The effect of chemotherapy on subjective cognitive function in younger early-stage breast cancer survivors treated with chemotherapy compared to older patients.

PURPOSE: To evaluate the impact of chemotherapy on subjective cognitive functioning according to age in a large cohort of breast cancer patients. METHODS: Within the UMBRELLA cohort, 715 patients with early-stage primary invasive breast cancer (T1-3N0-1M0) were selected. Subjective cognitive function was assessed by means of the EORTC QLQ-C30 up to 24 months and compared between patients treated with and without chemotherapy, for three different age strata (355 patients < 55 years, 240 patients aged 55-65 years, and 120 patients > 65 years). Differences between chemotherapy and non-chemotherapy patients by age at different time points were assessed by linear mixed-effect models correcting for age, tumor stage, educational level, endocrine therapy, anxiety, and depression. RESULTS: In total, 979 patients from the UMBRELLA cohort were included, of which 715 (73%) responded to baseline and at least one follow-up questionnaire. Questionnaire response rates ranged between 92 and 70%. The proportion of patients treated with chemotherapy decreased with age: 64% (n = 277) in patients < 55 years, 45% (n = 107) in patients 55-65 years, and 23% (n = 27) in patients > 65 years. Chemotherapy was associated with reduced subjective cognitive functioning. The impact of chemotherapy on subjective cognitive function was most pronounced in patients < 55 years, followed by those between 55 and 65 years. In the youngest age groups, patients treated with chemotherapy had significantly lower cognitive functioning up to 24 months. In women over 65 years, subjective cognitive functioning was comparable between patients treated with and without chemotherapy. CONCLUSION: This study confirms that chemotherapy is associated with impaired subjective self-reported cognitive functioning in breast cancer patients, and the effect persists at least up to 2 years after diagnosis. The impact of chemotherapy on self-reported cognitive functioning in the first 24 months is most pronounced in younger patients, especially those under 55 years of age.

Chemotherapy and healthcare utilisation near the end of life in patients with cancer.

The quality of medical care delivered to patients with cancer near the end of life is a significant issue. Previous studies have defined several areas suggestive of aggressive cancer treatment as potentially representing poor quality care. The primary objective of current analysis was to examine chemotherapy and healthcare utilisation in the last 3 months of life among patients with cancer that received palliative chemotherapy. Patients were selected from the hospital administration database of the Diakonessenhuis Utrecht, the Netherlands. Data were extracted from the medical files. A total of 604 patients were included for analysis (median age: 64 years). For 300 patients (50%) chemotherapy was given in the last 3 months (CT+). For 76% (n = 229) of CT+ patients unplanned hospital admissions were made in these last 3 months, compared to 44% (n = 133) of CT- patients (p < .001). Visits to the emergency room in last 3 months were made by 67% (n = 202) of CT+ patients compared to 43% (n = 132) of CT- patients (p < .001). Healthcare consumption was significantly higher in patients who received chemotherapy in the last 3 months of life. Being able to inform our patients about these aspects of treatment can help to optimise both the quality of life and the quality of dying in patients with cancer.

Evaluation and reporting of quality of life outcomes in phase III chemotherapy trials for poor prognosis malignancies.

BACKGROUND: Quality of life (QoL) should be included in trials where treatment is expected to have a limited impact on long-term survival. We set out to determine whether phase III chemotherapy trials addressing solid malignancies with a poor prognosis include QoL as a study objective and to assess the extent to which these data have been published. METHODS: We performed a search of the National Institutes of Health clinical trial registry website to identify phase III chemotherapy trials for poor prognosis solid malignancies. The retrieved protocols were subsequently reviewed, to assess whether QoL was included as an outcome measure. Subsequently, a Medline, Embase and world-wide-web search was performed to identify any full text publication or conference abstract regarding the outcome of trials including QoL, which were then reviewed to determine whether and to what extend quality of life results were included. RESULTS: For the 201 included studies, we found that 57 % of trials did not include QoL as a study objective. Of the remaining trials, 50 % have not reported the QoL results in a full text publication, or presented these only as a single sentence statement. CONCLUSION: Evaluation and publication of QoL results of phase III chemotherapy trials for poor prognosis solid malignancies remains limited. This must be improved in order to provide patients suffering from these malignancies with adequate information regarding the benefits and risks of the treatment in terms of both prolongation and quality of life.

