[Legal considerations in the care of patients with "terminal dehydration" in Germany]. / Rechtliche Rahmenbedingungen in der Versorgung von Patienten mit "terminaler Dehydration" in Deutschland.

BACKGROUND: The legal framework for fluid management in the palliative care setting varies between continents and even between countries. OBJECTIVES: What legal implications must be taken into account in Germany in dealing with "terminal" dehydration? MATERIALS AND METHODS: Relevant publications in English and German have been identified. Notably, German recommendations and guidelines were reviewed, whereas national mindsets were contrasted with those of other countries like the United Kingdom and Canada. RESULTS: Our legal considerations are in line with the recommendations of the German Federal Medical Association. Key components are "patient autonomy", "best possible symptom control" and a "steady therapeutic risk-benefit assessment". Dehydration should then continue to be regarded as a "symptom" that must be "controlled" as long as it can be improved by therapeutic means and as long as the patient is not opposed to this approach. However, if dehydration remains therapeutically refractory, it is justified either not to initiate clinically assisted hydration (CAH) or to stop the ongoing therapy. The "shared decision-making model" practiced in Canada is diametrically opposed to this approach, where paternalistic decision-making is possible, provided that patients or relatives appear to be ill-informed and unprepared to decide "correct" according to expert opinion. CONCLUSIONS: A "non-refractory" state of dehydration at the end of life must not be left untreated under German law and must not be used as an option to hasten the death process if the development of dehydration does not correspond to the patient's will or if this will cannot be determined.

[Ethical implications in the therapeutic management of dehydrated patients at the end of life]. / Ethische Implikationen bei der Therapie von dehydrierten Patienten am Lebensende.

BACKGROUND: The ethical framework for fluid management in the palliative care setting can vary. OBJECTIVES: What are the relevant ethical implications related to dehydration during end-of-life care and what are the special requirements we need to consider as far as "terminal dehydration" is concerned? MATERIALS AND METHODS: A comprehensive literature search was conducted to identify relevant articles published in English and German. RESULTS: Our inferences represent an attitude rather than an evidence-based position-a fact that is due to the underlying normative and ethical references which are hardly amenable to statistical evaluation. As far as ethical considerations are concerned, evidence is lacking to support clear decision-making and, thus, does not justify moving away from established concepts of clinically assisted hydration (CAH) at the end of life as long as measures can be effectually implemented. CONCLUSIONS: Dehydration must not be considered a measure to hasten death. Hence, dehydration in the palliative care setting must be regarded a "symptom" that should be "controlled" if it can be corrected by therapeutic means and if the patient's will does not contradict that approach. However, if CAH is futile, it is justified to refuse or stop it.

["Terminal" dehydration : Differential diagnosis and body of evidence]. / "Terminale" Dehydratation : Differenzialdiagnose und Evidenzlage.

Dehydration in palliative care patients can be associated with increased morbidity and mortality and is nevertheless therapeutically controversial. This article provides an overview of possible causes of dehydration at the end of life and places special emphasis on "terminal" dehydration in the dying. Empirical attitudes of healthcare professionals and persons concerned (patients and relatives) as well as evidence-based findings on "terminal" dehydration are elucidated and the limitations are described. Finally, it is concluded that the appropriate detection of the mode of dehydration (including its underlying pathophysiology) as well as the clinical evaluation of the "reversibility" of the symptoms after fluid therapy, is of central importance in establishing the indications for clinically assisted hydration (CAH).

How to manage terminal dehydration.

