Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy.

Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, data regarding CMV reactivation after chimeric antigen receptor T (CAR T) cell therapy are limited. In this single-center retrospective study, we report the incidence and outcomes of 95 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV infection (cs-CMV, viremia requiring antiviral treatment). Thirty-one patients (33%) had evidence of CMV reactivation (any viremia), and 10 patients (11%) had cs-CMV. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9-31). The cumulative incidence of CMV (any viremia) was significantly higher among patients with grade 3-4 cytokine release syndrome (67 vs. 28%; P=0.01), and those who received corticosteroids (39 vs. 21%; P=0.03), anakinra (56 vs. 28%; P=0.02), or ≥2 immunosuppressants (41 vs. 21%; P=0.02). Receipt of corticosteroids (18 vs. 0%; P=0.004), tocilizumab (14 vs. 0%; P=0.04), anakinra (33 vs. 7%; P=0.008), and ≥2 immunosuppressants (20 vs. 0%; P=0.001) were all associated with cs-CMV. Receiving ≥2 immunosuppressants was associated with a 2-fold increase in CMV reactivation in multivariate analyses (aOR 2.27, 95%CI 1.1-4.8, P=0.03). Overall, 1-year mortality was significantly higher in those with CMV reactivation (57% vs. 23%, P=0.001). Immunosuppression, particularly corticosteroids, for the management of CAR T cell toxicities is a major risk factor for CMV reactivation. CMV preventive strategies in high-risk CAR T recipients might improve outcomes.

Impact of COVID-19-related experiences on health-related quality of life in cancer survivors in the United States.

OBJECTIVE: Little evidence exists on the impact of the COVID-19 pandemic on cancer survivors, limiting recommendations to improve health-related quality of life (HRQoL) in this population. We describe survivors' pandemic experiences and examine associations between COVID-19-related exposures, psychosocial experiences, and HRQoL. METHODS: Between May 2020-April 2021, survivors completed cross-sectional questionnaires capturing COVID-19-related exposures (e.g., exposure to virus, job loss); psychosocial experiences (i.e., COVID-19-related anxiety/depression, disruptions to health care and daily activities/social interactions, satisfaction with providers' response to COVID, financial hardship, perceived benefits of the pandemic, social support, and perceived stress management ability); and HRQoL. RESULTS: Data were collected from N = 11,325 survivors in the United States. Participants were mostly female (58%), White (89%) and non-Hispanic (88%), and age 63 on average. Breast cancer was the most common diagnosis (23%). Eight percent of participants reported being exposed to COVID-19; 1% tested positive. About 6% of participants lost their jobs, while 24% lost household income. Nearly 30% avoided attending in-person oncology appointments because of the pandemic. Poorer HRQoL was associated with demographic (younger age; female; non-Hispanic White), clinical (Medicare; stage IV disease; hematologic/digestive/respiratory system cancer), and psychosocial factors (low perceived benefits and stress management ability; more disruption to health care and daily activities/social interactions; financial hardship). CONCLUSIONS: COVID-19-related stressors were associated with various psychosocial experiences in cancer survivors, and these psychosocial experiences were associated with HRQoL above and beyond demographic and clinical factors.

Associations between age and patient-reported outcomes, emergency department visits, and hospitalizations among lung cancer patients receiving immune checkpoint inhibitors.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) for lung cancer (LC) treatment have a more favorable safety profile and improved patient reported outcomes (PROs) compared to chemotherapy, suggesting that ICIs are advantageous for older populations. The impact of ICIs on PROs, clinical outcomes, and age in LC patients remains to be established. We examined associations between age and PROs, emergency department (ED) visits, and hospitalizations in LC patients receiving ICIs. METHODS: We performed retrospective analyses via My Wellness Check (MWC), an assessment and triage electronic medical record (EMR) integrated platform in LC patients receiving ICIs. Demographics, clinical characteristics, ED visits, and hospitalizations were extracted via EMR. Patient reported outcomes (PROMIS® anxiety, depression, fatigue, pain, physical function), and health-related quality of life (HRQOL; FACT-G7), were collected via MWC. We classified age into three categories (<65, 65-74, ≥75). Multiple regressions examined associations between PROs and age. Cox proportional hazards regressions assessed cumulative ED visits and hospitalizations. RESULTS: Among LC patients (N = 190) receiving ICIs, patients ≥75 had lower depression (ß = -5.80, p = 0.01) and higher HRQOL (ß = 2.47, p = 0.05) compared with patients <65. Relative to patients <65, patients 65-74 had lower anxiety (ß = -3.31, p = 0.05) and pain (ß = -4.18, p = 0.03). Patients 65-74 and ≥ 75 had lower risk of an ED visit (adjusted hazards ratio [aHR] = 0.45, p = 0.05 and aHR = 0.21, p = 0.05, respectively) and patients 65-74 had lower risk of hospitalization (aHR = 0.36, p = 0.02) relative to patients <65. CONCLUSIONS: Older LC patients (65-74; ≥75) have more favorable PROs and lower risk for negative clinical outcomes than younger (<65) patients.

Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Factors Associated With Unmet Supportive Care Needs and Emergency Department Visits and Hospitalizations in Ambulatory Oncology.

Importance: Patients with cancer experience multiple supportive care needs (eg, coping and financial counseling) that, if not addressed, may result in poor clinical outcomes. Limited work has assessed the factors associated with unmet needs in large and diverse samples of ambulatory oncology patients. Objective: To characterize the factors associated with unmet supportive care needs among ambulatory oncology patients and to assess whether such needs were associated with emergency department (ED) visits and hospitalizations. Design, Setting, and Participants: Between October 1, 2019, and June 30, 2022, cross-sectional retrospective analyses were performed in a large and diverse ambulatory cancer population via My Wellness Check, an electronic health record (EHR)-based supportive care needs and patient-reported outcomes (PROs) screening and referral program. Main Outcomes and Measures: Demographic characteristics, clinical characteristics, and clinical outcomes were extracted from EHRs. Data on PROs (ie, anxiety, depression, fatigue, pain, and physical function), health-related quality of life (HRQOL), and supportive care needs were also collected. Logistic regressions examined factors associated with unmet needs. Cumulative incidence of ED visits and hospitalizations were assessed by Cox proportional hazards regression models adjusting for covariates. Results: The 5236 patients in the study had a mean (SD) age of 62.6 (13.1) years and included 2949 women (56.3%), 2506 Hispanic or Latino patients (47.9%), and 4618 White patients (88.2%); 1370 patients (26.2%) indicated Spanish as their preferred language, according to their EHR. A total of 940 patients (18.0%) reported 1 or more unmet needs. Black race (adjusted odds ratio [AOR], 1.97 [95% CI, 1.49-2.60]), Hispanic ethnicity (AOR, 1.31 [95% CI, 1.10-1.55]), 1 to 5 years after diagnosis (AOR, 0.64 [95% CI, 0.54-0.77]), more than 5 years after diagnosis (AOR, 0.60 [95% CI, 0.48-0.76]), anxiety (AOR, 2.25 [95% CI, 1.71-2.95]), depression (AOR, 2.07 [95% CI, 1.58-2.70]), poor physical function (AOR, 1.38 [95% CI, 1.07-1.79]), and low HRQOL scores (AOR, 1.89 [95% CI, 1.50-2.39]) were associated with greater unmet needs. Patients with unmet needs had a significantly higher risk of ED visits (adjusted hazard ratio [AHR], 1.45 [95% CI, 1.20-1.74]) and hospitalizations (AHR, 1.36 [95% CI, 1.13-1.63]) relative to patients without unmet needs. Conclusions and Relevance: In this cohort study of ambulatory oncology patients, unmet supportive care needs were associated with worse clinical outcomes. Patients from racial and ethnic minority groups and those with greater emotional or physical burden were more likely to have 1 or more unmet needs. Results suggest that addressing unmet supportive care needs may be crucial for improving clinical outcomes, and targeted efforts should focus on specific populations.

Development and initial psychometric evaluation of a COVID-related psychosocial experiences questionnaire for cancer survivors.

