Nomograms are widely used for cancer prognosis, primarily because of their ability to reduce statistical predictive models into a single numerical estimate of the probability of an event, such as ...death or recurrence, that is tailored to the profile of an individual patient. User-friendly graphical interfaces for generating these estimates facilitate the use of nomograms during clinical encounters to inform clinical decision making. However, the statistical underpinnings of these models require careful scrutiny, and the degree of uncertainty surrounding the point estimates requires attention. This guide provides a nonstatistical audience with a methodological approach for building, interpreting, and using nomograms to estimate cancer prognosis or other health outcomes.
Cancer patients face an increased risk of arterial thromboembolism; however, it is uncertain when this excess risk begins. This study evaluated the risk of arterial thromboembolism before cancer ...diagnosis. Using the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, we identified 374 331 patients ≥67 years of age with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, gastric cancer, or non-Hodgkin lymphoma from 2005 through 2013. Cancer patients were individually matched by demographics and comorbidities to Medicare beneficiaries without cancer, who served as controls. Validated diagnosis codes were used to identify arterial thromboembolic events, defined as a composite of myocardial infarction or ischemic stroke. The Mantel-Haenszel estimator was used to compare risks of arterial thromboembolic events between cancer and noncancer groups during 30-day periods in the 360 days before date of cancer diagnosis. From 360 to 151 days before cancer diagnosis, the 30-day interval risks of arterial thromboembolic events were similar between cancer patients and matched controls. From 150 to 1 day before cancer diagnosis, the interval 30-day risks of arterial thromboembolic events were higher in cancer patients vs matched controls, progressively increasing as the cancer diagnosis date approached and peaking during the 30 days immediately before cancer diagnosis, when 2313 (0.62%) cancer patients were diagnosed with an arterial thromboembolic event vs 413 (0.11%) controls (odds ratio, 5.63; 95% confidence interval, 5.07-6.25). In conclusion, the risk of arterial thromboembolic events begins to increase 150 days before the date of cancer diagnosis in older persons and peaks in the 30 days before.
•Among 748 662 Medicare beneficiaries, the risk of arterial thromboembolic events was increased 69% in the year before cancer diagnosis.•The increased risk of arterial thromboembolic events began 5 months before cancer was officially diagnosed and peaked in the month prior.
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Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of ...limited access to tumor tissue.
We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer.
We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including temozolomide-associated mutations.
The study shows that CSF harbors clinically relevant genomic alterations in patients with CNS cancers and should be considered for liquid biopsies to monitor tumor evolution in the CNS.
Objective
A study was undertaken to examine the association between incident cancer and the subsequent risk of stroke.
Methods
Using the Surveillance, Epidemiology, and End Results–Medicare linked ...database, we identified patients with a new primary diagnosis of breast, colorectal, lung, pancreatic, or prostate cancer from 2001 through 2007. These patients were individually matched by age, sex, race, registry, and medical comorbidities to a group of Medicare enrollees without cancer, and each pair was followed through 2009. Validated diagnosis codes were used to identify a primary outcome of stroke. Cumulative incidence rates were calculated using competing risk survival statistics.
Results
Among 327,389 pairs of cancer patients and matched controls, the 3‐month cumulative incidence of stroke was generally higher in patients with cancer. Cumulative incidence rates were 5.1% (95% confidence interval CI = 4.9–5.2%) in patients with lung cancer compared to 1.2% (95% CI = 1.2–1.3%) in controls (p < 0.001), 3.4% (95% CI = 3.1–3.6%) in patients with pancreatic cancer compared to 1.3% (95% CI = 1.1–1.5%) in controls (p < 0.001), 3.3% (95% CI = 3.2–3.4%) in patients with colorectal cancer compared to 1.3% (95% CI = 1.2–1.4%) in controls (p < 0.001), 1.5% (95% CI = 1.4–1.6%) in patients with breast cancer compared to 1.1% (95% CI = 1.0–1.2%) in controls (p < 0.001), and 1.2% (95% CI = 1.1–1.3%) in patients with prostate cancer compared to 1.1% (95% CI = 1.0–1.2%) in controls (p = 0.085). Excess risks attenuated over time and were generally no longer present beyond 1 year.
