Are changes in patient-reported outcomes prognostic for diffuse large B-Cell lymphoma survival? Results from the GOYA trial.

In this hypothesis-generating analysis, we examined whether longitudinal changes in patient-reported outcomes (PROs), such as symptoms, over time would be prognostic for progression-free survival (PFS) and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) who were newly treated with obinutuzumab (G) in combination with CHOP (G-CHOP) or rituximab (R) with CHOP (R-CHOP), in the GOYA Phase 3 trial (NCT01287741). Our results show that from the study baseline to cycle 3 day 1, every 1-point increase (worsening) in fever symptoms was associated with a 41% higher risk of death (hazard ratio [HR], 1.41; P = 0.01). Every 1-point increase (worsening) in lumps or swelling symptoms was associated with a 27% higher risk of disease progression or death (PFS events) (HR, 1.27; P = 0.01) and a 29% higher risk of death (OS events) (HR, 1.29; P = 0.02). No significant associations were observed between survival and changes in other symptoms, such as itching. Our study suggests that changes in some PROs are related to survival in DLBCL patients.

Multisystem inflammatory syndrome in 1.2 million children: longitudinal cohort study of risk factors.

BACKGROUND: We identified patient characteristics associated with an increased risk of developing MIS-C. METHODS: We conducted a longitudinal cohort study of 1,195,327 patients aged 0-19 years between 2006 and 2021, including the first two waves of the pandemic (February 25-August 22, 2020 and August 23, 2020-March 31, 2021). Exposures included prepandemic morbidity, birth outcomes, and family history of maternal disorders. Outcomes included MIS-C, Kawasaki disease, and other Covid-19 complications during the pandemic. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for the association between patient exposures and these outcomes using log-binomial regression models adjusted for potential confounders. RESULTS: Among 1,195,327 children, 84 developed MIS-C, 107 Kawasaki disease, and 330 other Covid-19 complications during the first year of the pandemic. Prepandemic hospitalizations for metabolic disorders (RR 11.3, 95% CI 5.61-22.6), atopic conditions (RR 3.34, 95% CI 1.60-6.97), and cancer (RR 8.11, 95% CI 1.13-58.3) were strongly associated with the risk of MIS-C, compared with no exposure. These same exposures were also associated with Kawasaki disease and other Covid-19 complications. However, birth characteristics and history of maternal morbidity were not associated with MIS-C development. CONCLUSIONS: Children with pre-existing morbidity have a considerably elevated risk of MIS-C. IMPACT: Morbidities that predispose children to multisystem inflammatory syndrome (MIS-C) are unclear. In this study, prepandemic hospitalizations for metabolic disorders, atopic conditions, and cancer were associated with an elevated risk of MIS-C. Birth characteristics and family history of maternal morbidity were not, however, associated with MIS-C. Pediatric morbidities may play a greater role in MIS-C onset than maternal or perinatal characteristics, and may help clinicians better recognize children at risk for this complication.

Real-world impact of patient-reported outcome measurement on overall survival, healthcare use and treatment discontinuation in cancer patients.

Aim: The purpose of this retrospective, population-based, observational cohort analysis was to assess whether routine patient-reported outcomes (PRO) monitoring alone has an impact on real-world overall survival (OS) and hospitalizations among individuals diagnosed with lung, breast or colorectal cancer. The importance of follow-up care in post-PRO data collection was also discussed. Patients & methods: Administrative databases covering 17 cancer centers from Alberta, Canada were queried and individuals ≥18 years old and diagnosed with lung, breast or colorectal cancer from 1 January 2016 to 31 December 2019 were included and followed until 31 December 2020. Patients were stratified by whether they received routine PRO monitoring initiated within 120 days of diagnosis and matched 1:1 with use of propensity scores based on baseline characteristics. OS was assessed from the index date to death, and the respective Kaplan-Meier curves were estimated along with hazard ratios from Cox Proportional Hazard Models. Linear and logistic regression models were used to estimate mean differences and odds ratios (OR) respectively for healthcare resource utilization events including cancer physician visits, emergency department visits and outpatient ambulatory care encounters. Results: 4800 patients were included in each matched cohort. There was no statistically significant difference between PRO monitoring and non-monitoring cohorts in OS (HR = 1.01; 95% CI: 0.93-1.09; p = 0.836) and treatment discontinuation (OR = 0.98; 95% CI: 0.85-1.12; p = 0.75). Median OS was 51.5 months for unmonitored cohort (95% CI: 47.5-NA) versus 50.6 months for monitored cohort (95% CI: 47.6-55.7). Compared with PRO-monitored patients, unmonitored patients were associated with lower hospitalization risks (OR = 1.12; 95% CI: 1.03-1.22; p = 0.01). However, PRO-monitored patients experienced significantly fewer physician visits in comparison to unmonitored patients (MD = -1.036; 95% CI: -1.288 to -0.784, p < 0.001). Conclusion: Our results show that capturing patient-reported symptoms alone reduced the number of physician visits but neither reduced hospitalizations nor improved OS in this real-world cancer population. To drive more meaningful clinical impact, PRO monitoring programs must be met with rigorous follow-up response to the identified symptoms.