Although dehydration is a serious condition associated with significant morbidity and mortality in palliative care patients, as in any other patient group, treatment remains controversial. A narrative review of the causes of dehydration during end of life was conducted paying special attention to the nature of terminal dehydration. A comprehensive search of the literature was performed to identify relevant articles published in English and German languages between 1960 and 2018. Currently available options for bed-side evaluation and therapeutic approaches were critically appraised and areas of future research are emphasized. The following inferences can be derived: 1) the available evidence does not support a clear decision in favor or against fluid therapy during the dying phase. 2) There is inadequate precision of the term end of life care (ELC) and insufficient differentiation between modes of dehydration of palliative care patients. 3) Evaluation of dehydration based on its clinical appearance is considered the method of choice compared to invasive procedures. 4) Detailed clinical assessment of symptom reversibility in terminal dehydration by an appropriate fluid challenge is mandatory in the decision-making process. 5) If despite adequate rehydration measures, complete reversibility of the clinical picture of dehydration can no longer be achieved since organ systems are gradually deteriorating, the cessation of clinically assisted hydration (CAH) can be considered. 6) If symptoms of dehydration are reversible after fluid challenge and no other patient wishes to the contrary are known, fluid management should be continued in the context of symptom control. 7) Hyperhydration represents a considerable threat during fluid management that needs to be prevented by noninvasive monitoring procedures. In conclusion, if CAH is applied as a part of ELC the hydration status needs to be individually appraised and all therapeutic measures constantly need to be adapted to the findings of diligent monitoring procedures.

["Terminal" dehydration, part 2 : Medical indications and therapeutic approach]. / "Terminale" Dehydratation, Teil 2 : Medizinische Indikationsstellung und therapeutisches Vorgehen.

The approach in the clinical fluid management of the dying is still controversially discussed in specialist circles and also in the general population. In this article the importance of establishing the therapeutic indications is emphasized against the background of a lack of evidence. Options to achieve noninvasive objectification of assumed dehydration as well as assessment of the reversibility of the symptoms are shown and the importance of monitoring of all therapeutic actions is discussed. The pathophysiological foundation of reversible disorders of fluid homoeostasis are described and distinguished from the irreversible disorders leading to terminal dehydration. If clinically assisted hydration (CAH) is indicated, the hydration status must be assessed individually as well as in advance and all therapeutic measures must be constantly adjusted to the results of non-invasive monitoring procedures.

["Terminal" dehydration, part 1 : Differential diagnosis and body of evidence]. / "Terminale" Dehydratation, Teil 1 : Differenzialdiagnose und Evidenzlage.

Dehydration in palliative care patients can be associated with increased morbidity and mortality and is nevertheless therapeutically controversial. This article provides an overview of possible causes of dehydration at the end of life and places special emphasis on "terminal" dehydration in the dying. Empirical attitudes of healthcare professionals and persons concerned (patients and relatives) as well as evidence-based findings on "terminal" dehydration are elucidated and the limitations are described. Finally, it is concluded that the appropriate detection of the mode of dehydration (including its underlying pathophysiology) as well as the clinical evaluation of the "reversibility" of the symptoms after fluid therapy, is of central importance in establishing the indications for clinically assisted hydration (CAH).

Intraperitoneal bevacizumab for control of malignant ascites due to advanced-stage gastrointestinal cancers: A multicentre double-blind, placebo-controlled phase II study - AIO SUP-0108.

PURPOSE: Malignant ascites is debilitating for patients with advanced cancer. As shown previously, tumour cell production of vascular endothelial growth factor might be a major cause of the formation of malignant ascites. Intraperitoneal bevacizumab could therefore be an option for symptom control in refractory ascites. PATIENTS AND METHODS: Patients with advanced gastrointestinal cancer and malignant ascites who had undergone paracentesis at least twice within the past 4 weeks were randomly assigned in a 2:1 ratio to intraperitoneal bevacizumab (400 mg absolute) or placebo after paracentesis. During the 8-week treatment period, a minimum interval of 14 d was kept between the applications of the study drug. Primary end-point was paracentesis-free survival (ParFS). RESULTS: Fifty-three patients (median age 63 years) were randomised. Forty-nine patients received at least one study drug application and qualified for the main analysis. The proportion of patients with at least one common toxicity criteria grade III-V event was similar with 20/33 (61%) on bevacizumab and 11/16 (69%) on placebo. Median ParFS was 14 d (95% confidence interval [CI]: 11-17) in the bevacizumab arm and 10.5 d (95% CI: 7-21) on placebo (hazard ratio 0.74, 95% CI: 0.40-1.37; P = 0.16). The longest paracentesis-free period was 19 d on bevacizumab (range 6-66 d) and 17.5 d in the placebo arm (range 4-42) (P = 0.85). Median overall survival was 64 d (95% CI: 45-103) on bevacizumab compared to 31.5 d (95% CI: 20-117) on placebo (P = 0.31). CONCLUSION: Intraperitoneal bevacizumab was well tolerated. Overall, treatment did not result in a significantly better symptom control of malignant ascites. However, patients defined by specific immune characteristics may benefit.

