Treatment of lymphomatous and leukemic meningitis with liposomal encapsulated cytarabine

Liposomal encapsulated cytarabine (DepoCyte®, Mundipharma GmbH, Limburg/Lahn, Germany) is a slow-release formulation of conventional cytarabine. It is licensed for intrathecal use in patients with lymphomatous and leukemic meningitis. DepoCyte® obtained superior response rates, improved patient quality of life and improved the time to neurological progression in a randomized albeit small clinical trial. In this review we briefly summarize the clinical data and discuss them in light of clinical problems and possible treatment scenarios

Influence of Taxanes on Treatment Sequence in Gastric Cancer

Background: Adenocarcinoma of the stomach and esophagogastric junction (EGJ) remains a tumor entity with a poor prognosis. While meaningful advances have been made in the treatment of other solid tumors in the past years, numerous phase III studies in gastric cancer have had negative outcomes. Successes of targeted therapies so far include the introduction of trastuzumab in the first-line treatment of HER2-positive gastric cancer, and second-line anti-angiogenic treatment with the anti-VEGF-2 receptor antibody ramucirumab. Taxanes have become established in the perioperative setting and in second-line treatment and have set new standards. However, evidence for improved overall survival in the first-line treatment of advanced gastric cancer with taxanes is not convincing. Methodology: Expert consensus discussion on the scientific and clinical evidence for sequential systemic treatment for advanced gastric and EGJ cancer, taking into account data clinical outcomes from randomized controlled phase II and phase III trials. Summary: In first-line treatment of advanced gastric cancer, taxanes in combination with a platinum- and 5-fluorouracil-based regimen are generally not recommended because they lack a survival benefit and confer high toxicity. However, taxanes in first-line can be a treatment option for patients presenting with high tumor burden and strong pressure to achieve remission. Since the publication of several positive studies in second- and third-line therapy, sequential therapy is playing an increasingly important role in metastatic gastric and EGJ cancer. Key Message: Standard of care for the first-line treatment of gastric cancer is a platinum-fluoropyrimidine chemotherapy doublet combination. The standard of care after failure of platinum-based first-line therapy is ramucirumab in combination with paclitaxel. Data supporting this combination after previous taxane therapy are not yet available

Molecular analysis of desmoid tumors with a high-density single-nucleotide polymorphism array identifies new molecular candidate lesions

Background: Desmoid tumors are neoplastic proliferations of connective tissues. The mutation status of the gene coding for catenin (cadherin-associated protein) beta 1 (CTNNB1) and trisomy 8 on the chromosomal level have been described to have prognostic relevance. Patients and Methods: In order to elucidate new molecular mechanisms underlying these tumors, we carried out a molecular analysis with a genome-wide human high-density single-nucleotide polymorphism (SNP) array, in 9 patients. Results: Single samples showed numerical aberrations on chromosomes (Chrs) 20 and 6 with either trisomy 20 or monosomy 6. No trisomy 8 could be detected. Recurrent heterozygous deletions were found in Chr 5q (including the APC gene locus, n = 3) and Chr 8p23 (n = 4, containing coding regions for the potential tumor suppressor gene CSMD1). This novel deletion in 8p23 showed an association with local recurrence. In addition, structural chromosomal changes (gain of Chrs 8 and 20) were found in a minority of cases. Conclusion: The genomic alteration affecting the candidate gene CSMD1 could be important in the development of desmoid tumors

CoCStom trial: study protocol for a randomised trial comparing completeness of adjuvant chemotherapy after early versus late diverting stoma closure in low anterior resection for rectal cancer

