AbstractBackground.Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 (MDM2) is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of MDM2 amplification, not simply the presence of MDM2 amplification, may be biologically important to the actions of DDLPS.Patients and Methods.The distribution of MDM2 amplification in DDLPS was assessed using data from a commercial sequencing laboratory (n = 642) and The Cancer Genome Atlas (n = 57). Data from two retrospective clinical trials (n = 15, n = 16) and one prospective clinical trial (n = 25) were used to test MDM2’s utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines.Results.Genomic MDM2 amplification follows a highly reproducible log‐normal distribution. In patients with DDLPS treated with complete tumor resection, elevated MDM2 was associated with shortened time to recurrence as measured by genomic amplification (p = .003) and mRNA expression (p = .04). In patients requiring systemic therapy, higher MDM2 amplification was associated with reduced overall survival (p = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline MDM2 levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity.Conclusion. MDM2 amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of MDM2 as a predictive biomarker in DDLPS is warranted.Implications for Practice.No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 (MDM2) is currently used for diagnosis, the clinical relevance of MDM2 amplification has yet to be fully assessed. We demonstrate that MDM2 amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. This data suggests that MDM2 amplification may be a useful biomarker in DDLPS.
Evaluation of the Incorporation of Recurrence Score into the American Joint Committee on Cancer Eighth Edition Staging System in Patients with T1‐2N0M0, Estrogen Receptor‐Positive, Human Epidermal Growth Receptor 2‐Negative Invasive Breast Cancer: A…
AbstractBackground.The current study aimed to evaluate the predictive performance of the American Joint Committee on Cancer eighth edition staging system in patients with invasive breast cancer based on the Surveillance, Epidemiology, and End Results database.Subjects, Materials, and Methods.Patients diagnosed with T1‐2N0M0, estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative breast cancer from 2010 to 2014 were retrospectively recruited in this analysis. Patients were reassigned to different stages according to the anatomic staging system (AS), prognostic staging system (PS), and prognostic and genomic staging criteria downstaging patients with recurrence score (RS) lower than 11 (PGS_RS11). Cox models were conducted for multivariate analyses, and likelihood ratio (LR) χ2, Akaike information criterion (AIC), and Harrell's concordance index (C‐index) were calculated for the comparison of different staging systems. Additionally, adjustments were made to generate prognostic and genomic staging criteria downstaging patients with RS lower than 18 (PGS_RS18) and RS lower than 25 (PGS_RS25).Results.PGS_RS11 was an independent predictor for breast cancer‐specific survival, as were PS and AS. Adjusted for age and ethnicity, PGS_RS11 (AIC = 2,322.763, C‐index = 0.7482, LR χ2 = 113.17) showed superiority in predicting survival outcomes and discriminating patients compared with AS (AIC = 2,369.132, C‐index = 0.6986, LR χ2 = 60.80) but didn't outperform PS (AIC = 2,320.992, C‐index = 0.7487, LR χ2 = 114.94). The predictive and discriminative ability of PGS_RS18 was the best (AIC = 2297.434, C‐index = 0.7828, LR χ2 = 138.50) when compared with PS and PGS_RS11.Conclusion.PGS_RS11 was superior to AS but comparable with PS in predicting prognosis. Further validations and refinements are needed for the better incorporation of RS into staging systems.Implications for Practice.Staging systems are of critical importance in informing prognosis and guiding treatment. This study's objective was to evaluate the newly proposed staging system in the American Joint Committee on Cancer eighth edition staging manual, which combined biological and genomic information with the traditional TNM classification for the first time to determine tumor stages of breast cancer. The superiority of the prognostic and genomic staging system was validated in our cohort and possibly could encourage the utility of genomic assays in clinical practice for staging assessment and prognosis prediction.
