Neurocognitive function, brain-derived neurotrophic factor (BDNF) and IL-6 levels in cancer patients with depression.

BACKGROUND: Increased IL-6 and decreased brain-derived neurotrophic factor (BDNF) levels have been implicated in the pathophysiology of depression. The objective was to assess the influence of BDNF and IL-6 on cognitive function and depression in patients with cancer. METHODS: Serum BDNF and plasma IL-6 were measured in patients with metastatic cancer. Diagnosis of depression was established according to DSM-IV criteria. Cognitive function was assessed by the Verbal Learning and Memory Test (VLMT). RESULTS: A total of 59 patients were recruited in this study. Only IL-6 levels were significantly elevated in patients with clinical depression (35.7 vs. 6.9 pg/ml; p<0.001). There were no differences in hemoglobin levels (p=0.3) or BDNF levels (p=0.16). Patients with clinical depression showed significant impairment of short-term memory (STM) (24.4 vs. 37.5; p=0.01), but not of long-term memory (LTM) (3.9 vs. 2.8; p=0.3). STM was dependent on the level of BDNF and younger age (b=0.60; p=0.001; b= -0.63; p=0.003, respectively). IL-6 was not only strongly associated with depression, but was an independent predictor of BDNF level as well (b= -0.50; p=0.01). LTM was associated only with a good KPS (b=0.47; p=0.037). Hemoglobin levels and the prior number of chemotherapy lines were not predictive of memory performance. CONCLUSIONS: Low BDNF is associated with cognitive impairment, STM, in patients with cancer, however no influence on depression could be found. IL-6 is strongly associated with depression and an independent predictor of BDNF levels.

A survey of treatment approaches of malignant ascites in Germany and Austria.

BACKGROUND: Malignant ascites (MA) is a common manifestation of advanced cancer. Currently, there are no evidence-based guidelines for the management of MA. We conducted a survey with physicians throughout Germany and Austria, to get an overview of current approaches and opinions in the treatment of MA. METHODS: One hundred and twenty-eight medical oncologists (MO), gastroenterologists (GE), and gynecologists (GYN) completed an electronic questionnaire consisting of 33 questions. RESULTS: Ninety percent of the physicians were from Germany and 10% from Austria; 48% of those were MO, 30% were GYN, and 14% were GE. Most physicians treated an average of 34 patients (pts)/year with MA. Twenty-six percent of these pts suffered from ovarian, 20% from pancreatic, 17% from gastric, and 14% from colorectal cancer. The majority of the physicians associated MA with poor prognosis (92%) and significant reduction in quality of life (87%). One third felt that MA was a contraindication for full dosing of systemic chemotherapy. Paracentesis (PC) was performed in 70% of pts with symptom relieve and quality of life being the main reasons. Almost half of the pts required 3-5 PC, 50% even more than 5 PC during the course of their disease. Only 15% of pts needed multiple PC per week; the majority (79%) needed the procedure either once a week or every 14 days. In 61% of pts, 3-5 L of ascites fluid was drained. Only in 8%, 5 L and more were removed. Volume substitution with IV albumin was performed in 40% of pts. Most pts (55%) had to stay 1-3 h in a healthcare facility for the procedure. However, 21% had to stay ≥1 day. While almost all physicians (89%) performed a PC at some point in the treatment of MA, 75% felt that a systemic chemotherapy and 55% thought a concomitant diuretic therapy were a necessary adjunct. Seven percent of the pts received a targeted treatment with catumaxomab. CONCLUSIONS: Repeated PC is the main pillar of treatment of MA; its effect is only temporary and requires significant hospital resources. Further treatment strategies of MA have to be evaluated in prospective studies. Targeted therapies like catumaxomab and VEGF inhibitors should be integrated into these.

Influence of comorbidity, age and performance status on treatment efficacy and safety of cetuximab plus irinotecan in irinotecan-refractory elderly patients with metastatic colorectal cancer.

