First-line Therapy In Elderly Patients Research Articles

14-day pantoprazole- and amoxicillin-containing high-dose dual therapy for Helicobacter pylori eradication in elderly patients: A prospective, randomized controlled trial.

Background: Currently, the management of Helicobacter pylori (H. pylori) infection in elderly patients is controversial. We investigated whether high-dose dual therapy would serve as the first-line therapy in elderly patients. Methods: This was a single-center, randomized study of 150 elderly patients with H. pylori infection who were randomly assigned to 14-day therapy with pantoprazole 40mg 3 times daily and either amoxicillin 1,000mg 3 times daily or amoxicillin 1,000mg twice daily, clarithromycin 500mg twice daily and bismuth 220mg twice daily. H. pylori eradication was evaluated by a 13C-urea breath test 4 weeks after the completion of treatment. Results: Successful eradication was achieved in 89.3% of the high-dose dual therapy (HT) group in the intention-to-treat (ITT) analysis, 91.7% in the modified intention-to-treat (mITT) analysis, and 93.0% for per-protocol (PP) analysis which was similar to the bismuth-containing quadruple therapy (BQT) group (86.6%, 87.8%, and 90.3%, respectively). There were no significant difference between the HT group and the BQT group in the ITT analysis (p = 0.484), mITT analysis (p = 0.458), or PP analysis (p = 0.403). HT was associated with fewer side effects (10.6% of patients) than BQT (26.6%) (p = 0.026). Conclusion: In this trial, we found that 14-day HT had a similar eradication rate to BQT but fewer side effects, which may be better for elderly patients.

First-line therapy for elderly patients with advanced renal cell carcinoma in the immuno-oncology era: a network meta-analysis.

Tyrosine kinase inhibitors (TKI) or immune checkpoint blockade (ICB), either alone or in combination, confers a significant overall survival (OS) benefit for metastatic RCC in the first-line setting. However, guidance for optimal treatment selection in elderly patients remains limited. A database search was performed to identify eligible randomized controlled trials (RCTs) evaluating first-line regimens for patients with advanced RCC older than 65years old. The primary outcomes were progression-free survival (PFS) and OS. Indirect comparisons of available regimens were estimated using a random-effects network meta-analysis. A total of 14 and five RCTs were eligible for PFS and OS analyses. Compared with sunitinib, pembrolizumab plus axitinib (HR 0.68, 95% CI 0.48-0.97) and pembrolizumab plus lenvatinib (HR 0.61, 95% CI 0.4-0.94) were associated with improved OS. Pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and cabozantinib alone each showed improved PFS over sunitinib. Among these, pembrolizumab plus lenvatinib showed better PFS than pembrolizumab plus axitinib (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared to nivolumab plus cabozantinib (HR 0.63, 95% CI 0.39-1.03) and cabozantinib alone (HR 0.84, 95% CI 0.40-1.77). Network ranking showed pembrolizumab plus lenvatinib provided the favored OS and PFS benefit for elderly patients. The combination of ICB with TKI such as pembrolizumab plus lenvatinib needs to be considered over monotherapy in the elderly population, but further validation using real-world data or prospective trials is necessary to confirm the efficacy and safety of first-line regimens for the geriatric population with advanced RCC.

First-line therapy for elderly patients with advanced renal cell carcinoma (aRCC): A systemic review and network meta-analysis.

4532 Background: Multiple regimens incorporating tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI), either alone or in combination, confer a significant OS benefit in 1L metastatic clear cell RCC. However, guidance for optimal treatment selection in elderly patients remains limited. A network meta-analysis (NMA) was performed to compare the efficacy of 1L treatments for elderly patients with aRCC. Methods: Database search was performed through Pubmed, Embase, Web of Science, and Scopus. Eligible studies were randomized controlled trials (RCTs) evaluating first-line regimens for patients with aRCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Indirect comparisons of available regimens were estimated using a random-effects NMA. Results: 14 RCTs with more than 2,100 patients and 5 RCTs with 1,529 patients were eligible for PFS and OS analyses, respectively. Compared with sunitinib (Sun), the pembrolizumab (Pem) + axitinib (Axi) (HR 0.68, 95% CI 0.48-0.97) and Pem + lenvatinib (Len) (HR 0.61, 95% CI 0.4-0.94) regimens were associated with significantly improved OS. In comparing the TKI-ICI combinations with dual ICI nivolumab (Niv) + ipilimumab (Ipi), no significant OS differences were observed (Pem + Len: HR 0.71, 95% CI 0.40-1.27; Pem + Axi: HR 0.79, 95% CI 0.47-1.34; Avelumab (Ave) + Axi: HR 1.03, 95% CI 0.58-1.85; Niv + cabozantinib [Cab]: HR 1.03, 95% CI 0.57-1.93, using Niv + Ipi as a reference). Pem + Len, Niv + Cab, Pem + Axi, and Cab alone each showed improved PFS over Sun (Table). Among these, Pem + Len showed a PFS advantage compared to Pem + Axi (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared with the other regimens (vs Niv + Cab: HR 0.63, 95% CI 0.39-1.03; vs Cab alone: HR 0.84, 95% CI 0.40-1.77). Conclusions: Pem + Len and Pem + Axi provided the largest OS benefit in elderly patients for 1L aRCC. Pem + Len showed improved PFS compared with Pem + Axi, but no difference compared with Niv + Cab or Cab alone. Further validation using real-world data is needed to confirm the efficacy and safety of first-line regimens for the geriatric population with aRCC.[Table: see text]

