Pan-European, open-label dose titration study of fentanyl buccal tablet in patients with breakthrough cancer pain.

BACKGROUND: Fentanyl buccal tablet (FBT), a rapid onset opioid used to treat breakthrough cancer pain, must be titrated to an effective dose that provides adequate analgesia and minimizes undesirable events. This open-label, randomized study compared the percentage of patients achieving an effective dose of FBT when starting titration at 100 or 200 µg. METHODS: Opioid-tolerant patients with chronic cancer-related pain who experienced up to four breakthrough pain episodes daily were randomized to a starting dose of 100 or 200 µg for the titration period. The dose was increased until an effective dose (100, 200, 400, 600 or 800 µg) providing adequate analgesia with acceptable adverse events was achieved. Patients achieving an effective dose entered a treatment period during which they treated up to eight breakthrough pain episodes with their effective dose. RESULTS: A total of 442 patients from 135 sites in seven European countries were screened. Non-inferiority was established with the percentage of patients achieving an effective dose starting titration at 200 µg (81.4%) compared with the 100-µg (75.2%) starting dose. The most common effective doses of FBT were 200 µg (39.6%) and 400 µg (26.9%). No new safety concerns were identified with use of FBT at doses up to 800 µg per episode. CONCLUSIONS: This study involving a real clinical practice setting showed a similar percentage of patients safely achieving an effective dose by titration starting with 100 versus 200 µg of FBT.

Counseling cancer patients on complementary and alternative medicine. Background, theory, and implementation of nationwide counseling facilities.

BACKGROUND AND PURPOSE: Complementary and alternative medicine (CAM) is of high relevance in oncology. Only a minority of professionals feel competent in CAM. Our aim was to provide a strategy for establishing evidence-based counseling on CAM in oncology in the German health system. METHODS: We performed a systematic search of the literature on patient counseling concerning CAM. Of 811 articles identified in this search 51 met our inclusion criteria. Data from these articles were analyzed and adapted to the needs of German patients by a group of experts of the DEGRO ("Deutschen Gesellschaft für Radioonkologie") and the German Cancer Society. In the next step a strategy about how to integrate evidence-based counseling on CAM at cancer centers and oncological institutions was developed. RESULTS: First, evidence-based recommendations on CAM counseling were derived. The core of our strategy combines two levels of information provision: level 1 will be oncologists, radiotherapists and other specialists and level 2 oncological CAM experts. The latter group will serve as trainers and backup for complicated or advanced questions and for individual counseling of patients with complex needs. Professionals in level 1 will be offered special training. CONCLUSION: Evidence-based counseling on CAM is not only possible but also mandatory in order to meet patient information needs. Our proposal would allow for integrated counseling available at all oncological institutions and guarantee a high quality. Furthermore, provision of information on two different levels allows the effective use of resources (manpower and financing).

[Adjuvant therapy of melanoma. From non-specific immune stimulants into the future]. / Adjuvante Therapie des Melanoms. Von unspezifischen Immunstimulanzien in die Gegenwart.

Four decades of clinical and basic research have laid a solid base for clinicians to choose the best possible treatment for patients with melanoma. There has been a relative and absolute decrease in mortality despite increasing incidence. However, this decline in mortality is primarily the result of programs for primary and secondary prevention, not therapeutic advances. Conventional and high-dose immunomodulatory regimens and cytostatic therapy have failed to improve the prognosis. Whether the high-dose interferon-alpha therapy introduced by Kirkwood et al. 2001 can produce sustainable improvement in cure rate is controversial. Further developments such as treatment with recombinant cytokines (especially IL-2 and GM-CSF), specific blockade of neoplastic signal transduction and vaccination are the central issues in current research. In the future the task will be to offer an highly individualized therapy plan, based on specific prognostic and risk criteria defined in molecular genetic parameters. Indiscriminate use of newer therapeutic approaches is simply not affordable in this age of shrinking financial resources for health care.

Health economic analysis of fluoropyrimidine-based therapies of colorectal cancer from the perspective of statutory sickness funds.

AIMS: 1) to identify the treatment costs of different standard fluoropyrimidine-based therapies, i. e., the Mayo-Clinic and AIO/Ardalan regimens, under real-life conditions in settings routinely used for chemotherapy administration in Germany (inpatient, day-clinic or office-based oncologists) and 2) to investigate the cost implications of the routine use of capecitabine, an oral alternative for the treatment of metastatic colorectal cancer. METHODS: We analysed the actual fee-listings of office based oncologists and projected the results to several hospital-based treatment settings and to oral treatment with capecitabine from the perspective of statutory sickness funds. RESULTS: Office-based setting: the highest quarterly treatment costs of 9.874 were found for the AIO/Ardalan-regimen, followed by the Mayo-Clinic regimen, which incurred costs of 2.497. The cheapest treatment option was capecitabine with quarterly costs of 1.610. Day-clinic setting: the costs of the Mayo-Clinic protocol amounted to 2.036 in a municipal hospital and 8.455 in a university hospital. The respective costs for the AIO/Ardalan regime were 1.294 and 5.374. In-patient setting: the Mayo-Clinic protocol costs were 3.143 in a municipal hospital and 10.5609 in a university hospital. The respective costs found for the AIO/Ardalan-regimen were 1.998 and 6.717. CONCLUSION: From a health economic perspective, substantial cost savings for health insurance may be realised if patients with colorectal carcinoma were treated in the office-based setting with capecitabine instead of a hospital-based treatment. Economic consequences would be positive for municipal hospitals (avoided losses) and negative for university hospitals. Further savings could be realised if drug prices in hospital and retail pharmacies were harmonized.

