High Protein Oral Nutritional Supplements Enable the Majority of Cancer Patients to Meet Protein Intake Recommendations during Systemic Anti-Cancer Treatment:A Randomised Controlled Parallel-Group Study

ESPEN guidelines recommend a minimum protein intake of 1.0 g/kg body weight (BW) per day to maintain or restore lean body mass in patients with cancer. During anti-cancer treatment, optimal protein intake is difficult to achieve. We investigated whether a high-protein, low-volume oral nutritional supplement (ONS) supports patients in meeting recommendations. A multi-centre, randomised, controlled, open-label, parallel-group study was carried out in nine hospitals (five countries) between January 2019 and July 2021 in colorectal and lung cancer patients undergoing first-line systemic treatment with chemo(radio-) or immunotherapy. Subjects were randomised (2:1) to receive Fortimel Compact Protein® or standard care. Protein intake was assessed with a 3-day food diary (primary outcome). BW was a secondary outcome. Due to challenges in recruitment, the study was terminated prematurely with 42 patients randomised (intervention group (IG) 28; control group (CG) 14). At T1 and T2, protein intake was statistically significantly higher in the IG compared to the CG (1.40 vs. 1.07 g/kg/day at T1, p = 0.008; 1.32 vs. 0.94 g/kg/day at T2, p = 0.002). At baseline, only 65% (IG) and 45% (CG) of patients met ESPEN minimum protein intake recommendations. However, at T1 and T2 in the IG, a higher proportion of patients met recommendations than in the CG (88% vs. 55% and 40%). No statistically significant difference between study groups was observed for BW. Mean compliance to the ONS was 73.4%. A high-protein, low-volume ONS consumed twice daily enables the majority of patients to reach minimal ESPEN protein recommendations.</p

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19):an investigator-initiated, randomised, open-label, phase 2 trial

Background Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. Methods We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m(2) on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. Findings Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36.5 months (95% CI 34.2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6.2 months [95% CI 4.6-8.7]) than in the supportive care group (3.2 months [2.8-4.1]; hazard ratio [HR] 0.48 [95% CI 0.33-0.71]; p=0.0002). The benefit was confirmed by masked independent central review (HR 0.49 [0.33-0.72]; p=0.0002). Grade 3-4 adverse events occurred in 33 ( 52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. Interpretation Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma

Randomised trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer (EORTC 08972-22973)

A randomised phase III study was performed comparing sequential (S) and concurrent (C) chemo-radiotherapy (CRT) in non-small cell lung cancer (NSCLC) patients. Methods : One hundred and fifty-eight patients were randomised to receive two courses of Gemcitabine (1250 mg/m2 days 1, 8) and Cisplatin (75 mg/m2 day 2) prior to, or daily low-dose Cisplatin (6 mg/m2) concurrent with radiotherapy, consisting of 24 fractions of 2.75 Gy in 32 days, with a total dose of 66 Gy. Results : Acute haematological toxicity grade 3/4 was more pronounced in the sequential (S) (30% versus 6%), oesophagitis grade 3/4 more frequent in the concurrent (C) arm (5% versus 14%). Late oesophagitis grade 3 was 4% (S and C), pneumonitis grade 3/4 14% (S) and 18% (C). Because of the poor power of the study no significant differences in median survival (MS), overall survival (OS) and progression-free survival (PFS) could be detected. MS was 16.2 (S) and 16.5 (C) months, 2-year OS was 34% (S) and 39% (C), 3-year OS was 22% (S) and 34% (C). Conclusion : Radiotherapy 66 Gy given concurrently with daily low-dose Cisplatin or after two courses of Gemcitabine/Cisplatin was well tolerated. Due to early closure no conclusions can be reached on the relative merits; both arms showed good OS

Genetic polymorphism in ATIC is associated with effectiveness and toxicity of pemetrexed in non-small-cell lung cancer

Patients with advanced non-small-cell lung cancer who are treated with pemetrexed display a wide variation in clinical response and toxicity. In this prospective, multicentre cohort study, we investigated the association with treatment effectiveness and toxicity of 10 polymorphisms in nine candidate genes, covering the folate pathway (MTHFR), cell transport (SLC19A1/ABCC2/ABCC4), intracellular metabolism (FPGS/GGH) and target enzymes (TYMS/DHFR/ATIC) of pemetrexed. Adjusted for sex, ECOG performance score and disease stage, the association between ATIC (rs12995526) and overall survival (HR 1.59, 95% CI 1.06 to 2.39) was significant. Regarding toxicity, this ATIC polymorphism was significantly associated with severe laboratory (p=0.014) and clinical (p=0.016) chemotherapy-related adverse events, severe neutropenia (p=0.007) and all-grade diarrhoea (p=0.034) in multivariable analyses

Treatment satisfaction of patients with advanced non small cell lung cancer receiving platinum based chemotherapy:Results from a prospective cohort study (personal)

Introduction. In patients with advanced non–small-cell lung cancer, the treatment benefits and risks need to be constantly weighed. We explored patient-reported satisfaction with therapy (SWT) and assessed its value in addition to quality of life (QoL) and adverse events (AEs). Patients and methods. In a prospective multicenter cohort study, patients with stage IIIB/IV non–small-cell lung cancer received platinum-pemetrexed chemotherapy. They completed the World Health Organization Quality of Life-BREF (WHOQoL-BREF) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) before and during chemotherapy. After the last cycle, patients reported on SWT, expectations of therapy, and feelings about side effects (FSE) using the Cancer Therapy Satisfaction Questionnaire. The explained variance (R2) of QoL after treatment by SWT was calculated. Using multivariable linear regression, we examined the association of SWT with patient- and treatment-related variables, FSE, and AEs. Results. Eighty-nine patients finished 4 cycles of chemotherapy, 65 of whom completed the Cancer Therapy Satisfaction Questionnaire. Fifty-six patients (86.2%) would probably or definitely decide to undergo the same treatment again, regardless of deterioration or improvement in QoL or a high or low frequency of AEs during chemotherapy. The explained variance of QoL by SWT was greatest for the EORTC QLQ C-30 global health status/QoL scale (R2 = 0.170). Patient age (β = 0.43; 95% confidence interval [CI], 0.05-0.82), FSE (β = 0.17; 95% CI, 0.06-0.29), and tumor response (β = 7.93; 95% CI (1.64 to 14.22)) were independently associated with SWT. Conclusion. SWT could provide important supplementary information in addition to QoL assessments and treatment toxicities. Tumor response, older age, and FSE score were associated with better SWT. These insights could affect decision-making during palliative chemotherap

Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2–16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5–7.1) versus 1.9 months (95% CI 1.4–3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16–5.43). Corresponding median OS was 10.6 months (95% CI: 7.0–8.6) versus 4.7 months (95% CI: 3.2–8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46–9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice

Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2–16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5–7.1) versus 1.9 months (95% CI 1.4–3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16–5.43). Corresponding median OS was 10.6 months (95% CI: 7.0–8.6) versus 4.7 months (95% CI: 3.2–8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46–9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p &lt; 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice.</p