[State of integration of palliative care at Comprehensive Cancer Centers funded by German Cancer Aid]. / Integration der Palliativmedizin in die von der Deutschen Krebshilfe e. V. geförderten onkologischen Spitzenzentren.

BACKGROUND: Similarities and differences of integration of palliative care in clinical care, research and education structures at German Comprehensive Cancer Centers (CCC) are not known in detail. OBJECTIVE: Provide an overview of availability and the way of integration of specialized palliative care at CCCs funded by the German Cancer Aid (Deutsche Krebshilfe, DKH). METHOD: We conducted structured interviews from May to August 2014 with heads of palliative care departments (personally or by telephone). The interviews included a quantitative and a qualitative part. Other stakeholders of CCCs were asked the questions of the qualitative part. We evaluated the qualitative data using the content analysis by Mayring and MAXQDA 11.0. SPSS 21.0 was used for quantitative analysis. RESULTS: 26 interviews were realized in 13 CCCs with 14 sites, which received funding, by DKH till August 2014 (one CCC had two university hospitals). Of these, 12 sites had a palliative care unit (86%), 11 sites had palliative care consulting services available (79%). Participation of palliative care specialists in tumor boards is not provided in 3 institutions (21%) and is often not feasible on regular basis in the other institutions, due to staffing shortage. In 7 sites (50%) defined criteria to integrate palliative care into CCCs were available. In the last 5 years specialized palliative care of 4 sites received an invitation for a research project by another department within the CCC (29%). 10 sites (71%) had started own palliative care research projects. Chairs in palliative care were available in 4 CCCs (29%). CONCLUSION: The extent and depth of palliative care integration in the 14 CCC sites is heterogeneous.

Efficacy and safety of sorafenib in advanced hepatocellular carcinoma under daily practice conditions.

Sorafenib has recently been shown to be effective for the treatment of advanced hepatocellular carcinoma in randomized controlled trials. Here, we report the experience with sorafenib in 25 patients with advanced HCC under daily practice conditions. Tolerance to sorafenib was acceptable and side effects were manageable, although the ECOG performance status was reduced in all patients. The most prevalent grade 2/3 side effects were fatigue (40%) and diarrhea (24%), and withdrawal from therapy occurred in 29% of patients. Disease stabilization was documented in 60% of patients. The median treatment time was 2.7 months and overall survival was 11.0 months. No significant serum alpha-fetoprotein decline was noted at the time of the first radiological control in a subgroup of patients with baseline levels >50 ng/ml who achieved stable disease. In conclusion, in daily practice sorafenib is safe and disease stabilization can be achieved in the majority of patients. However, intolerance to sorafenib can affect treatment adherence substantially.

[Colorectal cancer liver metastases -- neoadjuvant concepts for preoperative down-sizing]. / Lebermetastasen kolorektaler Karzinome - Neoadjuvante Konzepte zum präoperativen Downstaging.

Liver resection for colorectal metastases disease can be performed with curative intent at low morbidity and mortality. Only 15-30 % of liver metastases are amenable to potentially curative resection. Five year survival following primary and repeat liver resection has consistently been reported as 25-40 %. Future strategies focus at widening the indication and extending therapeutic options. The aim of neoadjuvant treatment of irresectable liver metastasis is the conversion to secondary resectability either via increasing residual liver mass (portal vein embolisation/2-stage resection) and/or reducing tumor load via chemotherapy ("down-sizing"). Current data suggest resectability following neoadjuvant chemotherapy in around 8 % of cases but varying between 1-33 %.

Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases.

