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Background: Skeletal muscle mass (SMM) loss is common in metastatic colorectal cancer (mCRC) patients and associated with poor clinical outcomes, including increased treatment-related toxicities and reduced survival. Muscle loss may contribute to reduced health-related quality of life (HRQoL), including fatigue. Our aim was to study associations between changes in SMM and concomitant changes in patient-reported HRQoL., Methods: This was a secondary analysis of mCRC patients in the CAIRO3 randomized clinical trial who were-after initial treatment-randomized between maintenance treatment with capecitabine plus bevacizumab (CAP-B) and observation until first disease progression (PD1). Included patients had computed tomography images for SMM quantification, together with HRQoL assessments available at randomization and PD1. Changes in SMM (categorized as >2% loss, stable, and >2% gain) and HRQoL were computed between randomization and PD1. Changes in HRQoL score >10 points were considered clinically relevant. Associations between SMM and HRQoL changes were studied by multiple linear regression models. We also investigated whether associations differed by treatment arm for global health and the 13 other HRQoL subscales., Results: Of 221 patients included (mean age 63.5 ± 8.4 years), 24% lost, 27% remained stable, and 49% gained SMM. At randomization, mean global health status was 73.5 ± 15.9 in the CAP-B arm and 75.1 ± 17.5 in the observation arm (P = 0.48). A stable or gain in SMM was significantly associated with a clinically relevant improvement in global health status (9.9 and 14.7 points, respectively), compared with patients who lost SMM. From the subscales that did not show significant differences between the two treatment arms, we found significant and clinically relevant associations for stable or gain in SMM with improved role functioning (12.0 and 17.9, respectively) and with less fatigue (-10.0 and -15.0, respectively) and pain (-16.3 for SMM gain). From the subscales that did show significantly different associations with SMM between the two treatment arms, we only found significant results in the observation arm. Here, associations were found for stable or gain in SMM with clinically relevant improved physical (12.4 for SMM gain), cognitive (10.7 and 9.7, respectively), and social functioning (15.5 and 15.6, respectively) as well as reduced appetite loss (-28.5 and -30.7, respectively)., Conclusions: In mCRC, SMM preservation during CAP-B and observation treatment is associated with significant and clinically relevant improvements in global health status and multiple functional and symptom scales. Studies are warranted to investigate whether interventions targeting SMM lead to improved HRQoL, fewer symptoms, and better functioning., (© 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: The current study was a multicenter, single-arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, previously untreated, gastric or gastroesophageal adenocarcinoma., Methods: Tumor HER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m(2) , and oxaliplatin at a dose of 100 mg/m(2) (all on day 1) combined with capecitabine at a dose of 850 mg/m(2) twice daily (days 1-14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression-free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses., Results: Sixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2-10.9 months). The objective response rate was 70% (95% CI, 55%-83%) and the disease control rate was 96% (95% CI, 85%-99%). The median OS was 12.0 months (95% CI, 10.2-16.1 months). According to CTC-AE v4.0, the most common treatment-related grade ≥3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001)., Conclusions: The B-DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B-DOC. Docetaxel-based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434-1443. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Aim: Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity following 5-fluorouracil (5FU) or capecitabine (CAP) treatment. Uracil (U) can be used as a probe to determine systemic DPD activity. The present study was performed to assess the sensitivity and specificity of a U loading dose for detecting DPD deficiency., Methods: Cancer patients with Common Toxicity Score (CTC) grade III or IV toxicity after the first or second cycle of 5-FU or CAP treatment were asked to participate. Based on DPD activity in PBMCs, patients were divided into two groups: DPD activity in peripheral blood mononuclear cells (PBMCs) <5 nmol mg(-1) *h(-1) (deficient group) and ≥ 5 nmol mg(-1) *h(-1) . U 500 mg m(-2) was administered orally and plasma concentrations of U and dihydrouracil (DHU) were determined. In the deficient group, polymerase chain reaction amplification of all 23 coding exons and flanking intronic regions of DPYD was performed. A U pharmacokinetic model was developed and used to determine the maximum enzymatic conversion capacity (Vmax ) of the DPD enzyme for each patient. The sensitivity and specificity of Vmax, U concentration and the U/DHU concentration ratio were determined., Results: A total of 47 patients were included (19 DPD deficient, 28 DPD normal). Of the pharmacokinetic parameters investigated, a sensitivity and specificity of 80% and 98%, respectively, was obtained for the U/DHU ratio at t = 120 min., Conclusions: The high sensitivity of the U/DHU ratio at t = 120 min for detecting DPD deficiency, as defined by DPD activity in PBMCs, showed that the oral U loading dose can effectively identify patients with reduced DPD activity., (© 2015 The British Pharmacological Society.)