Real-World Biomarker Test Utilization and Subsequent Treatment in Patients with Early-Stage Non-small Cell Lung Cancer in the United States, 2011-2021.

INTRODUCTION: Biomarker testing is increasingly crucial for patients with early-stage non-small cell lung cancer (eNSCLC). We explored biomarker test utilization and subsequent treatment in eNSCLC patients in the real-world setting. METHODS: Using COTA's oncology database, this retrospective observational study included adult patients ≥ 18 years old diagnosed with eNSCLC (disease stage 0-IIIA) between January 1, 2011 and December 31, 2021. Date of first eNSCLC diagnosis was the study index date. We reported testing rates by index year for patients who received any biomarker test within 6 months of eNSCLC diagnosis and by each molecular marker. We also evaluated treatments received among patients receiving the five most common biomarker tests. RESULTS: Among the 1031 eNSCLC patients included in the analysis, 764 (74.1%) received ≥ 1 biomarker test within 6 months of eNSCLC diagnosis. Overall, epidermal growth factor receptor (EGFR; 64%), anaplastic lymphoma kinase (ALK; 60%), programmed death receptor ligand 1 (PD-L1; 48%), ROS proto-oncogene 1 (ROS1; 46%), B-Raf proto-oncogene (40%), mesenchymal epithelial transition factor receptor (35%), Kirsten rat sarcoma viral oncogene (29%), RET proto-oncogene (22%), human epidermal growth factor receptor 2 (21%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (20%) were the 10 most frequently tested biomarkers. The proportion of patients undergoing biomarker testing rose from 55.3% in 2011 to 88.1% in 2021. The most common testing methods were Sanger sequencing for EGFR (244, 37%), FISH (fluorescence in situ hybridization) for ALK (464, 75%) and ROS1 (357, 76%), immunohistochemical assay for PD-L1 (450, 90%), and next-generation sequencing testing for other biomarkers. Almost all the 763 patients who received the five most common biomarker tests had a test before the initiation of a systemic treatment. CONCLUSION: This study suggests a high biomarker testing rate among patients with eNSCLC in the US, with testing rates for various biomarkers increasing over the past decade, indicating a continuous trend towards the personalization of treatment decisions.

Multisystem inflammatory syndrome in adults: Comparison with other inflammatory conditions during the Covid-19 pandemic.

BACKGROUND: Multisystem inflammatory syndrome in adults (MIS-A) is an increasingly recognized complication of Covid-19. We assessed risk factors, clinical characteristics, and outcomes of patients with MIS-A compared with other inflammatory conditions. METHODS: We analyzed a cohort of patients ≥21 years hospitalized with MIS-A in Quebec, Canada between February 2020 and March 2021. We included comparison groups that share symptomatology or pathophysiology with MIS-A, including Kawasaki disease, toxic shock syndrome, and other Covid-19 complications. We examined characteristics of men and women at admission, and identified preexisting factors associated with MIS-A through odds ratios (OR) and 95% confidence intervals (CI) from adjusted logistic regression models. RESULTS: Among 22,251 patients in this study, 52 had MIS-A, 90 Kawasaki disease, 500 toxic shock syndrome, and 21,609 other Covid-19 complications. MIS-A was associated with an elevated risk of respiratory failure compared with Kawasaki disease (OR 7.22, 95% CI 1.26-41.24), toxic shock syndrome (OR 4.41, 95% CI 1.73-11.23), and other Covid-19 complications (OR 3.03, 95% CI 1.67-5.50). Patients with MIS-A had a greater risk of cardiac involvement, renal failure, and mortality. The data pointed towards sex-specific differences in presentation, with more respiratory involvement in women and cardiac involvement in men compared with patients that had other Covid-19 complications. Except for allergic disorders and cancer, prior medical risk factors were not associated with a greater likelihood of MIS-A. CONCLUSIONS: Patients with MIS-A have an elevated risk of mortality compared with other inflammatory conditions, with women having a predominance of respiratory complications and men cardiovascular complications.