AIMS: The liver is a frequent site of metastases from colorectal cancer. While these lesions are potentially amenable to surgical resection, they are usually very aggressive, and recurrence is frequent. Mutations of the proto-oncogene K- ras are thought to impart a strong growth signal to tumour cells and are closely associated with the development of malignancies of the colon and rectum. Hepatic metastases from colorectal cancer have notably elevated proliferative rates. The present study was performed to investigate the relationship between proliferation or K- ras mutation and prognosis following curative resection of colorectal liver metastases. METHODS: Colorectal liver metastases from 41 patients undergoing curative hepatic resection were examined for proliferation status and presence of K- ras mutations. The proliferative activity was assessed by Ki-67 immunohistochemistry. DNA from the same tissue samples was screened for point mutations in codon 12 of the K- ras gene using a novel microplate-based allelic-specific hybridization assay. Ki-67 scores and K- ras status were then related with patient survival as determined through retrospective analysis. RESULTS: Median survival was 40 months. Patients with high Ki-67 scores (> or = 50%) had significantly shorter median survival compared with those with low scores (30 vs 44 months, log-rank P=0.02). A high Ki-67 score was an independent negative prognostic factor by multivariate regression analysis (relative risk=3.04, P=0.036). K- ras point mutations were detected in 6/41 patients (15%), but mutational status did not correlate with Ki-67 score or survival. CONCLUSIONS: These findings suggest that the tumour proliferative index is a useful predictor of aggressive tumour behaviour and an indicator of patient survival. The presence of K- ras mutations does not appear to correlate with tumour proliferation status or patient survival.

Relevance of locoregional chemotherapy in patients with liver metastases from colorectal primaries.

Progression of colorectal cancer can occur primarily isolated in the liver. But, only the minority of the affected patients is eligible for surgery. Initially, systemic chemotherapy was ineffective in the treatment of unresectable hepatic metastases. For this reason, intraarterial chemotherapy was introduced as treatment alternative to the systemic chemotherapy. Long-term intraarterial chemotherapy regimens with FUDR in patients with colorectal liver metastases, using implantable pumps and ports, resulted in improved response rates, which was confirmed by several randomized trials. However, an improvement in median survival has not yet been demonstrated after regional chemotherapy of hepatic metastases. Since the intraarterial therapy with floxuridine (FUDR) had been reported to result in a high rate of local toxicity, 5-fluorouracil (5-FU) was introduced into regional chemotherapy of the liver. A randomized trial demonstrated superiority of intraarterial 5-FU versus intraarterial FUDR therapy. Despite these reports about high response rates, the benefit of intraarterial chemotherapy remains questionable, because it has not yet resulted in a prolongation of median survival. For this reason, long-term regional chemotherapy cannot be considered as standard treatment and should therefore not be conducted outside controlled clinical trials. Further evaluations on this technique should only be performed in experienced centers.

[Technique and pathophysiology of isolated hypoxic perfusion of the abdomen]. / Technik und Pathophysiologie der isolierten hypoxischen Perfusion des Abdomens.

Isolated hypoxic perfusion (IHP) is a commonly used technique in the treatment of abdominal malignancies. During a phase II-study the pathophysiology of this technique was explored in patients with advanced pancreatic cancer. Twenty perfusions of the abdomen were performed in 17 patients. Under general anesthesia, femoral vessels were dissected and two balloon catheters were inserted into aorta and vena cava cranial the celiac trunk and the hepatic veins. After instillation of 40 mg of Mitomycin C (MMC) into the running perfusion system, the perfusion was maintained for further 20 minutes. Blood samples were taken in 5-minute intervals to determine pH value, blood gases as well as concentrations of electrolytes, lactate and MMC in the arterial blood. Simultaneously, blood samples were taken from the perfusion blood via a side-port of the extracorporeal perfusion system. Additionally, perfusion pressures, arterial and central venous pressure, heart rate, and the pressure in the aorta distal the balloon catheter were registered continuously. All 20 perfusions had been undertaken without perioperative mortality. After inflating the balloon catheters, blood pressure and heart rate increased rapidly. Within 5 minutes of perfusion an increase in pCO2 and the concentrations of K+ and lactate in the perfusate were registered, while pH and pO2 decreased. Fifteen minutes after instillation of MMC, concentrations of MMC in arterial and perfusion blood were equal. Twenty-four hours after the perfusion all parameters had returned to normal values. IHP was well feasible in 20 consecutive perfusions without major technical problems. A distinct but tolerable combined acidosis resulted from IHP. Despite the exact positioning and control of the balloon catheters a complete isolation was not possible.

