Days spent in acute care hospitals at the end of life of cancer patients in four Swiss cantons: a retrospective database study (SAKK 89/09).

Number of days spent in acute hospitals (DAH) at the end of life is regarded as an important care quality indicator for cancer patients. We analysed DAH during 90 days prior to death in patients from four Swiss cantons. Claims data from an insurance provider with about 20% market share and patient record review identified 2086 patients as dying of cancer. We calculated total DAH per patient. Multivariable generalised linear modelling served to evaluate potential explanatory variables. Mean DAH was 26 days. In the multivariable model, using complementary and alternative medicine (DAH = 33.9; +8.8 days compared to non-users) and canton of residence (for patient receiving anti-cancer therapy, Zürich DAH = 22.8 versus Basel DAH = 31.4; for other patients, Valais DAH = 22.7 versus Ticino DAH = 33.7) had the strongest influence. Age at death and days spent in other institutions were additional significant predictors. DAH during the last 90 days of life of cancer patients from four Swiss cantons is high compared to most other countries. Several factors influence DAH. Resulting differences are likely to have financial impact, as DAH is a major cost driver for end-of-life care. Whether they are supply- or demand-driven and whether patients would prefer fewer days in hospital remains to be established.

A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.

BACKGROUND: The treatment of patients with metastatic melanomas that harbour BRAF V600E or V600K mutations with trametinib plus dabrafenib appears to be superior to treatment with vemurafenib alone. This treatment regimen is likely to become available in Switzerland in the near future. OBJECTIVES: To determine the cost-effectiveness of trametinib plus dabrafenib. METHODS: A Markov cohort simulation was conducted to model the clinical course of typical patients with metastatic melanoma. Information on response rates, clinical condition and follow-up treatments were derived and transition probabilities estimated based on the results of a clinical trial that compared treatment with trametinib plus dabrafenib vs. vemurafenib alone. RESULTS: Treatment with trametinib plus dabrafenib was estimated to cost an additional CHF199 647 (Swiss francs) on average and yield a gain of 0·52 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of CHF385 603 per QALY. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of CHF100 000 per QALY would not be reached at the current US price of trametinib. CONCLUSIONS: The introduction of trametinib in Switzerland at US market prices for the treatment of metastatic BRAF V600-mutated melanoma with trametinib plus dabrafenib is unlikely to be cost-effective compared with vemurafenib monotherapy. A reduction in the total price of the combination therapy is required to achieve an acceptable cost-effectiveness ratio for this clinically promising treatment.

Triple negative breast cancer: proposals for a pragmatic definition and implications for patient management and trial design.

In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics.

Selective intra-arterial chemotherapy with floxuridine as second- or third-line approach in patients with unresectable colorectal liver metastases.

BACKGROUND: An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI). METHODS: Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors. RESULTS: Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5-55.7 months), 3.9 months (range, 0.7-55.7 months), and 5.5 months (range, 1.6-55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07-0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P = 0.09). No differences were observed in OS (P = 0.69) or PFS (P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures. CONCLUSIONS: FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized.

Trastuzumab beyond progression: a cost-utility analysis.

BACKGROUND: The continuation of trastuzumab beyond progression in combination with capecitabine as secondary chemotherapy for HER2-positive metastatic breast cancer (MBC) prolongs progression-free survival without a substantial increase in toxicity. PATIENTS AND METHODS: A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Information on response rates and major adverse effects was derived, and transition probabilities were estimated, based on the results of the Breast International Group 03-05 clinical trial. Direct costs were assessed from the perspective of the Swiss health care system. RESULTS: The addition of trastuzumab to capecitabine is estimated to cost on average an additional of €33,980 and to yield a gain of 0.35 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of €98,329/QALYs gained. Probabilistic sensitivity analysis showed that the willingness-to-pay threshold of €60,000/QALY was reached in 12% of cases. CONCLUSION: The addition of trastuzumab to capecitabine in MBC patients is more expensive than what is typically regarded as cost-effective but falls within the value ranges found for established regimens in the treatment of MBC.

