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  • Optimum Imaging Strategies for Advanced Prostate Cancer: ASCO Guideline
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-15
    Edouard J. Trabulsi; R. Bryan Rumble; Hossein Jadvar; Thomas Hope; Martin Pomper; Baris Turkbey; Andrew B. Rosenkrantz; Sadhna Verma; Daniel J. Margolis; Adam Froemming; Aytekin Oto; Andrei Purysko; Matthew I. Milowsky; Heinz-Peter Schlemmer; Matthias Eiber; Michael J. Morris; Peter L. Choyke; Anwar Padhani; Jorge Oldan; Stefano Fanti; Suneil Jain; Peter A. Pinto; Kirk A. Keegan; Christopher R. Porter; Jonathan A. Coleman; Glenn S. Bauman; Ashesh B. Jani; Jeffrey M. Kamradt; Westley Sholes; H. Alberto Vargas

    PURPOSE Provide evidence- and expert-based recommendations for optimal use of imaging in advanced prostate cancer. Due to increases in research and utilization of novel imaging for advanced prostate cancer, this guideline is intended to outline techniques available and provide recommendations on appropriate use of imaging for specified patient subgroups.METHODS An Expert Panel was convened with members from ASCO and the Society of Abdominal Radiology, American College of Radiology, Society of Nuclear Medicine and Molecular Imaging, American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology to conduct a systematic review of the literature and develop an evidence-based guideline on the optimal use of imaging for advanced prostate cancer. Representative index cases of various prostate cancer disease states are presented, including suspected high-risk disease, newly diagnosed treatment-naïve metastatic disease, suspected recurrent disease after local treatment, and progressive disease while undergoing systemic treatment. A systematic review of the literature from 2013 to August 2018 identified fully published English-language systematic reviews with or without meta-analyses, reports of rigorously conducted phase III randomized controlled trials that compared ≥ 2 imaging modalities, and noncomparative studies that reported on the efficacy of a single imaging modality.RESULTS A total of 35 studies met inclusion criteria and form the evidence base, including 17 systematic reviews with or without meta-analysis and 18 primary research articles.RECOMMENDATIONS One or more of these imaging modalities should be used for patients with advanced prostate cancer: conventional imaging (defined as computed tomography [CT], bone scan, and/or prostate magnetic resonance imaging [MRI]) and/or next-generation imaging (NGI), positron emission tomography [PET], PET/CT, PET/MRI, or whole-body MRI) according to the clinical scenario.

    更新日期:2020-01-16
  • Role of Capecitabine in Early Breast Cancer
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Asya N. Varshavsky-Yanovsky; Lori J. Goldstein

    Systemic adjuvant or neoadjuvant chemotherapy, biologic, and hormone therapies have improved outcomes of patients with early-stage breast cancer. However, a substantial number of patients with early-stage breast cancer still develop recurrent disease, and there is need of additional improvement of systemic therapies. Triple-negative breast cancer (TNBC) comprises approximately 15% to 20% of all breast cancers and usually presents with a more aggressive clinical course and poorer outcomes compared with hormone receptor–positive and human epidermal growth factor receptor 2 (HER2) –positive breast cancer, leaving an unmet need for this patient population.1 To date, no targeted therapies have been approved for the treatment of early-stage TNBC.

    更新日期:2020-01-16
  • Has Mismatch Repair–Deficient Cancer Met Its MATCH?
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Landon C. Brown; Andrew J. Armstrong

    Mismatch repair (MMR) deficiency (dMMR) was first described in the familial condition Lynch syndrome, which is a result of germline mutations in one of four MMR genes (MLH1, MSH2, MSH6, or PMS2) or, less commonly, deletions near the MSH2 gene on chromosome 2p21 at the epithelial cell adhesion molecule–locus (EpCAM).1-4 The loss of function in an MMR gene leads to hypermutation and high microsatellite instability (MSI-H) as a result of failure to repair mutations in short repetitive DNA sequences. Sporadic cases of dMMR/MSI-H tumors are recognized most commonly in colorectal cancer (CRC), at approximately a 15% prevalence, but exist at a low prevalence across many common cancer types, including endometrial cancer, stomach and rectal adenocarcinomas, and prostate cancer.5 dMMR in these somatic nongermline cases generally results from epigenetic hypermethylation of the MLH1 promoter or, less likely, homozygous somatic mutations in an MMR gene, but can also result from somatic structural rearrangements or mutations in dMMR genes such as MSH2 or MSH6 in prostate cancer.6,7

    更新日期:2020-01-16
  • Improving Cancer Care for Patients With Chronic Kidney Disease
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Ben Sprangers; Kenar D. Jhaveri; Mark A. Perazella

    Patients with cancer frequently suffer from concurrent chronic kidney disease (CKD), with a prevalence ranging from 12%-53% at cancer diagnosis. Eighty-five percent of drug trials for the 5 most common malignancies published in high–impact factor journals excluded most patients with CKD.1 Of note, serum creatinine thresholds were the exclusion criteria in 62% of patients.1 CKD is common in patients with cancer, which excludes these patients from clinical trials, limiting their access to therapies that could potentially improve their outcomes and to information on adverse drug affects. The IRMA study found that potentially nephrotoxic drugs were used in 80.1% of chemotherapy sessions, with dose adjustment based on kidney function required in 79.9%.2 Because dose adjustments of chemotherapeutics are fundamental in the treatment of patients with cancer, kidney function must be measured accurately to avoid both underdosing and overdosing. These two issues must be considered by clinical oncology trialists and addressed in future cancer trials.

    更新日期:2020-01-16
  • Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Richard S. Finn; Baek-Yeol Ryoo; Philippe Merle; Masatoshi Kudo; Mohamed Bouattour; Ho Yeong Lim; Valeriy Breder; Julien Edeline; Yee Chao; Sadahisa Ogasawara; Thomas Yau; Marcelo Garrido; Stephen L. Chan; Jennifer Knox; Bruno Daniele; Scot W. Ebbinghaus; Erluo Chen; Abby B. Siegel; Andrew X. Zhu; Ann-Lii Cheng; on behalf of the KEYNOTE-240 investigators

    PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population.PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug.RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified.CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.

    更新日期:2020-01-16
  • Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01)
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Ana Lluch; Carlos H. Barrios; Laura Torrecillas; Manuel Ruiz-Borrego; Jose Bines; Jose Segalla; Ángel Guerrero-Zotano; Jose A. García-Sáenz; Roberto Torres; Juan de la Haba; Elena García-Martínez; Henry L. Gómez; Antonio Llombart; Javier Salvador Bofill; José M. Baena-Cañada; Agustí Barnadas; Lourdes Calvo; Laura Pérez-Michel; Manuel Ramos; Isaura Fernández; Álvaro Rodríguez-Lescure; Jesús Cárdenas; Jeferson Vinholes; Eduardo Martínez de Dueñas; Maria J. Godes; Miguel A. Seguí; Antonio Antón; Pilar López-Álvarez; Jorge Moncayo; Gilberto Amorim; Esther Villar; Salvador Reyes; Carlos Sampaio; Bernardita Cardemil; Maria J. Escudero; Susana Bezares; Eva Carrasco; Miguel Martín; on behalf of GEICAM Spanish Breast Cancer Group; CIBOMA (Iberoamerican Coalition for Research in Breast Oncology); and LACOG (Latin American Cooperative Oncology Group)

    PURPOSE Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC.PATIENTS AND METHODS Eligible patients were those with operable, node-positive—or node negative with tumor 1 cm or greater—TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms.RESULTS Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles.CONCLUSION This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.