Interpretation
Incident cancer is associated with an increased short‐term risk of stroke. This risk appears highest with lung, pancreatic, and colorectal cancers. Ann Neurol 2015;77:291–300
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often ...transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.
•Ibrutinib/methotrexate/rituximab combination treatment is safe and shows promising clinical activity in CNSL.•Analysis of ctDNA in CSF may be useful to monitor disease burden in patients with CNSL.
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The risk of arterial thromboembolism in patients with cancer is incompletely understood.
The authors aimed to better define this epidemiological relationship, including the effects of cancer stage.
...Using the Surveillance Epidemiology and End Results–Medicare linked database, the authors identified patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011. They were individually matched by demographics and comorbidities to a Medicare enrollee without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify arterial thromboembolism, defined as myocardial infarction or ischemic stroke. Cumulative incidence rates were calculated using competing risk survival statistics. Cox hazards analysis was used to compare rates between groups at discrete time points.
The authors identified 279,719 pairs of patients with cancer and matched control patients. The 6-month cumulative incidence of arterial thromboembolism was 4.7% (95% confidence interval CI: 4.6% to 4.8%) in patients with cancer compared with 2.2% (95% CI: 2.1% to 2.2%) in control patients (hazard ratio HR: 2.2; 95% CI: 2.1 to 2.3). The 6-month cumulative incidence of myocardial infarction was 2.0% (95% CI: 1.9% to 2.0%) in patients with cancer compared with 0.7% (95% CI: 0.6% to 0.7%) in control patients (HR: 2.9; 95% CI: 2.8 to 3.1). The 6-month cumulative incidence of ischemic stroke was 3.0% (95% CI: 2.9% to 3.1%) in patients with cancer compared with 1.6% (95% CI: 1.6% to 1.7%) in control patients (HR: 1.9; 95% CI: 1.8 to 2.0). Excess risk varied by cancer type (greatest for lung), correlated with cancer stage, and generally had resolved by 1 year.
Patients with incident cancer face a substantially increased short-term risk of arterial thromboembolism.
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Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration ...and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T
cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating T
cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated ...outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged ≥ 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged ≥ 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ipilimumab is a standard treatment for metastatic melanoma, but immune-related adverse events (irAEs) are common and can be severe. We reviewed our large, contemporary experience with ipilimumab ...treatment outside of clinical trials to determine the frequency of use of systemic corticosteroid or anti-tumor necrosis factor α (anti-TNFα) therapy and the effect of these therapies on overall survival (OS) and time to treatment failure (TTF).
We reviewed retrospectively the medical records of patients with melanoma who had received treatment between April 2011 and July 2013 with ipilimumab at the standard dose of 3 mg/kg. We collected data on patient demographics, previous and subsequent treatments, number of ipilimumab doses, irAEs and how they were treated, and overall survival.
Of the 298 patients, 254 (85%) experienced an irAE of any grade. Fifty-six patients (19%) discontinued therapy because of an irAE, most commonly diarrhea. Overall, 103 patients (35%) required systemic corticosteroid treatment for an irAE; 29 (10%) also required anti-TNFα therapy. Defining TTF as either starting a new treatment or death, estimated median TTF was 5.7 months. Twelve percent of patients experienced long-term disease control without receiving additional antimelanoma therapy. OS and TTF were not affected by the occurrence of irAEs or the need for systemic corticosteroids.
IrAEs are common in patients treated with ipilimumab. In our experience, approximately one-third of ipilimumab-treated patients required systemic corticosteroids, and almost one-third of those required further immune suppression with anti-TNFα therapy. Practitioners and patients should be prepared to treat irAEs and should understand that such treatment does not affect OS or TTF.
To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our ...knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients.
We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death.
CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab.
In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.
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