Objective: To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC)., Methods: In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5 mg/kg (day 1), docetaxel 50 mg/m(2) (day 1), oxaliplatin 100 mg/m(2) (day 1), capecitabine 850 mg/m(2) b.i.d. (days 1-14), and trastuzumab 6 mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6 months (observed in the ToGA trial) determined according to the lower limit of the 95 % confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS)., Results: Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17 months, median PFS was 10.8 months (95%CI: 9.0-NA), OS was 17.9 months (95%CI: 12.4-NA). One-year PFS and OS were 52 % and 79 %, respectively. The ORR was 74 % (95%CI: 52-90 %). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related grade ≥ 3 adverse events were: neutropenia (16 %), diarrhoea (16 %), and hypertension (16 %)., Conclusions: B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC.

Background: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial investigates the efficacy and safety of adjuvant exemestane alone and in sequence after tamoxifen in postmenopausal women with hormone-sensitive early breast cancer. As there was a nationwide participation in The Netherlands, we studied the variations in patterns of care in the Comprehensive Cancer Centre Regions (CCCRs) and compliance with national guidelines., Methods: Clinicopathological characteristics, carried out local treatment strategies and adjuvant chemotherapy data were collected., Results: From 2001 to January 2006, 2754 Dutch patients were randomised to the study. Mean age of patients was 65 years (standard deviation 9). Tumours were < or =2 cm in 46% (within CCCRs 39%-50%), node-negative disease varied from 25% to 45%, and PgR status was determined in 75%-100% of patients. Mastectomy was carried out in 55% (45%-70%), sentinel lymph node procedure in 68% (42%-79%) and axillary lymph node dissections in 77% (67%-83%) of patients, all different between CCCRs (P < 0.0001). Adjuvant chemotherapy was given in 15%-70% of eligible patients (P < 0.001)., Discussion: In spite of national guidelines, breast cancer treatment on specific issues widely varied between the various Dutch regions. These data provide valuable information for breast cancer organisations indicating (lack of) guideline adherence and areas for breast cancer care improvement.

Purpose: Breast cancer patients with treatment-induced menopause experience frequent and severe hot flashes (HF). We compared venlafaxine and clonidine for the treatment of HF with regard to side effects, efficacy, quality of life and sexual functioning., Methods: In a double-blind, cross-over study, 60 breast cancer patients experiencing HF were randomized to 8 weeks venlafaxine followed by 2 weeks wash-out, and 8 weeks clonidine or vice versa. HF frequency and severity, side effects, quality of life and sexuality were assessed., Results: Thirty patients started with venlafaxine and 30 with clonidine. Premature discontinuation for toxicity occurred in 14/59 during venlafaxine and 5/53 during clonidine (P = .038). Venlafaxine induced more side effects. Median reduction in HF score was 49% for venlafaxine and 55% for clonidine (ns)., Conclusion: Venlafaxine and clonidine are equally, but moderately effective in HF reduction. Side effects are the main reason for drug discontinuation, occurring more often with venlafaxine.

Background: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer., Methods: We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000., Findings: 17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16.3 (95% CI 14.3-18.1) months for sequential treatment and 17.4 (15.2-19.2) months for combination treatment (p=0.3281). The hazard ratio for combination versus sequential treatment was 0.92 (95% CI 0.79-1.08; p=0.3281). The frequency of grade 3-4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13%vs 7%; p=0.004)., Interpretation: Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.