    更新日期:2020-01-16
  • Nivolumab Is Effective in Mismatch Repair–Deficient Noncolorectal Cancers: Results From Arm Z1D—A Subprotocol of the NCI-MATCH (EAY131) Study
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Nilofer S. Azad; Robert J. Gray; Michael J. Overman; Jonathan D. Schoenfeld; Edith P. Mitchell; James A. Zwiebel; Elad Sharon; Howard Streicher; Shuli Li; Lisa M. McShane; Larry Rubinstein; David R. Patton; P. Mickey Williams; Brent Coffey; Stanley R. Hamilton; Nathan Bahary; J. Marie Suga; Hassan Hatoum; Jeffrey S. Abrams; Barbara A. Conley; Carlos L. Arteaga; Lyndsay Harris; Peter J. O'Dwyer; Alice P. Chen; Keith T. Flaherty

    PURPOSE The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, the largest national precision oncology study to date (> 1,100 sites) of patients with relapsed or refractory malignancies, assigned patients to targeted therapy in parallel phase II studies based on tumor molecular alterations. The anti–programmed death receptor 1 inhibitor nivolumab previously showed activity in mismatch repair (MMR)–deficient colon cancer. We hypothesized that nivolumab would have activity in patients with MMR-deficient, noncolorectal tumors.PATIENTS AND METHODS Eligible patients with relapsed or refractory tumors, good end-organ function, and Eastern Cooperative Oncology Group performance status of ≤ 1 underwent tumor biopsy for centralized screening of molecular alterations. MMR deficiency was defined by complete loss of nuclear expression of MLH1 or MSH2 MMR gene products by immunohistochemistry (IHC). Patients with MMR-deficient colorectal cancer were excluded. Nivolumab, 3 mg/kg every 2 weeks (28-day cycles) and 480 mg every 4 weeks after cycle 4, was administered intravenously. Disease reassessment was performed every 2 cycles. The primary end point was RECIST 1.1 objective response rate (ORR).RESULTS Two percent of 4,902 screened patients had an MMR-deficient cancer by IHC. Forty-two evaluable patients were enrolled, with a median age of 60 years and a median of 3 prior therapies. The most common histologies were endometrioid endometrial adenocarcinoma (n = 13), prostate adenocarcinoma (n = 5), and uterine carcinosarcoma (n = 4). ORR was 36% (15 of 42 patients). An additional 21% of patients had stable disease. The estimated 6-, 12-, and 18-month progression-free survival rates were 51.3% (90% CI, 38.2% to 64.5%), 46.2% (90% CI, 33.1% to 59.3%), and 31.4% (90% CI, 18.7% to 44.2%), respectively. Median overall survival was 17.3 months. Toxicity was predominantly low grade.CONCLUSION A variety of refractory cancers (2.0% of those screened) had MMR deficiency as defined in NCI-MATCH. Nivolumab has promising activity in MMR-deficient noncolorectal cancers of a wide variety of histopathologic types.

    更新日期:2020-01-16
  • Phase II Study of Nonmetastatic Desmoplastic Medulloblastoma in Children Younger Than 4 Years of Age: A Report of the Children’s Oncology Group (ACNS1221)
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Lucie Lafay-Cousin; Eric Bouffet; Douglas Strother; Vasilisa Rudneva; Cynthia Hawkins; Charles Eberhart; Craig Horbinski; Linda Heier; Mark Souweidane; Chris Williams-Hughes; Arzu Onar-Thomas; Catherine A. Billups; Maryam Fouladi; Paul Northcott; Giles Robinson; Amar Gajjar

    PURPOSE Nodular desmoplastic medulloblastoma (ND) and medulloblastoma with extensive nodularity (MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients.PATIENTS AND METHODS ACNS1221 was a prospective single-arm trial of conventional chemotherapy for nonmetastatic ND and MBEN based on a modified HIT SKK 2000 regimen excluding intraventricular methotrexate, aiming to achieve similar outcome (2-year progression-free survival [PFS] ≥ 90%) with reduced treatment-related neurotoxicity. Secondary objectives included feasibility of timely central pathology review and evaluation of tumor molecular profile.RESULTS Twenty-five eligible patients (15 males and 10 females; median age, 18.7 months) were enrolled. Eighteen patients had ND and 7 had MBEN histology. Three patients had residual disease at baseline. The study closed early because of a higher than expected relapse rate. Twelve patients experienced relapse—local (n= 6), distant (n = 3), and combined (n = 3)—at a median of 9.8 months from diagnosis (range, 8.9-13.7 months), and 2 patients died of disease. Two-year PFS and overall survival rates were 52% (95% CI, 32.4% to 71.6%) and 92% (95% CI, 80.8% to 100.0%) respectively. Patients older than 12 months of age (P = .036) and ND histology (P = .005) were associated with worse PFS. No patients with MBEN histology experienced relapse. All tumor samples clustered within the sonic hedgehog (SHH) group. Methylation analysis delineated 2 subgroups, SHH-I and SHH-II, which were associated with 2-year PFS rates of 30.0% (95% CI, 1.6% to 58.4%) and 66.7% (95% CI, 44.0% to 89.4%), respectively (P = .099).CONCLUSION The proposed modified regimen of conventional systemic chemotherapy without serial intraventricular methotrexate injection failed to achieve the targeted 2-year PFS of 90%. With this cohort, we prospectively confirmed the existence of two SHH subgroups and observed a trend toward worse outcome for SHH-I patients.

    更新日期:2020-01-16
  • Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Samah Hayek; Todd M. Gibson; Wendy M. Leisenring; Jennifer L. Guida; Maria Monica Gramatges; Philip J. Lupo; Rebecca M. Howell; Kevin C. Oeffinger; Smita Bhatia; Kim Edelstein; Melissa M. Hudson; Leslie L. Robison; Paul C. Nathan; Yutaka Yasui; Kevin R. Krull; Gregory T. Armstrong; Kirsten K. Ness

    PURPOSE To estimate the prevalence of frailty among childhood cancer survivors and to determine the direct and indirect effects of treatment exposures, lifestyle factors, and severe, disabling, and life-threatening chronic condition on frailty.METHODS Childhood cancer survivors (≥ 5 years since diagnosis), treated between 1970 and 1999 when < 21 years old (n = 10,899; mean age, 37.6 ± 9.4 years; 48% male, 86% white) and siblings were included (n = 2,097; mean age, 42.9 ± 9.4 years). Frailty was defined as ≥ 3 of the following: low lean mass, exhaustion, low energy expenditure, walking limitations, and weakness. Generalized linear models were used to evaluate direct and indirect associations between frailty and treatment exposures, sociodemographic characteristics, lifestyle factors, and chronic condition.RESULTS The overall prevalence of frailty among survivors was 3 times higher compared with siblings (6.4%; 95% CI, 4.1% to 8.7%; v 2.2%; 95% CI, 1.2% to 3.2%). Survivors of CNS tumors (9.5%; 95% CI, 5.2% to 13.8%) and bone tumors (8.1%; 95% CI, 5.1% to 11.1%) had the highest prevalence of frailty. Survivors exposed to cranial radiation, pelvic radiation ≥ 34 Gy, abdominal radiation > 40 Gy, cisplatin ≥ 600 mg/m2, amputation, or lung surgery had increased risk for frailty. These associations were partially but not completely attenuated when sociodemographic characteristics, lifestyle factors, and chronic conditions were added to multivariable models. Cranial radiation (prevalence ratio [PR], 1.47; 95% CI, 1.20 to 1.76), pelvic radiation ≥ 34 Gy (PR, 1.46; 95% CI, 1.01 to 2.11), and lung surgery (PR, 1.75; 95% CI, 1.28 to 2.38) remained significant after sociodemographic, lifestyle, and chronic conditions were accounted for.CONCLUSION Childhood cancer survivors reported a higher prevalence of frailty compared with siblings. Radiation and lung surgery exposures were associated with increased risk for frailty. Interventions to prevent, delay onset, or remediate chronic disease and/or promote healthy lifestyle are needed to decrease the prevalence of frailty and preserve function in this at-risk population.

    更新日期:2020-01-16
  • Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Hanneke C. Kluin-Nelemans; Eva Hoster; Olivier Hermine; Jan Walewski; Christian H. Geisler; Marek Trneny; Stephan Stilgenbauer; Florian Kaiser; Jeanette K. Doorduijn; Gilles Salles; Michal Szymczyk; Hervé Tilly; Lothar Kanz; Christian Schmidt; Pierre Feugier; Catherine Thieblemont; Josée M. Zijlstra; Vincent Ribrag; Wolfram Klapper; Christiane Pott; Michael Unterhalt; Martin H. Dreyling

    PURPOSE In an update of the randomized, open-label, phase III European Mantle Cell Lymphoma (MCL) Elderly trial (ClinicalTrials.gov identifier: NCT00209209), published in 2012, we aimed to confirm results on long-term outcome focusing on efficacy and safety of long-term use of rituximab maintenance.PATIENTS AND METHODS Five hundred sixty patients with newly diagnosed MCL underwent a first random assignment between rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, fludarabine, and cyclophosphamide (R-FC) induction, followed by a second random assignment in 316 responders between rituximab and interferon alfa maintenance, to be continued until progression. We compared progression-free survival from the second randomization and overall survival (OS) from the first or second randomizations.RESULTS After a median follow-up time of 7.6 years, the previously described difference in OS between the induction arms persisted (median, 6.4 years after R-CHOP [n = 280] v 3.9 years after R-FC [n = 280]; P = .0054). Patients responding to R-CHOP had median progression-free survival and OS times of 5.4 and 9.8 years, respectively, when randomly assigned to rituximab (n = 87), compared with 1.9 years (P < .001) and 7.1 years (P = .0026), respectively, when randomly assigned to interferon alfa (n = 97). In 58% and 32% of patients treated with R-CHOP, rituximab maintenance was still ongoing 2 and 5 years from start of maintenance, respectively. After R-FC, rituximab maintenance was associated with an unexpectedly high cumulative incidence of death in remission (22% at 5 years). Toxicity of rituximab maintenance was low after R-CHOP (grade 3-4 leukopenia or infection < 5%) but more prominent in patients on rituximab maintenance after R-FC, in whom grade 3-4 leukopenia (up to 40%) and infections were frequent (up to 15%).CONCLUSION The excellent results of R-CHOP followed by rituximab maintenance until progression for older patients with MCL persisted in a mature follow-up. Prolongation of rituximab maintenance beyond 2 years is effective and safe.

