate. Decades of investigation have established the impact on survival of neoadjuvant platinum-based chemotherapy as well as chemoradiation for locally advanced tumors. Distant recurrence remains the most common pattern of failure and efforts to improve therapeutic outcome should focus on optimizing systemic therapy. Induction chemotherapy before preoperative chemoradiation and postoperative adjuvant chemotherapy are approaches to intensify systemic therapy delivery and deserve further investigation. The integration of targeted therapies and development of predictive biomarkers to identify subgroups of patients who are likely to benefit will mark the future of neoadjuvant treatment in this disease.

Adjuvant Chemotherapy Use in Patients With Locally Advanced Rectal Cancer: A Single-Institution Experience.

BACKGROUND: National Comprehensive Cancer Network guidelines for the treatment of locally advanced rectal cancer advocate neoadjuvant chemoradiotherapy followed by total mesorectal excision and adjuvant chemotherapy (AC). The aim of this retrospective study was to determine our local patterns of AC use and to examine factors that influenced initiation and completion of AC among patients with stage II/III rectal cancer. PATIENTS AND METHODS: The study population consisted of stage II/III rectal cancer patients who were treated at the University of Rochester from 2011 to 2014. Chart reviews were conducted to determine rates of AC initiation and completion. The documented reasons for failure to initiate or complete AC were examined. A multivariate analysis was also completed to evaluate factors that may have influenced the initiation and use of AC. RESULTS: Eighty-one patients were included in the analysis. Median age was 62 years, and 53 (65.4%) were male. Median time from surgery to initiation of AC in those who received AC was 8.0 weeks. Forty-seven patients (58.0%) completed their prescribed AC course. Twenty-four patients (29.6%) did not start AC and 9 patients (11.1%) were unable to complete their course of AC. Primary reasons for not undergoing AC were patient preference (37.5%) and prolonged surgical recovery (33.3%). Primary reasons for not completing AC were treatment toxicities (55.5%) and patient preference (22.2%). Multivariate analysis identified a positive association between clinical stage III disease at diagnosis and initiation of AC. There was no independent association between pathologic response to neoadjuvant therapy at time of surgery and receipt of AC. CONCLUSION: A large proportion of patients at a single academic center did not start or complete their prescribed postoperative AC for locally advanced rectal cancer. Ongoing studies are investigating a total neoadjuvant approach, which may result in better chemotherapy adherence and further improve the pathologic downstaging rate.

Short course radiation therapy for rectal cancer in the elderly: can radical surgery be avoided?

Rectal cancer in elderly patients can be difficult to manage. Short course radiation therapy (SCRT) has shown to be effective when given immediately prior to surgery. Here we report outcomes of elderly patients who underwent SCRT either alone or prior to resection. Between 2010 and 2015, elderly patients with rectal cancer and no distant metastatic disease were identified. Symptoms at diagnosis, therapies, toxicities, and pathologic and clinical response were recorded from patient charts. The SCRT prescription dose was 5 Gy ×5 to the rectal tumor and 4 Gy ×5 to the mesorectum, omitting the iliac nodes. Twenty patients were identified with median age of 85 years (range, 71-93 years). No patient received systemic therapy. Sixty percent of patients were cT3 at diagnosis. Half underwent resection post SCRT and half received SCRT as definitive therapy. The 1- and 2-year overall survival was 75% and 54%. Overall survival did not differ between patients treated with SCRT and surgery compared to SCRT alone (P=0.8). Of the 10 surgical patients, 3 had a complete pathologic response at time of resection and 3 patients died within 2 weeks due to perioperative complications. Of patients treated with SCRT alone, 8 were symptomatic at presentation and 5 had a clinician defined symptomatic response. No patient treated with SCRT monotherapy required additional palliative measures for outflow obstruction, but 2 progressed locally and died. SCRT is well tolerated, results in pathologic complete responses in a small percentage of patients, and achieves 63% symptom improvement rate as monotherapy. A high peri-operative complication rate was observed in this small series. In elderly patients, SCRT as initial treatment with a watch and wait approach for surgery is feasible and should be evaluated prospectively.

Opportunities for cannabis in supportive care in cancer.

Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain. However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments. Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer. There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms. Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild. Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.

Chemotherapy-induced peripheral neuropathy clinical trials: Review and recommendations.

OBJECTIVE: To assess the design characteristics and reporting quality of published randomized controlled trials (RCTs) for treatments of chemotherapy-induced peripheral neuropathy (CIPN) initiated before or during chemotherapy. METHODS: In this systematic review of RCTs of preventive or symptomatic pharmacologic treatments for CIPN initiated before or during chemotherapy treatment, articles were identified by updating the PubMed search utilized in the CIPN treatment guidelines published in the Journal of Clinical Oncology in 2014. RESULTS: Thirty-eight articles were identified. The majority included only patients receiving platinum therapies (61%) and used a placebo control (79%). Common exclusion criteria were preexisting neuropathy (84%), diabetes (55%), and receiving treatments that could potentially improve neuropathy symptoms (45%). Ninety-five percent of studies initiated the experimental treatment before CIPN symptoms occurred. Although 58% of articles identified a primary outcome measure (POM), only 32% specified a primary analysis. Approximately half (54%) of the POMs were patient-reported outcome measures of symptoms and functional impairment. Other POMs included composite measures of symptoms and clinician-rated signs (23%) and vibration tests (14%). Only 32% of articles indicated how data from participants who prematurely discontinued chemotherapy were analyzed, and 21% and 29% reported the number of participants who discontinued chemotherapy due to neuropathy or other/unspecified reasons, respectively. CONCLUSIONS: These data identify reporting practices that could be improved in order to enhance readers' ability to critically evaluate RCTs of CIPN treatments and use the findings to inform the design of future studies and clinical practice. Reporting recommendations are provided.

Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.

IMPORTANCE: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. OBJECTIVE: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. DESIGN, SETTING, AND PARTICIPANTS: SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. INTERVENTIONS: Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. RESULTS: There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). CONCLUSIONS AND RELEVANCE: Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01658943.