Although treatment modalities for non-small cell lung cancer (NSCLC) are rapidly evolving, there is insufficient evidence that novel drugs reach elderly patients (aged ≥ 70 years) and improve their ...outcomes. The purpose of this study was to evaluate the access to treatment in the elderly population with stage IV NSCLC in a real life setting and its impact on survival (OS) over the past 10 years.
We compared elderly and younger patients with stage IV NSCLC treated at our tertiary cancer centre and its affiliated smaller hospitals. We collected patients and tumor characteristics such as age at diagnosis, gender, smoking history, histology, molecular subtyping, PDL1 expression status and data on treatment types as well as lines. We grouped the enrolled patients into four same size cohorts based on time and age at diagnosis: patients diagnosed 2005-2007 (elderly cohort-I) and 2015-2016 (elderly cohort-II) were compared to cohorts of patients <70 years old diagnosed during the same time periods (young cohorts-I and -II). The characteristics were analysed using Chi-square Test and survival related endpoints with Kaplan-Meier model. A log-rank test was used to test the equality of the survivor functions and a z-Test to assess the differences in survival proportions.
499 NSCLC cases were retrospectively analysed. Median OS significantly improved in both, the elderly and the young cohorts, over time. OS in the elderly cohort-I and -II was slightly lower (3.7 months and 5.3 months) compared to the young cohorts-I and -II (7.8 and 12.1 months). In the young group 12-months OS was significantly improved over the last 10 years (34% 95%CI 27%-42% and 52% 95%CI 43%-61%, p=0.049). There was no significant improvement in the elderly cohorts (18% 95%CI 11%-25% vs. 31% 95%CI 22%-39%, p=0.29). Therapy with any line of systemic treatment modalities remained lower in the elderly cohorts as compared to younger patients (53% versus 78%).
We observed a significant improvement in OS over the past 10 years in young patients, whereas a similar benefit was not found for the elderly. Our findings highlight a strong need in studying this growing population separately in elderly specific clinical trials.
The authors.
Has not received any funding.
S. Schmidt: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: TAKEDA; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Fruh: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.
Background:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare the effectiveness of ...rituximab (R) alone versus R combined with lenalidomide (L) as the initial treatment for symptomatic follicular lymphoma (FL). The primary endpoint analysis, which demonstrated higher complete remission (CR) rates with the combination therapy, was previously reported (Zucca et al. Blood 2019). This report provides a long-term analysis of time-to-event endpoints with a median follow-up of approximately 10 years.
Methods:A total of 154 eligible patients with untreated grade 1 to 3a FL requiring systemic therapy were centrally randomized to receive either R monotherapy (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 for responding patients) or R+L. In the combination arm, R was administered at the same schedule as the monotherapy, while L was taken orally at a daily dose of 15 mg, starting 14 days before the first R administration, and continued until 14 days after the last R administration, for a total of 18 weeks. Random assignment to treatment arms was stratified based on histological grade (1-2 vs 3a), bulky disease (<6 vs ≥6 cm), Follicular Lymphoma International Prognostic Index (FLIPI) score (1-2 vs ≥3), and centre, using the minimization method.
The sample size was determined to detect a 20% increase in the CR/CRu rate with 90% power, using a one-sided Z-test with a false positive rate of 10% to compare the two treatment arms. The assessed endpoints, including progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), duration of CR/CRu (DoR), and overall survival (OS), were defined according to NCI international standardized criteria (Cheson et al. J Clin Oncol 1999).
Results:Seventy-seven patients (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were assigned to the single-agent rituximab arm, and 77 patients (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) were assigned to the combination arm. The results for the primary endpoint were consistent with the positive initial analysis. At a median follow-up of 9.5 years, the overall survival was similar in both arms (77% vs. 78% at 10 years, p=0.881). However, significant, and sustained improvements were seen in all other time-to-event endpoints. Patients in the R+L arm had a longer PFS (median, 9.3 vs. 2.3 years; HR=0.58, 95% CI: 0.37-0.89; p=0.013) and TTNT (median, not reached vs. 2.1 years; HR=0.43, 95% CI: 0.27-0.67; p<0.001). DoR with R+L was also longer (median not reached vs 3.2 years with R only; HR=0.42, 95% CI: 0.21-0.86; p=0.014) and with over 60% of responders still in first remission at 10 years. The improved outcomes with R+L were not associated with unexpected toxicity. Grade ≥3 adverse events were more common with the combination regimen (56% vs. 22% of patients), with grade 3-4 neutropenia in 23% of patients receiving R+L and in 7% of those receiving R alone. Fatigue, diarrhea, and skin rash were more frequent with R+L, but mostly of grade 1-2 (grade 3 occurred in ≤ 5% in both arms, and no grade 4 was reported). The side effects were manageable, and there were no treatment-related deaths in either arm. Two cases of biopsy-proven into diffuse large B-cell lymphoma were reported in the R+L arm, and two cases of Hodgkin lymphoma were described in the R arm. Although their causal relationship with treatment is not completely clear, the number of second solid cancers was significantly higher in the R+L arm. Two cases of prostate cancer, two lung adenocarcinomas (one in situ), one small cell lung carcinoma, one rectal cancer, and four skin cancers (three squamous cell and one basal cell), were observed in the R+L arm, while only one solid tumor (prostate cancer) occurred in the R arm (p=0.09). Only one patient died of a second solid cancer (small cell lung carcinoma in the R+L arm). The rate of POD24 was 29% in the R+L arm vs. 34% in the R-arm (p=0.483).