    更新日期:2020-01-16
  • Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Michael Lübbert; Olga Grishina; Claudia Schmoor; Richard F. Schlenk; Edgar Jost; Martina Crysandt; Michael Heuser; Felicitas Thol; Helmut R. Salih; Marcus M. Schittenhelm; Ulrich Germing; Andrea Kuendgen; Katharina S. Götze; Hans-Walter Lindemann; Carsten Müller-Tidow; Gerhard Heil; Sebastian Scholl; Gesine Bug; Carsten Schwaenen; Aristoteles Giagounidis; Andreas Neubauer; Jürgen Krauter; Wolfram Brugger; Maike De Wit; Ralph Wäsch; Heiko Becker; Annette M. May; Justus Duyster; Konstanze Döhner; Arnold Ganser; Björn Hackanson; Hartmut Döhner; on behalf of the DECIDER Study Team

    PURPOSE DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all-trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML).PATIENTS AND METHODS Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety.RESULTS The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms.CONCLUSION The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

    更新日期:2020-01-16
  • Health-Related Quality of Life With Carboplatin-Paclitaxel or nab-Paclitaxel With or Without Pembrolizumab in Patients With Metastatic Squamous Non–Small-Cell Lung Cancer
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Julien Mazieres; Dariusz Kowalski; Alexander Luft; David Vicente; Ali Tafreshi; Mahmut Gümüş; Konstantin Laktionov; Barbara Hermes; Irfan Cicin; Jerónimo Rodríguez-Cid; Jonathan Wilson; Terufumi Kato; Rodryg Ramlau; Silvia Novello; Sreekanth Reddy; Hans-Georg Kopp; Bilal Piperdi; Xiaodong Li; Thomas Burke; Luis Paz-Ares

    PURPOSE In the phase 3 KEYNOTE-407 study, the addition of pembrolizumab to carboplatin-paclitaxel/nab-paclitaxel significantly improved overall survival, progression-free survival, and objective response rate in patients with previously untreated metastatic squamous non–small-cell lung cancer (NSCLC), with little impact on severe toxicity. We present patient-reported outcomes (PROs) from KEYNOTE-407.METHODS Patients were randomly assigned to receive 4 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus carboplatin plus paclitaxel or nab-paclitaxel, followed by pembrolizumab or placebo for an additional 31 cycles. Health-related quality of life (HRQoL) was evaluated using the European Organisation for Research and Treatment of Cancer Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13). Key PRO endpoints were change from baseline to weeks 9 and 18 (during and after platinum therapy) in the QLQ-C30 global health status/quality of life (GHS/QoL) score and time to deterioration in the composite endpoint of cough, chest pain, or dyspnea from the QLQ-C30 and QLQ-LC13. Two-sided, nominal P values are provided.RESULTS A total of 554 and 553 patients completed ≥ 1 QLQ-C30 or ≥ 1 QLQ-LC13 assessment, respectively. GHS/QoL score improved for the pembrolizumab-combination group (least squares [LS] mean [95% CI] change from baseline: week 9, 1.8 [−0.9 to 4.4]; week 18, 4.3 [1.7 to 6.9]) and deteriorated in the placebo-combination group (week 9, −1.8 [−4.4 to 0.7]; week 18, −0.57 [−3.3 to 2.2]). Between-group differences were improved for the pembrolizumab-combination group (difference in LS mean scores: week 9, 3.6 [95% CI, 0.3 to 6.9], nominal P = .0337; week 18, 4.9 [1.4 to 8.3], nominal P = .0060). Median time to deterioration in cough, chest pain, or dyspnea was not reached in either group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06]; nominal P = .125).CONCLUSION Addition of pembrolizumab to chemotherapy maintained or improved HRQoL measurements relative to baseline and improved HRQoL versus chemotherapy alone at weeks 9 and 18. These results support use of pembrolizumab plus chemotherapy as first-line therapy for metastatic squamous NSCLC.

    更新日期:2020-01-16
  • Camouflage
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Daniel Rayson

    I first met Kristin about 4 years ago on referral from one of my colleagues in the community. She was a 48-year-old government-based researcher, and her husband Andrew was a general practitioner. She had received one cycle of adjuvant chemotherapy for breast cancer when her staging CT scan came back demonstrating unequivocal liver metastases, thereby plunging her into a palliative treatment program as opposed to the curative-intent therapy initially discussed.

    更新日期:2020-01-16
  • Clarity Also Needed for Direct-to-Consumer Pharmacogenetic Tests
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Jai N. Patel; Howard L. McLeod

    The commentary by Kilbride et al1 emphasizes that there must be greater clarity for patients and providers on the actionability of genomic results from direct-to-consumer (DTC) tests, and we agree. The US Food and Drug Administration (FDA) regulatory review of DTC tests evaluates their analytical validity (whether tests reliably and accurately measure what they intend to measure) and clinical validity (whether the measurement is predictive of a certain state of health) but does not evaluate their clinical utility or the personal benefit a user of the test results should expect to receive from the intervention.2 The FDA also regulates the claims a company makes about the DTC test in hopes of providing better care for patients; however, it is apparent that certain regulatory language can cause significant confusion.

    更新日期:2020-01-16
  • Reply to Patel and McLeod
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Madison K. Kilbride; Susan M. Domchek; Angela R. Bradbury

    We thank Patel and McLeod1 for their thoughtful engagement with our recent Commentary in Journal of Clinical Oncology.2 In their correspondence, Patel and McLeod echo our concerns about the regulatory language of the US Food and Drug Administration (FDA) as it pertains to direct-to-consumer (DTC) genetic testing.1 In particular, they argue that greater clarity is needed for DTC pharmacogenetic tests, including the pharmacogenetic test from 23andMe. To our knowledge, this test is not yet being offered as part of the Health and Ancestry Service of 23andMe. The company did, however, receive FDA authorization in October 2018 to market its Personal Genome Service Pharmacogenetic Reports.3 This test, which may become available to consumers in the near future, genotypes 33 variants in 8 genes related to drug metabolism.3

    更新日期:2020-01-16
  • EMERGING-CTONG 1103: For Achieving High-Quality Evidence in a Randomized Phase II Trial
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Akiko Tateishi; Hiroto Ishiki; Emi Kubo; Eriko Satomi

    Zhong et al1 recently reported the results of the randomized phase II EMERGING-CTONG 1103 trial (ClinicalTrials.gov identifier: NCT01407822) that explored the safety and efficacy of erlotinib compared with gemcitabine plus cisplatin (GC chemotherapy) for neoadjuvant treatment of patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) with EGFR mutations in exon 19 or 21. The authors randomly assigned patients one of two groups that received either erlotinib 150 mg/day (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). They found that the erlotinib group achieved significant improvement in progression-free survival, a secondary end point, but the primary end point of overall response rate (42 days) and another secondary end point, overall survival (OS), were not met. We certainly recognize the clinical relevance of this topic and congratulate the authors for completing this trial. Using EGFR tyrosine kinase inhibitors (TKIs) as neoadjuvant therapy in patients with stage IIIA-N2 NSCLC is important, even though phase III trials of EGFR TKIs for adjuvant therapy have not been significantly superior to chemotherapy.2 However, we think there are several key points that require further discussion.

    更新日期:2020-01-16
  • Reply to A. Tateishi et al
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20
    Yi-Long Wu; Wen-Zhao Zhong; Hong-Hong Yan

    Tateishi et al1 made several important comments on the EMERGING-CTONG 1103 study. In EMERGING-CTONG 1103, the primary end point of objective response rate with 42 days of neoadjuvant erlotinib was not met, but the secondary end point of progression-free survival was significantly improved with stage IIIA-N2 EGFR-mutant non–small-cell lung cancer treated with neoadjuvant/adjuvant erlotinib compared with gemcitabine/cisplatin chemotherapy.2

    更新日期:2020-01-16
  • Erratum
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-20

    The December 1, 2019, article by Anderson et al entitled “Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin for Head and Neck Cancer” (J Clin Oncol 10.1200/JCO.19.01507) was published with errors.