BACKGROUND: Cancer survivors are at elevated risk of psychological problems related to COVID-19, yet no published measure adequately assesses their psychosocial experiences during the pandemic. PURPOSE: Describe the development and factor structure of a comprehensive, self-report measure (COVID-19 Practical and Psychosocial Experiences questionnaire [COVID-PPE]) assessing the pandemic's impact on US cancer survivors. METHODS: The sample (n = 10,584) was divided into three groups to assess COVID-PPE factor structure by conducting: (1) initial calibration/exploratory analysis of the factor structure of 37 items (n = 5070), (2) confirmatory factor analysis of the best-fitting model (36 items after item removal; n = 5140), and (3) post-hoc confirmatory analysis with an additional six items not collected in the first two groups (42 items; n = 374). RESULTS: The final COVID-PPE was divided into two sets of subscales, conceptualized as Risk Factors and Protective Factors. The five Risk Factors subscales were labeled Anxiety Symptoms, Depression Symptoms, Health Care Disruptions, Disruptions to Daily Activities and Social Interactions, and Financial Hardship. The four Protective Factors subscales were labeled Perceived Benefits, Provider Satisfaction, Perceived Stress Management Skills, and Social Support. Internal consistency was acceptable for seven subscales (αs = 0.726-0.895; ωs = 0.802-0.895) but poor or questionable for the remaining two subscales (αs = 0.599-0.681; ωs = 0.586-0.692). CONCLUSIONS: To our knowledge, this is the first published self-report measure comprehensively capturing psychosocial impact-both positive and negative-of the pandemic on cancer survivors. Future work should evaluate predictive utility of COVID-PPE subscales, particularly as the pandemic evolves, which may inform recommendations for cancer survivors and facilitate identification of survivors most in need of intervention.

Predictors of cancer rehabilitation medicine referral and utilization based on the Moving Through Cancer physical activity screening assessment.

PURPOSE: Cancer survivors experience high rates of physical inactivity that often go unaddressed. The My Wellness Check program (MWC) is an EHR-integrated screening and referral system that includes surveillance of physical activity and triage to cancer rehabilitation medicine services. This study examined assessment of physical activity and subsequent referrals to cancer rehabilitation medicine. METHODS: A secondary analysis was performed for survivors who completed the MWC between April 2021 and January 2022. Univariable and multivariable logistic regression modeled determinants of qualification for a physical activity referral and provider completion of referral to cancer rehabilitation medicine. Referral was based on responses to the Moving Through Cancer questionnaire. Adjusted odds ratios (aOR) and corresponding 95% confidence intervals (95% CI) were calculated. RESULTS: There were 1,174 survivors who completed the assessment, of which 46% (n = 540) reported physical inactivity. After controlling for group differences, individuals with moderate-severe physical dysfunction (aOR: 1.750; 95% CI: 1.137, 2.693) had higher odds, and self-reporting Hispanic or Latino ethnicity (aOR: 0.720; CI: 0.556, 0.932) had lower odds of physical inactivity. Only 31% (n = 168) received a completed physician referral to cancer rehabilitation medicine following identification of physical inactivity. No patient-level factors were associated with receiving a physician referral. Following referral, 8% (n = 13) utilized cancer rehabilitation medicine services. CONCLUSIONS: Patient-level and clinical factors may predict qualification for physical activity referrals; however, they don't appear to predict referral completion to cancer rehabilitation medicine. Future research should focus on potential provider- and organization-level factors that interact and influence access to cancer rehabilitation medicine services.

Difference between SARS-CoV-2, seasonal coronavirus, influenza, and respiratory syncytial virus infection in solid organ transplant recipients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been raging since the end of 2019 and has shown worse outcomes in solid organ transplant (SOT) recipients. The clinical differences as well as outcomes between respiratory viruses have not been well defined in this population. METHODS: This is a retrospective cohort study of adult SOT recipients with nasopharyngeal swab or bronchoalveolar lavage PCR positive for either SARS-CoV-2, seasonal coronavirus, respiratory syncytial virus (RSV) or influenza virus from January 2017 to October 2020. The follow up period was 3 months. Clinical characteristics and outcomes were evaluated. RESULTS: A total of 377 recipients including 157 SARS-CoV-2, 70 seasonal coronavirus, 50 RSV and 100 influenza infections were identified. The most common transplanted organ was kidney 224/377 (59.4%). Lower respiratory tract infection (LRTI) was found in 210/377 (55.7%) and the risk factors identified with multivariable analysis were SARS-CoV-2 infection, steroid use, and older age. Co- and secondary infections were seen in 77/377 (20.4%) recipients with bacterial pathogens as dominant. Hospital admission was seen in 266/377 (67.7%) recipients without significant statistical difference among viruses, however, ICU admission, mechanical ventilation and mortality were higher with SARS-CoV-2 infection. In the multivariable model, the risk factors for mortality were SARS-CoV-2 infection and older age. CONCLUSIONS: We found higher incidence of ICU admission, mechanical ventilation, and mortality among SARS-CoV-2 infected recipients. Older age was found to be the risk factor for lower respiratory tract infection and mortality for SARS-CoV-2, coronaviruses, RSV and influenza virus groups.