U.S. Food and Drug Administration Benefit‐Risk Assessment of Nilotinib Treatment Discontinuation in Patients with Chronic Phase Chronic Myeloid Leukemia in a Sustained Molecular Remission
AbstractOn December 22, 2017, the U.S. Food and Drug Administration (FDA) updated the product label for nilotinib to include information for providers on how to discontinue this drug in certain patients. With the updated dosing recommendations, select patients with chronic phase myeloid leukemia (CML) taking nilotinib for 3 years or more and whose leukemia has responded with sustained molecular remission (MR4.5, BCR‐ABL transcripts of ≤0.0032%) as determined by a FDA‐approved test may be eligible to discontinue nilotinib. The updated dosing regimen was based on the efficacy results from two trials that measured how long patients could stop taking nilotinib without the leukemia returning (treatment‐free remission). Trial results demonstrated that, among selected patients who received nilotinib as first‐line therapy or after transition from imatinib, approximately 50% continued to be in remission at 96 weeks after stopping therapy. Relapses continued to occur throughout the study, indicating that long‐term monitoring is needed for safety and disease monitoring. Discontinuation of treatment was associated with an increased risk of low grade musculoskeletal adverse events, some of which were prolonged. Overall, the results support the approval of updates to the dosing recommendations with regard to treatment discontinuation in selected patients who have received nilotinib for at least 3 years, are in a sustained molecular remission, and who can undergo appropriate monitoring.Implications for Practice.The updated dosing information provides eligibility criteria for treatment discontinuation, strict monitoring criteria after nilotinib discontinuation, and guidance for treatment reinitiation in eligible patients with chronic phase myeloid leukemia. About half of appropriately selected patients remained in remission 96 weeks after treatment discontinuation. Patients may experience musculoskeletal pain on withdrawal of treatment, incidence of which appears to decrease over time; however, some patients may have long lasting events. The decision to withdraw or continue treatment with nilotinib should be based on clinical condition and patient preferences.
Failure to Diagnose and Treat Hyperparathyroidism Among Patients with Hypercalcemia: Opportunities for Intervention at the Patient and Physician Level to Increase Surgical Referral
AbstractBackground.Hyperparathyroidism is both underdiagnosed and undertreated, but the reasons for these deficiencies have not been described. The purpose of this study was to identify reasons for underdiagnosis and undertreatment of hyperparathyroidism that could be addressed by targeted interventions.Materials and Methods.We identified 3,200 patients with hypercalcemia (serum calcium >10.5 mg/dL) who had parathyroid hormone (PTH) levels evaluated at our institution from 2011 to 2016. We randomly sampled 60 patients and divided them into three groups based on their PTH levels. Two independent reviewers examined clinical notes and diagnostic data to identify reasons for delayed diagnosis or referral for treatment.Results.The mean age of the patients was 61 ± 16.5 years, 68% were women, and 55% were white. Fifty percent of patients had ≥1 elevated calcium that was missed by their primary care provider. Hypercalcemia was frequently attributed to causes other than hyperparathyroidism, including diuretics (12%), calcium supplements (12%), dehydration (5%), and renal dysfunction (3%). Even when calcium and PTH were both elevated, the diagnosis was missed or delayed in 40% of patients. For 7% of patients, a nonsurgeon stated that surgery offered no benefit; 22% of patients were offered medical treatment or observation, and 8% opted not to see a surgeon. Only 20% of patients were referred for surgical evaluation, and they waited a median of 16 months before seeing a surgeon.Conclusion.To address common causes for delayed diagnosis and treatment of hyperparathyroidism, we must improve systems for recognizing hypercalcemia and better educate patients and providers about the consequences of untreated disease.Implications for Practice.This study identified reasons why patients experience delays in workup, diagnosis, and treatment of primary hyperparathyroidism. These data provide valuable information for developing interventions that increase rates of diagnosis and referral.
AbstractBackground.Ensuring older patients with advanced cancer and their oncologists have similar beliefs about curability is important. We investigated discordance in beliefs about curability in patient‐oncologist and caregiver‐oncologist dyads.Materials and Methods.We used baseline data from a cluster randomized trial assessing whether geriatric assessment improves communication and quality of life in older patients with advanced cancer and their caregivers. Patients were aged ≥70 years with incurable cancer from community oncology practices. Patients, caregivers, and oncologists were asked: “What do you believe are the chances the cancer will go away and never come back with treatment?” Options were 100%, >50%, 50/50, <50%, and 0% (5‐point scale). Discordance in beliefs about curability was defined as any difference in scale scores (≥3 points were severe). We used multivariate logistic regressions to describe correlates of discordance.Results.Discordance was present in 60% (15% severe) of the 336 patient‐oncologist dyads and 52% (16% severe) of the 245 caregiver‐oncologist dyads. Discordance was less common in patient‐oncologist dyads when oncologists practiced longer (adjusted odds ratio [AOR] 0.90, 95% confidence interval [CI] 0.84–0.97) and more common in non‐Hispanic white patients (AOR 5.77, CI 1.90–17.50) and when patients had lung (AOR 1.95, CI 1.29–2.94) or gastrointestinal (AOR 1.55, CI 1.09–2.21) compared with breast cancer. Severe discordance was more common when patients were non‐Hispanic white, had lower income, and had impaired social support. Caregiver‐oncologist discordance was more common when caregivers were non‐Hispanic white (AOR 3.32, CI 1.01–10.94) and reported lower physical health (AOR 0.88, CI 0.78–1.00). Severe discordance was more common when caregivers had lower income and lower anxiety level.Conclusion.Discordance in beliefs about curability is common, occasionally severe, and correlated with patient, caregiver, and oncologist characteristics.Implications for Practice.Ensuring older patients with advanced cancer and their caregivers have similar beliefs about curability as the oncologist is important. This study investigated discordance in beliefs about curability in patient‐oncologist (PO) and caregiver‐oncologist (CO) dyads. It found that discordance was present in 60% (15% severe) of PO dyads and 52% (16% severe) of CO dyads, raising serious questions about the process by which patients consent to treatment. This study supports the need for interventions targeted at the oncologist, patient, caregiver, and societal levels to improve the delivery of prognostic information and patients’/caregivers’ understanding and acceptance of prognosis.