Relevance of neoadjuvant and adjuvant treatment for patients with resectable liver metastases of colorectal carcinoma.

BACKGROUND: Excellent results after resection of colorectal liver metastases are associated with a high rate of recurrence. Influenced by positive results of palliative and adjuvant treatment in advanced cancer, various chemotherapy regimens were evaluated to improve long-term results. METHODS: The databases Medline and Cancerlit (1982-1998) gave information about 675 patients who were treated either by means of systemic, intra-arterial, intraportal or intraperitoneal administration before or after liver resection. RESULTS: In general, the feasibility of an adjuvant treatment was tested. Proof has been furnished for the practicability of systemic and arterial therapy and for immunotherapy after liver resection whereas, for peritoneal and portal treatment, further studies are necessary. In a few non-randomised trials, it has been possible to discern a trend towards an improvement due to adjuvant postoperative therapy using historical or matched-pair control groups. Until now, only one of five randomised studies has been published. Six months of postoperative adjuvant intra-arterial treatment using 5-fluorouracil (1000 mg/m(2) for 5 days every 28 days) and folinic acid (200 mg/m(2) for 5 days every 28 days) was compared with observation only. Neither in the intention-to-treat nor in the as-treated analysis was median survival time (34.5 months versus 40. 8 months and 39.7 months versus 44.8 months, respectively) significantly increased. As neoadjuvant treatment was successful in primary non-resectable patients, this approach is now being tested in resectable patients. CONCLUSION: Despite several theoretical reasons for post- or preoperative treatment in resectable patients, every approach should be tested using of controlled studies.

[The status of regional long-term chemotherapy in liver metastasis]. / Die Stellung der regionalen Langzeitchemotherapie bei Lebermetastasen.

In numerous tumors, metastasis can be limited to the liver. In non-resectable patients, regional treatment modalities, especially arterial cytostatic infusion, are favored in contrast to systemic chemotherapy, whereas intraportal or intraperitoneal application is not successful. Improved results with high response rates have been reported after development of intra-arterial (i.a.) long-term regimens with FUdR in patients with colorectal liver metastases using implantable pumps and ports. However, a survival benefit could only be demonstrated in comparison with a control group only treated symptomatically. Because of several reports on major local toxicity of i.a. FUdR treatment (i.e. chemical hepatitis and biliary sclerosis) several other effective i.a. 5-FU regimens have been developed. A randomized study has demonstrated superiority of i.a. 5-FU versus i.a. FUdR. In comparison with systemic treatment, superiority has only been demonstrated in patients with an intrahepatic tumor burden of < 25%. Publications about regional treatment of patients with breast, gastric cancer or carcinoid liver metastases are rare. Despite the high response rates reported, the benefit of arterial chemotherapy remains questionable. Overall, local long-term chemotherapy cannot be recommended outside of studies as a primary treatment. However, extensive experience and new drugs support the idea of conducting further regional studies.

Isolated hypoxic perfusion with mitomycin C in patients with advanced pancreatic cancer.

AIMS: Chemotherapy as a palliative therapy option for patients with advanced pancreatic cancer remains disappointing. Some authors have recently claimed high response rates and a prolongation of median survival after regional chemotherapy. Isolated perfusion may result in the highest drug concentrations within the target tissue without causing systemic side-effects. An established, commercially available system of isolated hypoxic perfusion (IHP) was therefore evaluated in patients with unresectable or recurrent pancreatic cancer. PATIENTS AND METHODS: IHP was performed in 17 patients with unresectable pancreatic cancer. Five women and 12 men with a median age of 61 years were treated. A 20-min isolated hypoxic perfusion was performed after 40 mg of mitomycin C (MMC) had been instilled into the running perfusion system over 5 min. Tumour response was evaluated by CT-scan 6 weeks after IHP. RESULTS: Twenty perfusions were carried out in 17 patients. Within 10 min of perfusion, the perfusate's PO2 decreased to 13% of the baseline value. Five minutes after the infusion of MMC a local concentration of 15.2 mg/litre was observed. Toxicity-related deaths did not occur. Nausea and vomiting (NCI> or =II: 12 episodes) were the most frequently observed toxicities after IHP. In five patients (29%) a deep vein thrombosis occurred. None of the treated patients responded to the regimen used in this trial. The median survival time after IHP was 4.2 months (range 1.3-21). CONCLUSIONS: The overall rate of side-effects and complications after IHP was high. In spite of some hopeful reports on this treatment in recent years, IHP did not show any benefit in terms of tumour response or median survival. On the basis of these experiences, this procedure should no longer be used as treatment for patients with unresectable or recurrent pancreatic cancer.