Background: Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin., Patients and Methods: A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients., Results: In first-line the incidence of grade 3-4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand-foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present., Conclusions: Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.

Background: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer., Patients and Methods: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR)., Results: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%., Conclusions: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.

Advanced adenocarcinoma of the pancreas has a very poor prognosis. The aim of this study was to assess the efficacy and tolerability of a combination of the chemotherapeutic agents gemcitabine and raltitrexed. Chemonaive patients with advanced adenocarcinoma of the pancreas were treated with a combination of raltitrexed (3.5 mg m(-2) on day 1 of a 21-day treatment cycle) and gemcitabine (800 mg m(-2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle). Between April 2000 and February 2003, 27 patients were enrolled onto the study. The mean duration of treatment was 11 weeks. Four of 27 patients experienced at least one episode of grade 3 or 4 neutropenia. One patient with grade 4 neutropenia died due to sepsis. Four of 27 patients experienced grade 4 diarrhoea. There was one partial remission (4%) and 12 patients experienced disease stabilisation (44%). The 6-month and 1-year survival rates were 37 and 11%, respectively. Symptomatic benefit occurred in seven (26%) patients. We conclude that a combination of raltitrexed and gemcitabine, using the schedule and doses in this study, cannot be recommended for patients with advanced pancreatic cancer.

A 48-year-old woman with exanthema, pruritus and eosinophilia was found upon further examination to have a small-cell bronchus carcinoma; after chemotherapy and radiotherapy there was an almost complete response and the skin symptoms disappeared. A 70-year-old man who was recently treated due to primary malignant fibrous histiocytoma associated with eosinophilia became cachectic and anaemic. He was found to have a metastased leiomyosarcoma and died shortly afterwards. Worldwide the most common cause of eosinophilia is a parasitic infection, whereas in Western Europe the most common causes are allergic reactions and medicine use. Paraneoplastic symptoms are present in 7-10% of adults with cancer. However, the frequency of eosinophilia as a paraneoplastic phenomenon is unknown. It is important to recognise this phenomenon of paraneoplastic eosinophilia for the timely diagnosis and treatment of the underlying disease.

We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.

Purpose: Fostriecin is an inhibitor of topoisomerase II catalytic activity. In a phase I trial we observed renal toxicity, documented as a rise in serum creatinine, which was reversible and non-dose-limiting. The purpose of this study was a detailed analysis of this toxicity., Methods: A total of 20 patients received fostriecin as a 1-h i.v. infusion daily x 5 at doses ranging from 2 to 20 mg/m2 per day. Serum creatinine determination and urinalysis were performed daily during drug administration. Renal hemodynamics were measured by means of clearance studies using 125I-iothalamate and (131)I-hippuran in eight patients at doses of > or =4 mg/m2 per day at baseline, on day 3 or 4 during the first course, and 3 weeks after the second course., Results: The rise in serum creatinine was maximal after one to two doses despite continued administration. This increase showed no correlation with the dose level at fostriecin doses of > or =4 mg/m2 per day. Urinary beta2-microglobulin concentrations increased 150-fold (median), which is compatible with impaired tubular reabsorption. The median change in the glomerular filtration rate (GFR) was -36% (range -28% to -44%), that in effective renal plasma flow (ERPF) was -23% (range -11% to -36%), and the filtration fraction (FF) decreased in all patients during the first course of treatment. The values measured 3 weeks after the second course, however, did not differ from baseline., Conclusions: Fostriecin induces reversible renal hemodynamic changes compatible with renal tubular damage.