Azacitidine/Venetoclax Combination as First-Line Therapy in Elderly Patients with Acute Myeloid Leukemias: A First Step

Background. The treatment of elderly patients with acute myeloid leukemias (AML) is one of the most formidable challenges in oncohematology. Hypomethylating drugs combined with venetoclax show relatively high efficacy and lower toxicity in elderly AML patients. Aim. To retrospectively analyze the efficacy and tolerability of the combined azacitidine/venetoclax therapy in AML primary patients of older age as well as to determine a spectrum of issues related to the implementation of this regimen in real-world clinical practice. Materials & Methods. The retrospective analysis enrolled a cohort of patients followed-up at the Botkin City Clinical Hospital (п = 35). The median age was 73 years (range 6090 years), 57 % of patients were over 70 years of age. The median follow-up duration was 5.2 months (range 1.6-42.6 months). By the time of final analysis 15 patients were still receiving the therapy. The median of overall survival was 11.1 months (95% confidence interval [95% CI] 8.1-14.1 months). The causes of death in 20 patients were AML progression (n = 3), non-COVID-19 infectious complications (n = 3), and COVID-19 (n = 10). In 4 patients the cause of death remained unidentified. Results. Complete remission (CR) was documented in 17 (48.5 %) patients; CR with incomplete hematologic recovery was identified in 9 (26 %) patients. The median time before achieving remission was 67 days (range 27-120 days). In 96 % of patients CR was achieved after 3 azacitidine/venetoclax cycles. The mean CR duration was 9.2 months (95% CI 5.7-12.6 months); the median time before loss of response was 19 months. Relapses were diagnosed in 5 patients. Neutropenia > grade 3 was identified in patients who achieved remission on subsequent therapy cycles in 100 % of cases (n = 26), anemia > grade 2 was reported in 9 (34 %) patients, and thrombocytopenia > grade 3 was detected in 13 (50 %) patients. Despite frequent neutropenia, patients with remission did not show any severe infectious complications. Conclusion. The combined azacitidine/venetoclax therapy in elderly patients yields remission in more than 70 % of cases and is not marked by any severe infectious complications, despite developing neutropenia. Due to its ease of administration and low toxicity, this regimen can be performed in outpatient units.

The CXCL12/CXCR4 Pathway As a Potential Target of Tipifarnib in Acute Myeloid Leukemia and Myelodysplastic Syndromes