Improving smoking cessation support for Quebec's smokers: an evaluation of Quebec's telephone quitline. / Améliorer l'aide à l'arrêt du tabagisme offerte aux fumeurs québécois : évaluation de la ligne téléphonique d'aide du Québec.

INTRODUCTION: Quitlines are an important and widespread intervention that support smokers in their efforts to quit smoking and engage them into treatment services. Quebec's quitline, called "la ligne J'ARRÊTE", has been in operation since 2002. The objectives of this study were to evaluate treatment reach, provide a description of caller characteristics and to provide results on cessation outcome measures for Quebec's smoking cessation quitline. METHODS: We collected data at intake, assessing new caller volume, caller characteristics and treatment reach. We used a one-group quasi-experimental design to assess 30-day and six-month quit rates, at six-month follow-up. Intake data were collected for 1292 new quitline callers, 18 years of age and older, over a one-year period. RESULTS: Results indicated that the service reached 9 in 10 000 Quebec smokers. With respect to the total population of smokers in Quebec, the quitline reached proportionately higher numbers of smokers who were women, were 55 years of age and older and had a high school diploma or less. At follow-up, the 30-day point prevalence abstinence rate was 26.7%, while the six-month prolonged abstinence rate was 18.8%. CONCLUSION: These results indicate that the quitline contributed to helping callers quit smoking. They are in line with findings for other quitlines in Canada and the United States. However, quitline reach is comparatively limited, suggesting that additional investment in promotional efforts and research into ways of recruiting underserved populations into the service would increase public health impact.

Pediatric surgery and future risk of cocaine, opioid, cannabis, and other substance use in women: longitudinal cohort study.

BACKGROUND: Substance use is problematic in young women, particularly in pregnancy. We sought to determine whether pediatric surgery is associated with the subsequent risk of adolescent or pregnancy-related illicit drug use, including cocaine, opioids, cannabis, and other drugs. METHODS: We analyzed a cohort of 167,119 girls aged five years or less in Canada with 4,693,444 person-years of follow-up. We tracked the girls over time between 1989 and 2018. The main exposure measure was pediatric surgery before 20 years of age. The main outcome included subsequent hospitalizations for substance use disorders and substance use in pregnancy. We estimated hazard ratios and 95% confidence intervals (CI) for the association of pediatric surgery with the later risk of substance use, using Cox proportional hazards regression models adjusted for patient characteristics. RESULTS: Pediatric surgery was associated with 2.08 times the risk of future hospitalization for substance use disorders (95% CI 1.96-2.22) and 1.48 times the risk of substance use in pregnancy (95% CI 1.35-1.62), compared with no surgery. Associations were stronger for girls who had surgery under general anesthesia and were present regardless of age at first surgery or total number of surgeries. Pediatric surgery was associated with the use of cocaine, opioids, cannabis, and other illicit substances later in life. CONCLUSIONS: This study suggests that pediatric surgery may be associated with future substance use disorders in women, including substance use at pregnancy. Further study is needed to determine whether surgery may have a causal role in later drug abuse by women.

Effect of publicly funded assisted reproductive technology on maternal and infant outcomes: a pre- and post-comparison study.

