AbstractLessons Learned.Perioperative capecitabine and oxaliplatin (CapeOx) therapy showed favorable efficacy with sufficient pathological response. Small sample size limited the statistical power of this result.Perioperative CapeOx therapy showed good feasibility.Further studies with larger sample size are required to validate this novel approach.Background.D2 gastrectomy followed by adjuvant S‐1 is the standard therapy for patients (pts) with stage III gastric cancer (GC) in Japan; however, the outcome is not satisfactory. We examined the efficacy of perioperative capecitabine and oxaliplatin (CapeOx) in pts with GC.Methods.The eligibility criteria included confirmed clinical T3(SS)/T4a(SE) N1‐3 M0 GC according to the Japanese Classification (JCGC; 3rd English Edition). Three cycles of neoadjuvant CapeOx (NAC; capecitabine, 2,000 mg/m2 for 14 days; oxaliplatin, 130 mg/m2 on day 1, every 3 weeks) were administered, followed by five cycles of adjuvant CapeOx (AC) after D2 gastrectomy. The primary endpoint was the pathological response rate (pRR) according to the JCGC (≥grade 1b).Results.Thirty‐seven pts were enrolled on CapeOx. An R0 resection rate of 78.4% (n = 29) and a pRR of 54.1% (n = 20, p = .058; 90% confidence interval [CI], 39.4–68.2) were demonstrated. Among 27 pts who initiated AC, 21 (63.6%) completed the treatment. Grade 3–4 toxicities during NAC included neutropenia (8%), thrombocytopenia (8%), and anorexia (8%) and during AC included neutropenia (37%), diarrhea (4%), and anorexia (4%).Conclusion.Perioperative CapeOx showed good feasibility and favorable efficacy with sufficient pathological response, although statistical significance at .058 did not reach the commonly accepted cutoff of .05. The data obtained using this novel approach warrant further investigations.
AbstractCabozantinib treatment prolonged progression‐free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number. NCT01835158.
AbstractGeriatric assessment (GA) is used in oncology to identify deficits in older patients with cancer that may affect treatment choice. We examine GA in 550 patients with early breast cancer, including both younger (<65 years) and older women (aged 65 years or older), to assess the potential value of this tool in younger, presumed “healthier” patients. Although older women have more GA‐identified deficits overall, younger patients are more anxious. Suboptimal physical function was problematic across the age spectrum. GA domains can identify major deficits in younger patients beyond those likely to be uncovered in routine investigation.
AbstractBackground.Studies have demonstrated worse breast cancer‐specific mortality with older age, despite an increasing risk of dying from other causes due to comorbidity (competing mortality). However, findings on the association between older age and recurrence risk are inconsistent. The aim of this study was to assess incidences of locoregional and distant recurrence by age, taking competing mortality into account.Materials and Methods.Patients surgically treated for nonmetastasized breast cancer between 2003 and 2009 were selected from The Netherlands Cancer Registry. Cumulative incidences of recurrence were calculated considering death without distant recurrence as competing event. Fine and Gray analyses were performed to characterize the impact of age (70–74 [reference group], 75–79, and ≥80 years) on recurrence risk.Results.A total of 18,419 patients were included. Nine‐year cumulative incidences of locoregional recurrence were 2.5%, 3.1%, and 2.9% in patients aged 70–74, 75–79, and ≥80 years, and 9‐year cumulative incidences of distant recurrence were 10.9%, 15.9%, and 12.7%, respectively. After adjustment for tumor and treatment characteristics, age was not associated with locoregional recurrence risk. For distant recurrence, patients aged 75–79 years remained at higher risk after adjustment for tumor and treatment characteristics (75–79 years subdistribution hazard ratio [sHR], 1.25; 95% confidence interval [CI], 1.11–1.41; ≥80 years sHR, 1.03; 95% CI, 0.91–1.17).Conclusion.Patients aged 75–79 years had a higher risk of distant recurrence than patients aged 70–74 years, despite the higher competing mortality. Individualizing treatment by using prediction tools that include competing mortality could improve outcome for older patients with breast cancer.Implications for Practice.In this population‐based study of 18,419 surgically treated patients aged 70 years or older, patients aged 75–79 years were at higher risk of distant recurrence than were patients aged 70–74 years. This finding suggests that patients in this age category are undertreated. In contrast, it was also demonstrated that the risk of dying without a recurrence strongly increases with age, and patients with a high competing mortality risk are easily overtreated. To identify older patients who may benefit from more treatment, clinicians should therefore take competing mortality risk into account. Prediction tools could facilitate this and thereby improve treatment strategy.