A pilot study on intensive weekly 24-hour intra-arterial infusion with 5-fluorouracil and folinic acid for colorectal liver metastases.

PURPOSE: A pilot study was performed to evaluate the tolerance and efficacy of a hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and folinic acid (FA) in patients with unresectable liver metastases from colorectal carcinoma. PATIENTS AND METHODS: In 11 patients, 135 applications of high-dose HAI of 5-FU/FA were administered. All patients had been intra-arterially pretreated, and 2 of them had received an additional intravenous therapy. The chemotherapy regimen consisted of a weekly HAI of FA 500 mg/m2 over 1 h, immediately followed by HAI of 5-FU over 24 h. Four patients received a 5-FU starting dose of 2,000 mg/m2 and 7 patients of 2,400 mg/m2. One course consisted of 12 weekly applications interrupted by 1 week after 6 applications and 4 weeks after 12 applications. RESULTS: The applied regimen caused only mild side effects. Nausea and vomiting were the most frequently side effects with 36 episodes out of 135 applications (WHO grade > or = 3: 2 episodes). Diarrhea was a minor problem occurring with 8 episodes (WHO grade > or = 3: 1 episode). There was no evidence of myelosuppression, hand-foot syndrome, neurotoxicity, and biliary sclerosis. A partial remission was observed in 3 patients, and a disease stabilization in 2 patients while the disease progressed in 6 patients under high-dose HAI of 5-FU/FA. CONCLUSION: The present pilot study demonstrates that the weekly high-dose HAI of 5-FU/FA is well tolerated and associated with very mild toxicity. Because of the encouraging response rate in patients, whose disease progressed under the conventional intra-arterial therapy either with 5-FU/FA or 5-fluorodeoxyuridine, this regimen seems to be an effective second-line treatment and should be evaluated in nonpretreated patients in a phase II study.

[Isolated hypoxic perfusion with mitomycin C confers no benefit for patients with advanced pancreatic carcinoma]. / Isolierte hypoxische Perfusion mit Mitomycin C bringt keinen Benefit für Patienten mit fortgeschrittenem Pankreaskarzinom.

Since therapy options in the treatment of advanced pancreatic cancer are rare, the present study has investigated whether patients with advanced pancreatic cancer may profit from isolated hypoxic perfusion (IHP) of the abdomen with mitomycin C. None of the 17 treated patients responded to IHP with mitomycin C, and the survival time corresponded to that of untreated patients. On the basis of these results, this procedure should no longer be used as treatment for patients with advanced pancreatic cancer.

The value of postoperative hepatic arterial infusion following curative liver resection.

Despite the increasing success of liver resection in treatment of metastatic colorectal cancer, at least 50% of patients will recur again in the remaining liver. In a non-randomized, prospective study we examined the benefit of regional adjuvant chemotherapy compared with surgical resection alone. Data from 81 consecutive patients who received curative liver resection and from 29 additional patients who underwent palliative liver resection were collected. Intraarterial adjuvant treatment with FUDR or 5-Fluorouracil was performed after liver resection in 60 patients. Mortality (5.5%) and morbidity (30%) were not increased by catheter implantation. Five or more cycles of intraarterial chemotherapy were completed in 39 (89%) of the curative resected patients. Depending on the treatment schedule the most frequent local and systemic side effects were stomatitis (13%) hepatobiliary toxicity and in two patients biliary sclerosis after a FUDR treatment of 14 days. In curative resected patients median time to intrahepatic recurrence was significantly delayed by adjuvant arterial treatment from 17 to 63 months (p = 0.015). Median survival time (overall 48 months) was increased from 33 months after surgery to 52 months (p = 0.064) and in case of 5 or more treatment cycles to 54 months (p = 0.046).