Mesothelin Expression Is a Predictive Factor for Peritoneal Recurrence in Curatively Resected Stage III Gastric Cancer
AbstractBackground.Mesothelin is overexpressed in many solid tumors, and recent studies have shown that mesothelin expression is associated with poor outcomes in several malignant tumors and may play a role in cancer progression. Clinical trials of mesothelin‐targeted immunotherapies are currently under way, but the correlation between mesothelin expression and gastric cancer prognosis is still unclear.Subjects, Materials, and Methods.Mesothelin expression in tumor cells was evaluated immunohistochemically in 958 patients with advanced gastric cancer and interpreted according to the intensity and extent of staining. Samples were scored from 0 to 2, with high expression defined as a score of 2. Clinicopathological factors, overall survival (OS), recurrence‐free survival (RFS), and sites of initial recurrence, including peritoneal recurrence, were evaluated. Staging was performed according to the American Joint Committee on Cancer 7th edition.Results.High mesothelin expression was observed in 49.7% of patients and significantly associated with high pathologic T (p = .021) and peritoneal recurrence (p = .018). Multivariate survival analysis showed that high mesothelin expression was independently associated with poor RFS (p = .001), OS (p = .001), and peritoneal recurrence (p = .002) in addition to stage, lymphovascular invasion, and Lauren classification. In a subgroup analysis of peritoneal recurrence, high mesothelin expression was also an independent prognostic factor in stage III (p = .013) and diffuse/mixed type gastric cancer (p = .010).Conclusion.High mesothelin expression is correlated with poor outcomes. In addition, mesothelin expression, Lauren classification, and stage are meaningful predictive factors for peritoneal recurrence. Moreover, mesothelin was a significant predictor of a high risk of peritoneal recurrence in patients with stage III gastric cancer.Implications for Practice.This study demonstrates that high mesothelin expression correlates with poor outcomes and is a significant predictor of peritoneal recurrence in patients with stage III gastric cancer. This study provides instrumental evidence for designing anti‐mesothelin antibody‐drug conjugate clinical trials in patients with diffuse‐type gastric cancer to reduce their high risk of peritoneal carcinomatosis.
AbstractBackground.Soft‐tissue sarcomas (STSs) are a group of rare cancers that can occur at any age. Prognostic outcomes of patients with STS are usually established at the time of the patient's initial disease presentation. Conditional survival affords a dynamic prediction of prognosis for patients surviving a given period after diagnosis. Estimates of conditional survival can provide crucial prognostic information for patients and caregivers, guide subsequent cancer follow‐up schedules, and impact decisions regarding management. This study aims to estimate conditional survival and prognostic factors in patients with STS according to age at diagnosis (≤75 years and ≥75 years).Subjects, Materials, and Methods.A total of 6,043 patients with nonmetastatic STS at first diagnosis who underwent complete surgical resection (R0 or R1) were assessed. Cox proportional hazards regression was used to establish prognostic factors of conditional metastasis‐free survival and overall survival at 1, 2, and 5 years after diagnosis.Results.Elderly patients have more adverse prognostic features at presentation and tend to receive less aggressive treatment than do younger patients. However, at baseline as well as at each conditional survival time point, the 5‐year estimated probability of metastatic relapse decreases in both young and elderly patients and is almost identical in both groups at 2 years and 5 years after initial diagnosis. Prognostic factors for metastatic relapse and death change as patient survival time increases in both young and elderly patients. Grade, the strongest prognostic factor for metastatic relapse and death at baseline, is no longer predictive of metastatic relapse in patients surviving 5 years after initial diagnosis. Leiomyosarcoma is the histological subtype associated with the highest risk of metastatic relapse and death in young patients surviving 5 years after initial diagnosis. The positive impact on the outcome of peri‐operative treatments tends to decrease and disappears in patients surviving 5 years after initial diagnosis.Conclusion.Conditional survival estimates show clinically relevant variations according to time since first diagnosis in both young and elderly patients with STS. These results can help STS survivors adjust their view of the future and STS care providers plan patient follow‐up.Implications for Practice.For patients with sarcoma who are followed up years after being treated for their disease, a common scenario is for the patient and caregivers to ask practitioners what the longer‐term prognosis may be. The question posed to practitioners may be, “Doc, am I now cured? It's been 5 years since we finished treatment.” Survival probability changes for patients who survive a given period of time after diagnosis, and their prognosis is more accurately described using conditional survival. By analyzing more than 6,000 sarcoma patients, an overall improvement was found in the risk of relapse as patients conditionally survive. Prognostic factors for metastatic relapse and death change as patient survival time increases in both young and elderly patients.