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.Canada has an established publicly funded health care system with a complex drug approval and funding process. After proof of efficacy (POE; key publication/presentation) and before becoming publicly accessible, each drug undergoes a Health Canada approval process, a health technology assessment (HTA), a pricing negotiation, and finally individual provincial funding agreements. We quantified potential life‐years lost during this process.Methods.We analyzed drugs for advanced lung, breast, and colorectal cancer that underwent the HTA process between 2011 and 2016. Life‐years lost were calculated by multiplying documented improvement in progression‐free and overall survival, number of eligible patients, and time from POE to first public funding. For conservative calculation, we assumed all eligible patients in Canada had access at the time of first public funding, whereas in reality provinces fund at different time points.Results.We analyzed 21 drugs. Of these, 15 have been funded publicly. The time from POE to first public funding ranged from 14.0 to 99.2 months (median 26.6 months). Total overall life‐years lost from POE to first public funding were 39,067 (lung 32,367; breast 6,691). Progression‐free life‐years lost from POE to first public funding were 48,037 (lung 9,139, breast 15,827, colorectal 23,071).Conclusion.The number of potential life‐years lost during the drug regulatory and funding process in Canada is substantial, largely driven by delays to funding of colorectal cancer drugs. Recognizing that interprovincial differences exist and that eligible patients may not all receive a given drug, if even a fraction does so, the impact of delays remains substantive. Collaborative national initiatives are required to address this major barrier to treatment access.Implications for Practice.Patients may spend lengthy periods of time awaiting access to new and effective cancer drugs. Patients with private drug insurance or personal funds or who reside in certain Canadian provinces may obtain some drugs sooner than others, potentially creating a two‐tiered access system. The cancer drug access and public funding system must be expedited to improve equity.
AbstractBackground.The end‐of‐life period is a crucial time in lung cancer care. To have a better understanding of the racial‐ethnic disparities in health care expenditures, access, and quality, we evaluated these disparities specifically in the end‐of‐life period for patients with lung cancer in the U.S.Materials and Methods.We used the Surveillance, Epidemiology, and End Results (SEER)‐Medicare database to analyze characteristics of lung cancer care among those diagnosed between the years 2000 and 2011. Linear and logistic regression models were constructed to measure racial‐ethnic disparities in end‐of‐life care cost and utilization among non‐Hispanic (NH) Asian, NH black, Hispanic, and NH white patients while controlling for other risk factors such as age, sex, and SEER geographic region.Results.Total costs and hospital utilization were, on average, greater among racial‐ethnic minorities compared with NH white patients in the last month of life. Among patients with NSCLC, the relative total costs were 1.27 (95% confidence interval [CI], 1.21–1.33) for NH black patients, 1.36 (95% CI, 1.25–1.49) for NH Asian patients, and 1.21 (95% CI, 1.07–1.38) for Hispanic patients. Additionally, the odds of being admitted to a hospital for NH black, NH Asian, and Hispanic patients were 1.22 (95% CI, 1.15–1.30), 1.47 (95% CI, 1.32–1.63), and 1.18 (95% CI, 1.01–1.38) times that of NH white patients, respectively. Similar results were found for patients with SCLC.Conclusion.Minority patients with lung cancer have significantly higher end‐of‐life medical expenditures than NH white patients, which may be explained by a greater intensity of care in the end‐of‐life period.Implications for Practice.This study investigated racial‐ethnic disparities in the cost and utilization of medical care among lung cancer patients during the end‐of‐life period. Compared with non‐Hispanic white patients, racial‐ethnic minority patients were more likely to receive intensive care in their final month of life and had statistically significantly higher end‐of‐life care costs. The findings of this study may lead to a better understanding of the racial‐ethnic disparities in end‐of‐life care, which can better inform future end‐of‐life interventions and help health care providers develop less intensive and more equitable care, such as culturally competent advanced care planning programs, for all patients.