    更新日期:2020-01-16
  • Pathological Fracture and Prognosis of High-Grade Osteosarcoma of the Extremities: An Analysis of 2,847 Consecutive Cooperative Osteosarcoma Study Group (COSS) Patients
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-13
    Lisa Marie Kelley; Miriam Schlegel; Stefanie Hecker-Nolting; Matthias Kevric; Bernhard Haller; Claudia Rössig; Peter Reichardt; Leo Kager; Thomas Kühne; Georg Gosheger; Reinhard Windhager; Katja Specht; Hans Rechl; Per-Ulf Tunn; Daniel Baumhoer; Thomas Wirth; Mathias Werner; Thekla von Kalle; Michaela Nathrath; Stefan Burdach; Stefan Bielack; Irene von Lüttichau

    PURPOSE The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities.METHODS We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients.RESULTS A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively (P = .007), and 5-year event-free survival (EFS) was 51% versus 58% (P = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% (P < .001), and 5-year EFS was 36% versus 56% (P < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS (P = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS (P = .263; HR, 1.312).CONCLUSION In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.

    更新日期:2020-01-14
  • Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-13
    Kimberly H. Allison; M. Elizabeth H. Hammond; Mitchell Dowsett; Shannon E. McKernin; Lisa A. Carey; Patrick L. Fitzgibbons; Daniel F. Hayes; Sunil R. Lakhani; Mariana Chavez-MacGregor; Jane Perlmutter; Charles M. Perou; Meredith M. Regan; David L. Rimm; W. Fraser Symmans; Emina E. Torlakovic; Leticia Varella; Giuseppe Viale; Tracey F. Weisberg; Lisa M. McShane; Antonio C. Wolff

    PURPOSE To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline.METHODS A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.RECOMMENDATIONS The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.

    更新日期:2020-01-14
  • Prospective Feasibility Trial of a Novel Strategy of Facilitated Cascade Genetic Testing Using Telephone Counseling
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Melissa K. Frey; Ryan M. Kahn; Eloise Chapman-Davis; Francesca Tubito; Maira Pires; Paul Christos; Samantha Anderson; Semanti Mukherjee; Bailey Jordan; Stephanie V. Blank; Thomas A. Caputo; Ravi N. Sharaf; Kenneth Offit; Kevin Holcomb; Steven Lipkin

    PURPOSE A powerful consequence of detecting cancer-associated pathogenic variants is the ability to test at-risk relatives (ARRs), termed cascade testing. However, historical studies suggest cascade testing uptake of 30% or less. Here, we tested the feasibility of a novel, streamlined method of cascade testing using telephone genetic counseling and mailed saliva-based genetic testing.PATIENTS AND METHODS Probands with newly diagnosed cancer-associated pathogenic variants were offered facilitated cascade testing whereby the genetics team identified and contacted ARRs by telephone to disclose the familial pathogenic variant and offer telephone counseling and mailed saliva testing. Results and guideline-based recommendations were reviewed by telephone and shared with the primary care physician.RESULTS Thirty probands were enrolled, and 114 ARRs were identified. Twelve ARRs were excluded (lived outside of the United States, n = 5; proband did not approve of contact, n = 7). Among 102 ARRs telephoned, contact was established with 95 (93%). Among 114 identified ARRs, 66 (58%) completed genetic testing. Among those completing testing, 27 (41%) carried the familial pathogenic variant. Surveys of ARRs at the time of genetic testing and 6 months later demonstrated low levels of anxiety, depression, distress, and uncertainty and high levels of satisfaction with testing. At 6 months, 7 ARRs with pathogenic variants had undergone cancer surveillance interventions and 4 had undergone cancer risk-reducing surgery.CONCLUSION Facilitated cascade testing with telephone genetic counseling and mailed saliva kits resulted in high testing uptake among ARRs. Positive genetic testing resulted in utilization of genetically targeted primary disease prevention at short-term follow-up. Facilitated cascade testing is a straightforward, low-cost, easily implemented strategy with significant potential to promote early detection for affected ARRs and reduce cancer mortality and should be evaluated in larger scale clinical trials.

    更新日期:2020-01-10
  • Cascading After Peridiagnostic Cancer Genetic Testing: An Alternative to Population-Based Screening
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Kenneth Offit; Kaitlyn A. Tkachuk; Zsofia K. Stadler; Michael F. Walsh; Hector Diaz-Zabala; Jeffrey D. Levin; Zoe Steinsnyder; Vignesh Ravichandran; Ravi N. Sharaf; Melissa K. Frey; Steven M. Lipkin; Mark E. Robson; Jada G. Hamilton; Joseph Vijai; Semanti Mukherjee

    PURPOSE Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information.METHODS Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size.RESULTS The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations.CONCLUSION Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

    更新日期:2020-01-10
  • Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Robin Q.H. Kloos; Rob Pieters; Florine M.V. Jumelet; Hester A. de Groot-Kruseman; Cor van den Bos; Inge M. van der Sluis

    PURPOSE In the DCOG ALL-11 protocol, polyethylene glycol–conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported.PATIENTS AND METHODS After induction with 3 fixed intravenous doses of 1,500 IU/m2 PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied.RESULTS The final median PEGasparaginase dose was lowered to 450 IU/m2. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification.CONCLUSION TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.

    更新日期:2020-01-10
  • Treatment of Nodular Lymphocyte Hodgkin Lymphoma: The Goldilocks Principle
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Nancy L. Bartlett

    The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

    更新日期:2020-01-10
  • What’s Old Is New Again: Revisiting Up-Front Chemotherapy in EGFR-Mutated Non–Small-Cell Lung Cancer
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Julia K. Rotow; Pasi A. Jänne

    The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has transformed the management of advanced non–small-cell lung cancer (NSCLC) bearing an activating EGFR mutation, offering improved survival and tolerability when compared with the use of up-front cytotoxic chemotherapy.1-3 Although response rates reach as high as 80% to the third-generation EGFR TKI osimertinib,4 response durations are limited, and subsequent disease progression is near inevitable. This has led to evaluation of combination therapy strategies up front and at disease progression with the intent to offer improved outcomes.

    更新日期:2020-01-08
  • Right to Try Requests and Oncologists’ Gatekeeping Obligations
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Holly Fernandez Lynch; Ameet Sarpatwari; Robert H. Vonderheide; Patricia J. Zettler

    Debate about appropriate gatekeeping for access to investigational drugs outside clinical trials has intensified in recent years, culminating in the enactment of the federal “Right to Try” Act in May 2018 and similar laws in 41 states.1,2 The premise of Right to Try is that regulatory bodies should not be party to doctor-patient decisions about how to respond to life-threatening disease, even when those decisions involve unapproved products.3 This contrasts with the longstanding pathway known as “Expanded Access”, which requires that pre-approval access be authorized by the US Food and Drug Administration (FDA) and institutional review boards.4 For both pathways, patients may access investigational drugs only if the manufacturer agrees to provide them.

    更新日期:2020-01-08
  • Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non–Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Yukio Hosomi; Satoshi Morita; Shunichi Sugawara; Terufumi Kato; Tatsuro Fukuhara; Akihiko Gemma; Kazuhisa Takahashi; Yuka Fujita; Toshiyuki Harada; Koichi Minato; Kei Takamura; Koichi Hagiwara; Kunihiko Kobayashi; Toshihiro Nukiwa; Akira Inoue; for the North-East Japan Study Group

    PURPOSE Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor combined with cytotoxic chemotherapy is highly effective for the treatment of advanced non–small-cell lung cancer (NSCLC) with EGFR mutations; however, little is known about the efficacy and safety of this combination compared with that of standard therapy with EGFR- tyrosine kinase inhibitors alone.METHODS We randomly assigned 345 patients with newly diagnosed metastatic NSCLC with EGFR mutations to gefitinib combined with carboplatin plus pemetrexed or gefitinib alone. Progression-free survival (PFS), PFS2, and overall survival (OS) were sequentially analyzed as primary end points according to a hierarchical sequential testing method. Secondary end points were objective response rate (ORR), safety, and quality of life.RESULTS The combination group demonstrated a better ORR and PFS than the gefitinib group (ORR, 84% v 67% [P < .001]; PFS, 20.9 v 11.9 months; hazard ratio for death or disease progression, 0.490 [P < .001]), although PFS2 was not significantly different (20.9 v 18.0 months; P = .092). Median OS in the combination group was also significantly longer than in the gefitinib group (50.9 v 38.8 months; hazard ratio for death, 0.722; P = .021). The rate of grade ≥ 3 treatment-related adverse events, such as hematologic toxicities, in the combination group was higher than in the gefitinib group (65.3% v 31.0%); there were no differences in quality of life. One treatment-related death was observed in the combination group.CONCLUSION Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations with an acceptable toxicity profile, although its OS benefit requires further validation.