Balancing the Hype with Reality: What Do Patients with Advanced Melanoma Consider When Making the Decision to Have Immunotherapy?
AbstractBackground.Immunotherapy has resulted in unprecedented improvements in survival and maintained quality of life for many patients with advanced melanoma. However, durable responses are observed in only a minority of patients, and severe treatment side effects are experienced by 5%–30%. There are no reliable tests that can differentiate between patients who are likely to respond to immunotherapy and those who will not. Hence, new challenges have arisen as clinicians try to facilitate patients in their decision‐making regarding immunotherapy. Furthermore, little is known about the real‐world patients’ experience and understanding of immunotherapy outside the clinical trial setting. Here, we explore the perspectives of patients undergoing immunotherapy for melanoma and focus on factors that influenced their treatment decision‐making.Materials and Methods.Twenty‐three in‐depth semistructured interviews were conducted with patients receiving pembrolizumab for stage IV melanoma at an Australian public cancer hospital. Patients were recruited at a range of time points after commencing therapy, and their experience of treatment was explored. Interviews were audio recorded, transcribed verbatim, coded, and analyzed thematically.Results.Immunotherapy is viewed as a symbol of hope, with high‐profile anecdotes reinforcing this perception. Only a minority of patients expressed a good understanding of the likely efficacy and potential treatment side effects. Patients are reliant on their clinicians’ recommendation regarding immunotherapy treatment decisions.Conclusion.Novel treatments such as immunotherapy provide significant hope for patients. This may influence their preference for immunotherapy over and above the usual considerations of the trade‐off between efficacy and toxicity. Careful counsel and individualized patient resources may further facilitate treatment decision‐making.Implications for Practice.This study highlighted some of the misconceptions held by patients that need to be addressed when discussing the possibility of receiving treatment with immunotherapy for advanced melanoma. Patients placed a lot of importance on high‐profile anecdotes rather than truly understanding likely outcomes of treatment based on personal circumstances. The majority of patients had a poor understanding of the potential side effects and long‐term implications of treatment with immunotherapy. Careful counsel is required in order to facilitate informed decision‐making about treatment and to ensure possible side effects are known and appreciated. Further research is needed to develop tools to aid decision‐making in everyday clinical practice.
AbstractBackground.Although recent pivotal trials (PROMID, CLARINET) have established somatostatin analogs (SSAs) as first‐line agents for neuroendocrine tumors (NETs), their use in clinical practice is largely unknown. We aimed to understand real‐world management and treatment of gastroenteropancreatic (GEP) NETs.Materials and Methods.Patients with metastatic GEP‐NETs treated with SSAs, lanreotide depot or octreotide long‐acting release (LAR), between January 1, 2015, and December 31, 2015, were identified from a U.S. claims database supplemented with chart review for a subset of patients. Descriptive statistics summarized patients’ demographics, clinical characteristics, treatment patterns, and healthcare resource use. Univariate and multivariate comparisons were made across SSA groups.Results.Among 548 patients treated with an SSA for metastatic GEP‐NET (lanreotide = 108; octreotide = 440), demographic and clinical characteristics were similar across groups, except more patients with pancreatic NETs were treated with lanreotide (38.7% vs. 6.3%, p < .01). More octreotide patients had a diagnosis of carcinoid syndrome compared with lanreotide patients (19.8% vs. 11.1%, p = .02). Approximately 1.1% of patients received lanreotide (>120 mg every 4 weeks [Q4W]) at a dose above label compared with 12.7% of octreotide patients (>30 mg Q4W; p < .01). At 1.5 years after SSA initiation, 85.7% (95% confidence interval, 74.3%–92.3%) were still on index SSA as reported by the physician. Variances between chart review and claims data were significant.Conclusion.SSAs were common in first‐line systemic intervention, but dose escalations and dosing deviations outside of label were noted. Variances between claims and chart review warrant additional research to compare methodologies. With an increasing focus on value‐based care in oncology, it is critical to understand the use of, and outcomes with, these agents in community practices.Implications for Practice.The aim of this study was to enhance understanding of real‐world management and treatment of metastatic neuroendocrine tumors (NETs), with particular focus on systemic therapy with a somatostatin analog (SSA). As per published guidelines, SSAs are common in first‐line systemic intervention, but dose escalations and dosing deviations outside of the label are noted for symptom control. Nevertheless, oncologists must weigh the implications of the use of above‐label dosing of SSAs to manage and treat patients with metastatic NET within a value‐based care framework.