Symptoms and Needs Monitoring in Diverse Ambulatory Oncology Patients: Usage Characteristics and Impact on Emergency Room Visits and Hospitalization.

PURPOSE: Symptoms and needs monitoring using patient-reported outcomes (PRO) is associated with improved clinical outcomes in cancer care. However, these improvements have been observed predominantly in non-Hispanic White patients using English assessments with high completion rates. The documented impact of such monitoring on system-level outcomes including emergency room (ER) visits and hospitalizations remains limited. We explored factors affecting the completion of PRO measures and evaluated clinical outcomes in an ambulatory oncology setting with a diverse racial, ethnic, and linguistic population. METHODS: A retrospective analysis (October 2019-February 2022) was performed for patients with cancer assigned to My Wellness Check (MWC), a patient-portal-administered and electronic health record-based PRO assessment that generates automated alerts to oncology providers. Patient demographics, clinical characteristics, and clinical outcomes were collected. Logistic regression models examined factors affecting the completion of MWC questionnaires. Cumulative incidence of ER visits and hospitalization were assessed by Cox proportional hazards regression models adjusting for demographics. RESULTS: We identified 9,553 patients; 43.1% (n = 4,117) answered one or more questions. Patients age 65 years or older (adjusted odds ratio [aOR], 0.77; P < .0001), male (aOR, 0.81; P < .0001), Hispanic/Latino ethnicity (aOR, 0.70; P < .0001), living without partners (aOR, 0.75; P < .0001), or receiving no treatment (aOR, 0.76; P < .0001) were less likely to answer MWC questionnaires. Patients who completed the entire MWC questionnaires had a reduced risk of an ER visit (adjusted hazard ratio, 0.78; P < .0001) and hospitalization (adjusted hazard ratio, 0.80; P = .0007) relative to patients who did not. CONCLUSION: Completing electronic health record-based PRO assessments was associated with significantly better clinical outcomes in a diverse cancer population. Specific patient groups were less likely to participate. Further research is needed to identify barriers to completing PRO measures and the long-term benefits of such programs.

Implementation and Feasibility of an Electronic Health Record-Integrated Patient-Reported Outcomes Symptom and Needs Monitoring Pilot in Ambulatory Oncology.

PURPOSE: Describe the feasibility and implementation of an electronic health record (EHR)-integrated symptom and needs screening and referral system in a diverse racial/ethnic patient population in ambulatory oncology. METHODS: Data were collected from an ambulatory oncology clinic at the University of Miami Health System from October 2019 to January 2021. Guided by a Patient Advisory Board and the Exploration, Preparation, Implementation, and Sustainment model, My Wellness Check was developed to assess physical and psychologic symptoms and needs of ambulatory oncology patients before appointments to triage them to supportive services when elevated symptoms (eg, depression), barriers to care (eg, transportation and childcare), and nutritional needs were identified. Patients were assigned assessments at each appointment no more than once in a 30-day period starting at the second visit. Assessments were available in English and Spanish to serve the needs of the predominantly Spanish-speaking Hispanic/Latino population. RESULTS: From 1,232 assigned assessments, more than half (n = 739 assessments; 60.0%) were initiated by 506 unique patients. A total of 65.4% of English and 49.9% of Spanish assessments were initiated. Among all initiated assessments, the majority (85.1%) were completed at home via the patient portal. The most common endorsed items were nutritional needs (32.9%), followed by emotional symptoms (ie, depression and anxiety; 27.8%), practical needs (eg, financial concerns; 21.7%), and physical symptoms (17.6%). Across the physical symptom, social work, and nutrition-related alerts, 77.1%, 99.7%, and 78.8%, were addressed, respectively, by the corresponding oncology health professional, social work team member, or nutritionist. CONCLUSION: The results demonstrate encouraging feasibility and initial acceptability of implementing an EHR-integrated symptom and needs screening and referral system among diverse oncology patients. To our knowledge, this is the first EHR-integrated symptom and needs screening system implemented in routine oncology care for Spanish-speaking Hispanics/Latinos.

Reinfection with SARS-CoV-2 in solid-organ transplant recipients: Incidence density and convalescent immunity prior to reinfection.