Multicenter phase II trial of preoperative induction chemotherapy followed by chemoradiation with docetaxel and cisplatin for locally advanced esophageal carcinoma (SAKK 75/02).

BACKGROUND: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma. PATIENTS AND METHODS: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery. RESULTS: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications. CONCLUSIONS: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial.

BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. RESULTS: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. CONCLUSION: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse.

[Molecular targeted therapy]. / Molekular zielgerichtete Therapie.

Until recently, cancer therapy was based on three modalities: surgery, radiotherapy, and cytostatic chemotherapy. In most instances treatment of solid tumors was a surgical domain. For patients with incomplete resection or relapse after surgery, radiotherapy and chemotherapy usually offered only partial response and mostly of limited duration. By the mid-1990s visions of antibody-based therapies, vaccination strategies, and even gene-specific therapies existed but seemed far from clinical practice. United States Federal Drug Administration approval of the humanized antibody rituximab (1997) and the tyrosine kinase inhibitor imatinib (2001) has changed perceptions of oncologic treatment. These drugs turned visions into reality and led the pharmaceutical industry, clinicians, and patients to new perspectives. This article gives an overview of the development of this fourth modality in cancer therapy, so-called targeted therapy.

Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: an evidence-based analysis.

The aim of this review was to assess the impact of transarterial chemoembolization (TACE) as a neoadjuvant therapy prior to orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). An electronic search on the Medline database (1990-2005) was used to identify relevant articles. The studies were reviewed and ranked according to their quality of evidence using the grading system proposed by the Oxford Centre for Evidence-based Medicine. As a bridge to OLT, pretransplant TACE does not improve long-term survival (grade C). There is currently no convincing evidence that TACE allows to expand the current selection criteria for OLT, nor that TACE decreases dropout rates on the waiting list (grade C). However, TACE does not increase the risk for postoperative complications (grade C). There is insufficient evidence that TACE offers any benefit when used prior to OLT, neither for early nor for advanced HCC. Well-designed randomized controlled trials are needed to define the role of TACE in OLT patients.

[Therapeutic advances in breast cancer]. / Mammakarzinom--therapeutische Fortschritte.

The treatment of breast cancer has made significant improvements during the past ten years. For early breast cancer with a clinically negative axilla sentinel node biopsy has become the preferred approach. For endocrine therapy of postmenopausal patients the selective aromatase inhibitors have become standard in metastatic as well as in early breast cancer. Trastuzumab (Herceptin) plays an important role in the treatment of HER2-positive breast cancer in the metastatic and since 2005 also in the adjuvant setting. When chemotherapy is used to treat metastatic breast cancer drug combinations are superior to monotherapy only in terms of response rates. By contrast, in the adjuvant setting combination drug therapy is the standard. New methods of tissue analysis including expression patterns of mRNA and proteins are promising research strategies to further advance the field.

Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG).

BACKGROUND: We sought to determine whether a high-risk group could be defined among patients with operable breast cancer in whom a search of occult central nervous system (CNS) metastases was justified. PATIENTS AND METHODS: We evaluated data from 9524 women with early breast cancer (42% node-negative) who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1999, and treated without anthracyclines, taxanes, or trastuzumab. We identified patients whose site of first event was CNS and those who had a CNS event at any time. RESULTS: Median follow-up was 13 years. The 10-year incidence (10-yr) of CNS relapse was 5.2% (1.3% as first recurrence). Factors predictive of CNS as first recurrence included: node-positive disease (10-yr = 2.2% for > 3 N+), estrogen receptor-negative (2.3%), tumor size > 2 cm (1.7%), tumor grade 3 (2.0%), < 35 years old (2.2%), HER2-positive (2.7%), and estrogen receptor-negative and node-positive (2.6%). The risk of subsequent CNS recurrence was elevated in patients experiencing lung metastases (10-yr = 16.4%). CONCLUSION: Based on this large cohort we were able to define risk factors for CNS metastases, but could not define a group at sufficient risk to justify routine screening for occult CNS metastases.

