Low skeletal muscle mass (LSMM) is increasingly recognized for its predictive value for adverse events in cancer patients. In specific, the predictive value of LSMM has been demonstrated for anti-cancer drug toxicity in a variety of cancer types and anti-cancer drugs. However, due to the limited sample size and study populations focused on a single cancer type, an overall predictive value of LSMM for anti-cancer drug toxicity remains unknown. Therefore, this review aims to provide a comprehensive overview of the predictive value of LSMM and perform a meta-analysis to analyse the overall effect. A systematic search was conducted of MEDLINE, Scopus, EMBASE, and Cochrane. Inclusion criteria were skeletal muscle mass (SMM) evaluated with computed tomography (CT) or magnetic resonance imaging (MRI), articles published in English, SMM studied in humans, SMM measurement normalized for height, and patients did not receive an intervention to treat or prevent LSMM. A meta-analysis was performed using a random-effects model and expressed in odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was assessed using χ² and I² statistics. The search yielded 907 studies. 31 studies were included in the systematic review. Sample sizes ranged from 21 to 414 patients. The occurrence of LSMM ranged from 12.2% to 89.0%. The most frequently studied cancer types were oesophageal, renal, colorectal, breast, and head and neck cancer. Patients with LSMM had a higher risk of severe toxicity (OR 4.08; 95% CI 2.48–6.70; p < 0.001) and dose-limiting toxicity (OR 2.24; 95% CI 1.28–3.92; p < 0.001) compared to patients without LSMM. To conclude, the predictive value of LSMM for anti-cancer drug toxicity can be observed across cancer types. This information increases the need for further research into interventions that could treat LSMM as well as the possibility to adapt treatment regimens based on the presence of LSMM.

Background Understanding molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC) has considerably improved in the last decades. As a result, novel therapeutic strategies have evolved, amongst which are epidermal growth factor receptor (EGFR)-targeted therapies. With the exception of cetuximab, targeted therapies for HNSCC have not yet been introduced into clinical practice. One important aspect of new treatment regimes in clinical practice is presence of robust biomarkers predictive for therapy response. Methods We performed a systematic search in PubMed, Embase and the Cochrane library. Articles were included if they investigated a biomarker for targeted therapy in the EGFR-PI3K-AKT-mTOR-pathway. Results Of 83 included articles, 52 were preclinical and 33 were clinical studies (two studies contained both a preclinical and a clinical part). We classified EGFR pathway inhibitor types and investigated the type of biomarker (biomarker on epigenetic, DNA, mRNA or protein level). Conclusion Several EGFR-PI3K-AKT-mTOR-pathway inhibitor biomarkers have been researched for HNSCC but few of the investigated biomarkers have been adequately confirmed in clinical trials. A more systematic approach is needed to discover proper biomarkers as stratifying patients is essential to prevent unnecessary costs and side effects.

Different antibiotics and chemotherapeutics were tested for therapeutic efficacy in rabbits, in an experimental model using a Pasteurella multocida strain which causes hyperacute septicaemia in this animal species. Only enrof1oxacin, administered in the drinking water at a concentration of 50-100 mg/l cured the rabbits, provided that a daily intake of 5 mg/kg body weight was achieved. The other drugs tested (tetracycline, spiramycin, erythromycin and a combination of sulfamerazine with trimethoprim), at doses recommended for rabbits, showed little or no activity at all, with the exception of chloramphenicol, which was only partially effective.

Low skeletal muscle mass (SMM) is associated with toxicities and decreased survival in head and neck cancer (HNC). Chemoradiotherapy (CRT) may exaggerate loss of SMM. We investigated the changes in SMM, their predictors, and prognostic impact of SMM in patients treated with CRT between 2012 and 2018. Skeletal muscle area (SMA) segmentation was performed on pre- and post-CRT imaging. Observed changes in SMM were categorized into: (I) Stable, (II) moderate gain (III), moderate loss, (IV) large gain, and (V) large loss. In total, 235 HNC patients were included, of which 39% had stable SMM, 55% moderate loss, 13% moderate gain, 0.4% large loss, and 0.4% large gain of SMM. After CRT, SMA decreased compared to pre-CRT (31.6 cm² versus 33.3 cm², p < 0.01). The key predictor was a body mass index (BMI) of ≥30 kg/m² (OR 3.6, 95% CI 1.4–9.3, p < 0.01). Low SMM at diagnosis (HR 2.1; 95% CI 1.1–4.1, p = 0.03) and an HPV-positive oropharyngeal tumor (HR 0.1; 95% CI 0.01–0.9, p = 0.04) were prognostic for overall survival. Changes in SMM were not prognostic for survival. Loss of SMM is highly prevalent after CRT and a high BMI before treatment may aid in identifying patients at risk.

Aims The aim of the study was to determine the effect of renal impairment and prior platinum‐based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum‐based (PB) chemotherapy. Methods A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CL_cr) = 50–79 ml min⁻¹], moderate [CL_cr = 30–49 ml min⁻¹], severe [CL_cr <30 ml min⁻¹]). Results Fifty‐nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration–time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non‐Asian patients with the same degree of renal impairment. Thirteen dose‐limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m⁻² day⁻¹, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m⁻² day⁻¹ for patients with moderate renal impairment (suggested dose 1.9 mg m⁻² day⁻¹ for non‐Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m⁻² day⁻¹ in this cohort. Conclusions Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.

Background: ModraDoc006 is an oral formulation of docetaxel, which is co‐administered with the cytochrome P450 3A4 and P‐glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration‐resistant prostate cancer (mCRPC).Aim: We assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.Methods: mCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose‐escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate‐specific antigen (PSA) and radiological evaluation.Results: Cohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30‐20/100‐100). The mean docetaxel area under the plasma concentration‐time curve (mAUC0‐inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30‐20/200‐200), the mAUC0‐inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30‐20/200‐100), the mAUC0‐inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20‐20/200‐100), the mAUC0‐inf was 558 ng/mL × h without DLTs. The mAUC0‐inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.Conclusion: The RP2D was established at weekly ModraDoc006/r 30‐20/200‐100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3‐weekly IV docetaxel in patients with mCRPC.