BackgroundCXCL12 is a chemokine that is essential for homing of myeloid cells in the bone marrow (BM). It has been postulated that a CXCL12 receptor present in myeloid cells, CXCR4, signals in part through HRAS, a protein that is uniquely dependent on farnesylation for activity. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT) that had been shown to provide clinical benefit in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS); however, no molecular target that could explain the activity of tipifarnib in AML and MDS has been identified. Based on initial observations in T cell lymphoma (Witzig EHA 2017), we investigated a role for CXCL12 and myeloid cell homing in BM as biomarkers of the activity of tipifarnib in AML and MDS studies.MethodsCTEP20 was a phase 2, multicenter, open-label study that investigated the efficacy and safety of tipifarnib in 158 older adults with previously untreated, poor-risk AML. AML301 was a phase 3 (N=457), multicenter, open-label study that evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients with newly diagnosed, de novo, or secondary AML. INT28 was a multicenter phase 2 study that evaluated tipifarnib in 82 pts with poor-risk MDS. Global gene expression data generated using the Affymetrix U133A gene chip from 34 pretreatment BM samples collected from CTEP20 pts (GSE8970) was analyzed with respect to pretreatment hematological parameters and study outcomes. The Kaplan-Meier method was employed to estimate survival and progression free survival (PFS) and the analysis of prognostic variables. Clinical trial information: NCT00027872, NCT00093990, NCT00050154.ResultsNine complete responses (CR) and 13 best responses of progression of disease (PD) were observed in 34 pts with available BM gene expression data in study CTEP20. Pts in the 3rd (upper) tertile of CXCL12 expression experienced 6 CRs and 2 PDs whereas 1 CR and 8 PDs were observed in the 1st (lower) tertile (p=0.015). BM homing of AML blasts correlated with CXCL12 expression: Median percentage of BM blasts (BMB) and peripheral blasts (PB) were, respectively, 45% and 0% in the upper CXCL12 tertile, and 30% and 26.5% in the lower tertile (p<0.001) (Figure, A). Pts with high tumor burden in BM (BMB blasts>40%) and low circulating blasts (PB<1%) (N=5) had high CXCL12 expression in BM (3423 vs 742 counts, P<0.001, N=27) and experienced prolonged clinical benefit, with 5 CRs and a median PFS of 431 days (431 vs 35 days, HR=0.23, P<0.001, N=27) (Figure, B). The effect of BM homing was then investigated in the phase 3 AML301 trial of tipifarnib vs BSC. While the overall study (N=457) failed to identify an increased efficacy of tipifarnib compared with BSC (median survival of 109 vs 107 days, hazards ratio, HR=1.02, ns), median survival approximately doubled in the tipifarnib am compared with BSC in the subset of patients with high BMB (>40%) and low PB (<10%) while no effect was observed in the control arm (201 vs 109 days, HR=0.58, p=0.02, N=82) (Figure, B). Since CXCL12 is also a potent chemotactic factor for normal neutrophils and syndromes of hyperactivation of the CXCL12/CXCR4 pathway present with neutropenia, we investigated whether neutropenia could be a surrogate of tipifarnib activity. In AML301 pts with WBC counts>LLN (no myelosuppression), increasing neutropenia correlated with increasing clinical benefit from tipifarnib that was due in part to a poorer prognosis of BSC in neutropenic pts (113 vs 80 days median OS, HR=0.81, p=0.036, N=109, for pts with baseline neutrophils<1 giga/L). Finally, we tested the effect of neutropenia on the activity of tipifarnib in INT28. Sixty seven of the 82 MDS pts were transfusion dependent (TD) at study entry. Overall conversion to transfusion independence (TI) and response rate (ORR: CR, CRp, PR) were respectively 16% and 7.5% in the TD pts. Pts with >1 giga/L neutrophils at study entry experienced 5% TI and no responses (N=37) while 30% TI, 2 CRs, 2 CRp and 1 PR were observed in the subset of neutropenic pts.ConclusionCXCL12 expression and BM homing constitute potential biomarkers of the activity of tipifarnib in AML and MDS supporting the hypothesis that the CXCL12 pathway is a potential target of FT inhibitors. [Display omitted] DisclosuresGualberto:Kura Oncology: Employment, Equity Ownership, Other: Chief Medical Officer, Patents & Royalties. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Janes:Wellspring Biosciences: Employment. Kessler:Kura Oncology: Employment. Raza:Kura Oncology: Research Funding; Syros Pharmaceuticals: Research Funding; Novartis: Speakers Bureau; Celgene Inc.: Research Funding; Genoptix: Speakers Bureau; Onconova Therapeutics: Research Funding, Speakers Bureau; Janssen R&D: Research Funding.

Efficacy and Safety of Decitabine As First-Line Therapy for Elderly Patients with Acute Myeloid Leukemia.a Real Life Multicentric Experience of the Northern Italy