AbstractIntroduction.Nivolumab alone and in combination with ipilimumab is approved for the treatment of patients with metastatic renal cell carcinoma (RCC) who received prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR‐TKI) and those who are treatment naive, respectively. However, the clinical activity of nivolumab in non‐clear cell RCC (nccRCC) is unknown, as these patients were excluded from the trials.Materials and Methods.We reviewed the records of patients who received nivolumab for nccRCC and ccRCC with >20% rhabdoid with the primary endpoint to assess the objective response rate (ORR). We assessed radiographic response using RECIST, v1.1. Secondary endpoints were progression‐free survival (PFS) and overall survival (OS). We also reviewed the literature to identify studies reporting on the clinical activity of immune checkpoint inhibitors in nccRCC, and performed a meta‐analysis of proportions for ORR and disease control rate (DCR).Results.Twelve patients (30%) had papillary histology, 11 (27.5%) had unclassified, 8 (20%) had ccRCC with rhabdoid component, 5 (12.5%) had chromophobe, 3 (7.5%) had translocation, and 1 (2.5%) had mucinous tubular and spindle cell carcinoma. Overall, seven patients (21.6%, 95% confidence interval [CI], 8.7%–37.9%) had an objective response, including three patients (8.8%, 95% confidence interval [CI], 1.9%–23.7%) who achieved a complete remission. At a median follow‐up of 24.5 monoths (95% CI, 17.7–32.6), median PFS was 4.9 monoths (95% CI, 3.53–10.27) and median OS was 21.7 monoths (95% CI, 7.83 mo to not reached). There were no treatment‐related deaths. We also identified two retrospective studies reporting best ORR in patients with nccRCC receiving PD‐1/PD‐L1 checkpoint blockade. The ORR and DCR for the total cohort were, respectively, 18.6% (95% CI, 11.9%–26.4%) and 53.4% (95% CI, 44.2%–62.5%).Conclusion.Nivolumab demonstrated activity in unclassified nccRCC and ccRCC with >20% rhabdoid; further randomized clinical trials are warranted.Implications for Practice.This article reports on the clinical activity and safety of immune checkpoint inhibitors in non‐clear cell kidney cancer. The retrospective data with the meta‐analysis provides a summary that will help guide the treatment of this rare and heterogeneous group of kidney cancers.
AbstractImmune checkpoint inhibitor treatment has been approved by the U.S. Food and Drug Administration for the treatment of a wide range of cancer types, including hepatocellular carcinoma. Workup and management of immune‐mediated hepatitis, pancreatitis, or cholangitis that develops during immune checkpoint inhibitor treatment can be challenging. Immune‐mediated hepatitis can be particularly challenging if patients have underlying viral hepatitis or autoimmune hepatitis. Patients with positive hepatitis B virus DNA should be referred to a hepatologist for antiviral therapy prior to immune checkpoint inhibitor treatment. With untreated hepatitis C virus (HCV) and elevated liver enzymes, a liver biopsy should be obtained to differentiate between HCV infection and immune‐mediated hepatitis due to anti‐programmed cell death protein 1 (PD‐1) therapy. If autoimmune serologies are negative, then this supports a case of immune‐mediated hepatitis secondary to anti‐PD‐1 therapy, rather than autoimmune hepatitis. In this case, an empiric steroid therapy is reasonable; however, if the patient does not respond to steroid therapy in 3–5 days, then liver biopsy should be pursued. The incidence of immune checkpoint‐induced pancreatitis is low, but when it does occur, diagnosis is not straightforward. Although routine monitoring of pancreatic enzymes is not generally recommended, when pancreatitis is suspected, serum levels of amylase and lipase should be checked. Once confirmed, a steroid or other immunosuppressant (if steroids are contraindicated) should be administered along with close monitoring, and a slow tapering dosage once the pancreatitis is under control. Patients should then be monitored for recurrent pancreatitis. Finally, immune therapy‐related cholangitis involves elevated bilirubin and alkaline phosphatase and, once diagnosed, is managed in the same way as immune‐mediated hepatitis.Key Points.Immune‐mediated hepatitis, pancreatitis, and cholangitis are found in patients receiving or who have previously received immune checkpoint inhibitors.To work up immune‐mediated