Background: Current evidence supports a diverting stoma in patients undergoing low anterior resection with total mesorectal excision for rectal cancer as it reduces clinical severity of anastomotic leakage. However, relevant stoma morbidity after rectal cancer surgery exists and has a significant impact on quality of life. Moreover, a diverting stoma has an influence on completeness of chemotherapy but it remains unclear in which way. There is no evidence regarding optimal timing for stoma closure in relation to adjuvant chemotherapy. Two randomised controlled trials have studied early stoma closure after low anterior resection in patients with rectal cancer, one of them showing that early closure around day 8 after resection is possible without increasing morbidity. Methods/Design: CoCStom is a randomised multicentre trial comparing completeness of adjuvant chemotherapy as primary endpoint after early (8–10 days after resection, before starting adjuvant therapy) versus late (~26 weeks after resection and completion of adjuvant therapy) stoma closure in patients with locally advanced rectal cancer undergoing low anterior resection after neoadjuvant therapy. After exclusion of post-operative anastomotic leakage 257 patients from 30 German hospitals are planned to be included in order to assure a power of 80 % for the confirmatory analysis of at least 214 evaluable cases. An absolute increase of 20 % for the rate of completely administered adjuvant chemotherapy is regarded as a clinically meaningful step forward and serves as basis for sample size calculation. Quality of life, stoma-related complications, individual completeness of chemotherapy rate, percentage of patients stopping adjuvant therapy or undergoing dose modifications or delay, oncological outcomes, cumulative days of hospitalisation and number of readmissions, rate of symptomatic anastomotic leaks after stoma closure, mortality, post-operative complications and toxicity of adjuvant chemotherapy are secondary endpoints. Discussion: The CoCStom trial aims to clarify optimal timing of stoma closure in the context of adjuvant chemotherapy. Depending on the results of the trial, patients could benefit either from early or late stoma closure in regard to long term oncological survival due to a higher rate of completeness of adjuvant chemotherapy treatment and thus better effectiveness. Trial registration: German Clinical Trials Register, DRKS00005113 . Registered 28 August 201

Skin toxicity and quality of life in patients with metastatic colorectal cancer during first-line panitumumab plus FOLFIRI treatment in a single-arm phase II study

Background: Integument-related toxicities are common during epidermal growth factor receptor (EGFR)-targeted therapy. Panitumumab is a fully human monoclonal antibody targeting the EGFR that significantly improves progression-free survival when added to chemotherapy in patients with metastatic colorectal cancer who have wild-type (WT) KRAS tumours. Primary efficacy and tolerability results from a phase II single-arm study of first-line panitumumab plus FOLFIRI in patients with metastatic colorectal cancer have been reported. Here we report additional descriptive tolerability and quality of life data from this trial. Methods: Integument-related toxicities and quality of life were analysed; toxicities were graded using modified National Cancer Institute Common Toxicity Criteria. Kaplan-Meier estimates of time to and duration of first integument-related toxicity were prepared. Quality of life was measured using EuroQoL EQ-5D and EORTC QLQ-C30. Best overall response was analysed by skin toxicity grade and baseline quality of life. Change in quality of life was analysed by skin toxicity severity. Results: 154 patients were enrolled (WT KRAS n = 86; mutant KRAS n = 59); most (98%) experienced integument-related toxicities (most commonly rash [42%], dry skin [40%] and acne [36%]). Median time to first integument-related toxicity was 8 days; median duration was 334 days. Overall, proportionally more patients with grade 2+ skin toxicity responded (56%) compared with those with grade 0/1 (29%). Mean overall EQ-5D health state index scores (0.81 vs. 0.78), health rating scores (72.5 vs. 71.0) and QLQ-C30 global health status scores (65.8 vs. 66.7) were comparable at baseline vs. safety follow-up (8 weeks after completion), respectively and appeared unaffected by skin toxicity severity. Conclusions: First-line panitumumab plus FOLFIRI has acceptable tolerability and appears to have little impact on quality of life, despite the high incidence of integument-related toxicity

A prospective, non-randomized phase II trial of Trastuzumab and Capecitabine in patients with HER2 expressing metastasized pancreatic cancer

Background: Pancreatic cancer is the fourth most common cause of cancer related death in Western countries. Advantages in surgical techniques, radiation and chemotherapy had almost no impact on the long term survival of affected patients. Therefore, the need for better treatment strategies is urgent. HER2, a receptor tyrosine kinase of the EGFR family, involved in signal transduction pathways leading to cell growth and differentiation is overexpressed in a number of cancers, including breast and pancreatic cancer. While in breast cancer HER2 has already been successfully used as a treatment target, there are only limited data evaluating the effects of inhibiting HER2 tyrosine kinases in patients with pancreatic cancer. Methods: Here we report the design of a prospective, non-randomized multi-centered Phase II clinical study evaluating the effects of the Fluoropyrimidine-carbamate Capecitabine (Xeloda (R)) and the monoclonal anti-HER2 antibody Trastuzumab (Herceptin (R)) in patients with non-resectable, HER2 overexpressing pancreatic cancer. Patients eligible for the study will receive Trastuzumab infusions on day 1, 8 and 15 concomitant to the oral intake of Capecitabine from day 1 to day 14 of each three week cylce. Cycles will be repeated until tumor progression. A total of 37 patients will be enrolled with an interim analysis after 23 patients. Discussion: Primary end point of the study is to determine the progression free survival after 12 weeks of bimodal treatment with the chemotherapeutic agent Capecitabine and the anti-HER2 antibody Trastuzumab. Secondary end points include patient's survival, toxicity analysis, quality of life, the correlation of HER2 overexpression and clinical response to Trastuzumab treatment and, finally, the correlation of CA19-9 plasma levels and progression free intervals