Introduction: Decitabine has been recently approved in Europe for treatment of AML patients (pts) aged more than 65 years and unfit to receive standard chemotherapy. However data on its efficacy and tolerability derive mainly from clinical trials performed in selected pts. Herein we report on a population based series of AML pts treated with decitabine and registered in observational prospective studies.Methods: Between June 2013 and June 2017, 150 elderly AML pts were diagnosed and treated at 17 Hematological center of Northern Italy. Their F/M ratio was 66/84, median age was 75 years (range 65-85); the ECOG performance status (PS) was >2 in 19 pts (13%). Median WBC count was 3.95 x10^3/mL (range 0.34 to 255); marrow blasts were between 20% and 30% in 30 pts (20%). AML was de novo in 79 (53%), therapy-related in 5 (3%) and secondary to myeloid neoplasms (s-AML) in 66 (44%) pts, respectively (52 post-myelodysplastic and 14 post-myeloproliferative disease). Karyotype (K), available in 126 cases, was normal (NK) in 54 pts (43%), t(8;21) in 4 (3%), with intermediate-risk abnormalities in 25 (20%), and with adverse-risk (adv) abnormalities according to ELN risk classification in 42 pts (33%). NPM1 mutation was detected in 9 of 40 (23%) evaluable pts with NK, with FLT3-ITD mutation in 4 of them. Decitabine was administered at the recommended dose of 20mg/mq/daily for 5 days every 4 weeks until toxicity or progression of AML.Results: The total number of cycles administered was 761, with a median of 3 cycles/pt (range 1-22). The overall response rate (ORR) was 47% (55/116 evaluable cases). Response was not evaluable in 34 pts (18 too early, 1 early death and 15 deaths during aplasia). A complete remission (CR) was obtained in 34 (29%) cases, partial response (PR) in 10(9%), and hematological improvement (HI) in 11(10%) pts, respectively. In 38 pts (33%) the AML remained stable (SD), whereas 23 (20%) were not responders (NR). The median time to best response was 3.5 months (ms) (range 1-8.5). The median response duration was 5 ms (2-23). Relapse/disease progression occurred in 9/55 responding pts (25.7%). Median survival was 12.5 ms (range 1-35); overall survival (OS) at 1 and 2 years were 52.7% +/- 5 (SE) and 13% +/-7 (SE) (Fig 1a). OS was not influenced by the type of AML (de novo 12.4 ms vs s-AML 16 ms; p 0.8), nor by age, PS, marrow blasts percentage or depth of response (CR vs PR+HI pts; p 0.55). However achieving any response was significantly better than having SD or NR [OS 22.3 ms in responders vs 8 ms in SD (p<0.0001) vs 3 ms in NR, respectively]. Moreover adv risk significantly worsened survival (median survival of 5.5 ms in adv and of 18.6 ms in not-adv K; log- rank p 0.0012) (Fig 1b). Overall, the treatment was well tolerated. Infections were the most frequent adverse event, occurring in 110 cases during 761 cycles (14%) and being responsible for 93% of hospitalizations. They were significantly more common before achieving hematological response during the first 3 cycles, (84 of 356; 23.6%), than in subsequent cycles (26 of 405; 6.4%) [p< 0.0001]. In detail, there were 41 pneumonia (37%), 23 sepsis (21%), 26 FUO (24%), and 20 further type of infections (18%).Ten of 30 (33%) pneumoniae occurring during the first 3 cycles were of fungal origin. Sixty-three pts (42%) died, 40 (63%) of them during the first 3 cycles (40/356 vs 23/405 p 0.0079). The main cause of death was disease progression (67%) followed by infection (19%) in the first 3 cycles and other causes (13%). Only one pt (1%) died of infection while in CR.Conclusion: These data confirm that decitabine is a feasible and effective first line treatment for elderly AML pts, even in a population-based setting. In this real life experience the ORR was 47% and these results were even better than those reported in clinical trials. In our observational study adverse K remains an unfavourable prognostic factor and pts with not-adverse K and obtaining CR was better survival (median survival: 22.3 ms). Safety profile was acceptable and the most important adverse events were infectious complications with a mortality infections related significantly higher in the first three cycles and in non responder patients. [Display omitted] DisclosuresRossi:Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Carboplatin With Nab-Paclitaxel Versus Docetaxel in Elderly Patients with Squamous-Cell Lung Cancer (CAPITAL): A Randomized, Multicenter, Open-Label, Phase III Trial

Efficacy and Safety of Carboplatin With Nab-Paclitaxel Versus Docetaxel in Elderly Patients with Squamous-Cell Lung Cancer (CAPITAL): A Randomized, Multicenter, Open-Label, Phase III Trial

Treatment rationale and design of the PROLONG study: safety and efficacy of pembrolizumab as first-line therapy for elderly patients with non-small cell lung cancer.

BackgroundPembrolizumab is recommended as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a Programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, the safety and efficacy were not investigated among patients who were ≥75 years old.MethodsThis open-label single-arm phase II study is designed to evaluate pembrolizumab as first-line therapy for patients who are ≥75 years old with advanced NSCLC and a PD-L1 TPS of ≥50% without driver mutations. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, objective response rate, safety, and quality of life. Recruitment started in October 2017 and is expected to continue for approximately 3 years.ConclusionsGiven the currently poor prognosis of elderly patients with advanced NSCLC, we hope that the findings of this study will facilitate more effective treatment in this setting.

