[Pharmacological pain management in cancer patients]. / Medikamentöse Schmerztherapie bei Patienten mit Tumorerkrankungen.

Pharmacological pain therapy in cancer patients is based on guideline recommendations, which, however, do not fully coincide in all aspects due to varying weighting of evidence. The present article discusses current issues including the decreasing significance of the World Health Organization (WHO) analgesic ladder, with its distinction between step 2 and 3 being increasingly questioned. Risks of nonopioid analgesics such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in older populations, are discussed. Paracetamol may potentially reduce the effectiveness of immunotherapies. Aspects of administering analgesics via a feeding tube are considered. Recommendations for the treatment of episodic pain, transitioning between different opioids, and some relevant interactions are also discussed.

Early Integration of Palliative and Oncological Care: Con.

For almost a decade, 'early integration' has become a buzzword in the palliative care community. Can this still be an issue of controversy? The goals of care in palliative medicine are beyond any criticism and in fact should be, at least in theory, goals of good oncological care. However, the reality presents a different picture. The care of cancer patients requires improvement, and the studies on the early integration of palliative care (EIPC) reveal deficits in the oncological practice. However, the limitations and methodological weaknesses of these EIPC studies are insufficiently analyzed and discussed. The main criticisms relate to the incomplete definition of primary endpoints, published analyses deviating from the study protocols and insufficient consideration for multiple testing. If this criticism is justified, a possible consequence would be to overrate the achievable effects of EIPC and to limit the use of these studies in guiding policies. Improving the care of cancer patients by fostering their primary care by oncologists could provide one of the alternative approaches, but needs to be evaluated in future studies. Unmet needs in physical, psychic, spiritual or social care need to be addressed. Whether this requires a multiprofessional team in all cases is another issue of discussion.

Overall Survival among Cancer Patients Undergoing Opioid Rotation to Methadone Compared to Other Opioids.

BACKGROUND: Methadone has been associated with lower overall survival (OS) in patients with chronic pain. There are no data available on the association of methadone with OS in cancer patients. OBJECTIVE: Our aim was to compare the OS in cancer outpatients undergoing opioid rotation (OR) to methadone and other strong opioids. DESIGN: Demographics, symptoms, and morphine equivalent daily dose (MEDD) were collected in patients who underwent OR from strong opioids to either methadone or other strong opioids and returned for a follow-up within six weeks. SETTING/SUBJECTS: Nine hundred thirty-eight consecutive outpatients to the supportive care center of a tertiary cancer center were reviewed. MEASUREMENTS: Kaplan-Meier curves were used to evaluate survival. RESULTS: Of a total of 164 eligible patients, 54/76 patients who underwent OR to methadone and 48/88 patients who underwent OR to other opioids returned for a follow-up visit. The median age was 56 years, 54% were male, and 87% had advanced cancer. There were no significant differences between the two groups in patient characteristics, performance status, MEDD, and pain scores. The Kaplan-Meier curves revealed no significant difference in median OS between all patients undergoing OR to methadone and other opioids [3.75 months (95% confidence interval, CI, 2.30-6.46) vs. 2.62 months (95% CI 1.74-4.33); p = 0.35] and also among those who returned for a follow-up following an OR to methadone and other opioids [5.15 months (95% CI 3.64-7.41) vs. 5.90 months (95% CI 2.62-9.28); p = 0.89]. CONCLUSIONS: We observed no significant difference in OS in cancer patients in methadone group compared to other opioids.

Patients' perspectives on palliative chemotherapy of colorectal and non--colorectal cancer: a prospective study in a chemotherapy- experienced population.

BACKGROUND: A better understanding of patients' views on the benefit and burden obtained from palliative chemotherapy would facilitate shared decision making. We evaluated palliative cancer patients' reported outcomes (PROs) for toxicity and investigated the survival threshold for which they would repeat chemotherapy (CTx). METHODS: Patients who had received a minimum of three months of palliative CTx for advanced colorectal (CRC) or non-colorectal (non-CRC: upper gastrointestinal, lung and head-and-neck) cancer were assessed by questionnaire. Patients were questioned about PROs for toxicity, subjective burden from side effects, and were asked for the survival threshold necessary for them to repeat CTx. Expected survival (sum of indicated survival threshold and median survival time with best supportive care) was compared to the patients' actual survival. RESULTS: One hundred and thirty-four patients (CRC: 58; non-CRC: 76) were surveyed. The most frequent PRO- grade 3/4 toxicities were acne (12.8%), fatigue (9.0%), and diarrhea (8.5%). The symptom causing the highest subjective burden was fatigue and was worse than expected in 29.9% of the patients. The median survival threshold for which patients would repeat CTx was significantly longer in CRC than in non-CRC patients (p=0.01). Median expected survival was significantly longer than actual median survival (CRC: 44.0 months [22.0-65.9] compared with 30.0 months of actual survival [20.9-39.1]; non-CRC: 22.0 months [15.3-28.6] compared with 19.0 months of actual survival [15.1-22.9], p=0.03). CONCLUSION: Fatigue deserves more attention when toxicity of treatment and symptoms of disease are explained to patients. Patients' survival expectations from palliative chemotherapy are higher than previously described, exceed the median survival time known from phase III trials, and are significantly longer than their actual survival.