The effect of oral etoposide on CA-125 serum levels was evaluated in 17 patients with epithelial ovarian cancer and progressive disease during, or relapsing after, prior chemotherapy. Only three patients had measurable lesions at extraperitoneal sites. Five had no measurable lesions. The oral etoposide dose was 50 mg b.d. for 7 days every 3 weeks, escalating to 10 or 14 days and continued until clinical progression. CA-125 after 4 courses was compared to baseline (CA-125 ratio). The rate of change of CA-125 (s, slope of the exponential regression curve) during the first 4 courses was compared to s over a similar period before treatment. One patient had a clinical partial response. Two other patients had a biochemical response (CA-125 ratio <0.5). Although the biochemical response rate was modest (12.5%), a decrease of s was observed in 14/16 patients (P = 0.02). The mean change of s represented an increase of mean doubling time from 52 to 693 days. No patients were withdrawn because of toxicity. General malaise, nausea, diarrhea, and anemia were the most important side effects. At the given dose schedule, oral etoposide shows activity in advanced ovarian cancer if the rate of change of CA-125 is used as a measure of activity.

Fostriecin is a novel antitumor antibiotic. In vitro studies showed that fostriecin inhibits DNA topoisomerase II (Topo II) catalytic activity, protein phosphatases involved with cell-cycle control and histone phosphatases. The relative contribution of these mechanisms to the antitumor activity has not been elucidated, but Topo II inhibition seems to be the major mechanism of action at in vitro cytotoxic fostriecin levels. Tumor cell lines with decreased Topo II content showed similar or increased sensitivity to fostriecin, compared to the parent cell lines. The reduced-folate carrier is probably responsible for the cellular uptake of fostriecin. The possible clinical consequences of these in vitro observations are discussed.

Prolonged oral etoposide monotherapy is an effective treatment in patients with small cell lung cancer (SCLC) and refractory malignant lymphoma. It shows remarkable activity in relapsed or refractory breast and ovarian cancer (response rates up to 35% and 26%), and was also active in refractory germ cell tumours. Results in small numbers of patients with haematological malignancies merit further investigation. There is considerable pharmacokinetic variability after oral etoposide administration and further investigations are needed to establish optimal dose. Side effects (in particular leucopenia and universal alopecia) should not be underestimated, especially in elderly bad risk patients.

The efficacy and toxicity of intraperitoneal (i.p.) cisplatin plus systemic etoposide were studied in 36 patients with small (< 2 cm) residual i.p. ovarian cancer after achieving a partial response to platinum-based, first-line chemotherapy. Treatment comprised 90 mg/m2 i.p. cisplatin with intravenous (i.v.) sodium thiosulphate (day 1) and 600-800 mg/m2 i.v. etoposide (days 1 and 2), every 4 weeks for four to six cycles. 7 patients achieved a pathological complete response (pCR), one a pathological partial response and 16 were clinically stable without evidence of disease. After a median follow-up of 13 months, the median progression-free survival (PFS) was 11 months (95% confidence interval 7-16 months). The actuarial PFS at 24 months is 22% (95% confidence interval 8-36%). Three of six relapses after achieving a pCR (50%) were sited i.p., and 9 of 14 other patients with disease progression (64%) had an i.p. relapse, indicating insufficient local efficacy. There was no renal toxicity, but grade 3-4 leucopenia occurred in 63% and grade 3-4 thrombocytopenia in 8% of cycles, while nausea, vomiting and complete alopecia were common. Although side-effects were acceptable, the efficacy of treatment with i.p. cisplatin plus i.v. etoposide is limited.

A small percentage (around 1.5%) of pancreatic malignancies are well treatable non-Hodgkin's lymphomas. Two patients with this disease are described. One patient was treated with both surgery and chemotherapy, the other with chemotherapy only. The results in both patients were excellent with complete responses being achieved. The literature on pancreatic non-Hodgkin's lymphomas is reviewed.

A case of a 69-year-old man with an extra-adrenal malignant phaeochromocytoma is described. Sputum cytology revealed metastatic cells, which have not been reported previously in malignant phaeochromocytoma. This case is also remarkable for the short duration of disease, rapid progression and extensive spread of metastases, the radiological aspect of metastatic lesions shown by chest X-ray, hypercalcaemia and extremely high levels of circulating catecholamines and urinary metabolites.