A Comparison of Leukotriene Receptor Antagonists to Low-Dose Inhaled Corticosteroids in the Elderly with Mild Asthma

Although elderly patients with asthma have clinical characteristics different from those of young adults, few studies or guidelines have focused on specific treatments for this population. This study compared the effectiveness of leukotriene receptor antagonists (LTRAs) versus inhaled corticosteroids (ICSs) in elderly patients with asthma in real-world settings. We extracted records for elderly patients with asthma who were newly prescribed LTRAs or low-dose ICSs from January 2003 to December 2010 from National Sample Cohort data of Korea. We defined the first prescription date for each medication as the index date. We compared the risks of asthma exacerbation between the 2 groups using Cox proportional-hazard regression after propensity score-based inverse probability of treatment weighting to balance covariates between treatment groups. We also compared asthma-related health care resource utilization and medication compliance in both groups using chi-square test and t test. The number of identified patients newly treated with LTRAs and low-dose ICSs was 1571 and 121, respectively. The risks of asthma exacerbation in the LTRA and low-dose ICS groups after weighting were not significantly different (hazard ratio, 0.98; 95% CI, 0.65-1.54). The proportion with high compliance (medication possession ratio ≥80%) in the LTRA group was higher than that in the low-dose ICS group. The effectiveness of LTRAs was not different from that of low-dose ICSs regarding the risk of asthma exacerbation in elderly patients with asthma in real-world settings. Given the practical benefits gained from convenient administration, LTRAs can be considered a reasonable alternative first-line therapy for elderly patients with mild asthma.

Assessing Outcomes and Prognostic Factors for First-Line Therapy in Elderly Patients With Metastatic Renal Cell Carcinoma: Real-Life Data From a Single United Kingdom Institution.

Elderly metastatic renal cell carcinoma (mRCC) patients are under-represented in clinical trials, whose results are therefore difficult to translate into routine management of older patients. We aimed at exploring treatment outcomes and prognostic factors in our real-life elderly mRCC cohort receiving first-line tyrosine kinase inhibitor (TKI) monotherapy. We retrospectively analyzed demographic and clinicopathological characteristics, and treatment data of elderly (≥ 70 years old at first-line start) mRCC patients starting either pazopanib or sunitinib as first-line treatment in our institution between March 2012 and April 2018. Baseline characteristics included age-adjusted Charlson comorbidity index (CCI). In total, the records of 35 elderly mRCC patients were identified and retrospectively analyzed. Overall response rate, median progression-free survival, and median overall survival were 20%, 9.7 months, and 21.6 months, respectively. Karnofsky performance status≤ 70%, sarcomatoid features, absolute neutrophil count greater than upper limit of normal, and treatment-related Grade 3 arterial hypertension were independently associated with survival after multivariate analysis. Age-adjusted CCI was significantly associated with survival in univariate analysis only. The overall incidence of Grade 3 to 5 toxicities was 74%. Seven patients (20%) received early crossover to either sunitinib or pazopanib because of toxicity. Dose reduction was applied in 24 (73%) of the 33 patients who completed at least 1 cycle. First-line TKI monotherapy provided clinical benefit in our elderly mRCC cohort. Relatively frequent dose reductions helped to maintain an acceptable tolerability profile. Further research is warranted to explore the significance of prognostic factors in elderly mRCC patients.

Compliance with biweekly SOX combination chemotherapy versus triweekly SOX as a first-line therapy for elderly patients with advanced gastric cancer.

e16075Background: Although the triweekly S-1 and oxaliplatin (SOX3) combination chemotherapy has yielded significant improvements in PFS, OS and RR, the high toxicities limit the use in elderly pat...

Pembrolizumab (pembro) as first-line therapy in elderly patients (pts) with poor performance status with cisplatin-ineligible advanced urothelial cancer (UC): Results from Keynote-052

Pembrolizumab (pembro) as first-line therapy in elderly patients (pts) with poor performance status with cisplatin-ineligible advanced urothelial cancer (UC): Results from Keynote-052

Peroral Endoscopic Myotomy Is Safe and Effective in Octogenarians

Although the adverse event rates reported for peroral endoscopic myotomy (POEM) for treatment of achalasia have been amazingly low, consensus recommendations do not support its use as first-line therapy in elderly patients. In one previous report, more than 60% of patients aged ≥75 years with achalasia were left untreated, presumably because of high perceived risk for procedure-related adverse events. To investigate the …

Increased Age Associated with Reduced Likelihood of Recurrence After Coiling of Ruptured Aneurysms