Improved assay for determination of busulfan by liquid chromatography using postcolumn photolysis.

A highly sensitive and time-reduced HPLC assay for the quantitative analysis of busulfan in plasma and aqueous samples is described. The assay is based on a precolumn derivatization of busulfan to 1,4-diiodobutane and UV-detection of iodide ions generated by a postcolumn photochemical dissociation of the derivative. The extraction and derivatization were carried out in a one-pot reaction without any solid phase extraction and is therefore suitable for high throughput analysis. Quantification was performed by using 1,5-pentanediol-bis-(methanesulfonate), a homologue of busulfan, as an internal standard. Linearity was demonstrated for concentrations from 50 to 10,000ng/ml. The limit of detection was found at 10ng/ml. Precision is indicated by an intra-day variety of 2.81% and by an inter-day variety of 6.61% for aqueous samples, 2.93 and 5.76% for plasma samples, respectively. The recovery of busulfan in plasma was more than 95%. No coelution with metabolites of busulfan or other drugs used in cancer therapy was found. The method was generated for measurements of busulfan in aqueous or plasma samples and applied in therapeutic drug monitoring of busulfan.

CNS blast crisis of chronic myelogenous leukemia in a patient with a major cytogenetic response in bone marrow associated with low levels of imatinib mesylate and its N-desmethylated metabolite in cerebral spinal fluid.

Imatinib mesylate (STI571) is a very effective treatment option for Ph(+) chronic myeloid leukemia (CML) in chronic phase. Secondary treatment failures have mostly been observed in patients with advanced stages of disease. We report the case of a patient who unexpectedly experienced blast crisis of the central nervous system although having achieved complete cytogenetic remission in the bone marrow. The levels of STI571 and its metabolite N-desmethyl STI were 40-fold lower in the cerebral spine fluid than in plasma. The risk of CNS disease has to be kept in mind when patients with CML in chronic phase who are at an increased risk for blastic transformation are treated with imatinib mesylate.

MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients.

Allelic variants of the MDR-1 gene have been shown recently to influence protein expression and P-glycoprotein (P-gp) function in healthy volunteers. Therefore, 405 acute myeloid leukemia patients were investigated for somatic genotypes of the three most frequent single nucleotide polymorphisms (SNPs) in exons 12, 21, and 26. In all three loci, homozygous wild-type alleles were classified as genotype A, heterozygous as B, and homozygous mutant (alternative) allele as C. Patients with the C genotype in exons 12 and 26 showed a lower median age (both P < 0.05). Additionally, the C genotype in exons 12 and 26 was associated with cytogenetic poor risk aberrations (both P < 0.05). A possible regulatory impact of the SNPs on MDR1 mRNA expression was investigated by a Real time-PCR assay. MDR1 expression was strongly correlated with a decreased complete remission rate (P = 0.01) but failed to predict decreased overall survival (OS). There was a significant association of the A genotype in exons 21 (P = 0.05) and 26 (P < 0.05) with lower MDR1 expression, whereas the B variants showed highest MDR1 values at all three investigated gene loci. The A genotype in exon 26 was associated with lower OS (P < 0,01). In these patients, worse OS is likely attributable to an increased risk of relapse (P < 0.001). We were able to detect a linkage disequilibrium of the investigated SNPs, indicating combined polymorphisms that could affect the regulation of MDR1 expression. The A genotype of all SNPs demonstrated both lowest MDR1 values and significantly decreased OS (P < 0.05) with a high probability of relapses (P < 0.01). These observations indicate that allelic variants of the MDR1 gene may influence therapy outcome by additional mechanisms, different from P-gp expression on acute myeloid leukemia blasts, possibly involving pharmacokinetic effects of P-gp.