Patient satisfaction and quality of life in cancer outpatients: results of the PASQOC study.

BACKGROUND: Satisfaction with care and quality of life (QoL) are indicative of the quality of care of cancer patients. The purpose of this study was to lay a cornerstone for patient-centred quality management by assessing the current status of satisfaction with care and QoL among oncological outpatients in Germany, and by identifying the key factors that determine a patient's willingness to recommend a medical facility. PATIENTS AND METHODS: A self-constructed and validated patient satisfaction questionnaire plus the SF-36 were distributed to a random sample of 3384 cancer patients who presented at 24 investigators' offices nationwide within a defined recruiting period and who met the inclusion criteria. The return rate was 81.9% (n=2772). A total of 2659 (78.6%) questionnaires were evaluable. The most common cancer types were breast (22.9%) and intestine (19.8%). RESULTS: Overall satisfaction was high, but specific reporting questions revealed many areas for improvement such as shared decision making, doctor-patient communication and organization of care. QoL was significantly impaired in many domains. Patient-provider relationship, facility setting and information on diagnosis and treatment options are major determinants of a patient's willingness to recommend a facility to a friend or relative if needed. CONCLUSIONS: This multicentre study focusing on patient perspectives highlights that, although the overall degree of satisfaction was quite high, there are numerous areas for improvement.

Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients.

There is increasing evidence that infections and vaccinations play an important role in the normal maturation of the immune system. It was therefore of interest to determine whether these immune events also affect the prognosis of melanoma patients. A cohort study of 542 melanoma patients in six European countries and Israel was conducted. Patients were followed up for a mean of 5 years and overall survival was recorded. Biometric evaluations included Kaplan-Meier estimates of survival over time and Hazard Ratios (HRs), taking into account all known prognostic factors. During the follow-up between 1993 and 2002, 182 of the 542 patients (34%) died. Survival curves, related to Breslow's thickness as the most important prognostic marker, were in accordance with those observed in previous studies where the cause of death was known to be due to disseminated melanoma. In a separate analysis of patients, vaccinated with vaccinia or Bacille Calmette-Guerin (BCG), HRs and the corresponding 95% Confidence Intervals (CIs) were 0.52 (0.34-0.79) and 0.69 (0.49-0.98), respectively. Joint analyses yielded HRs (and 95% CIs) of 0.55 (0.34-0.89) for patients vaccinated with vaccinia, 0.75 (0.30-1.86) with BCG, and 0.41 (0.25-0.69) with both vaccines. In contrast, infectious diseases occurring before the excision of the tumour had little, or, at the most, a minor influence on the outcome of the melanoma patients. These data reveal, for the first time, that vaccination with vaccinia in early life significantly prolongs the survival of patients with a malignant tumour after initial surgical management. BCG vaccination seems to have a similar, although weaker, effect. The underlying immune mechanisms involved remain to be determined.

Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis.

Between 1988 and 1996, the European Organisation for Research and Treatment of Cancer Melanoma Group (EORTC-MG) performed a prospective, randomised phase III adjuvant trial to evaluate the efficacy and toxicity of low dose recombinant interferon-alpha 2 b (rIFN-alpha2b) (1 MU) or recombinant interferon gamma (rIFN-gamma), (0.2 mg) both given subcutaneously (s.c.), every other day (qod), for 12 months in comparison with an untreated control group. The German Cancer Society (DKG) added a fourth arm with Iscador M, a popular mistletoe extract. High-risk stage II patients (thickness >3 mm) and stage III patients (positive lymph nodes) without distant metastasis were randomised and followed until their first progression or death. An intention-to-treat analysis was performed. From 1988 to 1996, a total of 830 patients were randomised: 423 in the three-arm EORTC 18871 trial and 407 patients in the four-arm DKG 80-1 trial. The median follow-up was 8.2 years and a total of 537 relapses and 475 deaths were reported. At 8 years, the disease-free interval (DFI) rate was 32.4% and the overall survival (OS) rate was 40.0%. In terms of the DFI, the hazard ratio estimates (95% Confidence Intervals (CI)) were: 1.04 (0.84, 1.30) for the comparison of rIFN-alpha2b versus control, 0.96 (0.77, 1.20) for rIFN-gamma versus control, and 1.32 (0.93, 1.87) for Iscador M versus control. In terms of OS, the corresponding estimates (95% CI) for the 3 treatment comparisons were: for IFN-alpha2b 0.96 (0.76, 1.21), for rIFN-gamma 0.87 (0.69, 1.10) and for Iscador M 1.21 (0.84, 1.75), respectively. The results show no clinical benefit for adjuvant treatment with low dose rIFN-alpha2b or rIFN-gamma or with Iscador M in high-risk melanoma patients.

Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study.

A significant correlation between a reduced risk of melanoma and BCG and vaccinia vaccination in early childhood or infectious diseases later in life has already been reported from the FEBrile Infections and Melanoma (FEBIM) multicentre case-control study. This correlation is further evaluated in this study based on 603 incident cases of malignant melanoma and 627 population controls in six European countries and Israel by means of a joint analysis of the influence of vaccinations and infectious diseases. In addition, the previously unconsidered impact of influenza vaccinations is evaluated for the whole study population. The strong effects of the frequently given BCG and vaccinia vaccinations in early childhood, as well as of uncommon previous severe infectious diseases, were apparently not cumulative. With the Odds Ratio (OR) being set at 1 in the absence of vaccinations and infectious diseases, the OR dropped to 0.37 (95% Confidence Interval (CI): 0.10-1.42) when subjects had experienced one or more severe infectious diseases, associated with a fever of > 38.5 degrees C, and had not been vaccinated with BCG or vaccinia. The OR was 0.29 (CI: 0.15-0.57) in those who had had a severe infectious disease and were vaccinated with either BCG or vaccinia and 0.33 (CI: 0.17-0.65) for those with 1 or more severe infectious diseases and who had received both vaccinations. We conclude that both vaccinations as well as previous episodes of having a severe infectious disease induced the same protective mechanism with regards to the risk of melanoma. Because of a 'masking effect' by the vaccinia vaccination, the protective effect of the BCG vaccination and of certain infectious diseases against cancer has remained undetected. The vaccinations contributed more to the protection of the population than a previous episode of having an infectious disease. In view of the termination of vaccinations with vaccinia in all countries and of BCG in many of them, these findings call for a re-evaluation of vaccination strategies.

Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment.

PURPOSE: To compare the efficacy and tolerability of fulvestrant (formerly ICI 182,780) and anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. PATIENTS AND METHODS: Patients (n = 451) with advanced breast cancer were randomized to receive fulvestrant 250 mg as a once-monthly (one x 5 mL) intramuscular injection or an oral dose of anastrozole 1 mg in this open, parallel-group, multicenter trial. The primary end point was time to progression (TTP). Secondary end points included objective response (OR) rates, defined as complete response (CR) or partial response (PR), duration of response (DOR), and tolerability. RESULTS: Patients were followed for a median period of 14.4 months. In terms of TTP, fulvestrant was as effective as anastrozole (hazard ratio, 0.98; confidence interval [CI], 0.80 to 1.21; P =.84). Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole. OR rates showed a numerical advantage for fulvestrant (20.7%) over anastrozole (15.7%) (odds ratio, 1.38; CI, 0.84 to 2.29; P =.20). Clinical benefit rates (CR + PR + stable disease > or = 24 weeks) were 44.6% for fulvestrant and 45.0% for anastrozole. Median DOR was 14.3 months for fulvestrant and 14.0 months for anastrozole. Both treatments were well tolerated, with 3.2% and 1.3% of fulvestrant- and anastrozole-treated patients, respectively, withdrawn from treatment because of an adverse event. CONCLUSION: Fulvestrant was as effective as anastrozole. These data confirm that fulvestrant is an additional, effective, and well-tolerated treatment for advanced breast cancer in postmenopausal women whose disease progressed on prior endocrine therapy.

High tPA-expression in primary melanoma of the limb correlates with good prognosis.

To investigate whether the course of primary melanoma disease correlates with expression of the various components of the proteolytic plasminogen activation (PA) system, immunohistochemical stainings for activators of plasminogen (tissue type (tPA) and urokinase type (uPA)), inhibitors of plasminogen activation (type 1 (PAI-1) and type 2 (PAI-2)) and the receptor for uPA (uPAR) were performed on 214 routinely processed melanoma lesions. All lesions were primary cutaneous melanomas, minimally 1.5 mm thick, and derived from patients with only local disease at the moment of diagnosis (clinically stage II (T(3-4)N(0)M(0)), American Joint Committee on Cancer). Median patient follow-up was 6.1 years. Single variables as immunohistochemical staining results (extent of tumour cell staining, pattern of tumour cell staining and for some components also staining of stromal cells), histopathological and clinical parameters as well as treatment variables were analysed in order to assess their prognostic importance, in terms of time to recurrence, time to distant metastasis and duration of survival. The extent of tPA tumour cell positivity, categorized as 0-5%, 6-50% and 51-100%, appeared to be of importance for these end-points. Lesions with 51-100% tPA-positive tumour cells were found to have the best prognosis, whereas lesions with 6-50% tPA-positive tumour cells had the worst. Moreover, the prognostic significance of Breslow thickness, microscopic ulceration and sex was confirmed in this study. Multivariate analyses, incorporating these relevant factors, showed that the extent of tPA tumour cell positivity was an independent prognostic factor for distant metastasis-free interval (P = 0.012) and for the duration of survival (P = 0.043).