BACKGROUND: Long-term protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains poorly characterized, particularly in solid organ transplant (SOT) patients. METHOD: We determined the incidence density of SARS-CoV-2 reinfection in a cohort of adult SOT recipients initially infected between March 1st, 2020 and March 30th, 2021 and included those with initial infection before or after transplantation. Incidence density was the total cases divided by total days after initial diagnosis with active graft. RESULTS: Of 210 infected recipients, five (2.4%) developed reinfection, including two who had received full mRNA vaccination, but none developed hypoxia. The incidence density for reinfection was 9.4 (95% confidence interval [CI] 3.9-22.6) and for primary infection the density was 9.1 (95% CI 7.9-10.5) cases/100,000 patient days. Two recipients had immunity evaluated in the weeks prior to reinfection, by measuring immunoglobulin-G (IgG) antibody titer to the SARS-CoV-2 receptor binding domain and virus-specific CD4+ and CD8+ T-cell reactivity following stimulation with SARS-CoV-2 peptide pools. Both mounted virus specific CD4 T-cell responses prior to reinfection (1.19% and 0.28% of total CD4 T cells) and both had reactive IgG testing (1.30 and 4.99 signal/cut off ratio). CONCLUSIONS: This suggests that SOT recipients infected with SARS-CoV-2 remain at high risk for reinfection even after generating cellular and humoral immune responses.

Clinical presentation and outcomes of COVID-19 following hematopoietic cell transplantation and cellular therapy.

BACKGROUND: One year into the pandemic, published data on hematopoietic cell transplantation (HCT) recipients with coronavirus disease 2019 (COVID-19) remain limited. METHODS: Single-center retrospective cohort study of adult HCT recipients with polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESULTS: Twenty-eight consecutive transplantation and cellular therapy patients (autologous, n = 12; allogeneic, n = 15; chimeric antigen receptor T-cell therapy [CAR-T], n = 1) with COVID-19 were identified. The median age was 57 years. The median time from HCT to COVID-19 diagnosis was 656 days (interquartile range [IQR], 33-1274). Patients were followed for a median of 59 days (IQR, 40-88). Among assessable patients (n = 19), 10 (53%) had documented virological clearance; median time to clearance was 34 days (range, 21-56). Out of 28, 12 (43%), 6 (21%), and 10 (36%) patients had mild, moderate, and severe/critical disease, respectively. Overall mortality was 25%, nearly identical for autologous and allogeneic HCT, and exclusively seen in hospitalized patients, older than 50 years of age with severe COVID-19. None of the patients with mild (n = 12) or moderate (n = 6) COVID-19 died whereas 7/10 patients (70%) with severe/critical COVID-19 died (P = .0001). Patients diagnosed with COVID-19 within 12 months of HCT exhibited higher mortality (57% vs 14%; P = .04). All-cause 30-day mortality (n = 4) was 14%. A higher proportion of patients who died within 30 days of COVID-19 diagnosis (3/4) were receiving ≥2 immunosuppressants, compared with patients who survived beyond 30 days after COVID-19 diagnosis (2/24; 75% vs. 8%; P = .01). CONCLUSIONS: Mortality in COVID-19 HCT patients is higher than that of the age-comparable general population and largely dependent on age, disease severity, timing from HCT, and intensity of immunosuppression.

Chemoradiotherapy Using Carboplatin plus Paclitaxel versus Cisplatin plus Fluorouracil for Esophageal or Gastroesophageal Junction Cancer.

BACKGROUND: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT. METHODS: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis. RESULTS: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2-7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4-8.9) on multivariable and IPTW sensitivity analyses. CONCLUSIONS: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.

Impact of adjuvant therapy in patients with a microscopically positive margin after resection for gastric and esophageal cancers.

