In several diseases, low muscle mass has been revealed as an unfavorable prognostic factor for outcome. Whether this holds true in patients with solid malignancies as well has increasingly been ...explored recently. However, this research field is severely hampered by a lack of consensus on how to determine muscle mass in cancer patients and on the definition of low muscle mass. Consequently, the prevalence of low muscle mass varies widely across several studies. Nevertheless, most studies show that, in patients with solid malignancies, low muscle mass is associated with a poor outcome. In the future, more research is needed to get better insight into the best method to determine muscle mass, the exact prognostic value of low muscle mass in diverse tumor types and stages, pathophysiology of low muscle mass in patients with cancer, and ways to intervene and improve muscle mass in patients. This review addresses the current literature on the importance of muscle mass in cancer patients and the methods of muscle measurement.
Implications for Practice:
An increasing number of studies underline the clinical value of low muscle mass as a prognostic factor for adverse outcomes in cancer patients. However, studies show large heterogeneity because of the lack of a standardized approach to measure muscle mass and the lack of reference populations. As a result, the interpretation of data and further progress are severely hampered, hindering the implementation of muscle measurement in oncological care. This review summarizes the methods of diagnosing low muscle mass in cancer patients, the difference between underlying syndromes such as sarcopenia and cachexia, and the association with clinical outcomes described so far.
Many studies underline the clinical value of low muscle mass as a prognostic factor for adverse outcomes in cancer patients, but there is no standardized approach for measuring muscle mass. This review summarizes the methods of diagnosing low muscle mass in cancer patients, the difference between underlying syndromes (sarcopenia and cachexia), and the association with clinical outcomes.
Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary ...analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow-up is presented. After 19.4 (range: 0 to 27.7) months of median follow-up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P <0.0001) and improved the overall response rate (83.8% versus 63.2%; P <0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% confidence interval, 0.12-0.29; P <0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow-up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse.
clinicaltrials.gov identifier: NCT02136134.
In the GLOW study, fixed-duration ibrutinib–venetoclax showed superior progression-free survival versus chlorambucil–obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia ...who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up.
GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18–64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib–venetoclax group (three cycles of ibrutinib lead-in 420 mg/day, orally, followed by 12 cycles of ibrutinib plus venetoclax 400 mg/day, orally, including a 5-week dose ramp-up) or the chlorambucil–obinutuzumab group (six cycles of chlorambucil 0·5 mg/kg, orally, on days 1 and 15 of each cycle, and obinutuzumab 1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2–6). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77).
Between May 4, 2018, and April 5, 2019, 211 patients (122 58% were male and 89 42% were female) were randomly assigned to receive ibrutinib–venetoclax (n=106) or chlorambucil–obinutuzumab (n=105). At a median of 46 months (IQR 43–47) of follow-up, progression-free survival remained superior for the ibrutinib–venetoclax group (hazard ratio 0·214 95% CI 0·138–0·334; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0–82·0) for ibrutinib–venetoclax and 24·8% (16·5–34·1) for chlorambucil–obinutuzumab. Following the primary analysis, one patient in the chlorambucil–obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib–venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil–obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib–venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil–obinutuzumab group (of which 10 were due to post-treatment infections).
After 4 years of follow-up, ibrutinib–venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option.
Janssen Research & Development and Pharmacyclics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Targeted time-limited treatment options are needed for patients with relapsed or refractory chronic lymphocytic leukaemia. The aim of this study was to investigate the efficacy of minimal residual ...disease (MRD)-guided, time-limited ibrutinib plus venetoclax treatment in this patient group.
HOVON141/VISION was an open-label, randomised, phase 2 trial conducted in 47 hospitals in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden. Eligible participants were aged 18 years or older with previously treated chronic lymphocytic leukaemia with or without TP53 aberrations; had not been exposed to Bruton tyrosine-kinase inhibitors or BCL2 inhibitors; had a creatinine clearance rate of 30 mL/min or more; and required treatment according to International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. Participants with undetectable MRD (<10−4; less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes) in peripheral blood and bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (weekly ramp-up 20 mg, 50 mg, 100 mg, 200 mg, up to 400 mg once daily) were randomly assigned (1:2) to ibrutinib maintenance or treatment cessation. Patients who were MRD positive continued to receive ibrutinib monotherapy. Patients who became MRD (>10−2) during observation reinitiated treatment with ibrutinib plus venetoclax. The primary endpoint was progression-free survival at 12 months after random assignment in the treatment cessation group. Progression-free survival was analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety assessment. The study is registered at ClinicalTrials.gov, NCT03226301, and is active but not recruiting.