    更新日期:2020-01-08
  • Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Vanita Noronha; Vijay Maruti Patil; Amit Joshi; Nandini Menon; Anuradha Chougule; Abhishek Mahajan; Amit Janu; Nilendu Purandare; Rajiv Kumar; Sucheta More; Supriya Goud; Nandkumar Kadam; Nilesh Daware; Atanu Bhattacharjee; Srushti Shah; Akanksha Yadav; Vaishakhi Trivedi; Vichitra Behel; Amit Dutt; Shripad Dinanath Banavali; Kumar Prabhash

    PURPOSE Standard first-line therapy for EGFR-mutant advanced non–small-cell lung cancer (NSCLC) is an epidermal growth factor receptor (EGFR)–directed oral tyrosine kinase inhibitor. Adding pemetrexed and carboplatin chemotherapy to an oral tyrosine kinase inhibitor may improve outcomes.PATIENTS AND METHODS This was a phase III randomized trial in patients with advanced NSCLC harboring an EGFR-sensitizing mutation and a performance status of 0 to 2 who were planned to receive first-line palliative therapy. Random assignment was 1:1 to gefitinib 250 mg orally per day (Gef) or gefitinib 250 mg orally per day plus pemetrexed 500 mg/m2 and carboplatin area under curve 5 intravenously every 3 weeks for four cycles, followed by maintenance pemetrexed (gefitinib plus chemotherapy [Gef+C]). The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), response rate, and toxicity.RESULTS Between 2016 and 2018, 350 patients were randomly assigned to Gef (n = 176) and Gef+C (n = 174). Twenty-one percent of patients had a performance status of 2, and 18% of patients had brain metastases. Median follow-up time was 17 months (range, 7 to 30 months). Radiologic response rates were 75% and 63% in the Gef+C and Gef arms, respectively (P = .01). Estimated median PFS was significantly longer with Gef+C than Gef (16 months [95% CI, 13.5 to 18.5 months] v 8 months [95% CI, 7.0 to 9.0 months], respectively; hazard ratio for disease progression or death, 0.51 [95% CI, 0.39 to 0.66]; P < .001). Estimated median OS was significantly longer with Gef+C than Gef (not reached v 17 months [95% CI, 13.5 to 20.5 months]; hazard ratio for death, 0.45 [95% CI, 0.31 to 0.65]; P < .001). Clinically relevant grade 3 or greater toxicities occurred in 51% and 25% of patients in the Gef+C and Gef arms, respectively (P < .001).CONCLUSION Adding pemetrexed and carboplatin chemotherapy to gefitinib significantly prolonged PFS and OS but increased toxicity in patients with NSCLC.

    更新日期:2020-01-08
  • Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Cecilie U. Rank; Benjamin O. Wolthers; Kathrine Grell; Birgitte K. Albertsen; Thomas L. Frandsen; Ulrik M. Overgaard; Nina Toft; Ove J. Nielsen; Peder S. Wehner; Arja Harila-Saari; Mats M. Heyman; Johan Malmros; Jonas Abrahamsson; Ulrika Norén-Nyström; Beata Tomaszewska-Toporska; Bendik Lund; Kirsten B. Jarvis; Petter Quist-Paulsen; Goda E. Vaitkevičienė; Laimonas Griškevičius; Mervi Taskinen; Ulla Wartiovaara-Kautto; Kristi Lepik; Mari Punab; Ólafur G. Jónsson; Kjeld Schmiegelow

    PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored.PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol.RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse.CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.

    更新日期:2020-01-08
  • Factors During a Child’s Illness Are Associated With Levels of Prolonged Grief Symptoms in Bereaved Mothers and Fathers
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Lilian Pohlkamp; Ulrika Kreicbergs; Josefin Sveen

    PURPOSE Previous research shows that bereaved parents are at an increased risk for intense and prolonged grief responses. To offer effective support to parents during a child’s cancer treatment and after their child’s death, more knowledge is needed about factors related to the child’s illness trajectory that may contribute to prolonged grief in bereaved parents and about possible sex differences related to such factors. Therefore, we examined possible contributing factors associated with prolonged grief in cancer-bereaved mothers and fathers 1 to 5 years after their child died of cancer.METHODS We studied data from a population-based nationwide survey, including 133 mothers and 92 fathers who had lost a child to cancer 1 to 5 years earlier, using univariable and multiple regression analyses to assess the associations between prolonged grief and possible contributing variables.RESULTS The variables associated with lower levels of prolonged grief symptoms for mothers were being able to talk about feelings within the family (P = .00) and trusting that health care professionals made every possible effort to cure the child (P = .01). The statistically significantly associated variables for fathers were having said farewell to the deceased child in the way they wanted (P = .00) and feeling that they had received practical support from health care professionals during the child’s illness trajectory (P = .01).CONCLUSION We found factors during the illness of children with cancer that contributed to prolonged grief for parents; these were different for mothers and fathers. The results may have implications for design of family bereavement support within pediatric oncology care, including addressing the differing needs of mothers and fathers more effectively.

    更新日期:2020-01-08
  • Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Laurie H. Sehn; Alex F. Herrera; Christopher R. Flowers; Manali K. Kamdar; Andrew McMillan; Mark Hertzberg; Sarit Assouline; Tae Min Kim; Won Seog Kim; Muhit Ozcan; Jamie Hirata; Elicia Penuel; Joseph N. Paulson; Ji Cheng; Grace Ku; Matthew J. Matasar

    PURPOSE Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component.METHODS Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression methods.RESULTS Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% v 17.5%; P = .026) and longer IRC-assessed PFS (median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; P < .001) and OS (median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; P = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% v 33.3%), anemia (28.2% v 17.9%), and thrombocytopenia (41% v 23.1%), but similar grade 3-4 infections (23.1% v 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients.CONCLUSION Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.

    更新日期:2020-01-08
  • Sassafras
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Cole P. Rodman

    “No doubt, few people understand either the purely subjective nature of the phenomenon of love, or how it creates a supplementary person who is quite different from the one who bears our beloved’s name in the outside world, and is mostly formed from elements within ourselves.”

    更新日期:2020-01-08
  • Bevacizumab Moonshots: An Important Outcome From the Latest Ovarian Cancer Mission
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Ian Edwin Haines; George L. Gabor Miklos

    In a recent article in Journal of Clinical Oncology, Tewari et al1 provided high-quality data on the final protocol-specified analysis of overall survival (OS) of 1,873 women treated with chemotherapy and/or bevacizumab for incompletely resected stage III or IV ovarian cancer. This randomized, three-arm, double-blind, placebo-controlled phase III trial (GOG-0218) revealed that after a median follow-up of nearly 9 years, there was no OS benefit from bevacizumab. Women receiving carboplatin and paclitaxel had median survival times equivalent to those receiving concurrent carboplatin, paclitaxel, and bevacizumab and those receiving concurrent carboplatin, paclitaxel, and bevacizumab plus bevacizumab maintenance (hazard ratios [HRs], 1.06 and 0.96; P = .34 and .53, respectively). These OS data are congruent with three earlier phase III trials for this indication: ICON7, AURELIA, and OCEANS (HRs, 0.99, 0.85, and 0.95; P = .85, .17, and .65, respectively). All four trials yielded unequivocal outcomes using the gold standard of OS. The high-probability conclusion is that bevacizumab-based targeting of vascular endothelial growth factor (VEGF) in ovarian cancer fails to increase median lifespan. The additional clinical concern is that bevacizumab contributes to many adverse events, including thromboembolism, GI perforation, hypertension, and proteinuria. These data have important implications for other more prevalent and incurable cancer types,2-4 where the lowered bar of progression-free survival (PFS) has controversially garnered US Food and Drug Administration approval for the use of bevacizumab.

    更新日期:2020-01-08
  • Bevacizumab As Maintenance Treatment in Patients With Ovarian Cancer: Wait for BRCA Testing
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Alberto Farolfi; Domenica Lorusso; Sandro Pignata; Ugo De Giorgi

    In their recent article published in Journal of Clinical Oncology, Tewari et al1 highlighted that in the GOG-0218 trial, neither first-line bevacizumab concurrent with chemotherapy nor bevacizumab concurrent with chemotherapy plus maintenance significantly improved overall survival (OS) compared with chemotherapy alone, even though bevacizumab administered throughout treatment has prolonged median progression-free survival (PFS) by approximately 4 months.2 Moreover, the authors demonstrated that germ line or somatic mutations in BRCA1/2 genes were prognostic, but not predictive, of bevacizumab efficacy.

