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.
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.
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.
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.
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.
AbstractTyrosine kinase inhibitors (TKIs) can cause cardiotoxicity, and some suggest routine monitoring of cardiac function during TKI use. We describe two cases of TKI‐induced heart failure (HF) that suggest the utility of monitoring with laboratory tests is questionable. One patient developed HF 5 days after starting pazopanib. The other developed HF while receiving 25 mg per day sunitinib, and had previously received a higher dose (50 mg per day) with no symptoms of cardiotoxicy. In addition, she later received 5 cycles of sunitinib (25 mg per day) without developing an abnormal left ventricular ejection fraction (LVEF) value by echocardiography or cardiac symptoms. Although the LVEF is commonly performed to monitor TKI cardiotoxicity, evidence for its predictive utility is limited. These cases raise questions regarding the practical utility of sequential measurement of LVEF in adults treated with TKIs. We suggest a simple daily activity such as stair climbing to monitor exercise tolerance.
AbstractBackground.Enhancing the effectiveness of docetaxel for men with metastatic castration‐resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high‐dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts.Materials and Methods.Men with chemotherapy‐naive mCRPC with a prostate‐specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m2) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two‐stage design.Results.Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58–81) were treated (median, 6 cycles; range, 2–11). Men had received prior systemic therapies (median, 1; range, 0–3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow‐up of 17 months, 18 (86%) men were deceased (15 castration‐resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3–19.6) and median PFS was 5.3 months (95% CI, 2.6–12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel.Conclusion.The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing.Implications for Practice.To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration‐resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.
AbstractMerkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun‐exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%–46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group.Implications for Practice.Merkel cell carcinoma (MCC) is an uncommon aggressive skin cancer associated with advanced age, UV light exposure, and immunosuppression. Up to 80% are associated with Merkel cell polyomavirus. MCC is a chemosensitive disease, but tumor responses in the advanced setting are short‐lived with no long‐term survivors. Recent clinical trials with immune checkpoint inhibitors (i.e., pembrolizumab, avelumab, nivolumab) have shown promising results, with avelumab becoming the first drug to receive regulatory approval for this orphan indication. Further follow‐up is needed, however, to define more adequately the long‐term benefits of these drugs, and continued research is warranted to optimize immunotherapeutic strategies in this setting.
AbstractBackground.Clinical behavior of non‐muscle‐invasive bladder cancer (NMIBC) is largely unpredictable, and even patients treated according to European Association of Urology recommendations have a heterogeneous prognosis. High‐grade T1 (HGT1) bladder cancer is the highest‐risk subtype of NMIBC, with an almost 40% rate of recurrence and 20% of progression at 5 years. Nomograms predicting risk of recurrence, progression, and cancer‐specific survival (CSS) are not available specifically within HGT1 bladder cancer, and the identification of robust prognostic biomarkers to better guide therapeutic strategies in this subgroup of patients is of paramount importance. Strategies to identify putative biomarkers in liquid biopsies from blood and urine collected from patients with bladder cancer have been intensively studied in the last few years.Subjects, Materials, and Methods.We here report the final analysis of a single‐center prospective study aimed to investigate the impact of circulating tumor cells (CTCs) on CSS and overall survival (OS) in 102 patients with HGT1 bladder cancer, in a median follow‐up of 63 months.Results.We here demonstrate that the presence of even a single CTC is predictive of shorter CSS and OS, as compared with the standard predictive variables. Points of attention in this multivariable analysis are the long‐term follow‐up and the adequate number of outcome events.Conclusion.The accurate risk stratification provided by CTCs might be essential for determining the best surveillance strategy for patients after diagnosis. A closer follow‐up, an early radical surgery, or even a systemic treatment might be recommended in patients with super‐high‐risk non‐muscle‐invasive bladder cancer.Implications for Practice.Circulating tumor cells identify patients with super‐high‐risk non‐muscle‐invasive bladder cancer who require closer monitoring for local recurrence and/or progression of disease. This super‐high‐risk subgroup of patients might also require more aggressive treatment interventions, which should be evaluated in large prospective cohorts.