The effect of patient age on the likelihood of recurrence of ruptured aneurysms after endovascular coil embolization is not well understood. Our aim was to compare the incidence of aneurysmal recurrence after coiling between young and old patients. We performed a retrospective cohort study on patients presenting to our institution with a ruptured intracranial aneurysm treated with endovascular coiling. Aneurysm recurrence was defined as a Modified Raymond Roy Classification (MRRC) grade of 3A or 3B performed on first follow-up angiography. Patients were dichotomized into young and old patient groups, with patients 65 years and older categorized as older adults. The relationship between patient age and the likelihood of aneurysm recurrence was then investigated using multivariate logistic regression analysis. There were 156 patients who met our inclusion criteria for analysis, 37 (23.7%) of whom were greater than or equal to 65 years of age. Elderly patients were less likely to experience aneurysm recurrence (27.0% vs. 42.9%, respectively; P= 0.085) or to undergo aneurysm retreatment (18.9% vs. 37.0%, respectively; P= 0.041). On multivariate analysis, after adjusting for smoking status, aneurysmal size, coil-embolization ratio, and MRRC grade at time of treatment, elderly age was independently associated with a reduced risk of aneurysm recurrence (odds ratio, 0.33; 95% confidence interval, 0.11-0.92; P= 0.034). Our results suggest that elderly age may confer a reduced risk of aneurysmal recurrence after endovascular coiling, providing further evidence that coiling should be considered a first-line therapy in elderly patients with a ruptured aneurysm.

O1-19-4 - Phase II Study of Tegafur/Uracil and Leucovorin plus Bevacizumab for Elderly Patients with Advanced Colorectal Cancer

Background/Objective: Oral tegafur/uracil and leucovorin (UFT/LV) therapy is effective and safe for elderly patients with advanced or metastatic colorectal cancer (CRC). However, there are few studies on the combination of bevacizumab with UFT/LV. This clinical study evaluated the efficacy and safety of UFT/LV plus bevacizumab as a first-line therapy for elderly patients with advanced or metastatic CRC. Methods: Forty patients with advanced or metastatic CRC aged elder than 75 years were enrolled in this multicenter, open-label, single-arm phase II study. All patients received oral UFT (300-600 mg) and LV (50 mg) twice daily on days 1-21 and intravenous bevacizumab (5 mg/kg) on days 1 and 15 of a 4-week cycle (University Hospital Medical Information Network No. UMIN000003447). Results: The median follow-up period was 14.7 months. The response rate was 20.0% [95% confidence interval (CI): 9.1-35.6], median progression-free survival was 8.9 months (95% CI: 5.3-11), and median overall survival was 21.7 months (95% CI: 13.7-23.4). The only grade 3 hematological toxicity was neutropenia (3.0%), and the incidence rates of grade 3 non-hematological toxicity were low at less than 10%. Conclusion: UFT/LV plus bevacizumab is a promising first-line regimen for elderly patients with advanced or metastatic CRC. The combination is well tolerated and efficacious. Background/Objective: Oral tegafur/uracil and leucovorin (UFT/LV) therapy is effective and safe for elderly patients with advanced or metastatic colorectal cancer (CRC). However, there are few studies on the combination of bevacizumab with UFT/LV. This clinical study evaluated the efficacy and safety of UFT/LV plus bevacizumab as a first-line therapy for elderly patients with advanced or metastatic CRC. Methods: Forty patients with advanced or metastatic CRC aged elder than 75 years were enrolled in this multicenter, open-label, single-arm phase II study. All patients received oral UFT (300-600 mg) and LV (50 mg) twice daily on days 1-21 and intravenous bevacizumab (5 mg/kg) on days 1 and 15 of a 4-week cycle (University Hospital Medical Information Network No. UMIN000003447). Results: The median follow-up period was 14.7 months. The response rate was 20.0% [95% confidence interval (CI): 9.1-35.6], median progression-free survival was 8.9 months (95% CI: 5.3-11), and median overall survival was 21.7 months (95% CI: 13.7-23.4). The only grade 3 hematological toxicity was neutropenia (3.0%), and the incidence rates of grade 3 non-hematological toxicity were low at less than 10%. Conclusion: UFT/LV plus bevacizumab is a promising first-line regimen for elderly patients with advanced or metastatic CRC. The combination is well tolerated and efficacious.

Bevacizumab plus chemotherapy as first-line therapy for elderly patients with metastatic colorectal cancer: Interim results of the noninterventional CASSIOPEE study.

3555Background: Approximately half of the patients (pts) with metastatic colorectal cancer (mCRC) are elderly. A real-life setting study was conducted in elderly pts (≥ 75 years-old) with mCRC trea...

