Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study.

PURPOSE: To describe the health-related quality of life (HRQoL) of an unselected population of patients with chronic lymphocytic leukaemia (CLL) including untreated patients. METHODS: HRQoL was measured by the EORTC QLQ-C30 including the CLL16 module, EQ-5D, and VAS in an observational study over multiple years. All HRQoL measurements per patient were connected and analysed using area under the curve analysis over the entire study duration. The total patient group was compared with the general population, and three groups of CLL patients were described separately, i.e. patients without any active treatment ("watch and wait"), chlorambucil treatment only, and patients with other treatment(s). RESULTS: HRQoL in the total group of CLL patients was compromised when compared with age- and gender-matched norm scores of the general population. CLL patients scored statistically worse on the VAS and utility score of the EQ-5D, all functioning scales of the EORTC QLQ-C30, and the symptoms of fatigue, dyspnoea, sleeping disturbance, appetite loss, and financial difficulties. In untreated patients, the HRQoL was slightly reduced. In all treatment stages, HRQoL was compromised considerably. Patients treated with chlorambucil only scored worse on the EORTC QLQ-C30 than patients who were treated with other treatments with regard to emotional functioning, cognitive functioning, bruises, uncomfortable stomach, and apathy. CONCLUSIONS: CLL patients differ most from the general population on role functioning, fatigue, concerns about future health, and having not enough energy. Once treatment is indicated, HRQoL becomes considerably compromised. This applies to all treatments, including chlorambucil, which is considered to be a mild treatment.

The standardised mortality ratio: the proper quality indicator in acute leukaemia?

BACKGROUND: The standardised mortality ratio (SMR) is a quality indicator used to measure quality of care in the Netherlands. It is subject to much criticism, which was the reason to study the value of the SMR as a quality indicator for the treatment of acute leukaemia. METHODS: A retrospective analysis was performed in patients with acute leukaemia admitted to a Santeon hospital during the period 2005-2009. SMR values were calculated and compared with the overall survival (OS). RESULTS: During the study period, 455 unique patients were admitted with acute leukaemia. SMR calculation was based on 992 admissions. SMR analysis yielded a high mortality ratio in hospital 1, 2, 3 and 4 in comparison with the national average (100), significant for hospital 1 and 4 (180 [CI 95% 126-257] and 187 [CI 95% 134-261], respectively) OS analysis also showed a significantly different outcome between hospitals. However, using OS as outcome parameter, hospital 2 and 6 showed the lowest performance as compared with hospital 1 and 4 using SMR as parameter. After multivariate analysis, age (HR 1.04; CI 95% 1.03-1.05; p < 0.001) and hospital (hospital 5 compared with 6: HR 0.54; CI 95% 0.30- .98; p = 0.043; hospital 2 compared with 1: HR 1.51; CI 95% 1.02-2.23; p = 0.039) were the only significant variables that influenced OS. CONCLUSION: Outcome according to SMR is not equivalent to outcome according to OS. This study shows that the use of the SMR as a quality indicator for the treatment of acute leukaemia does not appear to be justified.

Real-world costs of chronic lymphocytic leukaemia in the Netherlands.

We performed a comprehensive cost calculation identifying the main cost drivers of treatment of chronic lymphocytic leukaemia in daily practice. In our observational study 160 patient charts were reviewed repeatedly to assess the treatment strategies from diagnosis till the study end. Ninety-seven patients (61%) received ≥1 treatment lines during an average follow-up time of 6.4 years. The average total costs per patient were €41,417 (€539 per month). The costs varied considerably between treatment groups and between treatment lines. Although patients were treated with expensive chemo(immuno-)therapy, the main cost driver was inpatient days for other reasons than administration of chemo(immuno-)therapy.

Chronic lymphocytic leukaemia in the Netherlands: trends in incidence, treatment and survival, 1989-2008.

We present trends in incidence, early treatment and survival of Chronic Lymphocytic Leukaemia (CLL) between 1989 and 2008, based on population-based data from the Netherlands Cancer Registry. Incidence rates were stable at 5.1 per 100,000 person-years for males, but increased from 2.3 to 2.5 for females, especially for females aged 50-64 years (from 3.6 to 4.3). Patients were less likely to receive chemotherapy within six months, i.e. from 29% to 24% among males and from 25% to 21% among females. Five-year relative survival increased from 61% in 1989-1993 to 70% 2004-2008 for males, and from 71% to 76% for females. The relative excess risk of dying decreased in time to 0.7 (males) and 0.9 (females) in 2004-2008, reference 1989-1993, and increased with age to 2.9 (males) and 1.8 (females) in patients aged 75-94 years, reference 30-64 years. The increasing incidence among females aged 50-64 coincided with the introduction of mass screening for breast cancer, which resulted in a large group of women under increased surveillance and possibly led to increased detection of CLL. The increase in survival might be underestimated due to possible decreased or delayed registration of indolent cases and the retroactive effect of the introduction of new therapies.

Independent prognostic effect of co-morbidity in lymphoma patients: results of the population-based Eindhoven Cancer Registry.