AbstractPurpose.This study aimed to develop a prognostic nomogram in diffuse large B‐cell lymphoma (DLBCL) and compare it with traditional prognostic systems.Materials and methods.We included 1,070 consecutive and nonselected patients with DLBCL in the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, between 2006 and 2012. A nomogram based on the Cox proportional hazards model was developed.Results.The entire group were divided into the primary (n = 748) and validation (n = 322) cohorts. The 5‐year overall survival (OS) rate was 64.1% for the entire group. Based on a multivariate analysis of the primary cohort, seven independent prognostic factors including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status score, lactate dehydrogenase, β2‐microglobulin, CD5 expression, and Ki‐67 index were identified and entered the nomogram. The calibration curve showed the optimal agreement between nomogram prediction and actual observation. In addition, the concordance index (C‐index) of the nomogram for OS prediction was 0.77 (95% confidence interval [CI], 0.73–0.81) in the primary cohort and 0.76 (95% CI, 0.70–0.81) in the validation, superior to that of the international prognostic index (IPI), revised IPI (R‐IPI), and National Comprehensive Cancer Network (NCCN)‐IPI (range, 0.69–0.74, p<.0001). Moreover, in patients receiving rituximab plus CHOP (R‐CHOP) or R‐CHOP‐like regimens, compared with IPI (C‐index, 0.73; 95% CI, 0.69–0.77), R‐IPI (C‐index, 0.70; 95% CI, 0.66–0.74), or NCCN‐IPI (C‐index, 0.71; 95% CI, 0.66–0.75), the DLBCL‐specific nomogram showed a better discrimination capability (p < .0001).Conclusions.The proposed nomogram provided an accurate estimate of survival of patients with DLBCL, especially for those receiving R‐CHOP or R‐CHOP‐like regimens, allowing clinicians to optimized treatment plan based on individualized risk prediction.Implications for Practice.A diffuse large B‐cell lymphoma (DLBCL)‐specific prognostic nomogram was developed based on Chinese patients with DLBCL. As a tertiary hospital, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences is the number 1 ranked cancer center in China, with more than 800,000 outpatients in 2018. Patients included in this study were nonselected and came from 29 different provinces, municipalities, and autonomous regions in China. Thus, the data is believed to be representative to an extent.
AbstractBackground.Inflammatory breast cancer (IBC) is a rare yet aggressive variant of breast cancer with a high recurrence rate. We hypothesized that patterns of metastasis differ between IBC and non‐IBC. We focused on the patterns of bone metastasis throughout disease progression to determine statistical differences that can lead to clinically relevant outcomes. Our primary outcome of this study is to quantify and describe this difference with a view to applying the findings to clinically relevant outcomes for patients.Subjects, Materials, and Methods.We retrospectively collected data of patients with nonmetastatic IBC (n = 299) and non‐IBC (n = 3,436). Probabilities of future site‐specific metastases were calculated. Spread patterns were visualized to quantify the most probable metastatic pathways of progression and to categorize spread pattern based on their propensity to subsequent dissemination of cancer.Results.In patients with IBC, the probabilities of developing bone metastasis after chest wall, lung, or liver metastasis as the first site of progression were high: 28%, 21%, and 21%, respectively. For patients with non‐IBC, the probability of developing bone metastasis was fairly consistent regardless of initial metastasis site.Conclusion.Metastatic patterns of spread differ between patients with IBC and non‐IBC. Selection of patients with IBC with known liver, chest wall, and/or lung metastasis would create a population in whom to investigate effective methods for preventing future bone metastasis.Implications for Practice.This study demonstrated that the patterns of metastasis leading to and following bone metastasis differ significantly between patients with inflammatory breast cancer (IBC) and those with non‐IBC. Patients with IBC had a progression pattern that tended toward the development of bone metastasis if they had previously developed metastases in the liver, chest wall, and lung, rather than in other sites. Selection of patients with IBC with known liver, chest wall, and/or lung metastasis would create a population in whom to investigate effective methods for preventing future bone metastasis.