Phase I Study of Non-Engrafting Allogeneic, Mismatched, Unmanipulated Peripheral Blood Mononuclear Cell Infusions to Treat Poor-Prognosis Acute Myeloid Leukemia

BACKGROUND: Non-engrafting or microchimeric allogeneic immunotherapies might dramatically benefit patients with acute myeloid leukemia (AML). Mismatched G-CSF-mobilized peripheral blood (PB) and NK cells administered after chemotherapy increase complete remission (CR) and overall survival rates in poor-prognosis AML, without significant risk of graft-versus-host disease (GVHD). For example, as first-line therapy in elderly patients, the G-CSF-mobilized approach increased disease-free survival from 10% to 39% in a randomized trial (Guo et al, Blood 2011). By contrast, this trial addresses the safety of unprimed, unselected HLA-mismatched cell therapy in chemorefractory or relapsed AML, to avoid exposing donors to G-CSF and further minimize the risk of GVHD. Secondary objectives include describing the incidence of CR, GVHD, prolonged aplasia, and infusion reactions. METHODS/PATIENTS: Seven patients (median 63, range 57-68 years) with primary refractory AML (n = 1) or 1st (n = 4) or 2nd (n = 2) marrow relapse at a median of 2.9 (range, 1.6-8.0) months after completing consolidation were enrolled on this ongoing dose-escalation trial (NCT 1793025). Four had intermediate-risk caryotypes or FLT3 -ITD, 3 high-risk - including 2 with extremely complex and monosomal caryotypes and deleted or mutated TP53. One had therapy-related AML, 1 likely evolved from MDS, while 1 relapsed with bilineage leukemia (myeloid + T cell). Participants were ineligible for allotransplant due to comorbidities or adverse AML genetics. They had 14%-92% marrow blasts before re-induction, with either NoVE (n = 5), high-dose ara-C/VP16 (n = 1), or high-dose ara-C/mitoxantrone (n = 1). Donors were mismatched to recipients in varying degrees (n = 3 haploidentical and 4 with 0-3/10 allele-level matches). Target CD3+ cell dose was 1 x 107/kg for the 1st 4 patients and 5 x 107/kg for the next 3. Unmanipulated PB mononuclear cells were infused 24-48 hours after the last dose of re-induction chemotherapy (''day 0''). Marrow was evaluated on day 14 and upon hematopoietic recovery. RESULTS: SAFETY: Two patients experienced neutropenic fever from several hours to 5 days after cell infusion, but we observed no definite acute or delayed infusion reactions and no GVHD. One patient with cirrhosis developed septic shock with liver/renal failure prior to the infusion and declined dialysis; his long-term endpoints could not be assessed but he tolerated the infusion well. Sustained platelets &gt; 100 × 109/L and neutrophils &gt; 1 × 109/L occurred at +16-31 days and +14-39 days respectively in patients who achieved CR. RESPONSES: One patient achieved near morphologic CR (≤6% marrow blasts, normal PB) at day +29 and was consolidated with an HLA-identical sibling transplant at day +49; she remains in CR 28 months later. Two achieved CR lasting 77 and 164 days in the absence of further therapy. Three had persistent AML. BIOLOGY:Products contained mainly T cells (72%-80%) with varying proportions of NK (9%-17%), NK/T (0.6%-6%), B (7%-14%), and CD14+ (10%-17%) cells. Two broad patterns of total lymphocyte counts were observed: dramatic bursts from ≤ 0.2 to ≥ 1.0 (up to 1.4) × 109/L peaking days 5-8 post infusion, vs. stability/gradual recovery; numbers are too small to draw conclusions about any association with CR (p = 0.4 Fisher exact test). Lymphocyte bursts were not seen in 45 historical controls treated with chemotherapy alone (p = 0.02 for association with cell therapy). No patient-donor pairs were predicted to exhibit NK alloreactivity mediated by C1 or C2 KIR-ligand mismatching, and only 1 pair each had predicted Bw4-mediated donor-vs-recipient and recipient-vs-donor reactivity, respectively. When tested, marrow macrochimerism was undetected (n = 2). CONCLUSIONS: The incidence of life-threatening infections and duration of aplasia in the heavily-pretreated patients observed thus far do not exceed that expected with chemotherapy alone. Cell infusion is well-tolerated. The 42% (95% CI, 25%-84%) CR rate warrants continued dose escalation per protocol, especially because (1) we administer only 1 infusion and (2) our patients are treated with relapsed/refractory AML baring extremely poor prognostic features. Our results suggest that rejection of donor cells protects against engraftment and GVHD, and might sometimes be associated with a lymphocyte burst. Biologic correlations to identify ways to optimize anti-leukemic effects will be performed. Disclosures No relevant conflicts of interest to declare.

Management of diffusely infiltrating glioma in the elderly.