hepatitis, viral, and autoimmune serologies, liver imaging will help to differentiate immune‐mediated hepatitis from hepatitis of other etiology.Hepatology consult may be considered in patients with a history of chronic liver disease who developed hepatitis during immune checkpoint inhibitor treatment.Liver biopsy should be considered to clarify the diagnosis for case in which the hepatitis is refractory to steroid or immunosuppressant treatment.Immune‐mediated pancreatitis is treated with steroid or other immunosuppressant with a slow tapering and should be monitored for recurrence.Implications for Practice.All patient receiving or who have previously received immune checkpoint inhibitors should be monitored closely for immune‐mediated hepatitis, pancreatitis, and cholangitis. Workup and management of immune‐mediated hepatitis, pancreatitis, and cholangitis should follow the package insert of immune checkpoint inhibitors. Hepatology consultation should be considered in patients with a history of chronic liver disease.
AbstractLessons Learned.HyperAcute Renal immunotherapy was well tolerated and demonstrated antitumor activity in patients requiring salvage‐line treatment for metastatic renal cell carcinoma (mRCC).HyperAcute Renal immunotherapy was safely administered with concomitant salvage‐line treatments for mRCC, and it may be a candidate for inclusion in novel combinations for salvage treatment of mRCC because of its unique mechanism of action.Background.HyperAcute Renal (HAR) immunotherapy exploits a naturally occurring barrier to xenotransplantation and zoonotic infections in humans to immunize patients against metastatic renal cell carcinoma (mRCC) cells. HAR consists of two allogeneic renal cancer cell lines genetically modified to express α(1,3)Gal, to which humans have an inherent pre‐existing immunity.Methods.Patients with refractory mRCC were eligible for this phase I dose‐escalation trial. Concomitant treatment was permitted after the initial 2 months of HAR monotherapy. HAR was injected intradermally weekly for 4 weeks then biweekly for 20 weeks, totaling 14 immunizations. The primary endpoint was safety and determination of a maximum tolerated dose (MTD).Results.Among 18 patients enrolled, two grade 3 adverse events (AEs) were attributed to HAR, lymphopenia and injection site reaction, and no grade 4/5 AEs occurred. The recommended phase II dose (RP2D) was 300 million cells. One patient had a partial response and eight patients had stable disease, for a disease control rate of 50% (9/18). Median overall survival with low‐dose HAR was 14.2 months and was 25.3 months with high‐dose HAR.Conclusion.In pretreated mRCC, HAR immunotherapy was well tolerated and demonstrated antitumor activity. HAR immunotherapy may be a candidate for inclusion in novel combinations for salvage treatment of mRCC.
AbstractAs the use of immune checkpoint inhibitors for several different malignancies becomes more mainstream, their side‐effect profile raises new challenges. In 2011, the Food and Drug Administration approved the first checkpoint inhibitor for the treatment of advanced melanoma, and since then, checkpoint inhibitors have demonstrated efficacy in many other tumor types. Given the frequent use of immune checkpoint inhibitors in a wide range of cancers today, the diagnosis and management of their immune‐mediated toxicities need special attention. One of the most common is immune‐mediated colitis. Workup and management of immune‐mediated colitis can be challenging and is the purpose of this review.Key Points.Rate of immune mediated colitis differ from different kind of immune checkpoint inhibitor treatment.To work up immune‐mediated colitis, tests to rule out infectious etiologies of diarrhea, colonoscopy and abdominal image will help to differentiate immune mediated colitis from colitis from other etiology.Patients with mild colitis can be managed with supportive therapies alone, but more severe cases may require immunomodulators such as steroid. Refractory cases may require tumor necrosis factor (TNF) inhibitors, such as infliximab in addition to steroid treatment.Implications for Practice.Immune‐mediated colitis in patients who are receiving or have received immune checkpoint inhibitor requires early recognition, prompt and aggressive medical treatment to avoid severe colitis, which can be life‐threatening or lead to a colectomy.