AbstractBackground.T‐lymphoblastic lymphoma (T‐LBL) is a highly aggressive neoplasm of lymphoblasts of T‐cell origin. Although promising improvements have been recently achieved, one third of patients experience relapse or refractory T‐LBL. Therefore, optimal strategies for identifying high‐risk patients are urgently needed.Materials and Methods.In the present study, 75 newly diagnosed adult patients (aged ≥15 years) with T‐LBL were identified and the predictive value of complete blood count (CBC) abnormalities, including lymphocyte‐monocyte ratio (LMR), neutrophil‐lymphocyte ratio (NLR), and platelet‐lymphocyte ratio (PLR) on clinical outcomes, was analyzed.Results.Using the receiver operating characteristic curve to determine the best cutoff values based on survival, it was found that patients with T‐LBL with LMR ≤2.8, NLR ≥3.3, and PLR ≥200 had both inferior progression‐free survival (PFS) and inferior overall survival (OS), in which the differences were much more remarkable in the international prognostic index score 0–2 subgroup. In the multivariable analysis, NLR ≥3.3 together with age >40 years and central nervous system (CNS) involvement were identified to be independently associated with shortened PFS, whereas PLR ≥200 and CNS involvement were identified to be independent risk factors for OS. LMR, NLR, and PLR were integrated to generate a “CBC score” model, which well separated adult patients with T‐LBL into three risk groups, and the 3‐year OS was 84%, 53%, and 30% for low‐, intermediate‐, and high‐risk patients, respectively.Conclusion.Overall, a “CBC score” model was initially promoted for stratification in adult patients with T‐LBL using simple, widely available, and easy to interpret parameters in the largest adult T‐LBL cohort to date.Implications for Practice.Optimal strategies for identifying high‐risk patients with T‐lymphoblastic lymphoma (T‐LBL) are urgently needed. In the largest adult T‐LBL cohort to date, simple, inexpensive, widely available parameters were applied and revealed that patients with lymphocyte‐monocyte ratio (LMR) ≤2.8, neutrophil‐lymphocyte ratio (NLR) ≥3.3, and platelet‐lymphocyte ratio (PLR) ≥200 had both inferior progression‐free survival and inferior overall survival (OS), in which the differences were much more remarkable in the international prognostic index score 0–2 subgroup. LMR, NLR, and PLR were integrated to generate a “complete blood count score” model, in which the 3‐year OS was 84%, 53%, and 30% for low‐, intermediate‐, and high‐risk patients, respectively.
AbstractBackground.HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti‐epidermal growth factor receptor (EGFR) treatment.Subjects and Methods.Patients with KRAS exon 2 wild‐type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2‐negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti‐EGFR treatment.Results.From August 2012 to April 2018, a total of 100 HER2‐positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild‐type screened patients (6.7%). HER2‐positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15–3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10–2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22–1.11; p = .088). HER2‐positive patients who received treatment with anti‐EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression‐free survival, 5.7 months vs. 7 months, p = .087).Conclusion.Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2‐amplified metastatic CRC are less likely to respond to anti‐EGFR therapy.Implications for Practice.Patients with HER2‐amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti‐epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression‐free survival in response to previous anti‐EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2‐targeted double blockade independently of previous anti‐EGFR treatment.
AbstractBackground.In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health‐related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses.Materials and Methods.In a prospective observational cohort study (2014–2016), outpatients with stage IV lung cancer completed demographic and EQ‐5D‐3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT‐brain (FACT‐Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses).Results.Of 519 patients with 1,686 EQ‐5D‐3L‐derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT‐Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK‐rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT‐Br and tests of NCF.Conclusion.Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene‐addicted tumors have superior HUS.Implications for Practice.In the setting of EGFR mutations or ALK rearrangement non‐small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ‐5D questionnaire is associated with measures of health‐related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.
AbstractObjective.Polypharmacy has been associated with morbidity and mortality in patients with cancer. Data about polypharmacy among patients with ovarian cancer are limited. The primary objective of this study was to evaluate polypharmacy in a cohort of patients with ovarian cancer and to assess the evolution of polypharmacy from initial presentation to 2 years posttreatment. A secondary objective was to evaluate differences in polypharmacy between a subset of patients primarily treated in our comprehensive cancer center (CCC) and our safety net hospital (SNH).Methods.Women treated for ovarian cancer between January 1, 2011, and December 31, 2016, were included. Data were abstracted from the electronic medical record. Medication safety was assessed using the established Anticholinergic Burden (ACB) scale and the Beers criteria. Statistical analyses were performed using paired t tests and Cox proportional hazards models, with significance set at p < .05.Results.The study included 152 patients. The majority of patients had high‐grade serous carcinoma. Hypertension was the most common medical problem. The mean number of medications at the time of diagnosis was 3.72. Paired testing demonstrated significant patient‐level increases in the number medications at 2 years following initial diagnosis (4.16 vs. 7.01, p < .001). At the CCC, 47.4% of patients met criteria for polypharmacy at diagnosis compared with 19.4% at the SNH (p < .001). By 2 years postdiagnosis, 77.6% of patients at the CCC met criteria for polypharmacy compared with 43.3% at the SNH (p = .001). The use of any medications on the ACB scale (p < .001) increased significantly between initial diagnosis and 2 years for the entire population. Polypharmacy was not a significant predictor of overall survival.Conclusion.Polypharmacy worsens as women go through ovarian cancer treatment. Both at initial presentation and at 2 years postdiagnosis, rates of polypharmacy were higher at the CCC. Polypharmacy did not have an effect on survival in this cohort.Implications for Practice.Awareness of escalating numbers of medications and potentially adverse interactions is crucial among women with ovarian cancer, who are at high risk for polypharmacy.