STUDY QUESTION: Does publicly funded assisted reproductive technology result in improved maternal and infant outcomes? SUMMARY ANSWER: Publicly funded ART in Quebec was associated with reduced risks of preeclampsia, cesarean delivery, preterm birth, low birth weight and other adverse outcomes. WHAT IS KNOWN ALREADY: Publicly funded ART programs that provide free access to single embryo transfer are known to decrease the rate of multiple pregnancy, but the impact on other pregnancy outcomes is unknown. STUDY DESIGN, SIZE, DURATION: We conducted a pre- and post-comparison study of 597 416 pregnancies conceived between July 2008 and September 2015 in Quebec, Canada, a region where public funding of ART began in August 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included all pregnant women who conceived by ART (n = 14 309) or spontaneously (n = 583 107) and delivered a live or stillborn infant in hospitals of Quebec. The main exposure measure was conception before versus during the publicly funded ART program. Outcomes included measures of maternal and infant morbidity and mortality. We estimated risk ratios (RR) and 95% confidence intervals for the association of publicly funded ART with maternal and infant outcomes using log-binomial regression models adjusted for maternal characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: In this study, 2638 pregnancies were conceived by ART before, and 11 671 were conceived by ART, during public funding. Compared with no public funding, ART funding was associated with reduced risks of severe maternal morbidity (RR 0.64, 95% CI 0.50-0.83), preeclampsia (RR 0.55, 95% CI 0.44-0.68), cesarean delivery (RR 0.83, 95% CI 0.77-0.89), preterm birth (RR 0.67, 95% CI 0.60-0.75), low birth weight (RR 0.63, 95% CI 0.55-0.72), severe neonatal morbidity (RR 0.75, 95% CI 0.57-0.99) and neonatal intensive care unit admission (RR 0.65, 95% CI 0.53-0.78). When multiple pregnancies were excluded, ART funding continued to be associated with a lower risk of preeclampsia (RR 0.61, 95% CI 0.48-0.79) and preterm birth (RR 0.85, 95% CI 0.73-0.99). However, ART funding was associated with increased risk of gestational diabetes. LIMITATIONS, REASONS FOR CAUTION: We had no information on the type of ART, number of in-vitro fertilization cycles or number of embryos transferred. We lacked data on body mass index, ethnicity and smoking and cannot rule out residual confounding. WIDER IMPLICATION OF THE FINDINGS: Our findings suggest that publicly funded ART programs that encourage single embryo transfer may have substantial benefits for a range of maternal and infant outcomes, beyond prevention of multiple births. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grant 6D02363004 from the Public Health Agency of Canada. N.A. acknowledges a career award from the Fonds de recherche du Québec-Santé (34695). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Maternal use of illicit drugs, tobacco or alcohol and the risk of childhood cancer before 6 years of age.

BACKGROUND: Previous studies provide conflicting evidence of a link between maternal substance use and risk of childhood cancer. METHODS: We analyzed a cohort of 785,438 newborns in Quebec (2006-2016). We identified infants whose mothers had problematic illicit drug, tobacco, or alcohol use before or during pregnancy. The primary outcomes were childhood hematopoietic cancer or solid tumors within 0-5 years of age. Using Cox proportional hazards models, we computed hazard ratios (HR) and 95% confidence intervals (CI) for the association between maternal substance use and childhood cancer, adjusted for potential confounders. RESULTS: A total of 925 cases of cancer occurred during 3.5 million person-years of follow-up. Children exposed to any maternal substance use had marginally elevated cancer incidence rates compared with unexposed children (29.4 vs. 26.1 per 100,000 person-years). Maternal illicit drug use was associated with the risk of acute lymphoblastic leukemia (HR 1.63, 95% CI 0.79-3.36) and fibrosarcoma (HR 2.11, 95% CI 0.86-5.16). Maternal tobacco use was associated with acute myeloid leukemia (HR 2.01, 95% CI 0.72-5.60) and fibrosarcoma (HR 2.13, 95% CI 1.05-4.32), but a weak association with neuroblastoma (HR 1.21, 95% CI 0.61-2.40) and renal tumors (HR 1.14, 95% CI 0.42-3.13) also appeared to be present. CONCLUSIONS: We found a potential association between maternal substance use and certain types of early childhood cancer. Although effects were modest, maternal substance use may contribute to some types of childhood cancer, especially leukemia and fibrosarcoma.

Increased risk of hemangioma after exposure to neonatal phototherapy in infants with predisposing risk factors.

AIM: To determine the relationship between neonatal phototherapy and future risk of clinically significant hemangioma. METHODS: We analysed a cohort of 678 879 infants born after 34 weeks gestation comprising 3 975 242 person-years of follow-up over 11 years (2006-2016). The exposure was phototherapy the first 28 days of life. The outcome was hemangioma that required in-hospital treatment during follow-up. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of phototherapy with risk of hemangioma, accounting for preterm birth, low birthweight and congenital anomalies. RESULTS: The incidence of hemangioma was greater in neonates who received phototherapy than in untreated infants, but there was no association in adjusted models (HR 1.19, 95% CI 0.89-1.58). Risk of hemangioma was elevated in infants who received phototherapy and were born late preterm (HR 2.35, 95% CI 1.51-3.64), with low birthweight (HR 1.91, 95% CI 1.12-3.24), or with anomalies (HR 5.09, 95% CI 3.42-7.58). Without phototherapy, these three risk factors were more weakly associated with hemangioma. CONCLUSION: Neonatal phototherapy in infants with predisposing risk factors may increase the chance of hemangioma, but confirmation in further studies is needed.