Geriatric consultation can aid in complex treatment decisions for elderly cancer patients.

Treatment decisions for elderly cancer patients can be challenging. A geriatric assessment may identify unknown medical conditions, give insight on patients' ability to tolerate treatment and guide treatment decisions. Our aim was to study the value of a geriatric consultation in oncological decision-making. Data on cancer patients referred for geriatric consultation for clinical optimisation or due to uncertainty regarding their optimal treatment strategy were prospectively analysed. Outcome of geriatric evaluations, non-oncological interventions and suggested adaptations of oncological treatment proposals were evaluated. Seventy-two patients were referred for consultation, over half of which in a curative treatment setting. Prevalence of geriatric syndromes was 93%, previously undiagnosed conditions were identified in 49% of patients and non-oncological interventions were initiated in 56%. Time was spent discussing patients' priorities (53% of consultations), expectations on treatment (50%) and advance care planning (14%). For 82% of patients, suggestions were made regarding the optimal treatment decision: a more intensive treatment was recommended in 39%, a less intensive therapy for 42% and in 19% only supportive care was suggested. The results demonstrate that a geriatric consultation can aid in complex treatment decisions and may allow for a reduction in over- and undertreatment of elderly cancer patients.

Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

The additive value of restaging-CT during neoadjuvant chemotherapy for gastric cancer.

INTRODUCTION: Computed tomography (CT) is used for restaging of gastric cancer patients during neoadjuvant chemotherapy (NAC). The treatment strategy could be altered after detection of distant interval metastases, possibly leading to a reduction in unnecessary chemotherapy cycles, its related toxicity, and surgical procedures. The aim of this study was to evaluate the additive value of restaging-CT during NAC in guiding clinical decision making in gastric cancer. MATERIALS AND METHODS: This retrospective, multicenter cohort study identified all patients with surgically resectable gastric adenocarcinoma (cT1-4a-x, N0-3-x, M0-x), who started NAC with curative intent. Restaging-CT was performed after 2 out of 3 cycles of NAC. The primary outcome was treatment alterations made based on restaging-CT by a multidisciplinary tumor board. Confirmation of metastases was obtained by surgery or biopsy. RESULTS: Between 2007 and 2015, CT-restaging was performed in 122 out of 152 included patients and timed after 2 cycles (n = 76) or after 3 cycles (n = 46) of NAC. Restaging-CT revealed a metastasis in 1 out of 122 restaged patients (1%) after which surgical resection was omitted, whereas 4 patients (3%) with distant interval metastases were not identified by restaging-CT and underwent a futile laparotomy. In 5 out of 76 patients (7%) disease progression was detected while undergoing NAC, leading to omission of the 3rd cycle of chemotherapy. CONCLUSION: The additive value of restaging-CT during NAC in gastric cancer is limited in guiding clinical decision making and therefore not recommended. Further studies may identify subgroups that may benefit of alternative diagnostic modalities.

Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) specifically associated with Wegener's granulomatosis were found to be directed against a saline-soluble glycoprotein triplet that migrates on SDS gels as distinct bands of Mr 29,000, 30,500, and 32,000 and is present in the azurophilic granules. This antigen was specifically recognized by all cytoplasmic-staining (C)-ANCA-positive sera from patients with Wegener's disease. C-ANCA antigen bound [3H]diisopropylfluorophosphate, which indicates that it is a serine protease, but it could clearly be distinguished from the serine proteases elastase and cathepsin G. Stimulation of cytochalasin B-treated neutrophils with FMLP induced release of C-ANCA antigen. This indicates that in vivo C-ANCA might interact with the C-ANCA antigen after its release upon inflammatory stimulation. We further demonstrate that in some perinuclear staining (P-ANCA) patients' sera autoantibodies against other myeloid lysosomal enzymes can be detected, such as antimyeloperoxidase and antielastase. C-ANCA and P-ANCA thus represent a novel class of autoantibodies directed against myeloid lysosomal enzymes. The originally described Wegener-specific C-ANCA show an apparently uniform specificity for the 29,000 serine protease. In contrast, P-ANCA may recognize myeloperoxidase as well as elastase and/or other antigens.

Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats.

The purpose of this study was to optimise intraperitoneal chemotherapy by combining this modality with regional hyperthermia. In vitro data demonstrated that both the uptake of cisplatin into CC531 tumour cells and cytotoxicity were increased at temperatures of 40 degrees C (factor 4) and 43 degrees C (factor 6) compared to 37 degrees C. The increase of intracellular platinum concentration correlated well with the decrease in survival of these cells. In vivo, rats were treated intraperitoneally with cisplatin (5 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3) degrees C and outside the peritoneal cavity 40.5 (0.3) degrees C. Enhanced platinum concentrations were found in peritoneal tumours (factor 4.1) and kidney, liver, spleen and lung (all around a factor 2.0), after combined cisplatin-hyperthermia treatment. The platinum distribution in peritoneal tumours was more homogeneous after the combined treatment than after cisplatin alone, possibly due to increased penetration of cisplatin into peritoneal tumours. Pharmacokinetic data demonstrated an increased tumour exposure for unfiltered platinum in the peritoneal cavity (area under the curve [AUC] increased from 339 mumol/l/min to 486 mumol/l/min at 37 degrees C and 41.5 degrees C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 mumol/min and for ultrafiltered platinum from 22.2 to 107 mumol/l/min at 37 degrees C and 41.5 degrees C respectively. The latter might be due to a slower elimination of platinum from the blood. The combined treatment, intraperitoneal cisplatin and regional hyperthermia, also increased toxicity. The thermal enhancement ratio (TER) using lethality as endpoint was 1.8.

Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action.

We have studied the cellular pharmacokinetics of carboplatin (CBDCA), as part of the evaluation of the antitumor activity of CBDCA in cancers limited to the peritoneal cavity in comparison with cisplatin (cDDP). The uptake of CBDCA into L1210 (lymphosarcoma), CC531 (colonic carcinoma), COV413.B (human ovarian carcinoma) and NB1 (human neuroblastoma) cells was 1.5 to 13 times lower than the uptake of cDDP. The uptake of CBDCA into human ovarian carcinoma cells, taken directly from patients, was also 8-20 times lower than cDDP. Platinum concentrations, expressed as a percentage of the total intracellular Pt concentration, were similar for CBDCA and cDDP in cytosol and nucleus/membrane fractions. A second major difference between the drugs was their binding to DNA. Less CBDCA-DNA than cDDP-DNA adducts were formed after incubation at equimolar amounts of drug with isolated salmon sperm DNA (5-25 times less). A 16-69 times higher concentration of CBDCA than cDDP was needed to induce similar changes in cell growth activity (50% [3H]thymidine inhibition) in CC531 and COV413.B cells, indicating that equitoxicity can only be achieved when tumor cells are exposed to higher concentrations of CBDCA than cDDP. Similar toxicity was achieved in CC531 cells after incubation with a 16-fold higher CBDCA dose than cDDP. Comparable intracellular platinum concentrations, however, were obtained with a 10-fold higher CBDCA dose, suggesting that cellular pharmacokinetics of the drugs are different. Regarding drug uptake and pharmacokinetics the mechanism of action of CBDCA differed from cDDP at a cellular level.

A case of isodicentric 7p as sole abnormality in a patient with acute myeloid leukemia.

The detection of isochromosomes in the leukemias and in solid tumors has been well described in the literature, the most common being the i(17q), which is found in the blast crisis of CML and terminal stages of acute myeloid leukemia. Reports of isochromosome 7 have, however, been less well represented, particularly isochromosomes of the short arm of chromosome 7, which represent approximately 1% of all reported isochromosomes in neoplasia. We present here a case report of an elderly female patient with AML-M2 who manifested an idic(7p) in the majority of her bone marrow cells. Fluorescence in situ hybridization (FISH) studies with both centromere-7--and chromosome-7--specific DNA probes verified the diagnosis of idic(7p). To the best of our knowledge, this is the first report of this type of leukemia with an acquired idic(7p) as the sole cytogenetic abnormality.

