Effects of dignity therapy on psychological distress and wellbeing of palliative care patients and family caregivers - a randomized controlled study.

BACKGROUND: This study extended the original Dignity Therapy (DT) intervention by including partners and family caregivers (FCs) of terminally-ill cancer patients with the overall aim of evaluating whether DT can mitigate distress in both patients nearing the end of life and their FCs. METHODS: In this multicenter, randomized controlled trial (RCT), a total of 68 patients with life expectancy < 6 months and clinically-relevant stress levels (Hospital Anxiety Depression total score; HADStot ≥ 8) including their FCs were randomly assigned to DT, DT + (including their FCs), or standard palliative care (SPC) in a 1:1:1 ratio. Study participants were asked to complete a set of questionnaires pre- and post-intervention. RESULTS: The coalesced group (DT and DT +) revealed a significant increase in patients' perceived quality of life (FACIT-Pal-14) following the intervention (mean difference 6.15, SD = 1.86, p < 0.01). We found a statistically significant group-by-time interaction effect: while the HADStot of patients in the intervention group remained stable over the pre-post period, the control group's HADStot increased (F = 4.33, df = 1, 82.9; p < 0.05), indicating a protective effect of DT. Most patients and their FCs found DT useful and would recommend it to other individuals in their situation. CONCLUSIONS: The DT intervention has been well-received and shows the potential to increase HRQoL and prevent further mental health deterioration, illness burden and suffering in terminally-ill patients. The DT intervention holds the potential to serve as a valuable tool for facilitating end-of-life conversations among terminally-ill patients and their FCs. However, the implementation of DT within the framework of a RCT in a palliative care setting poses significant challenges. We suggest a slightly modified and less resource-intensive version of DT that is to provide the DT inventory to FCs of terminally-ill patients, empowering them to ask the questions that matter most to them over their loved one's final days. TRIAL REGISTRATION: This study was registered with Clinical Trial Registry (ClinicalTrials.gov -Protocol Record NCT02646527; date of registration: 04/01/2016). The CONSORT 2010 guidelines were used for properly reporting how the randomized trial was conducted.

Adjuvant treatment recommendations for patients with ER-positive/HER2-negative early breast cancer by Swiss tumor boards using the 21-gene recurrence score (SAKK 26/10).

BACKGROUND: To evaluate the effect of Recurrence Score® results (RS; Oncotype DX® multigene assay ODX) on treatment recommendations by Swiss multidisciplinary tumor boards (TB). METHODS: SAKK 26/10 is a multicenter, prospective cohort study of early breast cancer patients: Eligibility: R0-resection, ≥10% ER+ malignant cells, HER2-, pN0/pN1a. Patients were stratified into low-risk (LR) and non-low-risk (NLR) groups based on involved nodes (0 vs 1-3) and five additional predefined risk factors. Recommendations were classified as hormonal therapy (HT) or chemotherapy plus HT (CT + HT). Investigators were blinded to the statistical analysis plan. A 5%/10% rate of recommendation change in LR/NLR groups, respectively, was assumed independently of RS (null hypotheses). RESULTS: Two hundred twenty two evaluable patients from 18 centers had TB recommendations before and after consideration of the RS result. A recommendation change occurred in 45 patients (23/154 (15%, 95% CI 10-22%) in the LR group and 22/68 (32%, 95% CI 22-45%) in the NLR group). In both groups the null hypothesis could be rejected (both p < 0.001). Specifically, in the LR group, only 5/113 (4%, 95% CI 1-10%) with HT had a recommendation change to CT + HT after consideration of the RS, while 18/41 (44%, 95% CI 28-60%) of patients initially recommended CT + HT were subsequently recommended only HT. In the NLR group, 3/19 (16%, 95% CI 3-40%) patients were changed from HT to CT + HT, while 19/48 (40%, 95% CI 26-55%) were changed from CT + HT to HT. CONCLUSION: There was a significant impact of using the RS in the LR and the NLR group but only 4% of LR patients initially considered for HT had a recommendation change (RC); therefore these patients could forgo ODX testing. A RC was more likely for NLR patients considered for HT. Patients considered for HT + CT have the highest likelihood of a RC based on RS.

Cancer-related therapies at the end of life in hospitalized cancer patients from four Swiss cantons: SAKK 89/09.