Genetic, epigenetic, and expression analyses have refined the traditional, histopathology-based classification of diffusely infiltrating gliomas. This review summarizes these trends and implications for elderly patients. The vast majority of diffusely infiltrating gliomas in elderly patients share an unfavorable molecular phenotype, that is, telomerase reverse transcriptase promoter mutation in the absence of isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. Histopathologically, these are mostly astrocytic tumors and treatment is guided by the methylation status of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. 1p/19q codeletion indicates oligodendroglial histology and benefit from the addition of procarbazine, chlorethyl-cyclohexyl-nitroso-urea/lomustine, and vincristine polychemotherapy to radiotherapy. These tumors are almost exclusively associated with IDH mutations, but their molecular profile is rare in elderly patients. Two large phase III trials, RTOG 0825 and AVAglio, failed to demonstrate an overall survival benefit from antiangiogenic therapy with bevacizumab added to combined chemoradiotherapy (TMZ) in patients with newly diagnosed glioblastoma, but a trend toward improved survival with increasing age can be noted. Ongoing clinical trials in elderly patients with diffusely infiltrating glioma will clarify the role of combined chemoradiotherapy, and of bevacizumab or other antiangiogenic agents as an adjunct to radiotherapy. The choice of first-line therapy in elderly patients with diffusely infiltrating glioma is between postoperative hypofractionated radiotherapy and chemotherapy, guided by MGMT methylation in most patients.

Phase II Study of Oral Tegafur/Uracil and Leucovorin plus Bevacizumab as a First-Line Therapy for Elderly Patients with Advanced or Metastatic Colorectal Cancer

Background/Objective: Oral tegafur/uracil and leucovorin (UFT/LV) therapy is effective and safe for elderly patients with advanced or metastatic colorectal cancer (CRC). However, there are few studies on the combination of bevacizumab with UFT/LV. This clinical study evaluated the efficacy and safety of UFT/LV plus bevacizumab as a first-line therapy for elderly patients with advanced or metastatic CRC. Methods: Forty patients with advanced or metastatic CRC aged ≥75 years were enrolled in this multicenter, open-label, single-arm phase II study. All patients received oral UFT (300-600 mg) and LV (50 mg) twice daily on days 1-21 and intravenous bevacizumab (5 mg/kg) on days 1 and 15 of a 4-week cycle (University Hospital Medical Information Network No. UMIN000003447). Results: The median follow-up period was 14.7 months. The response rate was 20.0% [95% confidence interval (CI): 9.1-35.6], median progression-free survival was 8.9 months (95% CI: 5.3-11), and median overall survival was 21.7 months (95% CI: 13.7-23.4). The only grade 3 hematological toxicity was neutropenia (3.0%), and the incidence rates of grade 3 nonhematological toxicity were low at ≤10%. Conclusion: UFT/LV plus bevacizumab is a promising first-line regimen for elderly patients with advanced or metastatic CRC. The combination is well tolerated and efficacious.

Doublets versus single-agent therapy as first-line therapy for elderly patients with advanced non-small cell lung cancer? A systematic review of randomised controlled trials

Although the standard treatment for advanced non-small cell lung cancer (NSCLC) patients is platinum-based doublet chemotherapy, single-agent therapy is still preferred in elderly patients. Comparison of the efficacy of various combinations of doublets with single-agent chemotherapy is somehow contradictory. This study conducted a systematic review to evaluate the efficacy and tolerability of the third-generation agent-based doublets vs. single-agent chemotherapy in elderly NSCLC patients. Electronic (PubMed, EMBASE and Cochrane Library database) and manual searches were conducted to collect data from published, randomised, phase 2 and 3 trials which compared doublets with a third-generation single-agent chemotherapy in elderly patients. Pooled relative risks (RRs) were calculated for the incidences of overall response rate (ORR), 1-year survival rate (1-y SR), and grade 3/4 toxicities. Seven eligible trials (2219 patients) were selected from 1170 studies that were initially identified. A significant difference in ORR favouring doublets over single agents was observed [RR, 1.59; 95% confidence interval (95% CI), 1.36-1.86; p<0.0001] with a slightly, but not significantly improved 1-y SR (RR, 1.19; 95% CI, 0.98-1.45, p=0.007). Subgroup analysis suggested that platinum (RR, 1.94; 95% CI, 1.47-2.55, p<0.0001) or non-platinum- (RR, 1.45; 95% CI, 1.20-1.75, p<0.0001) based doublets could improve ORR, and the grade 3/4 thrombocytopaenia (RR, 6.64; 95% CI, 1.78-24.86, p=0.005) and anaemia (RR, 2.86; 95% CI, 1.62-5.05, p<0.0001) were preferred to occur in platinum-based doublets. Doublets appear to be more effective and tolerable than single-agent therapy for treating elderly advanced NSCLC patients, and therefore could be considered as a treatment option for elderly populations with good physical status.