Peripheral Blood Markers Identify Risk of Immune‐Related Toxicity in Advanced Non‐Small Cell Lung Cancer Treated with Immune‐Checkpoint Inhibitors
AbstractBackground.Immune‐checkpoint inhibitors (ICIs) are now standard of care for advanced non‐small cell lung cancer (NSCLC). Unfortunately, many patients experience immune‐related adverse events (irAEs), which are usually mild and reversible, but they require timely management and may be life threatening. No predictive markers of irAEs are available.Materials and Methods.The neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) were evaluated in patients with NSCLC consecutively treated with ICIs. Prespecified cutoff values of NLR and PLR were used and related to outcome and onset of irAEs. A control group of patients with advanced NSCLC not receiving ICIs was included.Results.The study included 184 patients: 26 (14.1%) received pembrolizumab upfront, and 142 (77%) received ICIs (pembrolizumab, nivolumab or atezolizumab) after one or more lines of chemotherapy. The median number of ICIs cycles was six (range, 1–61). The median progression‐free survival and overall survival were 4.8 (95% CI, 3.4–6.3) and 20.6 (95% CI, 14.7–26.5) months, respectively. Sixty patients (32.6%) developed irAEs, mainly grade 1–2 (65.0%), causing ICI interruption in 46 cases (25.0%). Low NLR and low PLR at baseline were significantly associated with the development of irAEs (odds ratio [OR], 2.2; p = .018 and OR, 2.8; p = .003, respectively). Multivariate analyses confirmed PLR as independent predictive marker of irAEs (OR, 2.3; p = .020).Conclusion.NLR and PLR may predict the appearance of irAEs in non‐oncogene‐addicted aNSCLC, although this conclusion warrants prospective validation.Implications for Practice.This study was designed to investigate the role of blood biomarkers in predicting the occurrence of immune‐related adverse events (irAEs) in patients with advanced non‐small cell lung cancer receiving immunotherapy. The results of the study suggest a potential predictive role of neutrophil‐to‐lymphocyte ratio and platelet‐to‐lymphocyte ratio as markers for irAE development in this category of patients. These data provide rationale for an easy and feasible application to be validated in clinical practice.
AbstractLessons Learned. Single‐agent selinexor has limited activity in heavily pretreated patients with metastatic triple‐negative breast cancer.Selinexor 60 mg by mouth twice weekly was generally well tolerated with a side‐effect profile consistent with previous clinical trials.Future studies of selinexor in this population should focus on combination approaches and a biomarker‐driven strategy to identify patients most likely to benefit.Background.This phase II trial evaluated the safety, pharmacodynamics, and efficacy of selinexor (KPT‐330), an oral selective inhibitor of nuclear export (SINE) in patients with advanced triple‐negative breast cancer (TNBC).Methods.This phase II trial was designed to enroll 30 patients with metastatic TNBC. Selinexor was given at 60 mg orally twice weekly on days 1 and 3 of each week, three of each 4‐week cycle. The primary objective of this study was to determine the clinical benefit rate (CBR), defined as complete response + partial response + stable disease (SD) ≥12 weeks.Results.Ten patients with a median age of 60 years (range 44–71 years) were enrolled between July 2015 and January 2016. The median number of prior chemotherapy lines was 2 (range 1–5). A planned interim analysis for the first stage per protocol was performed. Three patients had SD and seven had progressive disease. On the basis of these results and predefined stoppage rules, the study was halted.Conclusion.Selinexor was fairly well tolerated in patients with advanced TNBC but did not result in objective responses. However, clinical benefit rate was 30%, and further investigation of selinexor in this patient population should focus on combination therapies.
