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The New England Journal of Medicine Jan 2017Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors.
METHODS
We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here.
RESULTS
At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame.
CONCLUSIONS
Treatment with Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
Topics: Aged; Antineoplastic Agents; Delayed-Action Preparations; Disease-Free Survival; Drug Administration Schedule; Female; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Nausea; Neuroendocrine Tumors; Octreotide; Organometallic Compounds
PubMed: 28076709
DOI: 10.1056/NEJMoa1607427 -
The Oncologist Aug 2022Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost... (Review)
Review
Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost burden of chemotherapy-induced neutropenia/FN in the US, and summarizes recommendations for FN prophylaxis, including the interim guidance that was recommended during the coronavirus disease 2019 (COVID-19) pandemic. This review indicates that neutropenia/FN place a significant burden on patients in terms of hospitalizations and mortality. Most patients with neutropenia/FN presenting to the emergency department will be hospitalized, with an average length of stay of 6, 8, and 10 days for elderly, pediatric, and adult patients, respectively. Reported in-hospital mortality rates for neutropenia/FN range from 0.4% to 3.0% for pediatric patients with cancer, 2.6% to 7.0% for adults with solid tumors, and 7.4% for adults with hematologic malignancies. Neutropenia/FN also place a significant cost burden on US healthcare systems, with average costs per neutropenia/FN hospitalization estimated to be up to $40 000 for adult patients and $65 000 for pediatric patients. Evidence-based guidelines recommend prophylactic granulocyte colony-stimulating factors (G-CSFs), which have been shown to reduce FN incidence while improving chemotherapy dose delivery. Availability of biosimilars may improve costs of care. Efforts to decrease hospitalizations by optimizing outpatient care could reduce the burden of neutropenia/FN; this was particularly pertinent during the COVID-19 pandemic since avoidance of hospitalization was needed to reduce exposure to the virus, and resulted in the adaptation of recommendations to prevent FN, which expanded the indications for G-CSF and/or lowered the threshold of use to >10% risk of FN.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Chemotherapy-Induced Febrile Neutropenia; Child; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Pandemics; COVID-19 Drug Treatment
PubMed: 35552754
DOI: 10.1093/oncolo/oyac074 -
The New England Journal of Medicine Nov 2016The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).
METHODS
In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10.
RESULTS
The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10 for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval [CI], 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.
CONCLUSIONS
Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).
Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Letrozole; Middle Aged; Neoplasm Staging; Nitriles; Purines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Triazoles
PubMed: 27717303
DOI: 10.1056/NEJMoa1609709 -
Journal of Clinical Oncology : Official... Jan 2022Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and...
PURPOSE
Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years).
METHODS
We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed.
RESULTS
The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of , , , , , and was noted in partial responders compared with patients with complete response.
CONCLUSION
IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.
Topics: Adenine; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Female; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Progression-Free Survival; Rituximab; Sequence Analysis, RNA; Time Factors; Exome Sequencing
PubMed: 34797699
DOI: 10.1200/JCO.21.01797 -
Cancer Journal (Sudbury, Mass.)Venetoclax has transformed the therapeutic landscape of acute myeloid leukemia (AML). Hypomethylating agents with venetoclax (HMA-VEN) have significantly improved...
Venetoclax has transformed the therapeutic landscape of acute myeloid leukemia (AML). Hypomethylating agents with venetoclax (HMA-VEN) have significantly improved outcomes and have become the standard therapy for older/unfit patients with newly diagnosed AML and are comparable to intensive chemotherapy in salvage setting. Venetoclax with intensive chemotherapy have shown high response rates in both frontline and salvage setting in younger patients, and triplet combinations with HMA-VEN and FLT3 inhibitors have shown encouraging results in FLT3mut AML. While patients with NPM1mut, IDH1/2mut experience favorable outcomes, those with TP53mut and secondary AML may experience minimal benefit from the addition of venetoclax. Despite improved outcomes, severe cytopenias and infectious complications are common with venetoclax-based regimens. Early response evaluation, dose reductions, venetoclax interruptions, use of growth factors, and prophylactic antimicrobials may minimize such myelosuppression and risk of infections. Outcomes after failure of frontline HMA-VEN are dismal, and novel approaches are needed to abrogate primary and acquired resistance.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 35072368
DOI: 10.1097/PPO.0000000000000567 -
JAMA Oncology Dec 2023Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
IMPORTANCE
Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen.
OBJECTIVE
To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]).
DESIGN, SETTING, AND PARTICIPANTS
This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021.
INTERVENTIONS
Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine.
MAIN OUTCOMES AND MEASURES
The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety.
RESULTS
Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia.
CONCLUSIONS AND RELEVANCE
This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01356290.
Topics: Humans; Male; Child; Child, Preschool; Adolescent; Female; Medulloblastoma; Etoposide; Quality of Life; Administration, Metronomic; Brain Neoplasms; Cerebellar Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37883081
DOI: 10.1001/jamaoncol.2023.4437 -
Journal of Feline Medicine and Surgery Aug 2021The aim of this study was to assess the efficacy and tolerability of lomustine, methotrexate and cytarabine chemotherapy as rescue treatment for feline lymphoma.
OBJECTIVES
The aim of this study was to assess the efficacy and tolerability of lomustine, methotrexate and cytarabine chemotherapy as rescue treatment for feline lymphoma.
METHODS
The medical records of 13 cats treated with lomustine, methotrexate and cytarabine for relapsed high-grade feline lymphoma, at a single institution between 2013 and 2018, were examined. All anatomical types were included. Data were analysed using descriptive statistics.