Workload and Quality of Life of Medical Doctors in the Field of Oncology in Germany - a Survey of the Working Group Quality of Life of the AIO for the Study Group of Internal Oncology

Background: An increasing number of surveys have investigated professional stress and satisfaction among oncologists. Coevally, structural development has changed the oncological working environment. This survey investigated the quality of life and job stress among German oncological physicians. Methods: A 48-item questionnaire, which included the ‘Stress questionnaire of physicians and nurses' (FBAS), was developed by the ‘Quality of life' working group of the Internal oncology study group (AIO), and distributed anonymously at the annual meeting of the AIO working group in 2010. Descriptive statistics as well as univariate and multivariate analysis were performed. Results: 261 oncologists, mostly male (64%), older than 40 years (38%), and medical specialists (78%), took part in the survey. ‘Structural conditions' were identified as causing the highest mean stress levels, followed by ‘professional and private life'. Female participants showed a significantly lower global quality of life than male participants (p = 0.020). ‘Structural conditions' induced more stress among younger oncologists < 50 years old (p < 0.001). Qualification status was influenced by gender (p < 0.001); the multivariate analysis described the dependence of gender (p = 0.0045), working situation (p = 0.0317) and global stress (p = 0.0008). Conclusion: Structural conditions, age younger than 50 years and female gender were identified as stress risk factors among the AIO members, and showed that job stress is present in German oncology. Further research is warranted to develop evidence-based intervention strategies

Total Neoadjuvant Therapy for Rectal Cancer in the CAO/ARO/AIO-12 Randomized Phase 2 Trial: Early Surrogate Endpoints Revisited

Background: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. Methods: Distribution of pCR, TRG and NAR score was analyzed using the Pearson’s chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. Results: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, ArmB:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63–1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). Conclusion: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution

Patient preferences for palliative treatment of locally advanced or metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction: a choice-based conjoint analysis study from Germany

Background: Decisions on palliative chemotherapy (CT) for locally advanced or metastatic gastric cancer (mGC) require trade-offs between potential benefits and risks for patients. Healthcare providers and payers agree that patient-preferences should be considered. We conducted a choice-based conjoint (CBC) analysis study in pre-treated patients from Germany with mGC or locally advanced or metastatic adenocarcinoma of the gastroesophageal junction (mGEJ-Ca), to evaluate their preferences when hypothetically selecting a CT regimen. Methods: German oncologists and gastroenterologists were contacted to identify patients with mGC or mGEJ-Ca who had completed ≥2 cycles of palliative CT in first or later lines of therapy (CT ongoing or complete). The primary objective was to quantify patient preferences for palliative CT by CBC analysis. Six in-depth qualitative interviews identified 3 attributes: treatment tolerability, quality of life in terms of ability of self-care, and additional survival benefit. The CBC matrix was constructed with 4 factor levels per attribute and each participant was presented with 15 different iterations of these levels. A minimum of 50 participants was needed. Consenting patients completed the CBC survey, choosing systematically among profiles. CBC models were estimated by multinomial logistic regression (MLR) and hierarchical Bayesian (HB) analysis. Estimates of importance for each attribute and factor-level were calculated. Results: Fifty-five patients participated in the CBC survey (78.2% male, median age 63 years, 81.8% currently receiving CT). Across this sample, low treatment toxicity was ranked highest (44.6% relative importance, MLR analysis), followed by ability to self-care (32.3%), and an additional survival benefit of up to 3 months (3 months 23.1%, 2 months 18.3%, 1 month 11.2%). The MLR analysis showed high validity (certainty 37.9%, chi square p < 0.01, root-likelihood 0.505). The HB analysis yielded similar results. Conclusions: Patients’ preferences related to a new hypothetical palliative CT of mGC or mGEJ-Ca can be assessed by CBCanalysis. Although in real-life, patients initially need to decide on CT before they have any experience, and patients’ varied experiences with CT will have impacted specific responses, low toxicity and self-care ability were considered as most important by this group of patients with mGC or mGEJ-Ca