AbstractBackground.The objective of this study was to characterize the clinicopathologic features of sicca syndrome associated with immune checkpoint inhibitor (ICI) therapy.Subjects, Materials, and Methods.Consecutive patients with new or worsening xerostomia in the setting of ICI treatment for benign or malignant neoplastic disease were evaluated, including labial salivary gland biopsy (LSGB).Results.Twenty patients (14 male; median age 57 years) had metastatic melanoma (n = 10), metastatic carcinoma (n = 6), or recurrent respiratory papillomatosis (n = 4) and were being treated with avelumab (n = 8), nivolumab (n = 5), pembrolizumab (n = 4), nivolumab/ipilimumab (n = 2), and M7824, a biologic targeting programmed cell death ligand 1 (PD‐L1) and transforming growth factor ß (n = 1). Four had pre‐existing autoimmune disease. Nineteen had very low whole unstimulated saliva flow; six had new dry eye symptoms. The median interval between ICI initiation and dry mouth onset was 70 days. Rheumatoid factor and anti‐Sjögren's Syndrome‐related Antigen A (Anti‐SSA) were both positive in two subjects. LSGB showed mild‐to‐severe sialadenitis with diffuse lymphocytic infiltration and architectural distortion. There were lymphocytic aggregates in eight patients, composed mainly of CD3+ T cells with a slight predominance of CD4+ over CD8+ T cells. ICI targets (e.g., programmed cell death 1 and PD‐L1) were variably positive. In direct response to the advent of the sicca immune‐related adverse event, the ICI was held in 12 patients and corticosteroids were initiated in 10. Subjective improvement in symptoms was achieved in the majority; however, salivary secretion remained very low.Conclusion.ICI therapy is associated with an autoimmune‐induced sicca syndrome distinct from Sjögren's syndrome, often abrupt in onset, usually developing within the first 3 months of treatment, and associated with sialadenitis and glandular injury. Improvement can be achieved with a graded approach depending on severity, including withholding the ICI and initiating corticosteroids. However, profound salivary flow deficits may be long term.Implications for Practice.Sicca syndrome has been reported as an immune‐related adverse event (irAE) of immune checkpoint inhibitor therapy (ICI) for neoplastic diseases. Severe dry mouth (interfering with eating or sleeping) developed abruptly, typically within 90 days, after initiation of ICI therapy. Salivary gland biopsies demonstrated mild‐to‐severe sialadenitis distinct from Sjögren's syndrome, with diffuse T‐cell lymphocytic infiltration and acinar injury. Recognition of the cardinal features of ICI‐induced sicca will spur appropriate clinical evaluation and management, including withholding of the ICI and corticosteroid, initiation. This characterization should help oncologists, rheumatologists, and oral medicine specialists better identify patients that develop ICI‐induced sicca to initiate appropriate clinical evaluation and therapy to reduce the likelihood of permanent salivary gland dysfunction.
Toward an Expert Level of Lung Cancer Detection and Classification Using a Deep Convolutional Neural Network
AbstractBackground.Computed tomography (CT) is essential for pulmonary nodule detection in diagnosing lung cancer. As deep learning algorithms have recently been regarded as a promising technique in medical fields, we attempt to integrate a well‐trained deep learning algorithm to detect and classify pulmonary nodules derived from clinical CT images.Materials and Methods.Open‐source data sets and multicenter data sets have been used in this study. A three‐dimensional convolutional neural network (CNN) was designed to detect pulmonary nodules and classify them into malignant or benign diseases based on pathologically and laboratory proven results.Results.The sensitivity and specificity of this well‐trained model were found to be 84.4% (95% confidence interval [CI], 80.5%–88.3%) and 83.0% (95% CI, 79.5%–86.5%), respectively. Subgroup analysis of smaller nodules (<10 mm) have demonstrated remarkable sensitivity and specificity, similar to that of larger nodules (10–30 mm). Additional model validation was implemented by comparing manual assessments done by different ranks of doctors with those performed by three‐dimensional CNN. The results show that the performance of the CNN model was superior to manual assessment.Conclusion.Under the companion diagnostics, the three‐dimensional CNN with a deep learning algorithm may assist radiologists in the future by providing accurate and timely information for diagnosing pulmonary nodules in regular clinical practices.Implications for Practice.The three‐dimensional convolutional neural network described in this article demonstrated both high sensitivity and high specificity in classifying pulmonary nodules regardless of diameters as well as superiority compared with manual assessment. Although it still warrants further improvement and validation in larger screening cohorts, its clinical application could definitely facilitate and assist doctors in clinical practice.