AbstractBackground.Real‐world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real‐world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).Subjects, Materials, and Methods.Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health‐related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical‐trial‐eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non‐clinical‐trial‐eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups.Results.Six hundred fifty‐seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment‐related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups.Conclusion.PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real‐world clinical setting.Implications for Practice.PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real‐world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first‐line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months.
AbstractBackground.The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Multiple clinical trials have demonstrated that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment‐free remission. TKI discontinuation is now offered to select patients in routine clinical care. In order to better support patient decision making, we explored patients’ views on TKI discontinuation and the factors patients consider when making this decision.Materials and Methods.Patients were recruited from three U.S. academic cancer centers. Qualitative interviews were recorded, transcribed, and content analyzed.Results.We interviewed 22 patients, half of whom wanted to try TKI discontinuation. Eleven factors relevant to the decision emerged, and patients weighed these factors differently. Commonly mentioned factors included perceived risk of relapse, TKI side effects, financial considerations, polypharmacy, and willingness to change something that was working (status quo). There were notable differences in patients’ understanding of the likelihood of achieving a treatment‐free remission, with patients who did not want to stop TKIs more accurately reporting the risk of relapse than patients who wanted to stop.Conclusion.This is a novel decision that will become more common as the prevalence of patients with well‐controlled CML continues to increase. These results highlight the need for patient education and decision support so that patients and providers can make shared decisions that are informed and values based.Implications for Practice.The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Clinical trials have shown that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment‐free remission. TKI discontinuation is now being offered to patients outside of clinical trials. This study explored factors that patients who are eligible to try TKI discontinuation considered when making this decision. Factors relevant to the decision included risk of relapse, side effects, financial considerations, polypharmacy, and willingness to change something that was working. This is a novel decision that will become more common as the prevalence of patients with well‐controlled CML continues to increase. These results highlight the need for decision support and outline the factors that should be included so that patients and providers can make shared decisions that are informed and values based.
AbstractSeveral immune checkpoint inhibitor therapies (CPIs) have been approved to treat metastatic urothelial cell carcinoma (mUC). Because of the favorable toxicity profile of CPI compared with chemotherapy, oncologists may have a low threshold to prescribe CPI to patients near the end of life. We evaluated trends in initiation of end‐of‐life systemic therapy in 1,637 individuals in the Flatiron Health Database who were diagnosed with mUC between 2015 and 2017 and who died. Rates of systemic therapy initiation in the last 30 and 60 days of life were 17.0% and 29.8%, respectively. The quarterly proportion of patients who initiated CPI within 60 days of death increased from 1.0% to 23% during the study period (ptrend < .001). After CPI approval, end‐of‐life CPI initiation significantly increased among patients with poor performance status (ptrend = .020) and did not significantly change among individuals with good performance status. The quarterly proportion of patients who initiated any systemic therapy at the end of life doubled (17.4% to 34.8%) during the study period, largely explained by increased CPI use. These findings suggest a dramatic rise in CPI use at the end of life in patients with mUC, a finding that may have important guideline and policy implications.
AbstractLorlatinib is a novel, highly potent, brain‐penetrant, third‐generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad‐spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second‐generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100 mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid‐lowering agent. Prescription of supportive therapy should also consider the potential for drug‐drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100 mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK‐positive metastatic non‐small cell lung cancer previously treated with a second‐generation ALK TKI.Implications for Practice.Despite the advancement of second‐generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK‐positive non‐small cell lung cancer. Lorlatinib is a potent, brain‐penetrant, third‐generation, macrocyclic ALK/ROS1 TKI, with broad‐spectrum potency against most known resistance mutations that can develop during treatment with existing first‐ and second‐generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
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