The use of cancer-related therapies in cancer patients hospitalized at the end of life has increased in many countries over time. Given the scarcity of published Swiss data, the objective of this study was to evaluate the influence of hospital type and other factors on the delivery of health care during the last month before death. Claims data were used to assess health care utilization of cancer patients (identified by cancer registry data of four participating Swiss cantons) who deceased between 2006 and 2008. Primary endpoints were delivery of cancer-related therapies during the last 30 days before death. Multivariate logistic regression assessed the explanatory value of hospital type, patient and geographic characteristics. Of 3,809 identified cancer patients in the claims database, 2,086 patients dying from cancer were hospitalized during the last 30 days before death, generating 2,262 inpatient episodes. Anticancer drug therapy was given in 22.2% and radiotherapy in 11.7% of episodes. Besides age and cancer type, the canton of residence and hospital type showed independent, statistically significant associations with intensity of care, which was highest in university hospitals. These results should initiate a discussion among oncologists in Switzerland and may question the compliance with standard of care guidelines for terminal cancer patients.

Delivery of health care at the end of life in cancer patients of four swiss cantons: a retrospective database study (SAKK 89/09).

BACKGROUND: The use of cancer related therapy in cancer patients at the end-of-life has increased over time in many countries. Given a lack of published Swiss data, the objective of this study was to describe delivery of health care during the last month before death of cancer patients. METHODS: Claims data were used to assess health care utilization of cancer patients (identified by cancer registry data of four participating cantons), deceased between 2006-2008. Primary endpoints were hospitalization rate and delivery of cancer related therapies during the last 30 days before death. Multivariate logistic regression assessed the explanatory value of patient and geographic characteristics. RESULTS: 3809 identified cancer patients were included. Hospitalization rate (mean 68.5%, 95% CI 67.0-69.9) and percentage of patients receiving anti-cancer drug therapies (ACDT, mean 14.5%, 95% CI 13.4-15.6) and radiotherapy (mean 7.7%, 95% CI 6.7-8.4) decreased with age. Canton of residence and insurance type status most significantly influenced the odds for hospitalization or receiving ACDT. CONCLUSIONS: The intensity of cancer specific care showed substantial variation by age, cancer type, place of residence and insurance type status. This may be partially driven by cultural differences within Switzerland and the cantonal organization of the Swiss health care system.

CNS relapses in patients with HER2-positive early breast cancer who have and have not received adjuvant trastuzumab: a retrospective substudy of the HERA trial (BIG 1-01).

BACKGROUND: Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. METHODS: We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5-4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. RESULTS: Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 [2%] of 1703 patients) and the observation group (32 [2%] of 1698; p=0·55 [Gray's test]). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 [57%] of 227) than in the group given trastuzumab for 1 year (88 [47%] of 186; p=0·06 [Gray's test]). Most CNS relapses were symptomatic (189 [87%] of 217). CONCLUSION: Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. FUNDING: None.

Chemotherapy before liver resection of colorectal metastases: friend or foe?

OBJECTIVE: We conducted a systematic review of the published literature to critically assess benefits and risks of the use of preoperative chemotherapy in patients presenting with colorectal liver metastases. BACKGROUND: In many centers, chemotherapy is used before hepatic resection of colorectal metastases, even in the presence of a single lesion. Application of chemotherapy requires clear conceptual distinction between patients presenting with resectable lesions (neoadjuvant) versus patients presenting with unresectable lesions, for which chemotherapy is used to reach a resectable situation (downsizing). METHODS: The literature (PubMed) was systematically reviewed for publications related to liver surgery and chemotherapy according to the methodology recommended by the Cochrane Collaboration. RESULTS: For unresectable liver metastases, combination regimens result in enhanced tumor response and resectability rates up to 30%, although the additional benefit from targeted agents such as bevacizumab or cetuximab is marginal. For resectable lesions, studies on neoadjuvant chemotherapy failed to convincingly demonstrate a survival benefit. Most reports described increased postoperative complications in a subset of patients due to parenchymal alterations such as chemotherapy-associated steatohepatitis or sinusoidal obstruction syndrome. CONCLUSION: Preoperative standard chemotherapy can be recommended for downsizing unresectable liver metastases, but not for resectable lesions, for which adjuvant chemotherapy is preferred.

Expression of the extracellular matrix protein periostin in liver tumours and bile duct carcinomas.