RESULTS
Nine cats received all three drugs and four cats received only two drugs owing to progressive disease. In cats that received (or in which there was intention to treat with) all three drugs, 6/13 (46%) demonstrated a complete or partial response to chemotherapy. Treatment was generally well tolerated, although two cats experienced Veterinary Comparative Oncology Group (VCOG) grade 3 neutropenia and one cat experienced VCOG grade 3 thrombocytopenia. The median progression-free survival was 61 days (range 16-721 days).
CONCLUSIONS AND RELEVANCE
CHOP-(cyclophosphamide, doxorubicin, vincristine, prednisolone) and COP-based protocols are established first-line chemotherapy for feline lymphoma, but standard rescue protocols are lacking. Lomustine has become a popular single-agent option, but prolonged or cumulative myelosuppression can result in treatment delays, risking relapse. Therefore, a multidrug lomustine-based protocol may be advantageous, and, from first principles, should also better overcome resistance. This study suggests that lomustine, methotrexate and cytarabine may represent an efficacious and well-tolerated protocol for feline lymphoma rescue.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cat Diseases; Cats; Cyclophosphamide; Cytarabine; Lomustine; Lymphoma; Methotrexate; Neoplasm Recurrence, Local
PubMed: 33176543
DOI: 10.1177/1098612X20972066 -
Nutrition (Burbank, Los Angeles County,... Jan 2020Malnutrition is the most common complication of patients with esophageal cancer and can lead to poor prognosis and death. Good nutritional status has been shown to help... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Malnutrition is the most common complication of patients with esophageal cancer and can lead to poor prognosis and death. Good nutritional status has been shown to help improve patient outcomes and reduce complications. In the absence of specific evidence on the effect of nutrition in patients with esophageal cancer, the purpose of this study was to investigate the effect of whole-course nutrition management on the prognosis and complications of chemoradiotherapy in patients with esophageal cancer through a randomized controlled trial.
METHODS
A total of 96 patients with esophageal cancer treated with concurrent chemoradiation were randomized to an intervention group (treated with whole-course nutrition management from the Nutrition Support Team) and a control group (treated with the general nutritional method) for approximately 6 wk. Dietary surveys and body measurements were conducted at baseline and every day thereafter. Patient-generated Subjective Global Assessment score, blood index, quality of life, and psychological condition were assessed at baseline and every week before discharge. Complications (e.g., radiation esophagitis, myelosuppression, and skin symptoms), completion rates of therapy, short-term efficacy evaluation, as well as clinical outcomes were measured.
RESULTS
A total of 85 patients completed the study (intervention group = 45; control group = 40). There were significant differences in the changes of serum albumin and total protein between the two groups throughout the trial (P < 0.05). Complications (e.g., radioactive esophagitis, skin symptom of complications) and quality of life were statistically different before and after the intervention (P < 0.05). The difference in the change of other indicators was not statistically significant.
CONCLUSIONS
Whole-course nutrition management can improve the nutritional status of patients with esophageal cancer treated with concurrent chemoradiotherapy, reduce the severity of radiation esophagitis and radiation skin reactions, improve the quality of life, and relieve depressive symptoms.
Topics: Aged; Chemoradiotherapy; Esophageal Neoplasms; Female; Humans; Male; Malnutrition; Middle Aged; Nutrition Therapy; Nutritional Status; Quality of Life; Treatment Outcome
PubMed: 31526964
DOI: 10.1016/j.nut.2019.110558 -
Pediatric Blood & Cancer Aug 2021Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Temozolomide with irinotecan versus temozolomide, irinotecan plus bevacizumab for recurrent medulloblastoma of childhood: Report of a COG randomized Phase II screening trial.
BACKGROUND
Approximately 30% of children with medulloblastoma (MB) experience recurrence, which is usually incurable. This study compared the overall survival (OS) of patients receiving temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan, and bevacizumab for recurrent MB/central nervous system (CNS) primitive neuroectodermal tumor (PNET).
METHODS
Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m /day PO on days 1-5) and irinotecan (50 mg/m /day IV on days 1-5) with or without bevacizumab (10 mg/kg IV on days 1 and 15).
RESULTS
One hundred five patients were eligible and treated on study. Median OS was 13 months in the standard arm and 19 months with the addition of bevacizumab; median event-free survival (EFS) was 6 months in the standard arm and 9 months with the addition of bevacizumab. The hazard ratio for death from the stratified relative-risk regression model is 0.63. Overall, 23 patients completed 12 courses of planned protocol therapy, 23% (12/52) in the experimental arm with bevacizumab versus 21% (11/53) in the standard arm. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is three of 52 (5.8%) (95% CI 1.2-16%). Events included myelosuppression, electrolyte abnormalities, diarrhea, and elevated transaminases. One intracranial hemorrhage event was observed in each arm.
CONCLUSION
The addition of bevacizumab to TMZ/irinotecan significantly reduced the risk of death in children with recurrent MB. The combination was relatively well tolerated in this heavily pretreated cohort. The three-drug regimen demonstrated a sufficient risk reduction to warrant further investigation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Child; Humans; Irinotecan; Medulloblastoma; Neuroectodermal Tumors, Primitive; Temozolomide
PubMed: 33844469
DOI: 10.1002/pbc.29031 -
Current Hematologic Malignancy Reports Dec 2017The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era. (Review)
Review
PURPOSE OF REVIEW
The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era.
RECENT FINDINGS
Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
Topics: Humans; Primary Myelofibrosis
PubMed: 29098608
DOI: 10.1007/s11899-017-0403-0