BACKGROUND: We investigated the influence of comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status and age on the efficacy and safety profile of cetuximab and irinotecan in elderly irinotecan-pretreated patients with mCRC. METHODS: 497 patients with mCRC were entered in the database of this non-interventional study (NIS). Comorbid conditions were recorded. RESULTS: A total of 247 and 250 patients aged <65 and >65 years, respectively, with a median age of 66 y were documented; 78% of the patients showed a reduced ECOG status. Grade III/IV toxicities occurred in 18% of patients without any difference between age groups although older patients had more comorbidities with a higher Charlson Comorbidity Index (CCI) (p = 0.002). Skin rash was strongly related to response (p = 0.006). Age, line of therapy, ECOG, gender and CCI had no influence on response. The objective response rates were similar: 38.1% for age <65 years versus 36.4% for age >65 years (p = 0.57). Progression-free survival (PFS) did not differ between patients 18-65 years (6.0 months) and patients >65 years (6.2 months; p = 0.99). Only PS had a negative impact on PFS (hazard ratio (HR): 0,499; 95% confidence interval (CI) 0.34-0.72; p=0.002), whereas the presence of skin toxicity (grade>1) influenced PFS and response rate (RR) positively (HR: 2.04; 95% CI, 1.6-2.6; p<0.001). CONCLUSIONS: Only PS and age had a negative influence on PFS irrespective of CCI or age. There were no significant differences in response rate and safety profile for elderly patients when treated with cetuximab and irinotecan. Comorbidities and age had no influence on efficacy or toxicity.

Influence of age, performance status, cancer activity, and IL-6 on anxiety and depression in patients with metastatic breast cancer.

Depression and anxiety are the core disorders causing emotional distress in patients (pts) with metastatic breast cancer. The aim of our study was to screen metastatic breast cancer outpatients for anxiety and depression, and to investigate the influence of age, Karnofsky Performance Status (KPS), cancer activity, and inflammation as represented by IL-6 levels on these two mood disorders. Pts treated with chemotherapy for metastatic breast cancer (n = 70) were assessed using the Hospital Anxiety and Depression Scale (HADS) for symptoms (scores 0-21) and caseness (score ≥11) of clinical depression and anxiety. Blood samples for IL-6 concentrations were collected at 10:00 a.m. A total of 22 (31.4 %) pts were diagnosed with caseness of clinical depression and 23 (32.9 %) pts with clinical anxiety, while 12 pts were diagnosed positive for both mood disorders. Depression and anxiety were positively but moderately correlated (Spearman's r (2) = 0.24, p < 0.001). IL-6 was significantly correlated with symptoms of depression (r (2) = 0.42, p < 0.001) and to a lesser extent to symptoms of anxiety (r (2) = 0.16, p = 0.001). In addition, IL-6 was positively associated with tumor progression (p < 0.001). Multiple linear regression analysis showed that tumor progression (standardized b = 0.226, p = 0.047), symptoms of anxiety (b = 0.292, p = 0.016), and IL-6 (b = 0.314, p = 0.007) were independently associated with clinical depression, whereas anxiety was linked to tumor progression (b = 0.238, p = 0.030), symptoms of depression (b = 0.407, p < 0.001) and age (b = -0.381, p < 0.001), but not to IL-6 (b = 0.168, p = 0.134). Even though a positive correlation between depression and anxiety exists, clinical parameters like age, cancer activity, KPS, and IL-6 do influence depression and anxiety differently. Unlike clinical depression, anxiety is not associated with increased IL-6 levels, however, shows a reciprocal correlation with age.

Cetuximab-based therapy in elderly comorbid patients with metastatic colorectal cancer.

BACKGROUND: Clinical trials under-represent patients (pts) >65 years. Non-interventional studies (NISs) help to evaluate therapies in daily practice. This NIS evaluates efficacy and safety of cetuximab in combination with chemotherapy in metastatic colorectal cancer (mCRC) pts aged >65 years vs ≤ 65 years. METHODS: A total of 657 pts were recruited into the NIS and analysed applying descriptive statistics and χ(2) or Fisher's exact test. RESULTS: A total of 309 and 305 pts aged ≤ 65 and >65 years, respectively, were documented; 80% showing a reduced ECOG status of 1-2 and 95% having received at least one palliative treatment. Cetuximab was combined with irinotecan according to approval status. Grade III/IV toxicities occurred in 20% of pts without any difference between age groups although the older pts had significantly more pre-existing comorbidities (P=0.001). A total of 64.2% of the pts developed skin rash, which was strongly related to response (P<0.0002) without any difference between age groups (P=0.34). The objective response rates were 37.9% for ages 18-65 years vs 35.4% for >65 years. Progression-free survival (PFS) did not differ between pts 18-65 years old (6.5 months) in comparison with pts >65 years (7.0 months). In a multivariate analysis only ECOG status had a negative impact on PFS (HR: 0,675; 95% Cl, 0.53-0.87; P=0.0019). CONCLUSION: This NIS reports one of the largest mCRC collectives >65 years and reduced performance status. Cetuximab has a similar efficacy and safety profile for pts aged ≤ 65 and >65 years.