AbstractTesticular cancer is one of the few tumor types that have not yet benefited from targeted therapy. Still no new active agents for treating this cancer have been identified over the past 15 years. Once patients are refractory to cisplatin‐based chemotherapy, they will be expected to die from testicular cancer. This report describes a 21‐year‐old man who was refractory to chemotherapy and immunotherapy. Whole exome sequencing and low‐depth whole genome sequencing confirmed the KRAS gene amplification, which may lead to the tumor cells’ progression and proliferation. After discussion at the molecular tumor board, the patient was offered paclitaxel, carboplatin, and sorafenib (CPS) based on a phase III clinical trial of melanoma with KRAS gene copy gains. After treatment with CPS, the patient achieved excellent curative effects. Because of a nearly 50% frequency of KRAS amplification in chemotherapy‐refractory testicular germ cells, CPS regimen may provide a new therapy, but it still warrants further validation in clinical studies.Key Points.Chemotherapy‐refractory testicular cancer has a very poor prognosis resulting in a lack of effective targeted therapies.
KRAS gene amplification occurs in nearly 20% of testicular cancer and 50% of chemotherapy‐refractory testicular cancer.
KRAS amplification may activate the MAPK signaling pathway, and inhibition of MAPK by sorafenib combined with paclitaxel and carboplatin could be a viable option based on a phase III clinical trial of melanoma.To the authors’ knowledge, this is the first report of response to sorafenib‐based combination targeted therapy in a patient with chemotherapy‐refractory testicular cancer.Clinical genomic profiling can confirm copy number variation of testicular cancer and provide insights on therapeutic options.
AbstractBackground.Oncology research increasingly involves biospecimen collection and data sharing. Ethical challenges emerge when researchers seek to use archived biospecimens for purposes that were not well defined in the original informed consent document (ICD). We sought to inform ongoing policy debates by assessing patient views on these issues.Materials and Methods.We administered a cross‐sectional self‐administered survey to patients with cancer at an academic medical center. Survey questions addressed attitudes toward cancer research, willingness to donate biospecimens, expectations regarding use of biospecimens, and preferences regarding specific ethical dilemmas.Results.Among 240 participants (response rate 69%), virtually all (94%) indicated willingness to donate tissue for research. Most participants (86%) expected that donated tissue would be used for any research deemed scientifically important, and virtually all (94%) expected that the privacy of their health information would be protected. Broad use of stored biospecimens and data sharing with other researchers increased willingness to donate tissue. For three scenarios in which specific consent for proposed biobank research was unclear within the ICD, a majority of patient's favored allowing the research to proceed: 76% to study a different cancer, 88% to study both inherited (germline) and tumor specific (somatic) mutations, and 70% to permit data sharing. A substantial minority believed that research using stored biospecimens should only proceed with specific consent.Conclusion.When debates arise over appropriate use of archived biospecimens, the interests of the research participants in seeing productive use of their blood or tissue should be considered, in addition to addressing concerns about potential risks and lack of specific consent.Implications for Practice.This survey evaluated views of patients with cancer regarding the permissible use of stored biospecimens from cancer trials when modern scientific methods are not well described in the original informed consent document. The vast majority of patients support translational research and expect that any biospecimens they donate will be used to advance knowledge. When researchers, policy makers, and those charged with research oversight debate use of stored biospecimens, it is important to recognize that research participants have an interest in productive use of their blood, tissue, or data, in addition to considerations of risks and the adequacy of documented consent.