    更新日期:2020-01-08
  • Reply to Farolfi et al and Haines et al
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Krishnansu S. Tewari; Bradley J. Monk; Robert A. Burger

    We thank Farolfi et al1 and Haines et al2 for their correspondence. Noting that the progression-free survival (PFS) benefit in GOG-0218 was observed only in the bevacizumab concurrent with chemotherapy plus maintenance arm,3 Farolfi et al had reservations with our proposed algorithm to combine bevacizumab with chemotherapy while awaiting genetic testing.4 Their team studied systemic inflammatory markers and provided an elegant molecular rationale to account for the observed improvements in PFS attributed to bevacizumab in BRCA wild-type patients.5 Accordingly, they recommended waiting for BRCA results before incorporating antiangiogenesis therapy. Because a predictive biomarker to guide anti–vascular endothelial growth factor (VEGF) therapy remains elusive, the proposed biologic explanation, which invokes the tumor microenvironment, is interesting. However, it is hypothesis generating and requires prospective validation before changing practice. Following on the heels of AVANOVA2 (ClinicalTrials.gov identifier: NCT02354131), which demonstrated significant activity of niraparib plus bevacizumab in platinum-sensitive recurrent disease,6 the randomized phase III frontline PAOLA-1 trial (ClinicalTrials.gov identifier: NCT02477644) of combined maintenance bevacizumab plus olaparib was recently reported to have met its primary end point in tumor BRCA-mutated and non-BRCAmut homologous recombination–deficient patients.7 The magnitude of benefit in the subpopulations studied was presented at the European Society for Medical Oncology 2019 Congress in Barcelona, Spain.

    更新日期:2020-01-08
  • Working Up Group 4 Equivocal HER2 Samples Tested by Fluorescence in Situ Hybridization in a Reference Laboratory Setting: Past, Present, and Future
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-10
    Katherine B. Geiersbach; Reid G. Meyer; Daniel R. Sill; Taofic Mounajjed; Beiyun Chen; William R. Sukov; Robert B. Jenkins

    In an article published in 2016,1 we described our method for resolving group 4 equivocal results after fluorescence in situ hybridization (FISH) testing under the 2013 ASCO/College of American Pathologists (CAP) guidelines for HER2 testing in breast cancer.2 We had a total of 2,851 breast cancer tissue samples that had been submitted for human epidermal growth factor receptor 2 (HER2) testing in our reference laboratory. That study included 405 samples (14.2%) in group 4 (HER2/centromere ratio < 2 with average HER2 copy number ≥ 4.0 but < 6.0), of which 212 (7.4% of all samples tested by FISH) were ultimately reported as HER2 positive after D17S122 (Mayo Clinic, Rochester, MN) reflex FISH testing. That study also included 35 samples (1.3%) in group 2 (HER2/centromere ratio > 2 and average HER2 copy number < 4.0) and 86 samples (3%) in group 3 (HER2/centromere ratio < 2 and average HER2 copy number ≥ 6.0). The group 2 and group 3 samples were reported as being FISH positive without further reflex testing.

    更新日期:2020-01-08
  • Patient-Reported Functional Outcomes After Hypofractionated or Conventionally Fractionated Radiation for Prostate Cancer: A National Cohort Study in England
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Julie Nossiter; Arunan Sujenthiran; Thomas E. Cowling; Matthew G. Parry; Susan C. Charman; Paul Cathcart; Noel W. Clarke; Heather Payne; Jan van der Meulen; Ajay Aggarwal

    PURPOSE The aim of the current study was to determine patient-reported functional outcomes in men with prostate cancer (PCa) undergoing moderately hypofractionated (H-RT) or conventionally fractionated radiation therapy (C-RT) in a national cohort study.PATIENDS AND METHODS All men diagnosed with PCa between April 2014 and September 2016 in the English National Health Service undergoing C-RT or H-RT were identified in the National Prostate Cancer Audit and mailed a questionnaire at least 18 months after diagnosis. We estimated differences in patient-reported urinary, bowel, sexual, and hormonal function—Expanded Prostate Cancer Index Composite short-form 26 domain scores on a 0 to 100 scale—and health-related quality of life—EQ-5D-5L on a 0 to 1 scale—using linear regression with adjustment for patient, tumor, and treatment-related factors in addition to GI and genitourinary baseline function, with higher scores representing better outcomes.RESULTS Of the 17,058 men in the cohort, 77% responded: 8,432 men received C-RT (64.2%) and 4,699 H-RT (35.8%). Men in the H-RT group were older (age ≥ 70 years: 67.5% v 60.9%), fewer men had locally advanced disease (56.5% v 71.3%), were less likely to receive androgen-deprivation therapy (79.5% v 87.8%), and slightly more men had pretreatment genitourinary procedures (24.2% v 21.2%). H-RT was associated with small increases in adjusted mean Expanded Prostate Cancer Index Composite short-form 26 sexual (3.3 points; 95% CI, 2.1 to 4.5; P < .001) and hormonal function scores (3.2 points; 95% CI, 1.8 to 4.6; P < .001). These differences failed to meet established thresholds for a clinically meaningful change. There were no statistically significant differences in urinary or bowel function and quality of life.CONCLUSION This is the first national cohort study comparing functional outcomes after H-RT and C-RT reported by patients. These real-world results further support the use of H-RT as the standard for radiation therapy in men with nonmetastatic PCa.

    更新日期:2020-01-04
  • Assessing Patient-Reported Outcomes: A Negotiated Process
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Kevin P. Weinfurt; Kathryn E. Flynn

    In his recent editorial, Vickers1 expressed concern about the field of patient-reported outcomes (PROs) and about some specific PRO measures (PROMs). First, we agree wholeheartedly with the statement by Vickers1 that “there is no room for complacency about the current state of the PRO literature,”1(p1) as we hope there is no room for complacency about any scientific field. The assessment of health status is a dynamic field that continues to evolve. Of course, there are those who fall into routinized and unreflective scientific activities, as is the case in all fields, and so we would not disagree that published PRO studies vary in their degree of thoughtfulness. Vickers1 rightly criticizes the wide overuse and underspecification of the “reliable and valid measure” phrasing. But within our field, we strive to hold researchers accountable to the methodologic standards and best practices that have been developed.2

    更新日期:2020-01-04
  • The Case for Maintenance Pemetrexed Plus Bevacizumab
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Nasser Hanna; Shadia Jalal

    Ramalingam et al1 reported the results of a phase III trial, ECOG-ACRIN 5508, which compared maintenance bevacizumab versus pemetrexed versus the combination in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) who had stable or responding disease after induction carboplatin plus paclitaxel plus bevacizumab. The authors stated that “we can definitively conclude that the combination of bevacizumab and pemetrexed cannot be recommended as maintenance therapy.”

    更新日期:2020-01-04
  • Maintenance Therapy for Advanced Nonsquamous Non–Small-Cell Lung Cancer: More Questions Than Answers
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Li Xie; Xingwen Fan; Biyun Qian

    We read the article by Ramalingam et al1 that described the ECOG-ACRIN 5508 study. This randomized, controlled, phase III trial found that the combination of bevacizumab and pemetrexed, compared with bevacizumab or pemetrexed as maintenance therapy, for advanced nonsquamous non–small-cell lung cancer (NSCLC) significantly improved progression-free survival (PFS) but lacked overall survival (OS) benefit and had higher toxicity. Therefore, single-agent bevacizumab or pemetrexed was recommended as maintenance therapy for advanced nonsquamous NSCLC. However, some aspects of the study warrant closer attention.

    更新日期:2020-01-04
  • Reply to K.P. Weinfurt et al
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Andrew J. Vickers

    I find little to disagree with in a letter to the editor from Weinfurt and Flynn1 in response to my recent article in Journal of Clinical Oncology titled “Validation of patient-reported outcomes: A low bar.”2 The target of the critique in my editorial was a narrow view of questionnaire validation and implementation. In brief, show that a questionnaire correlates well with something that it should, and less well with something it should not, and you are done: the questionnaire is ready for use in research and the clinic, and even the most trivial change would render it invalid.

    更新日期:2020-01-04
  • Is Gefitinib Combined With Platinum-Doublet Chemotherapy a Counterpart to Osimertinib Monotherapy in Advanced EGFR-Mutated Non–Small-Cell Lung Cancer in the First-Line Setting?
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Tomohiro Tanaka; Hiroto Ishiki; Emi Kubo; Sayuri Yokota; Masaki Shimizu; Daisuke Kiuchi; Eriko Satomi

    Noronha et al1 reported in Journal of Clinical Oncology a randomized phase III trial (Clinical Trial Registry-India identifier: CTRI/2016/08/007149) comparing gefitinib plus pemetrexed and carboplatin with gefitinib alone for the treatment of advanced non–small-cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation. As part of the rationale for the study, the authors assumed that oral tyrosine kinase inhibitors (TKIs) and pemetrexed have synergistic effects based on in vitro experiments. The trial demonstrated that gefitinib plus chemotherapy significantly improved median progression-free survival (PFS; the primary end point), median overall survival, and objective response rate in the intent-to-treat population of 350 patients.