AIMS: To study the relevance of periostin, known to be involved in epithelial-mesenchymal transition (EMT), in hepatocellular and bile duct cancer. METHODS AND RESULTS: Immunohistochemical periostin expression was semiquantitatively analysed in normal liver tissue (n = 20), hepatocellular carcinoma (HCC; n = 91), liver-cell adenoma (n = 9), focal nodular hyperplasia (n = 13) and bile duct carcinomas (BDC; n = 116) using tissue microarrays. Normal bile ducts, gallbladder epithelium and hepatocytes showed weak cytoplasmic periostin expression. In HCC, there was strong epithelial periostin expression in 19/91 (20.9%) and strong stromal periostin expression in 10/91 cases (11%). Epithelial expression in tumour cells was significantly associated with a higher tumour grade (P < 0.05) and hepatitis B virus infection (P = 0.007). Importantly, there was no strong periostin expression in benign liver tumours. Strong stromal periostin expression was detected in 78/116 (67.2%) BDC and strong epithelial expression in 39/116 (33.6%) BDC. pT stage, differentiation grade and proliferation rate in primary BDC were independent of periostin expression. Epithelial periostin expression was associated with reduced overall survival on univariate and multivariate analysis. CONCLUSIONS: The EMT protein periostin is expressed in the stroma and epithelium of a subset of BDC and HCC. Epithelial periostin expression is a marker for malignant transformation of hepatocytes and a novel prognostic marker in BDC.

Equivalence of pegfilgrastim and filgrastim in lymphoma patients treated with BEAM followed by autologous stem cell transplantation.

OBJECTIVE: To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin's and non-Hodgkin's lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim. METHODS: We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed. RESULTS: Fourteen (26%) patients with Hodgkin's lymphoma and 40 (74%) patients with non-Hodgkin's lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 µg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38). CONCLUSION: Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients.

Hyperlipidemic myeloma: review of 53 cases.

Hyperlipidemic myeloma is a rare and poorly understood variant of multiple myeloma. We report the case of a 53-year-old woman with hyperlipidemic myeloma, skin xanthomas and hyperviscosity syndrome who underwent allogeneic bone marrow transplantation. A comprehensive literature search identified 52 additional cases with plasma cell disease and hyperlipidemia. A detailed analysis revealed several characteristics of these patients as compared to multiple myeloma with normal lipid status: (1) IgA paraprotein was present in the majority (53% vs. 21% in classical multiple myeloma). (2) Skin xanthomas, especially in the palmar creases, elbows, and knees were common (70%). (3) Hyperviscosity syndrome occurred more often (26% vs. 2-6%). While conventional lipid-lowering therapy had only marginal effects, successful anti-myeloma therapy also reduced hyperlipidemia. Analyses of the mechanisms leading to hyperlipidemia documented complexes of paraprotein and lipoprotein in 75% of the 32 cases tested, suggesting an inhibitory role of the paraprotein on lipid degradation. In conclusion, the clinical characteristics, the therapeutic options, and the pathophysiologic mechanisms of hyperlipidemic myeloma are comprehensively reported using the available data from all 53 published cases in the literature.

Limited predictive value of FDG-PET for response assessment in the preoperative treatment of esophageal cancer: results of a prospective multi-center trial (SAKK 75/02).

BACKGROUND: Only responding patients benefit from preoperative therapy for locally advanced esophageal carcinoma. Early detection of non-responders may avoid futile treatment and delayed surgery. PATIENTS AND METHODS: In a multi-center phase ll trial, patients with resectable, locally advanced esophageal carcinoma were treated with 2 cycles of induction chemotherapy followed by chemoradiotherapy (CRT) and surgery. Positron emission tomography with 2[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) was performed at baseline and after induction chemotherapy. The metabolic response was correlated with tumor regression grade (TRG). A decrease in FDG tumor uptake of less than 40% was prospectively hypothesized as a predictor for histopathological non-response (TRG > 2) after CRT. RESULTS: 45 patients were included. The median decrease in FDG tumor uptake after chemotherapy correlated well with TRG after completion of CRT (p = 0.021). For an individual patient, less than 40% decrease in FDG tumor uptake after induction chemotherapy predicted histopathological non-response after completion of CRT, with a sensitivity of 68% and a specificity of 52% (positive predictive value 58%, negative predictive value 63%). CONCLUSIONS: Metabolic response correlated with histopathology after preoperative therapy. However, FDG-PET did not predict non-response after induction chemotherapy with sufficient clinical accuracy to justify withdrawal of subsequent CRT and selection of patients to proceed directly to surgery.