AbstractBackground.The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non‐small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor‐related skin adverse events (ERSEs).Materials and Methods.This placebo‐controlled, double‐blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily.Results.Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex‐16 after treatment were significantly different among arms (mean ± SD: −5.2 ± 8.6 for arm 1, −11.7 ± 14.2 for arm 2, and − 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm.Conclusion.EGF ointment is effective for managing ERSEs. It can also improve patients’ QoL compared with placebo. Clinical trial identification number. NCT02284139Implications for Practice.Patients with non‐small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor‐related skin adverse events.
AbstractBackground.Nuclear protein of the testis (NUT) carcinoma is a rare and aggressive malignancy associated with rearrangements of the nuclear protein of the testis (NUT) gene on chromosome 15q14. Because of its rarity, this tumor is often underdiagnosed and underreported, and there is limited literature regarding its biology and optimal management.Methods and Results.We report our experience of five patients with pediatric NUT carcinoma, all of whom presented with midline head and neck mass. In spite of aggressive multimodality treatment, only one patient survives.Conclusion.NUT carcinoma has a dismal prognosis in spite of aggressive multimodality management (surgery and adjuvant chemotherapy and/or radiation). Novel strategies are required to improve outcomes of patients with this tumor.
AbstractBackground.With the accelerated development of next‐generation sequencing (NGS), identified variants, and targeted therapies, clinicians who confront the complicated and multifarious genetic information may not effectively incorporate NGS‐based circulating tumor DNA (ctDNA) analysis into routine patient care. Consequently, standardized ctDNA testing reports are of vital importance. In an effort to guarantee high‐quality reporting performance, we conducted an investigation of the current detection and reporting practices for NGS‐based ctDNA analysis.Materials and Methods.A set of simulated ctDNA samples with known variants at known allelic frequencies and a corresponding case scenario were distributed to 66 genetic testing laboratories for ctDNA analysis. Written reports were collected to evaluate the detection accuracy, reporting integrity, and information sufficiency using 21 predefined criteria.Results.Current reporting practices for NGS‐based ctDNA analysis were found to be far from satisfactory, especially regarding testing interpretation and methodological details. Only 42.4% of laboratories reported the results in complete concordance with the expected results. Moreover, 74.2% of reports only listed aberrations with direct and well‐known treatment consequences for the tumor type in question. Genetic aberrations for which experimental agents and/or drug access programs are available may thus be overlooked. Furthermore, methodological details for the interpretation of results were missing from the majority of reports (87.9%).Conclusion.This proof‐of‐principle study suggests that the capacity for accurate identification of variants, rational interpretation of genotypes, comprehensive recommendation of potential medications, and detailed description of methodologies need to be further improved before ctDNA analysis can be formally implemented in the clinic.Implications for Practice.Accurate, comprehensive, and standardized clinical sequencing reports can help to translate complex genetic information into patient‐centered clinical decisions, thereby shepherding precision oncology into daily practice. However, standards, guidelines, and quality requirements for clinical reports of next‐generation sequencing (NGS)‐based circulating tumor DNA (ctDNA) analysis are currently absent. By using a set of simulated clinical ctDNA samples and a corresponding case scenario, current practices were evaluated to identify deficiencies in clinical sequencing reports of ctDNA analysis. The recommendations provided here may serve as a roadmap for the improved implementation of NGS‐based ctDNA analysis in the clinic.