Conclusions:The long-term results of the SAKK 35/10 trial demonstrated a durable benefit for the R+L combination compared to R alone. Notably, the adopted R+L schedule is considerably shorter than the standard R2 regimen (18 vs. 120 weeks). This provides a promising alternative when treatment is required but durable immunosuppression is undesirable.
The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated ...follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval CI, 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.
•Compared with rituximab only, a short rituximab-lenalidomide regimen improved CR rate and PFS in untreated symptomatic follicular lymphomas.•Excellent OS in both arms suggests that chemotherapy-free strategies should be further explored in follicular lymphoma.
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Introduction
Offspring of obese women have both short‐term and long‐term increased morbidities. We investigated the relationship between maternal 2‐h plasma glucose level determined by an oral ...glucose tolerance test, degree of obesity, gestational weight gain and total fat, abdominal fat, and fat‐free masses in the offspring of obese mothers.
Material and methods
Obese mother–newborn dyads were recruited and 2‐h plasma glucose levels were assessed during gestational weeks 27–30; neonatal body composition was measured by dual‐energy X‐ray absorptiometry scanning (DXA) within 48 h of birth.
Results
Among 264 term, healthy, and singleton infants eligible for inclusion, 248 were included. Of these, 205 (83%) obese mother–newborn dyads had a DXA scan and 2‐h plasma glucose measurements. Linear regression analysis showed that birthweight z‐scores correlated with 2‐h plasma glucose levels (p = 0.002) after adjusting for gestational weight gain, maternal age, education, smoking, prepregnancy degree of obesity, parity, and birth length. Total (p = 0.012) and abdominal (p = 0.039) fat masses correlated with 2‐h plasma glucose levels after adjusting for gestational weight gain, maternal age, education, smoking, prepregnancy degree of obesity, parity, gestational age, and newborn sex. There was no association between total (p = 0.88) and abdominal (p = 0.61) fat‐free masses and 2‐h plasma glucose.
Conclusion
At 27–30 weeks of gestation, 2‐h plasma glucose levels are related to total and abdominal newborn fat masses, but not to fat‐free mass. Interventions targeting maternal postprandial glucose levels may induce more appropriate birthweight, thereby reducing the risk of subsequent morbidity.
Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded ...protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).
Studies suggest that dairy-derived calcium supplements have additional beneficial properties compared with other calcium supplements in relation to bone health.
We investigated the postprandial ...calcium absorption from a milk-derived calcium permeate (CP) compared with calcium carbonate (CC).
In this randomized double-blinded cross-over study, 10 healthy postmenopausal females (age 50-65 y) received maltodextrin (placebo), 800 mg calcium from CP or from CC provided in 6 capsules on separate days. A fasting blood sample was collected at baseline, 60, 120, 240, and 360 min after ingestion. At baseline and 360 min, spot-urine samples were collected. Serum-ionized calcium, intact parathyroid hormone, phosphorus, and magnesium were analyzed, as were urinary calcium, phosphorus, and magnesium. A linear mixed model was applied.
Serum-ionized calcium concentration after the CC supplement was higher at 240 min compared with the CP supplement between-group difference; 95% confidence interval (CI): 0.039 mmol/L; 95% CI: 0.017-0.061; P = 0.00078. Serum-ionized calcium concentration after the CC supplement was significantly higher than placebo at all postprandial time points except at 60 min. Urinary calcium concentration in 360 min spot urine was higher after intake of CC compared with CP between-group difference; 95% CI: 2.47 mmol/L; 95% CI: 1.90-3.03; P = 0.0042.
Postprandial calcium absorption from CP was lower than that of CC, and concurrently, urinary concentration reflected increased serum appearance by CC compared with CP, highlighting different metabolic responses. The long-term and clinical implications should be studied further.
Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is ...downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412).
Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints.
Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥ 3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood.
Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted.
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