    更新日期:2020-01-04
  • Contradiction Between Stated Statistical Analysis Method and Displayed Survival Curves
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Fei Liang

    In their recent article, Noronha et al1 reported that adding pemetrexed and carboplatin chemotherapy to gefitinib significantly prolonged progression-free survival (PFS) and overall survival (OS). I have some concerns about their statistical analysis methods. As the authors reported in the Patients and Methods section, PFS and OS were estimated using the Kaplan-Meier method, and the 2 arms were compared using the log-rank test. However, the curves in Figure 3 of their article, which showed Kaplan-Meier estimates of PFS and OS in the full analysis set, are highly unlike survival curves of the Kaplan-Meier method. In a Kaplan-Meier survival curve, a turning point represents the occurrence of at least 1 event, and the x-axis of the turning point indicates the actual time of the event. In the OS survival curve of the gefitinib arm in Figure 3B, there were 21 turning points, and the authors reported that 80 patients died in the gefitinib arm. Therefore, it can be inferred that 80 patients died at only 21 time points during the 24 months of follow-up, with an average of 4 deaths per day for these 21 days, and that for the remaining 699 days (assuming 30 days per month), not a single patient died. Furthermore, according to the number of turning points on the x-axis, patients died only on the first day of each month, and no patients died on any other days of the month, which means patients died in a well-organized way at regular 1-month intervals. Similar characteristics can be seen in the OS curve of the gefitinib plus pemetrexed and carboplatin arm and PFS curves of the 2 arms.

    更新日期:2020-01-04
  • Reply to K.P. Weinfurt et al
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Nnenaya Q. Agochukwu; Daniela Wittmann; Nicholas R. Boileau; Rodney L. Dunn; James Montie; Tae Kim; David C. Miller; James Peabody; Noelle E. Carlozzi

    Patient-reported outcomes (PROs) have the potential to transform patient-related care.1 PROs are reported directly from patients without interpretation by others and introduce a unique element into the patient-physician encounter.2 Although PROs have clear advantages, we agree with our colleagues that they are far from perfect, owing largely to their subjectivity.3 We would add that it is not just their subjectivity that is their limitation, but that, individually, they do not even approximate the complexity of human experience. Despite this, PROs offer unique insight into a patient’s experience and provide information on outcomes beyond morbidity and mortality, which is critical to patient care.4 Establishing the clinical usefulness of PROs is an ongoing process, and no one study can provide all the answers about the measurement properties of PROs.5 In addition, although measurement properties may be supported in some samples and under certain conditions, these same measurement properties may not be supported universally. It is important that we use PROs as part of a multimodal assessment of the patient experience if we wish to deliver top-notch personalized care to our patients.

    更新日期:2020-01-04
  • Anti–B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Max S. Topp; Johannes Duell; Gerhard Zugmaier; Michel Attal; Philippe Moreau; Christian Langer; Jan Krönke; Thierry Facon; Alexey V. Salnikov; Robin Lesley; Karl Beutner; James Kalabus; Erik Rasmussen; Kathrin Riemann; Alex C. Minella; Gerd Munzert; Hermann Einsele

    PURPOSE The anti–B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma.PATIENTS AND METHODS In this first-in-human study, up to 10 cycles of AMG 420 were given (4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/104 bone marrow cells by flow cytometry.RESULTS Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year.CONCLUSION In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.

    更新日期:2020-01-04
  • Reply to N. Hanna et al and L. Xie et al
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Suresh S. Ramalingam; Suzanne E. Dahlberg

    We thank Hanna et al1 and Xie et al2 for their comments on our recent publication of the ECOG-ACRIN 5508 maintenance therapy trial.3 Hanna and Jalal contend that the combination of bevacizumab and pemetrexed should be considered for clinical use under selected circumstances on the basis of consistent improvement in progression-free survival data observed across trials. They also accurately point out that not a single trial has demonstrated significant improvement in overall survival with the combination regimen. In fact, the results of ECOG-ACRIN 5508 are consistent with observations from other trials. The hazard ratio for overall survival was 0.9 in this trial. The AVAPERL4 and COMPASS5 studies mentioned by the authors reported hazard ratios for overall survival of 0.87 in each. Our article about ECOG-ACRIN 5508 had been accepted for publication by the Journal of Clinical Oncology before the presentation of the results of the COMPASS study; hence, we did not have the opportunity to cite those results. The fact that all of the trials demonstrate a modest numerical improvement in survival for the combination regimen without a statistically significant overall survival benefit cannot be accepted as sufficient grounds to recommend this strategy.

    更新日期:2020-01-04
  • Reply to T. Tanaka et al and F. Liang
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Vanita Noronha; Vijay M. Patil; Amit Joshi; Nandini Menon; Anuradha Chougule; Kumar Prabhash

    We thank Tanaka et al1 and Liang2 for their critical comments on our report.3 We extensively discussed the primary end point while planning the protocol. Considering the question, limitations of the center, and examples in prior landmark studies, including IPASS, ENSURE, EURTAC, OPTIMAL,4 and the recently reported NEJ009 study,5 investigator-assessed progression-free survival (PFS) was felt to be a valid primary end point. Apart from PFS, our other end points, including PFS after second-line treatment and overall survival (OS), were in the same direction, suggesting that the observed benefit in efficacy was in the right direction. Independent central radiologic review requires significant resources, which is a major limitation in investigator-initiated studies. It is unclear whether blinded independent central review (BICR) is always necessary; several studies have found no difference between investigator-assessed PFS and BICR,6-8 and some have suggested that BICR may actually lead to an exaggeration of PFS.9

    更新日期:2020-01-04
  • Statistical Methods in Precision Oncology
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-02
    Ying Lu; J. Jack Lee; James M. Ford

    We are proud to alert the readership of Journal of Clinical Oncology (JCO) to a recent series of publications in JCO Precision Oncology that describe novel statistical methods for precision oncology (https://ascopubs.org/po/collections/statistical-methods-precision-oncology).1-14 Most articles focus on state-of-the-art methods in precision drug development in oncology but also include expert discussion on discovery, precision oncology care, and decision making. They cover the development and validation of risk models, the identification and validation of predictive markers, drug discovery, early phase dose determination, model-assisted designs, phase II biomarker-driven trials, phase III confirmatory trials, companion diagnostics, master protocols for basket trials and umbrella trials, subgroup analysis, selection of estimands for clinical trials, and clinical trials for rare tumors and pediatric cancer.

    更新日期:2020-01-04
  • Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Kim-Hien T. Dao; Jason Gotlib; Michael M.N. Deininger; Stephen T. Oh; Jorge E. Cortes; Robert H. Collins Jr; Elliot F. Winton; Dana R. Parker; Hyunjung Lee; Anna Reister; Schultz; Samantha Savage; Stevens; Chase Brockett; Nan Subbiah; Richard D. Press; Philipp W. Raess; Michael Cascio; Jennifer Dunlap; Yiyi Chen; Catherine Degnin; Julia E. Maxson; Cristina E. Tognon; Tara Macey; Brian J. Druker; Jeffrey W. Tyner

    PURPOSE Colony-stimulating factor-3 receptor (CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status.METHODS We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival.RESULTS ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed.CONCLUSION Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.

    更新日期:2019-12-29
  • Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Ahmad A. Tarhini; Sandra J. Lee; F. Stephen Hodi; Uma N. M. Rao; Gary I. Cohen; Omid Hamid; Laura F. Hutchins; Jeffrey A. Sosman; Harriett M. Kluger; Zeynep Eroglu; Henry B. Koon; Donald P. Lawrence; Kari L. Kendra; David R. Minor; Carrie B. Lee; Mark R. Albertini; Lawrence E. Flaherty; Teresa M. Petrella; Howard Streicher; Vernon K. Sondak; John M. Kirkwood

    PURPOSE Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI.PATIENTS AND METHODS E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI.RESULTS Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti–programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P ≤ .001).CONCLUSION Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

    更新日期:2019-12-29
  • Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: COMPASS (WJOG5610L)
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Takashi Seto; Koichi Azuma; Takeharu Yamanaka; Shunichi Sugawara; Hiroshige Yoshioka; Kazushige Wakuda; Shinji Atagi; Yasuo Iwamoto; Hidetoshi Hayashi; Isamu Okamoto; Hideo Saka; Shigeki Mitsuoka; Daichi Fujimoto; Kazumi Nishino; Atsushi Horiike; Haruko Daga; Takashi Sone; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yoichi Nakanishi

    PURPOSE Patients with non–small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy.PATIENTS AND METHODS Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment.RESULTS Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens.CONCLUSION In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.