BACKGROUND: A microscopically positive (R1) resection margin following resection for gastric and esophageal cancers has been documented to be a poor prognostic factor. The optimal strategy and impact of different modalities of adjuvant treatment for an R1 resection margin remain unclear. METHODS: A retrospective analysis was performed for patients with gastric and esophageal adenocarcinoma treated at the Princess Margaret Cancer Centre (PMCC) from 2006-2016. Electronic medical records of all patients with an R1 resection margin were reviewed. Kaplan-Meier and Cox proportional hazards methods were used to analyze recurrence free survival (RFS) and overall survival (OS) with stage and neoadjuvant treatment as covariates in the multivariate analysis. RESULTS: We identified 69 gastric and esophageal adenocarcinoma patients with a R1 resection. Neoadjuvant chemoradiation was used in 13% of patients, neoadjuvant chemotherapy in 12%, surgery alone in 75%. Margins involved included proximal in 30%, distal in 14%, radial in 52% and multiple margins in 3% of patients. Pathological staging showed 3% with stage I disease, 20% stage II and 74% stage III. Adjuvant therapy was given in 52% of R1 pts (28% CRT, 20% chemotherapy alone, 3% radiation alone, 1% reoperation). Median RFS was 14.1 months [95% confidence interval (CI), 11.1-17.2]. The site of first recurrence was 72% distant, 12% mixed, 16% locoregional alone. Median OS was 34.5 months (95% CI, 23.3-57.9) for all patients. There was no significant difference in RFS (adjusted P=0.26) or OS (adjusted P=0.83) comparing modality of adjuvant therapy. CONCLUSIONS: Most patients with positive margins after resection for gastric and esophageal cancer had advanced pathologic stage and prognosis was poor. Our study did not find improved RFS or OS with adjuvant treatment and only one patient had reresection. The main failure pattern was distant recurrence, suggesting that patients being considered for adjuvant radiotherapy (RT) should be carefully selected. Further studies are required to determine factors to select patients with good prognosis despite a positive margin, or those who may benefit from adjuvant treatment.

Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma.

BACKGROUND: The goal of surveillance testing is to enable curative salvage therapy through early disease detection, however supporting evidence in gastroesophageal adenocarcinoma is limited. We evaluated frequency of successful salvage therapy and outcomes in patients who underwent surveillance. METHODS: A single-site, retrospective cohort study was conducted to identify all patients who received curative resection for gastroesophageal adenocarcinoma. Surveillance testing were those investigations not triggered by abnormal symptoms, physical examination, or blood tests. Successful salvage therapy was any potentially curative therapy for disease recurrence which resulted in postrecurrence disease-free survival ≥2 years. Time-to-event data were analyzed using the Kaplan-Meier method and log rank tests. RESULTS: Between 2011 and 2016, 210 consecutive patients were reviewed. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%) or multimodality therapy (71%). Adjuvant therapy was administered in 35%. At median follow-up of 38.3 months, 5-year overall survival (OS) rate was 56%. Among 97 recurrences, 53% were surveillance-detected, and 46% were symptomatic. None was detected by surveillance endoscopy. Median time-to-recurrence (TTR) was 14.8 months. Recurrences included locoregional only (4%), distant (86%), and both (10%). Salvage therapy was attempted in 15 patients, 4 were successful. Compared to symptomatic recurrences, patients with surveillance-detected recurrences had longer median OS (36.2 vs 23.7 months, P = .004) and postrecurrence survival (PRS, 16.5 vs 4.6 months, P < .001), but similar TTR (16.2 vs 13.3 months, P = .40) and duration of palliative chemotherapy (3.9 vs 3.3 months, P = .64). CONCLUSIONS: Among patients surveyed, 96% of recurrences were distant, and salvage therapy was successful in only 1.9% of patients. Longer OS in patients with surveillance-detected compared to symptomatic recurrences was not associated with significant earlier disease detection, and may be contributed by differences in disease biology. Further prospective data are warranted to establish the benefit of surveillance testing in gastroesophageal adenocarcinoma.

Capecitabine in early breast cancer: A meta-analysis of randomised controlled trials.

PURPOSE: Capecitabine is an effective therapy for metastatic breast cancer. Its role in early breast cancer is uncertain due to conflicting data from randomised controlled trials (RCTs). METHODS: PubMed and major conference proceedings were searched to identify RCTs comparing standard chemotherapy with or without capecitabine in the neoadjuvant or adjuvant setting. Hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS), as well as odds ratios (ORs) for toxicities were extracted or calculated and pooled in a meta-analysis. Subgroup analysis compared triple-negative breast cancer (TNBC) to non-TNBC and whether capecitabine was given in addition to or in place of standard chemotherapy. Meta-regression was used to explore the influence of TNBC on OS. RESULTS: Eight studies comprising 9302 patients were included. In unselected patients, capecitabine did not influence DFS (hazard ratio [HR] 0.99, p = 0.93) or OS (HR 0.90, p = 0.36). There was a significant difference in DFS when capecitabine was given in addition to standard treatment compared with in place of standard treatment (HR 0.92 versus 1.62, interaction p = 0.002). Addition of capecitabine to standard chemotherapy was associated with significantly improved DFS in TNBC versus non-TNBC (HR 0.72 versus 1.01, interaction p = 0.02). Meta-regression showed that adding capecitabine to standard chemotherapy was associated with improved OS in studies with higher proportions of patients with TNBC (R = -0.967, p = 0.007). Capecitabine increased grade 3/4 diarrhoea (odds ratio [OR] 2.33, p < 0.001) and hand-foot syndrome (OR 8.08, p < 0.001), and resulted in more frequent treatment discontinuation (OR 3.80, p < 0.001). CONCLUSION: Adding capecitabine to standard chemotherapy appears to improve DFS and OS in TNBC, but increases adverse events in keeping with its known toxicity profile.