Neonatal phototherapy and future risk of childhood cancer.

We sought to determine if neonatal phototherapy is associated with a greater risk of childhood cancer. We conducted a retrospective cohort study of 786,998 infants born in hospitals of Quebec, Canada between 2006 and 2016, with 4,660,868 person-years of follow-up over an 11-year period. The exposures were neonatal phototherapy (32,314 or 4.1% of infants) and untreated jaundice (91,855 or 11.7% of infants). The outcome was hospitalization for solid or hematopoietic childhood tumours between 2 months and 11 years of age. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association of phototherapy with childhood cancer, adjusted for infant characteristics. The incidence of childhood cancer was higher for infants with phototherapy (25.1 per 100,000 person-years) and untreated jaundice (23.0 per 100,000) compared to unexposed infants (21.6 per 100,000). Phototherapy appeared to be associated with late onset solid tumours, including brain/central nervous system cancers. Between age 4 and 11 years, children who received neonatal phototherapy had more than 2 times the risk of any solid tumour compared to unexposed children (HR 2.26, 95% CI 1.34-3.81). Results were similar for phototherapy compared against untreated jaundice. A similar trend was however less apparent for hematopoietic cancer. We conclude that neonatal phototherapy may be associated with a slightly increased risk of solid tumours in childhood, but cannot rule out an effect of bilirubin. Minimizing unnecessary exposure to phototherapy through adherence to recommended thresholds for treatment is encouraged.

Mortality inequality in populations with equal life expectancy: Arriaga's decomposition method in SAS, Stata, and Excel.

PURPOSE: Life expectancy is used to measure population health, but large differences in mortality can be masked even when there is no life expectancy gap. We demonstrate how Arriaga's decomposition method can be used to assess inequality in mortality between populations with near equal life expectancy. METHODS: We calculated life expectancy at birth for Quebec and the rest of Canada from 2005 to 2009 using life tables and partitioned the gap between both populations into age and cause-specific components using Arriaga's method. RESULTS: The life expectancy gap between Quebec and Canada was negligible (<0.1 years). Decomposition of the gap showed that higher lung cancer mortality in Quebec was offset by cardiovascular mortality in the rest of Canada, resulting in identical life expectancy in both groups. Lung cancer in Quebec had a greater impact at early ages, whereas cardiovascular mortality in Canada had a greater impact at older ages. CONCLUSIONS: Despite the absence of a gap, we demonstrate using decomposition analyses how lung cancer at early ages lowered life expectancy in Quebec, whereas cardiovascular causes at older ages lowered life expectancy in Canada. We provide SAS/Stata code and an Excel spreadsheeet to facilitate application of Arriaga's method to other settings.

Does cigarette smoking mitigate the severity of skin disease in systemic sclerosis?

Cigarette smoking has significant negative effects on vascular, pulmonary and gastrointestinal outcomes in systemic sclerosis (SSc). The objective of this study was to study the effect of cigarette smoking on the extent of skin disease in SSc. Subjects were patients enrolled in the Canadian Scleroderma Research Group cohort. Smoking history was obtained by patient self-reports. The extent of skin involvement was measured using the modified Rodnan skin score. The effect of smoking on the skin score was assessed using the comprehensive smoking index (CSI), which integrates smoking intensity, duration and time since cessation into a single covariate of smoking effect. The regression model was adjusted for gender, ethnicity and disease duration. This study included 606 SSc patients, of which 87 % were women and 90 % were white; mean disease duration was 11 (±9) years, and mean modified Rodnan skin score was 10 (±9). Of these, 16 % were current, 42 % past and 42 % never smokers. There was a 16 % reduction in skin score (odds ratio 0.84, 95 % confidence interval 0.75, 0.95, p = 0.0029) for every 0.1 unit change in CSI. The effect of smoking on skin disease appeared cumulative and irreversible. Smoking was significantly associated with less extensive skin disease in SSc. This hypothesis-generating study provides new avenues of research, especially insofar as the role of nicotine in SSc is concerned and given that safe nicotine replacement therapy exists.

Modeling smoking in systemic sclerosis: a comparison of different statistical approaches.