Bleomycin and scuba diving: to dive or not to dive?

Bleomycin is to treat patients with testicular cancer and lymphoma. Bleomycin can bind to DNA and chelate iron. The resulting complex can form an intermediate capable of interacting with oxygen to produce reactive oxygen species, particularly superoxide. Administrating high-inspired oxygen concentrations (e.g. during anaesthesia or acute illness) has been reported to exacerbate pulmonary injury. The duration of risk after bleomycin chemotherapy is unknown. Here we discuss our advice to a young male patient, who was successfully treated with bleomycin for testicular cancer, concerning the safety to return to scuba diving. Since scuba divers are exposed to high partial oxygen pressures (depending on the depth of the dive) we discouraged this patient from resuming scuba diving.

Coeliac disease clinically manifest after vagotomy and oesophagectomy.

The clinical onset of coeliac disease may be precipitated by upper digestive tract surgery. A 66-year-old woman with asymptomatic coeliac disease that became clinically evident after oesophagectomy and vagotomy is presented. The surgery was performed for a squamous carcinoma of the hypopharynx. There had been no signs or symptoms of coeliac disease preoperatively. Persistent untreatable hypocalcaemia after the operation suggested the diagnosis. The role of surgery in unmasking asymptomatic coeliac disease is discussed.

Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer.

BACKGROUND: Weekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles. PATIENTS AND METHODS: In this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb-IV EOC were randomised to six cycles PCw (paclitaxel 90mg/m(2), cisplatin 70mg/m(2) or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175mg/m(2), cisplatin 75mg/m(2) or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity. RESULTS: Of 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3years (range 7.1-14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9-21.0) months for PCw and 16.4 (95% CI 13.5-19.2) months for PC3w (p=0.78). Median OS was 44.8 (95% CI 33.1-56.5) months for PCw and 41.1 (95% CI 34.4-47.7) months for PC3w (p=0.98). CONCLUSIONS: There was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.

A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma.

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 phase I study of a fixed dose of cisplatin with increasing doses of raltitrexed (Tomudex) in the treatment of patients with locally advanced or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: A phase I trial of raltitrexed in combination with cisplatin in patients with locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Eligible patients had locally advanced or metastatic SCCHN. Cohorts of patients were treated with escalating doses of raltitrexed (2.0 mg/m2 to 3.5 mg/m2) as a 15-minute intravenous infusion immediately followed by cisplatin (80 mg/m2) administered over four hours every three weeks to determine the maximum tolerated dose (MTD). RESULTS: A total of 17 patients was administered 60 courses of an escalating dose of raltitrexed. Starting dose of cisplatin was initially 100 mg/m2 in the first three patients treated at the first dose level. Due to cisplatin-induced nephrotoxicity expressed as a creatinine clearance decrease by more than 50%, the cisplatin dose was reduced to 80 mg/m2 for all subsequent treatment cycles. Dose-limiting toxicity was observed at raltitrexed dose of 3.5 mg/m2 in two out of five patients. Dose-limiting grade 4 (CTC) neutropenia, grade 4 diarrhoea, grade 3 lethargy and elevation of transaminases and bilirubine was seen in these two patients. One patient treated at the level of the MTD, died 23 days after the first cycle with unresolved gastro-intestinal toxicity. In all other dose levels toxicity was very limited. The recommended dose for further study was raltitrexed 3.0 mg/m2 in combination with cisplatin 80 mg/m2. In 15 evaluable patients, we observed 9 WHO objective responses (1 complete and 8 partial). At the recommended dose level 3 partial responses were observed in five evaluable patients. CONCLUSION: The regimen of raltitrexed 3.0 mg/m2 followed by cisplatin 80 mg/m2 on day 1, every three weeks has manageable toxicity and these doses are recommended for phase II evaluation. Results indicate that this combination is active for the treatment of patients with locally advanced or metastatic SCCHN. Recently, a phase II study has been started.