Impact of Docetaxel on blood-brain barrier function and formation of breast cancer brain metastases.

BACKGROUND: Breast cancer (BC) is the most frequent malignant tumor in females and the 2nd most common cause of brain metastasis (BM), that are associated with a fatal prognosis. The increasing incidence from 10% up to 40% is due to more effective treatments of extracerebral sites with improved prognosis and increasing use of MRI in diagnostics. A frequently administered, potent chemotherapeutic group of drugs for BC treatment are taxanes usually used in the adjuvant and metastatic setting, which, however, have been suspected to be associated with a higher incidence of BM. The aim of our study was to experimentally analyze the impact of the taxane docetaxel (DTX) on brain metastasis formation, and to elucidate the underlying molecular mechanism. METHODS: A monocentric patient cohort was analyzed to determine the association of taxane treatment and BM formation. To identify the specific impact of DTX, a murine brain metastatic model upon intracardial injection of breast cancer cells was conducted. To approach the functional mechanism, dynamic contrast-enhanced MRI and electron microscopy of mice as well as in-vitro transendothelial electrical resistance (TEER) and tracer permeability assays using brain endothelial cells (EC) were carried out. PCR-based, immunohistochemical and immunoblotting analyses with additional RNA sequencing of murine and human ECs were performed to explore the molecular mechanisms by DTX treatment. RESULTS: Taxane treatment was associated with an increased rate of BM formation in the patient cohort and the murine metastatic model. Functional studies did not show unequivocal alterations of blood-brain barrier properties upon DTX treatment in-vivo, but in-vitro assays revealed a temporary DTX-related barrier disruption. We found disturbance of tubulin structure and upregulation of tight junction marker claudin-5 in ECs. Furthermore, upregulation of several members of the tubulin family and downregulation of tetraspanin-2 in both, murine and human ECs, was induced. CONCLUSION: In summary, a higher incidence of BM was associated with prior taxane treatment in both a patient cohort and a murine mouse model. We could identify tubulin family members and tetraspanin-2 as potential contributors for the destabilization of the blood-brain barrier. Further analyses are needed to decipher the exact role of those alterations on tumor metastatic processes in the brain.

Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial.

OBJECTIVE: To evaluate the morbidity of pancreaticoduodenectomy after neoadjuvant chemotherapy for resectable pancreatic cancer and to assess its histologic and metabolic response. BACKGROUND: Adjuvant chemotherapy improves the outcome of pancreatic cancer, but 25% of patients remain unfit after surgery. Neoadjuvant chemotherapy can be offered to all patients in a multimodality approach, but its efficacy and surgical morbidity are unknown. METHODS: Patients with resectable, cytologically proven adenocarcinoma of the pancreatic head received 4 bi-weekly cycles of gemcitabine (1000 mg/m(2)) and cisplatin (50 mg/m(2)) in this prospective phase II trial. Staging and restaging included chest x-ray, abdominal computed tomography (CT), positron emission tomography (PET)/CT, endoscopic ultrasound, and laparoscopy. Fluorodeoxyglucose uptake was quantified by the standard-uptake value (SUV) on baseline and restaging PET/CT. Immunohistochemistry for GLUT-1 and Ki-67 was performed. The histologic response, cytopathic effects, and surgical complications were graded by respective scores. RESULTS: Twenty-four of 28 patients had resection for histologically confirmed adenocarcinoma. The surgical morbidity was low without perioperative death and one pancreatic fistula. Histologic response was documented in 54% and cytopathic effects in 83% of the patients. A significant SUV decrease occurred during chemotherapy (P = 0.031), which correlated with the baseline SUV (P = 0.001), Ki-67 expression (P = 0.016), and histologic response (P = 0.01). Neither the metabolic nor the histologic response was predictive of the median disease-free (9.2 months) or overall survival (26.5 months). CONCLUSION: Neoadjuvant chemotherapy induced a significant metabolic and histologic response, which was best predicted by PET. Most importantly, surgery after neoadjuvant chemotherapy for pancreatic cancer was safe.

Contrast-enhanced 18F-FDG PET/CT: 1-stop-shop imaging for assessing the resectability of pancreatic cancer.