OBJECTIVE: To determine the effect of different methods of modeling smoking on vascular outcomes in rheumatic diseases. METHODS: Data from the Canadian Scleroderma Research Group Registry were used. Patients self-reported their smoking history. Vascular outcomes were severity of Raynaud's phenomenon, presence of finger ulcers, and severity of finger ulcers. Several models were developed to capture the experience of smoking: 1) ever compared to never smoking; 2) current and past smoking compared to never smoking; 3) never, past, and current smoking compared using polynomial contrasts; 4) smoking intensity, duration, and time since cessation assessed separately; and 5) smoking modeled using the Comprehensive Smoking Index (CSI), which integrates intensity, duration, and time since cessation into a single covariate. RESULTS: This study included 606 patients, of which 16% were current, 42% were past, and 42% were never smokers. Current and past smokers smoked a mean±SD of 25±17 and 17±18 pack-years, respectively. Smoking duration was shorter in past compared to current smokers (18.3 versus 31.7 years). Past smokers reported having stopped smoking approximately mean±SD 16±12 years prior, although this ranged from 1 to 50 years. Smoking had no effect on vascular outcomes in the simplest model comparing ever to never smokers. Models that isolated past smokers revealed the presence of a healthy smoker bias in that group. The model using the CSI demonstrated a strong negative effect of smoking on vascular outcomes. CONCLUSION: Proper modeling of the effect of smoking is essential in studies of vascular outcomes of rheumatic diseases.

Cigarette smoking in patients with systemic sclerosis.

OBJECTIVE: To determine the effects of cigarette smoking on vascular, gastrointestinal, and respiratory outcomes in patients with systemic sclerosis (SSc). METHODS: Subjects were patients enrolled in the Canadian Scleroderma Research Group cohort. Smoking history was obtained by patient self-report. The effect of smoking was assessed using multiple regression analysis of each SSc clinical outcome of interest (vascular, gastrointestinal, and respiratory). Smoking was modeled both as categorical variables (current, past, and never) and using the Comprehensive Smoking Index (CSI), which integrates smoking intensity, duration of smoking, and time since cessation into a single covariate of smoking effect. All regression models were adjusted for age, sex, disease duration, and limited or diffuse skin involvement. RESULTS: This study included 606 patients with SSc, of whom 87% were women and 90% were white, and the mean age was 55 years, mean disease duration was 11 years, and 36% had diffuse disease. Of these patients, 16% were current smokers, 42% were past smokers, and 42% were never smokers. The regression analyses showed that smoking had a significant negative effect on almost all vascular, gastrointestinal, and respiratory outcomes. The effects of smoking were in some cases long-lasting (e.g., persistent respiratory abnormalities), and smoking cessation appeared beneficial with respect to some outcomes (e.g., reduced severity of Raynaud's phenomenon). CONCLUSION: Physicians caring for patients with SSc should prioritize smoking cessation as a recommendation to patients, and resources directed to supporting smoking cessation in patients with SSc should be more readily available.

Releasing the brake on the immune system: ipilimumab in melanoma and other tumors.

Advanced melanoma has proven difficult to treat for many years, and no previous agent has shown improved survival in a phase 3 trial. The deepening understanding of tumor immunobiology and the complexity of the interactions between host T cells and cancer have led to novel treatment approaches. Among these, ipilimumab is a first-in-class T-cell potentiator that works by blocking cytotoxic T-lymphocyte antigen-4, a critical negative regulator of the antitumor T-cell response. From phase 1 studies, ipilimumab has shown encouraging activity in melanoma and other cancers, with unusual response patterns and mechanism-related, predictable toxicities that are medically manageable and mostly reversible but can sometimes be life threatening unless recognized and treated early. Early indications of a survival benefit in phase 2 studies have been confirmed recently in the first randomized phase 3 trial; the primary endpoint of the trial, overall survival (OS), was met with ipilimumab significantly prolonging median OS both as a single agent (10.1 months; p = 0.003) and combined with gp100 vaccine (10.0 months; p < 0.001) compared with vaccine control (6.4 months). Even more noteworthy was the improvement in long-term survival at 24 months from 13.7% (gp100 alone) to 21.6% and 23.5% for the combination and single ipilimumab, respectively. The addition of gp100 vaccine did not appear to impact OS since data for ipilimumab alone were similar to those for the combination with vaccine. Re-induction with ipilimumab in selected patients who progressed gave further clinical benefits. Ipilimumab has also shown promising activity in melanoma patients with brain metastases, and patients with non-small cell lung cancer, renal cell cancer, and castrate-resistant prostate cancer. Ipilimumab not only has a novel mechanism of action but demonstrates unique immune-related toxicities that require particular care in their recognition and treatment.