First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN).

BACKGROUND: Cisplatin is one of the most active chemotherapeutic agents used in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). However, its clinical efficacy is limited by its renal and hematotoxicity profile. In a randomized, multicenter phase III trial, we replaced conventional cisplatin by a liposomal formulation of cisplatin (lipoplatin) and compared the safety and efficacy profiles of patients in the two treatment arms. PATIENTS AND METHODS: Main inclusion criteria were: histologically confirmed SCCHN, age between 18-75 years with sufficient renal function. Main endpoints for this interims analysis were hemato- and nephrotoxicity. First response data were collected. RESULTS: Forty-six patients were evaluable for outcome and toxicity. Grade III and IV hematotoxicity were more frequent in the cisplatin arm (31.7% vs. 12%), with grade IV leucopenia occurring in 22.2%. However, 16% of the patients in that treatment arm experienced grade III anemia compared to only 9.5% treated with the cisplatin regimen. A total 4% of the patients in the lipoplatin arm developed grade IV neuropathy, whereas in the cisplatin arm, 19% developed grade III neuropathy and none developed grade IV. The renal toxicity profile of both drugs also showed marked differences. In the cisplatin arm, 23.8% of patients suffered grade III toxicity. In contrast, no grade III or IV renal toxicity occurred in patients treated with lipoplatin. The efficacy results showed 38.8% objective partial remission in the cisplatin arm vs. 19% in the lipoplatin arm. However 64% of the patients achieved stable disease while being treated with lipoplatin/5-fluorouracil (5-FU), vs. 50% in the cisplatin/5-FU arm. CONCLUSION: Liposomal cisplatin seems to reduce both the renal and hematological toxicity to a clinically relevant extent as compared to conventional cisplatin. The clinical benefit rate is similar for both regimens.

Pharmacokinetics of liposomal cisplatin (lipoplatin) in combination with 5-FU in patients with advanced head and neck cancer: first results of a phase III study.

BACKGROUND: Lipoplatin, a novel liposomal formulation of cisplatin, is composed of cisplatin and liposomes based on dipalmityl phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC-3), cholesterol and methoxypolyethylene glycol-distearoyl phosphatidylethanolamine (mPEG2000-DSPE). Liposomal encapsulation of cisplatin is designed to increase safety and tolerability by decreasing, e.g., nephrotoxicity through decreased exposure of organs to cisplatin, while effectively delivering the drug to the tumor. In an ongoing phase III trial comparing cisplatin to lipoplatin (both in combination with infusional high-dose 5-Fluoruracil) in advanced head and neck cancer (HNC), a sub-study to determine the pharmacokinetic profile of lipoplatin in comparison to conventional cisplatin was undertaken. MATERIALS AND METHODS: In total, twelve patients with advanced HNC received a combination chemotherapy with either lipoplatin/5-FU or cisplatin/5-FU. Plasma samples were analyzed for concentration of total platinum in patients from both arms. RESULTS: All twelve patients from the pharmacokinetic sub-study were male Caucasians at a mean age of 60 years. There was no difference in age or kidney function between the two treatment groups. The total body clearance for cisplatin was 1.25 L/(hxm2) for the liposomal formulation, compared to 0.62 L/(hxm2) for conventional cisplatin. The terminal half life was half as long for lipoplatin (10.98 h) as compared to cisplatin (24.5h). Even though the maximum observed concentration in the plasma (C(max) was greater for lipoplatin than for cisplatin, the area under the concentration time-curve (AUC) was less (6.5 microg/ml vs. 4.07 microg/ml and 66.85 microg/h/ml vs. 130.33 microg/h/ml, respectively). CONCLUSION: The pharmacokinetic profile of lipoplatin (in combination with 5-FU) suggests that the liposomal formulation results in a greater body clearance and shorter half life than conventional cisplatin, which confirms the clinical observation of decreased taxicity, especially renal deterioration.