UNLABELLED: Patients with pancreatic cancer continue to have a poor prognosis, with a 5-y survival rate of less than 5%. Surgery is the only treatment that offers a potential cure. Determining resectability is the principal goal of staging in pancreatic cancer patients. Our objective was to evaluate the value of combined contrast-enhanced (18)F-FDG PET/CT in assessing the resectability of pancreatic cancer and to compare enhanced PET/CT with the performance of PET alone and unenhanced PET/CT. METHODS: Fifty patients (25 women and 25 men; mean age, 64.3 y; range, 39-84 y) with biopsy-proven pancreatic adenocarcinoma underwent enhanced (18)F-FDG PET/CT for the evaluation of resectability. Criteria for unresectability were distant metastases, peritoneal carcinomatosis, arterial infiltration, or invasion of neighboring organs other than the duodenum. The performance of enhanced PET/CT regarding resectability was compared with that of PET alone and unenhanced PET/CT. Histology, intraoperative findings, and follow-up CT with clinical investigations were used as the reference standard. RESULTS: According to the reference standard, 27 patients had disease that was not resectable because of distant metastases (n=17), peritoneal carcinomatosis (n=5), or local infiltration (n=5). In the assessment of resectability, PET alone had a sensitivity of 100%, specificity of 44%, accuracy of 70%, positive predictive value of 61%, and negative predictive value of 100%; unenhanced PET/CT had respective values of 100%, 56%, 76%, 66%, and 100%; and enhanced PET/CT, 96%, 82%, 88%, 82%, and 96%. In 5 patients, unresectability was missed by all imaging methods and was diagnosed intraoperatively. Enhanced PET/CT was significantly superior to PET alone (P=0.035), and there was a trend for enhanced PET/CT to be superior to unenhanced PET/CT (P=0.070). CONCLUSION: The use of enhanced PET/CT as a 1-stop-shop imaging protocol for assessing the resectability of pancreatic cancer is feasible and accurate. Enhanced PET/CT is significantly superior to PET alone.

Infectious port complications are more frequent in younger patients with hematologic malignancies than in solid tumor patients.

BACKGROUND: We assessed longevity and complications of totally implantable venous access devices in oncology patients. METHODS: 197 patients received a total of 201 port devices via the subclavian vein for delivery of chemotherapy between January 1, 2005, and December 31, 2006. We reviewed the patient charts for port-related complications and risk factors until July 31, 2007. RESULTS: A total of 47,781 catheter days were analyzed (median, 175 days; range, 1-831). Forty-six different complications occurred (0.96 complications/1,000 catheter days). The only risk factor significantly associated with a higher complication rate was younger age. Older patients had a lower risk for developing complications with a risk reduction of 2.4% for each year. There were no differences regarding underlying tumor, gender, access side, method of placement (subclavian/cephalic vein) or implanting team (thoracic versus visceral surgery). A trend was seen for shorter port longevity in hematologic patients compared to oncologic patients (p = 0.059). The former developed significantly more port-associated infections than solid tumor patients [11/53 cases (21%) versus 2/148 cases (1.4%); p < 0.0001]. CONCLUSIONS: Port-associated infections were mostly observed in younger patients with hematologic neoplasms. Prospective trials should be performed to evaluate the benefit of a prophylactic antimicrobial lock in these selected patients.

Hemorrhage associated with hepatic artery pseudoaneurysms after regional chemotherapy with floxuridine: case report.

Pseudoaneurysms of the hepatic artery are a rare complication in patients with primary or secondary liver tumors treated with intra-arterial chemotherapy. We present two patients who developed this complication after placement of a catheter system into the gastroduodenal artery and initiation of regional chemotherapy with floxuridine. Diagnosis was made after symptomatic bleeding occurred, necessitating emergency angiography with coil embolization. Pseudoaneurysms usually occur after mechanical damage of the vessel wall, but the chemical toxicity of floxuridine may add to the development of vascular impairment.

Is an aggressive surgical approach worthwhile in biliary cancer?