A Phase II Trial of Concurrent Temozolomide and Hypofractionated Stereotactic Radiotherapy for Complex Brain Metastases
AbstractPurpose.Complex brain metastases (BMs), such as large lesions, lesions within or close to eloquent locations, or multiple recurrent/progressive BMs, remain the most challenging forms of brain cancer because of decreased intracranial control rates and poor survival. In the present study, we report the results from a single institutional phase II trial of concurrent temozolomide (TMZ) with hypofractionated stereotactic radiotherapy (HFSRT) in patients with complex brain metastases, including assessment of its feasibility and toxicity.Patients and Methods.Fifty‐four patients with histologically proven primary cancer and complex BMs were enrolled between 2010 and 2015. All the patients were treated with concurrent HFSRT and TMZ (administrated orally at a dosage of 75 mg/m2 per day for at least 20 days). The primary endpoint was overall survival (OS).Results.The median follow‐up time was 30.6 months. The local control rates at 1 and 2 years were 96% and 82%, respectively. The median OS was 17.4 months (95% confidence interval [CI], 12.6–22.2), and the OS rates at 1 and 2 years were 65% (95% CI, 52%–78%) and 33% (19%–47%). Only six patients (15.8%) died of intracranial disease. The median brain metastasis‐specific survival was 46.9 months (95% CI, 35.5–58.4). Treatment‐related grade 3–4 adverse events were rare and included one grade 3 hematological toxicity and two grade 3 liver dysfunctions.Conclusion.Treatment using HFSRT concurrent with TMZ was well tolerated and could significantly extend OS compared with historical controls in complex BMs. Large randomized clinical trials are warranted. Trial registration ID: NCT02654106.Implications for Practice.The treatment using hypofractionated stereotactic radiotherapy concurrent with temozolomide appeared to be safe and could significantly extend overall survival compared with historical control in complex brain metastases. Large randomized clinical trials are warranted to verify our results.
Italian Cohort of Nivolumab Expanded Access Program in Squamous Non‐Small Cell Lung Cancer: Results from a Real‐World Population
AbstractBackground.Nivolumab has shown a survival benefit compared with docetaxel as second‐line treatment for patients with previously treated advanced squamous non‐small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program.Patients and methods.Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information.Results.The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2–9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any‐grade and grade 3–4 adverse events was 29% and 6%, respectively. Treatment‐related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment‐related deaths.Conclusion.To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real‐world setting are consistent with those obtained in clinical trials.Implications for Practice.Nivolumab is approved in the U.S. and Europe for the treatment of advanced non‐small cell lung cancer (NSCLC) after failure of prior platinum‐based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real‐world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.
Addressing the Financial Burden of Cancer Clinical Trial Participation: Longitudinal Effects of an Equity Intervention
AbstractBackground.The financial burden experienced by patients with cancer represents a barrier to clinical trial participation, and interventions targeting patients’ financial concerns are needed. We sought to assess the impact of an equity intervention on clinical trial patients’ financial burden.Materials and Methods.We developed an equity intervention to reimburse nonclinical expenses related to trials (e.g., travel and lodging). From July 2015 to July 2017, we surveyed intervention and comparison patients matched by age, sex, cancer type, specific trial, and trial phase. We longitudinally assessed financial burden (e.g., trial‐related travel and lodging cost concerns, financial wellbeing [FWB] with the COmprehensive Score for financial Toxicity [COST] measure) at baseline, day 45, and day 90. We used longitudinal models to assess intervention effects over time.Results.Among 260 participants, intervention patients were more likely than comparison patients to have incomes under $60,000 (52% vs. 24%, p < .001) and to report travel‐related (41.0% vs. 6.8%, p < 0.001) and lodging‐related (32.5% vs. 2.0%, p < .001) cost concerns at baseline. Intervention patients were more likely to report travel to appointments as their most significant financial concern (24.0% vs. 7.0%, p = .001), and they had worse FWB than comparison patients (COST score: 15.32 vs. 23.88, p < .001). Over time, intervention patients experienced greater improvements in their travel‐related (−10.0% vs. +1.2%, p = .010) and lodging‐related (−3.9% vs. +4.0%, p = .003) cost concerns. Improvements in patients reporting travel to appointments as their most significant financial concern and COST scores were not statistically significant.Conclusion.Cancer clinical trial participants may experience substantial financial issues, and this equity intervention demonstrates encouraging results for addressing these patients’ longitudinal financial burden.Implications for Practice.Clinical trials are critical for developing novel therapies for patients with cancer, yet financial barriers may discourage some patients from participating in cancer clinical trials. This study found that patients who received financial assistance from an equity intervention experienced significant improvements over time in their concerns about the cost of travel and lodging associated with clinical trials compared with comparison patients who did not receive financial assistance from the equity intervention. Among cancer clinical trial participants, an equity intervention shows potential for addressing patients' concerns regarding clinical trial‐related travel and lodging expenses.
Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild‐Type Non‐Small Cell Lung Cancer
AbstractBackground.Seribantumab (MM‐121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)‐mediated ErbB3 signaling and induce receptor downregulation. This open‐label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non‐small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild‐type tumors and describe the potential predictive power of HRG.Materials and Methods.Patients with EGFR wild‐type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses.Results.One hundred twenty‐nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression‐free survival (PFS) in the unselected intent‐to‐treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p = .059, HRG‐by‐treatment interaction, p value = .0016).Conclusion.The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216).Implications for Practice.The poor prognosis of patients with non‐small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open‐label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin‐positive advanced adenocarcinoma.
“How Long Have I Got?”—A Prospective Cohort Study Comparing Validated Prognostic Factors for Use in Patients with Advanced Cancer
AbstractBackground.The optimal prognostic factors in patients with advanced cancer are not known, as a comparison of these is lacking. The aim of the present study was to determine the optimal prognostic factors by comparing validated factors.Materials and Methods.A multicenter, prospective observational cohort study recruited patients over 18 years with advanced cancer. The following were assessed: clinician‐predicted survival (CPS), Eastern Cooperative Oncology Group performance status (ECOG‐PS), patient reported outcome measures (anorexia, cognitive impairment, dyspnea, global health), metastatic disease, weight loss, modified Glasgow Prognostic Score (mGPS) based on C‐reactive protein and albumin, lactate dehydrogenase (LDH), and white (WCC), neutrophil (NC), and lymphocyte cell counts. Survival at 1 and 3 months was assessed using area under the receiver operating curve and logistic regression analysis.Results.Data were available on 478 patients, and the median survival was 4.27 (1.86–7.03) months. On univariate analysis, the following factors predicted death at 1 and 3 months: CPS, ECOG‐PS, mGPS, WCC, NC (all p < .001), dyspnea, global health (both p ≤ .001), cognitive impairment, anorexia, LDH (all p < .01), and weight loss (p < .05). On multivariate analysis ECOG‐PS, mGPS, and NC were independent predictors of survival at 1 and 3 months (all p < .01).Conclusion.The simple combination of ECOG‐PS and mGPS is an important novel prognostic framework which can alert clinicians to patients with good performance status who are at increased risk of having a higher symptom burden and dying at 3 months. From the recent literature it is likely that this framework will also be useful in referral for early palliative care with 6–24 months survival.Implications for Practice.This large cohort study examined all validated prognostic factors in a head‐to‐head comparison and demonstrated the superior prognostic value of the Eastern Cooperative Oncology Group performance status (ECOG‐PS)/modified Glasgow Prognostic Score (mGPS) combination over other prognostic factors. This combination is simple, accurate, and also relates to quality of life. It may be useful in identifying patients who may benefit from early referral to palliative care. It is proposed ECOG‐PS/mGPS as the new prognostic domain in patients with advanced cancer.
AbstractBackground.Less than 3% of older patients with cancer are enrolled in clinical trials. To reverse this underrepresentation, we compared older patients enrolled with older‐patient‐specific trials, defined as those designed for older patients with cancer, with those enrolled in age‐unspecified trials.Materials and Methods.We focused on individual patient data from those ≥65 years (younger patients excluded) and included all Alliance phase III adjuvant breast cancer trials from 1985–2012.Results.Among 2,277 patients, 1,014 had been enrolled to older‐patient‐specific and 1,263 to age‐unspecified trials. The median age (range) in the older‐patient‐specific trials was 72 (65–89) years compared with 68 (65–84) years in the cohort of older patients in age‐unspecified trials; p < .0001. A greater percentage of patients 75 years or older had enrolled in older‐patient‐specific trials compared with the cohort of age‐unspecified trials: 26% versus 6% (p < .0001). Median overall survival (OS) was 12.8 years (95% confidence interval [CI], 11.9–13.7) and 13.5 years (95% CI, 12.9–14.1) for older‐patient‐specific and age‐unspecified trials, respectively. OS was comparable (hazard ratio [HR], 1.08; 95% CI, 0.92–1.28; p = .34; referent: age‐unspecified trials), after adjusting for age, estrogen receptor status, tumor size, and lymph node status. Similar findings were reached for recurrence‐free survival. A lower rate of grade 3–5 adverse events (hematologic and nonhematologic) was reported in older‐patient‐specific trials (43% vs. 58%; p < .0001). Sensitivity analysis with chemotherapy only trials and subset analysis, adjusted for performance score, yielded similar OS results.Conclusion.Older‐patient‐specific trials appear to address this underrepresentation of older patients with ostensibly comparable outcomes. Clinical trial identification numbers. NCT00003088 (CALGB 9741); NCT00024102 (CALGB 49907); NCT00068601 (CALGB 40401); NCT00005970 (NCCTG N9831)Implications for Practice.This work underscores the importance of clinical trials that focus on the recruitment of older patients with cancer.
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