Between July 12, 2017, and Jan 21, 2019, 230 patients were enrolled, 225 of whom were eligible. 188 (84%) of 225 completed treatment with ibrutinib plus venetoclax and were tested for MRD at cycle 15. After cycle 15, 78 (35%) patients had undetectable MRD and 72 (32%) were randomly assigned to a treatment group (24 to ibrutinib maintenance and 48 to treatment cessation). The remaining 153 patients were not randomly assigned and continued with ibrutinib monotherapy. Median follow-up of 208 patients still alive and not lost to follow-up at data cutoff on June 22, 2021, was 34·4 months (IQR 30·6–37·9). Progression-free survival after 12 months in the treatment cessation group was 98% (95% CI 89–100). Infections (in 130 58% of 225 patients), neutropenia (in 91 40% patients), and gastrointestinal adverse events (in 53 24% patients) were the most frequently reported; no new safety signals were detected. Serious adverse events were reported in 46 (40%) of 116 patients who were not randomly assigned and who continued ibrutinib maintenance after cycle 15, eight (33%) of 24 patients in the ibrutinib maintenance group, and four (8%) of 48 patients in the treatment cessation group. One patient who was not randomly assigned had a fatal adverse event (bleeding) deemed possibly related to ibrutinib.
These data point to a favourable benefit–risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukaemia, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population.
AbbVie and Janssen.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ...ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia. Methods This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0–2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov , number NCT00802737. Findings Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the allocated intervention (withdrawal of consent). The median follow-up was 19·1 months (IQR 10·3–28·8). Progression-free survival was improved in patients assigned to the ofatumumab group (29·4 months, 95% CI 26·2–34·2) compared with those assigned to observation (15·2 months, 11·8–18·8; hazard ratio 0·50, 95% CI 0·38–0·66; p<0·0001). The most common grade 3 or higher adverse events up to 60 days after last treatment were neutropenia (56 24% of 237 patients in the ofatumumab group vs 23 10% of 237 in the observation group) and infections (31 13% vs 20 8%). 20 (8%) of 237 patients in the ofatumumab group and three (1%) of 237 patients in the observation group had adverse events that led to permanent discontinuation of treatment. Up to 60 days after last treatment, two deaths related to adverse events occurred in the ofatumumab treatment group and five deaths related to adverse events occurred in the observation group; no deaths were attributed to the study drug. Interpretation These data are important for the development of optimum maintenance strategies in patients with relapsed chronic lymphocytic leukaemia, notably in the present era of targeted drugs, many of which are to be used until progression. Funding GlaxoSmithKline and Genmab.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We investigated the effect of trastuzumab on cardiac function in a real‐world historic cohort of patients with HER2‐positive metastatic breast cancer (MBC) with reduced baseline left ventricular ...ejection fraction (LVEF). Thirty‐seven patients with HER2‐positive MBC and baseline LVEF of 40% to 49% were included. Median LVEF was 46% (interquartile range IQR 44%‐48%) and median follow‐up was 18 months (IQR 9‐34 months). During this period, the LVEF did not worsen in 24/37 (65%) patients, while 13/37 (35%) patients developed severe cardiotoxicity defined as LVEF <40% with median time to severe cardiotoxicity of 7 months (IQR 4‐10 months) after beginning trastuzumab. Severe cardiotoxicity was reversible (defined as LVEF increase to a value <5%‐points below baseline value) in 7/13 (54%) patients, partly reversible (defined as absolute LVEF increase ≥10%‐points from nadir to a value >5%‐points below baseline) in 3/13 (23%) patients and irreversible (defined as absolute LVEF increase <10%‐points from nadir and to a value >5%‐points below baseline) in 3/13 (23%) patients. Likelihood of reversibility was numerically higher in patients who received cardio‐protective medications (CPM), including ACE‐inhibitors, beta‐blockers and angiotensine‐2 inhibitors, compared to those who did not receive any CPM (71% vs 13%, P = .091). Sixty‐five percent of patients who received trastuzumab for HER2‐positive MBC did not develop severe cardiotoxicity during a median follow‐up of 18 months, despite having a compromised baseline LVEF. If severe cardiotoxicity occurred, it was at least partly reversible in more than two‐thirds of the cases. Risks and benefits of trastuzumab use should be balanced carefully in this vulnerable population.
What's new?
While trastuzumab improves long‐term survival in patients with HER2‐positive metastatic breast cancer (MBC), it is contraindicated in those with reduced baseline left ventricular ejection fraction (LVEF). Here, to better understand risks to cardiac function, cardiac status was examined in a real‐world cohort of trastuzumab‐treated HER2‐positive MBC patients with low baseline LVEF. Data show that severe cardiotoxicity was absent in 65% of patients with reduced baseline LVEF. In more than two‐thirds of patients who experienced cardiotoxicity, effects on LVEF were reversed at least partly possibly by cardio‐protective medications. These observations warrant further investigation of trastuzumab for patients with HER2‐positive MBC with reduced baseline LVEF.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. ...Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval CI, 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.
•In a multicenter, randomized phase 3 trial, MPR-R was not superior over MPT-T with respect to response rate, PFS, and OS.•Grade 3/4 hematologic toxicity requiring growth factor support occurred with MPR-R vs clinically significant neuropathy with MPT-T.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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