Downstaging colorectal liver metastases by concomitant unilateral portal vein ligation and selective intra-arterial chemotherapy.

BACKGROUND: Although selective intrahepatic arterial chemotherapy successfully downstaged irresectable colorectal liver metastases in a previous study, curative resection was rarely possible, as the remnant healthy liver volume was inadequate. This pilot study evaluated the efficacy of concomitant unilateral portal vein ligation and selective intrahepatic arterial chemotherapy in downstaging such tumours. METHODS: The study included 11 patients with irresectable colorectal liver metastases. Selective intrahepatic arterial chemotherapy was delivered using a subcutaneous pump, and each patient underwent concomitant unilateral portal vein ligation of the hemiliver judged to have the higher tumour load. Chemotherapy involved serial administration of floxuridine for 2 weeks every 4 weeks. RESULTS: All patients developed significant atrophy of the hemiliver subjected to portal vein ligation and contralateral hypertrophy. There was no increase in tumour load within 6 months of therapy, and the load decreased by 60 per cent in the hemiliver ipsilateral to the ligated vein. At 3 months, six of 11 patients showed a significant response to chemotherapy. In four patients, downstaging allowed curative resection after only three cycles of chemotherapy. These patients survived at least 20 months afterwards. CONCLUSION: Combined unilateral portal vein ligation and selective intrahepatic arterial chemotherapy produced substantial atrophy of the ipsilateral hemiliver along with contralateral hypertrophy, without increased tumour growth in the regenerating hemiliver.

[Current diagnosis and treatment of pancreatic cancer]. / Moderne Diagnostik und Therapie des Pankreaskarzinoms.

Adenocarcinoma of the pancreas (pancreatic cancer) is the most frequent tumor entity in the pancreas. While the results of surgical therapy of pancreatic cancer were disappointing in the past due to high perioperative mortality rates, resection of pancreatic cancer nowadays represents the standard treatment for non-metastatic cancer with a mortality rate below 5%. This decrease in perioperative mortality of the Whipple operation is inversely correlated to the case load of the hospital and the responsible surgeon, and is mainly related to improvements in the intensive care management, the surgical technique and patient selection. In particular, the perioperative use of octreotide resulted in a significant decrease in the rate of pancreatic fistula. Furthermore, modern staging examinations such as diagnostic laparoscopy, PET, or endoscopic ultrasound resulted in improved patient selection. In addition, the long-term results of the surgical treatment of pancreatic cancer has been improved by adjuvant and neoadjuvant chemotherapy in the past 10 years. Similar progress has been made in the palliative treatment of metastatic or locally advanced cancer. Nowadays, endoscopic procedures can replace surgical palliation of obstructive jaundice in most cases and sometimes even gastric outlet obstruction. Moreover, systemic chemotherapy using gemcitabine-based protocols has resulted in a significant prolongation of survival. However, further progress in the treatment of pancreatic cancer can only be achieved by an interdisciplinary management of this disease.

[Systemic therapy for colorectal cancer]. / Systemtherapie des kolorektalen Karzinoms.

Drug treatment of colorectal cancer has made impressive progress during the past 10 years. In addition to the traditional 5-fluorouracil, newer anticancer drugs are available including irinotecan and oxaliplatin. Monoclonal antibodies like bevacizumab and cetuximab have been integrated into modern treatment regimens. Based on randomized clinical trials we can formulate rational treatment strategies as outlined in this article.

[New antibodies in cancer treatment]. / Neue Antikörper in der Krebsbehandlung.

Since the development of hybridoma technology in 1975 monoclonal antibodies with pre-defined specificity can be produced. Only twenty years later did it become possible to make therapeutic use of monoclonal antibodies in oncology. To this end it was necessary to attach the antigen-binding site of a mouse antibody onto the scaffold of a human antibody molecule. Such chimeric or "humanized" antibodies may be used in passive immunotherapy without eliciting an immune response. Rituximab and trastuzumab are such humanized antibodies. They are used today routinely in the treatment of malignant lymphoma and breast cancer, respectively. These antibodies are usually used in combination with conventional cytostatic anticancer drugs.