    更新日期:2019-12-29
  • Value of Biomarker Expression for Randomized Clinical Trial Design: One (More) Missed Opportunity
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Francisco E. Vera-Badillo; Andrew J. Robinson; David M. Berman; Christopher M. Booth

    Rosenberg et al1 recently reported the outcomes of a phase II, single-arm, multicenter trial assessing efficacy and toxicity of enfortumab vedotin (EV) in patients who had progressed to a median of 3 lines of treatment. Results of this novel therapy in a heavily treated population are encouraging. We congratulate the authors for proceeding with a phase III trial to confirm their findings.

    更新日期:2019-12-29
  • Reply to F.E. Vera-Badillo et al
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Jonathan E. Rosenberg; Daniel P. Petrylak

    We would like to thank Vera-Badillo et al1 for their comments on our article, “Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy.”2 Their letter raises interesting questions about the overall state of oncology drug development, particularly targeted therapies.

    更新日期:2019-12-29
  • Another Victory for Immune Checkpoint Blockade in Melanoma: Adjuvant Ipilimumab Over Interferon
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Allison Betof Warner; Michael A. Postow

    Before the immune checkpoint blockade era, patients with surgically resected, high-risk melanoma faced difficult prognoses. Recurrence rates were high, overall survival (OS) was poor, and treatment options were limited to interferon alfa-2b. Interferon offered patients improvement in recurrence-free survival (RFS), but its use was limited by significant adverse effects and controversial impact on OS.

    更新日期:2019-12-29
  • Pharmacogenomics and Endocrine Therapy in Breast Cancer
    J. Clin. Oncol. (IF 28.245) Pub Date : 2019-12-27
    Daniel F. Hayes; James M. Rae

    In 1896, Sir George Beatson reported that removal of the ovaries from three young women with locally advanced breast cancer resulted in substantial tumor shrinkage.1 Beatson’s report set the stage for what is arguably the anticancer treatment with the most impact in regards to lives saved: endocrine therapy (ET) for breast cancer.2 Nonetheless, ET is far from 100% effective, which raises the question, Why doesn’t ET work for all patients? McGuire and colleagues3 first reported that estrogen receptor (ER) is a very potent predictive factor for ET, and subsequent studies have demonstrated that ER-negative cancers are completely refractory to ET.2 Since then, investigators have focused principally on identifying acquired somatic tumor alterations in ER-positive cancers that might confer resistance to ET, including upregulation of alternative pathways such as human epidermal growth factor 2 (HER2)4 or the appearance of mutations in ESR1 (the gene that encodes for ER5) or in PIK3CA.6

    更新日期:2019-12-29
  • Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-01
    Aurelien Marabelle; Dung T. Le; Paolo A. Ascierto; Anna Maria Di Giacomo; Ana De Jesus-Acosta; Jean-Pierre Delord; Ravit Geva; Maya Gottfried; Nicolas Penel; Aaron R. Hansen; Sarina A. Piha-Paul; Toshihiko Doi; Bo Gao; Hyun Cheol Chung; Jose Lopez-Martin; Yung-Jue Bang; Ronnie Shapira Frommer; Manisha Shah; Razi Ghori; Andrew K. Joe; Scott K. Pruitt; Luis A. Diaz Jr

    PURPOSE Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.PATIENTS AND METHODS Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.RESULTS Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.CONCLUSION Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

    更新日期:2019-12-29
  • Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability–High/Mismatch Repair–Deficient Metastatic Colorectal Cancer: KEYNOTE-164
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-01
    Dung T. Le; Tae Won Kim; Eric Van Cutsem; Ravit Geva; Dirk Jäger; Hiroki Hara; Matthew Burge; Bert O’Neil; Petr Kavan; Takayuki Yoshino; Rosine Guimbaud; Hiroya Taniguchi; Elena Elez; Salah-Eddin Al-Batran; Patrick M. Boland; Todd Crocenzi; Chloe E. Atreya; Yi Cui; Tong Dai; Patricia Marinello; Luis A. Diaz Jr; Thierry André

    PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC).METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

    更新日期:2019-12-29
  • Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-01
    Michael S. Khodadoust; Alain H. Rook; Pierluigi Porcu; Francine Foss; Alison J. Moskowitz; Andrei Shustov; Satish Shanbhag; Lubomir Sokol; Steven P. Fling; Nirasha Ramchurren; Robert Pierce; Asa Davis; Richard Shine; Shufeng Li; Sophia Fong; Jinah Kim; Yi Yang; Wendy M. Blumenschein; Jennifer H. Yearley; Biswajit Das; Rajesh Patidar; Vivekananda Datta; Erin Cantu; Justine N. McCutcheon; Chris Karlovich; P. Mickey Williams; Priyanka B. Subrahmanyam; Holden T. Maecker; Steven M. Horwitz; Elad Sharon; Holbrook E. Kohrt; Martin A. Cheever; Youn H. Kim

    PURPOSE To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).PATIENTS AND METHODS CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.RESULTS Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.CONCLUSION Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

    更新日期:2019-12-29
  • Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-01
    Kirsten K. Ness; Juan C. Plana; Vijaya M. Joshi; Russell V. Luepker; Jean B. Durand; Daniel M. Green; Robyn E. Partin; Aimee K. Santucci; Rebecca M. Howell; Deo Kumar Srivastava; Melissa M. Hudson; Leslie L. Robison; Gregory T. Armstrong

    PURPOSE Exercise intolerance, associated with heart failure and death in general populations, is not well studied in survivors of childhood cancer. We examined prevalence of exercise intolerance in survivors exposed or not to cardiotoxic therapy, and associations among organ system function, exercise intolerance, and mortality.METHODS Participants consisted of 1,041 people who had survived cancer ≥ 10 years (and had or did not have exposure to anthracyclines and/or chest-directed radiation) and 285 control subjects. Exercise intolerance was defined as peak oxygen uptake < 85% predicted from maximal cardiopulmonary exercise testing; organ functions were ascertained with imaging or clinical testing. Multivariable regression of the data was performed to compare exercise capacity between survivors exposed or unexposed to cardiotoxic therapy and control subjects, and to evaluate associations between treatment and organ function, and organ function and exercise intolerance. Propensity score methods in time-to-event analyses evaluated associations between exercise intolerance and mortality.RESULTS Survivors (mean age ± standard deviation [SD], 35.6 ± 8.8 years) had lower mean (± SD) peak oxygen uptake (exposed: 25.74 ± 8.36 mL/kg/min; unexposed: 26.82 ± 8.36 mL/kg/min) than did control subjects (32.69 ± 7.75 mL/kg/min; P for all < .001). Exercise intolerance was present in 63.8% (95% CI, 62.0% to 65.8%) of exposed survivors, 55.7% (95% CI, 53.2% to 58.2%) of unexposed survivors, and 26.3% (95% CI, 24.0% to 28.3%) of control subjects, and was associated with mortality (hazard ratio, 3.9; 95% CI, 1.09 to 14.14). Global longitudinal strain (odds ratio [OR], 1.71; 95% CI, 1.11 to 2.63), chronotropic incompetence (OR, 3.58; 95% CI, 1.75 to 7.31); forced expiratory volume in 1 second < 80% (OR, 2.59; 95% CI, 1.65 to 4.09), and 1 SD decrease in quadriceps strength (OR, 1.49; 95% CI, 1.23 to 1.82) were associated with exercise intolerance. Ejection fraction < 53% was not associated with exercise intolerance.CONCLUSION Exercise intolerance is prevalent among childhood cancer survivors and associated with all-cause mortality. Treatment-related cardiac (detected by global longitudinal strain), autonomic, pulmonary, and muscular impairments increased risk. Survivors with impairments may require referral to trained specialists to learn to accommodate specific deficits when engaging in exercise.

    更新日期:2019-12-29
  • Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma
    J. Clin. Oncol. (IF 28.245) Pub Date : 2020-01-01
    Matthias Begemann; Sebastian M. Waszak; Giles W. Robinson; Natalie Jäger; Tanvi Sharma; Cordula Knopp; Florian Kraft; Olga Moser; Martin Mynarek; Lea Guerrini-Rousseau; Laurence Brugieres; Pascale Varlet; Torsten Pietsch; Daniel C. Bowers; Murali Chintagumpala; Felix Sahm; Jan O. Korbel; Stefan Rutkowski; Thomas Eggermann; Amar Gajjar; Paul Northcott; Miriam Elbracht; Stefan M. Pfister; Udo Kontny; Ingo Kurth

    PURPOSE The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete.METHODS Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series.RESULTS We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors.CONCLUSION Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

    更新日期:2019-12-29
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