BACKGROUND: Biliary cancer includes cancer of the gallbladder as well as extrahepatic and intrahepatic cholangiocarcinoma. Surgery is the only curative treatment option available. Recently, much more aggressive surgical approaches have been employed. Therefore, we have investigated outcome of biliary cancer before and after establishment of an aggressive surgical approach. METHODS: Retrospective single-center analysis comparing two time periods of 5 years each. During the second period new surgical expertise and a much more aggressive surgical approach were used. RESULTS: In the first time period (5/1995-4/2000) only 29 patients with biliary cancer were treated at our institution, while a total of 85 patients were treated during the second time period (5/2000-4/2005). Surgical resection was attempted in 55% during the first period versus 62% in the second; resection was complete in 37.5% and 58.5%, respectively. Patients undergoing resection during the second time period were more likely to be without relapse compared with patients undergoing resection in the first time period. No patient from the first period is without evidence of disease, compared to 11 patients operated in the second period. Resected patients had better survival compared with unresected patients for all tumor locations (gallbladder, extrahepatic and intrahepatic cholangiocarcinomas). Overall survival of patients was not significantly different between patients treated during the first versus the second time period. CONCLUSION: In patients with biliary cancer surgical resection should be attempted whenever possible. However, long-term survival can be achieved only when a complete resection is obtained.

Phase II study of capecitabine and oxaliplatin in first- and second-line treatment of advanced or metastatic colorectal cancer.

PURPOSE: To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS: Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS: The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m(2) at an initial dose of 1,250 mg/m(2) bid in nonpretreated patients and at a dose of 1,000 mg/m(2) bid in pretreated patients.

Living donor liver transplantation and tolerance: a potential strategy in cholangiocarcinoma.

BACKGROUND: Donor-specific immune tolerance has been reported in isolated cases of kidney transplantation associated with bone marrow transplantation. The following is a description of a living donor liver transplantation for a hilar cholangiocarcinoma in a previous recipient of an allogeneic bone marrow transplant. METHOD: A right hemi-liver transplantation was performed using a liver allograft obtained from the same previous bone marrow donor. A neoadjuvant chemo-irradiation protocol was implemented before the procedure. Because of the presence of full chimerism, no immunosuppression has been necessary for the last 22 months. RESULTS: Liver graft function has remained excellent, and a magnetic resonance imaging scan at one and a half years has shown no tumor recurrence. A control liver biopsy at 1 year showed no rejection. CONCLUSIONS: Neoadjuvant chemo-irradiation therapy and removal of all immunosuppression after liver transplantation formed the basic structure of this approach. Additional benefits provided by living donor liver transplantation included limitation of tumor progression by diminishing the pretransplantation waiting time, radical excision of the tumor through a complete hepatectomy, and optimal timing of the transplant procedure within a neoadjuvant chemo-irradiation protocol.

Gemcitabine-associated hemolytic-uremic syndrome.

BACKGROUND: Gemcitabine has mild renal toxicity, but cases of gemcitabine-associated hemolytic-uremic syndrome (HUS) have been reported. METHODS: A case is presented of a 45-year-old woman on prolonged gemcitabine treatment for ovarian cancer who developed HUS and recovered after drug discontinuation. A mini-review of the literature based on a MEDLINE search follows. RESULTS: Including our own patient, a total of 26 cases of gemcitabine-associated HUS were identified. Median patient age was 52 years. Treatment was for various tumors at advanced stages, and in some patients, other anticancer drugs previously had been administered. Mean time between initiation of gemcitabine therapy and onset of HUS was 7.4 +/- 3.5 months, or 21.9 +/- 10.9 doses of gemcitabine. The calculated median cumulative dose of gemcitabine was 20,000 mg/m(2) (range, 2,450 to 48,000 mg/m(2), or a total of 70,000 mg). The onset of disease was noted up to 2 months after the last gemcitabine infusion. Diagnosis of HUS was confirmed histologically in 13 patients and based on clinical findings in the other 15. Treatment included drug discontinuation, steroids, fresh frozen plasma, hemodialysis, absorption chromatography, plasmapheresis, and various combinations thereof. Of 23 patients with reported outcome, 11 died within a few weeks. In two cases, death was believed to be a direct consequence of HUS. Reexposure to the drug was reported in three patients but was uncomplicated in only one. CONCLUSION: There are only a few confirmed cases of gemcitabine-associated HUS despite the widespread use of the drug. This potentially fatal complication is difficult to treat and should be widely known.

Gemcitabine-related pulmonary toxicity.

BACKGROUND: Gemcitabine is an increasingly used and generally well tolerated anticancer drug. Rarely, it leads to potentially fatal pulmonary toxicity. CASE DESCRIPTIONS AND RESULTS: We describe the clinical features of 5 patients with gemcitabine-related pulmonary toxicity. Due to early diagnosis, prompt discontinuation of the drug, and treatment with steroids, toxicity was reversible in all cases. CONCLUSION: Early recognition of gemcitabine-related pulmonary toxicity is mandatory.