AbstractBackground.Advanced‐stage Hodgkin lymphoma (HL) is a curable malignancy, although outcomes remain poor in certain patients. It remains unclear if recent advances have improved their population‐level survival over time.Materials and Methods.Using the Surveillance, Epidemiology, and End Results database, we identified patients aged ≥18 years with stage III or IV classical HL as the first primary malignancy, diagnosed between 2000 and 2014 and treated with chemotherapy. Patients were stratified by date of diagnosis into three groups (2000–2004, 2005–2009, 2010–2014) to assess the trends in overall survival (OS).Results.A total of 9,042 patients with a median age of 41 years were included. The use of frontline radiation therapy decreased in each period (21.3% [2000–2004] vs. 15.5% [2005–2009] vs. 10.7% [2010–2014]; p < .001). Three‐year OS was significantly higher for patients diagnosed between 2010 and 2014 (81.8%) and 2005 and 2009 (80.6%) compared with 2000 and 2004 (78.5%; p = .0008 and .02, respectively). Whereas outcomes were poorest in the age >60 cohort, similar improvements were also seen in 3‐year OS over the three time periods within this patient population. On multivariate analysis, diagnosis in the earlier period and minority race were associated with higher mortality. Females and married patients had significantly lower mortality risk.Conclusion.Survival of patients with advanced‐stage HL has continued to improve over time, suggesting the impact of evolving treatment approaches. Three‐year OS in the contemporary period remains inadequate at 81.8%, highlighting the need for continued research to improve their outcomes.Implications for Practice.This article evaluates contemporary outcomes for advanced‐stage Hodgkin lymphoma (HL) in the U.S. using the Surveillance, Epidemiology, and End Results database. Although overall survival (OS) has improved in each 5‐year period since 2000, the 3‐year OS from 2010 to 2014 remains inadequate at 81.8% and is limited by patient demographics. New therapies are indicated to improve clinical outcomes in advanced‐stage HL.
AbstractLessons Learned.Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)‐resistant breast cancer are limited.Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor‐positive and AI‐resistant disease in this phase II, single‐arm study.The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage.Background.Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR‐positive triple‐negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)‐positive and AR‐positive advanced breast cancer.Methods.A Simon's two‐stage, phase II, single‐arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ≥4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression‐free survival (PFS), and tolerability.Results.A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow‐up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated.Conclusion.Bicalutamide in combination with another AI did not show synergistic activity in patients with ER‐positive breast cancer and AI resistance. Results suggest that no more large‐sample clinical trials should be conducted in this population for overcoming endocrine resistance.
AbstractBackground.The prognostic value of 1q21 gain in newly diagnosed multiple myeloma (NDMM) remains controversial. Our aim was to investigate the prognostic value of 1q21 gain in a Chinese population.Materials and Methods.We retrospectively identified 565 patients with NDMM from multiple centers in China.Results.We detected 1q21 gain in 222 (39.3%) patients, among whom 144 had three copies of 1q21, 57 had four copies of 1q21, and 21 had at least five copies of 1q21. Copy number variation did not show any effect on the disease outcome. Multivariate analysis indicated that 1q21 gain was an independent factor for poor prognosis, but we found that 1q21 gain was strongly associated with other high‐risk factors, such as del(17p), t(4;14), t(14;16), lactate dehydrogenase (LDH) level >300 U/L and International Scoring System (ISS) stage II–III (p < .001). Further analysis revealed that in the absence of other high‐risk factors, isolated 1q21 gain resulted in similar progression‐free survival (PFS; 52.0 vs. 52.8 months, p = .810) and overall survival (OS; not reached vs. not reached, p = .833); additionally, when present with other high‐risk cytogenetic abnormalities or increased LDH levels, 1q21 gain lost its prognostic power. However, the presence of 1q21 gain increased the adverse impact of ISS stage. Furthermore, 1q21 gain predicted poor PFS and OS in patients who received bortezomib‐based regimens. Moreover, autologous stem cell transplantation reversed the poor prognosis in patients with 1q21 gain.Conclusion.Our results show that heterogeneity exists among patients with 1q21 gain and suggest that we should assess the impact of 1q21 gain on prognosis according to different treatment regimens and accompanying high‐risk factors.Implications for Practice.1q21 gain is one of the most common chromosomal aberrations in multiple myeloma (MM); however, the prognostic value of 1q21 gain remains controversial. This study investigated the prognostic value of 1q21 gain in a Chinese population with newly diagnosed MM. The results showed that heterogeneity exists among patients with 1q21 gain and suggested that the impact of 1q21 gain on prognosis should be assessed according to different treatment regimens and accompanying high‐risk factors. These results could help stratify risk in patients with MM and guide treatment decisions.
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