Poor efficacy of the phosphorylated high-molecular-weight neurofilament heavy subunit serum level, a biomarker of axonal damage, as a marker of chemotherapy-induced peripheral neuropathy.

The phosphorylated form of the high-molecular-weight neurofilament heavy subunit (pNF-H) is a major structural protein in axons. The pNF-H level is elevated in the serum of certain patients with central nervous disorders, including chemotherapy-induced cognitive impairment. The present study was conducted to elucidate the potential role of pNF-H as a marker of chemotherapy-induced peripheral neuropathy (CIPN). A total of 71 patients with early breast cancer in various stages of treatment (following 1, 3 or 7 cycles of chemotherapy, or a previous history of breast cancer chemotherapy) were assessed with a self-administered PainDETECT questionnaire [pain location, pain intensity on an 11-point numeric rating scale (NRS), and various pain qualities] and a single serum pNF-H measurement. Patients were divided into two groups based on the presence or absence of bilateral symmetric pain in the distal portions of the extremities [CIPN(+) or CIPN(-)]. The χ2 and Mann-Whitney tests were used for statistical analyses. Among the participants, only 8 patients complained of CIPN. Their pain intensity was 3.5±1.9 (mean ± standard deviation) compared with 1.5±1.8 in the CIPN(-) group (P<0.01). The NRS of numbness in the CIPN(+) group was significantly higher (2.4±1.4) than that of the CIPN(-) group (1.0±1.0). Increased pNF-H levels were observed in 37.5% of the CIPN(+) patients and in 23.8% of CIPN(-) patients (P=0.40). In conclusion, CIPN is observed in the most distal portions of the peripheral nerves that are composed of dendrites but not axons. Although serum pNF-H is a biomarker of axonal damage, it is not useful as a marker of CIPN.

Potential role of pNF-H, a biomarker of axonal damage in the central nervous system, as a predictive marker of chemotherapy-induced cognitive impairment.

PURPOSE: Chemotherapy-induced cognitive impairment (CICI) is a clinically significant problem. Previous studies using magnetic resonance imaging indicated structural changes in the cerebral white matter of patients with CICI. Phosphorylated neurofilament heavy subunit (pNF-H), a major structural protein in axons, was recently reported to be elevated in the serum of patients with some central nervous system disorders. We performed a cross-sectional analysis of neuropsychological test results and serum pNF-H levels in patients undergoing adjuvant chemotherapy for breast cancer. Our hypothesis was that CICI is accompanied by axonal damage that can be detected by elevated serum pNF-H levels. EXPERIMENTAL DESIGN: Seventy-six patients with early breast cancer in various phases of treatment (naïve to chemotherapy; after one, three, or seven cycles of chemotherapy; or with a history of chemotherapy) were assessed by self-administered neuropsychological tests and a single pNF-H measurement. The χ(2) and Mann-Whitney tests were used for statistical analysis. RESULTS: Increased pNF-H levels were observed in 28.8% of the patients who underwent chemotherapy, but in none of the chemotherapy-naïve patients or patients with a history of chemotherapy. The pNF-H-positive rate increased significantly in proportion to the number of chemotherapy cycles (one cycle, 5.0%; three cycles, 31.6%; seven cycles, 55.0%; P < 0.05). No significant differences in neuropsychological test results were observed among the groups. CONCLUSIONS: The serum pNF-H level in patients undergoing chemotherapy for breast cancer increased in a cumulative dose-dependent manner, suggesting its potential application as a biomarker of neural damage after chemotherapy.