The prevalence of co-morbidity among elderly lymphoma patients is associated with a decrease in the use of chemotherapy. This study assessed the independent prognostic effect of co-morbidity in 1551 unselected lymphoma patients, diagnosed between 1995 and 2001 in the area of the population-based Eindhoven Cancer Registry. The prevalence of serious co-morbidity was 58% for patients with Hodgkin's disease (HD) who were over 60 years of age and 66% for patients with non-Hodgkin's lymphoma (NHL) who were over 60 years of age. The administration of chemotherapy declined in the presence of co-morbidity for elderly patients with early-stage HD and elderly patients with aggressive NHL. Co-morbidity was associated with a 10-20% decline in 5-year survival. Whether less frequent application of chemotherapy in the presence of co-morbidity is justified as far as complications, prognosis and quality of life are concerned requires further investigation.

Compassionate use programme of irinotecan in colorectal cancer patients in The Netherlands.

BACKGROUND: Irinotecan is an effective treatment for metastatic colorectal cancer. However, its use may be associated with troublesome adverse effects such as delayed diarrhoea, acute cholinergic syndrome and neutropenic infection. The manufacturer decided to release irinotecan for compassionate use in The Netherlands prior to its regulatory approval (June 1998) and first introduction for second-line treatment of metastatic colorectal cancer. In view of the drug's adverse effect profile this was done in a carefully controlled manner. METHODS: Irinotecan was made available to patients with colorectal cancer with elaborate precautions. Treating physicians requesting irinotecan for compassionate use received a protocol, providing recommendations for the proper use and the prevention/management of potentially troublesome adverse events. Limited demographic, toxicity and efficacy data were collected. RESULTS: Between June 1997 and September 1998, 112 patients were registered for this programme, 103 of whom actually received irinotecan. The percentage of patients experiencing grade 3-4 adverse effects was relatively low: delayed diarrhoea in 17%, nausea and vomiting 17%, acute cholinergic syndrome 6%, febrile neutropenia 4% and neutropenic infection 2%. Five partial tumour responses and a high proportion of patients with 'no change' were noted. CONCLUSIONS: The carefully controlled release of irinotecan for compassionate use with a very detailed protocol for guidance and advice on safety precautions seems to have contributed to the relatively safe use of the drug outside the setting of a formal clinical trial.

Organisational design for an integrated oncological department.

OBJECTIVE: The outcomes of a Strength, Weakness, Opportunities and Threat (SWOT) analysis of three Integrated Oncological Departments were compared with their present situation three years later to define factors that can influence a successful implementation and development of an Integrated Oncological Department in- and outside (i.e. home care) the hospital. RESEARCH DESIGN: Comparative Qualitative Case Study. METHODS: Auditing based on care-as-usual norms by an external, experienced auditing committee. RESEARCH SETTING: Integrated Oncological Departments of three hospitals. RESULTS: Successful multidisciplinary care in an integrated, oncological department needs broad support inside the hospital and a well-defined organisational plan.

Amyloid and peripheral nervous system disease.

The peripheral nervous system can be involved in the following amyloid deposition diseases. (1) Amyloid deposition composed of beta 2-microglobulin in patients on long term hemodialysis causing a carpal tunnel syndrome; (2) deposition of light chain immunoglobulin derived amyloid leading to polyneuropathy, carpal tunnel syndrome and autonomic nervous system involvement in patients with primary amyloidosis, or amyloidosis secondary to or associated with multiple myeloma, Waldenström's macroglobulinemia, non-Hodgkin's lymphoma, and solid neoplasms like hypernephroma; and (3) several types of heredofamilial amyloid polyneuropathies, which are mainly caused by a point-mutation in the transthyretin gene on chromosome 18. The clinical and biochemical features of these three groups will be discussed, with special attention for recently developed therapy. In clinical practice, amyloid polyneuropathy should be considered in case of familial occurrence of a polyneuropathy and when a patient presents with a polyneuropathy and a monoclonal gammopathy.

Cutaneous leukocytoclastic vasculitis in relation to streptokinase.

The case history is presented of a patient who developed a cutaneous leukocytoclastic vasculitis after he had been treated with intravenous streptokinase because of an acute myocardial infarction. Leukocytoclastic vasculitis is a seldom reported side effect of streptokinase and may be caused by a type III-hypersensitivity reaction.

Bone marrow transplantation or chemotherapy as post-remission treatment of adult acute myelogenous leukemia.

We compared three consolidation regimens in patients with acute myelogenous leukemia in first remission. Thirty-four patients received only intensive consolidation chemotherapy (SIC); 28 patients were scheduled to undergo an autologous bone marrow transplant (auto-BMT) and 44 patients an allogeneic BMT (allo-BMT). Twenty-seven of them were referred in first remission for allo-BMT. Nineteen patients achieved a complete remission after salvage treatment. All other patients obtained a remission after one or two courses of a standard combination of cytosine arabinoside and daunorubicin. Except for the patients who were referred in remission, all patients received intermediate dose cytosine arabinoside and amsacrine as a first consolidation treatment. The median ages of the three groups were 48 (SIC), 39 (auto-BMT) and 33 years (allo-BMT). Two patients relapsed before auto-BMT and 1 before allo-BMT. The median interval from the date of complete remission to the auto- or allo-BMT was 3 months. In total, 80% of the patients of the SIC group relapsed, compared to 50% of the patients belonging to the auto-BMT group and 35% of the 44 patients who were scheduled to receive an allo-BMT. The overall median disease-free survival was 14 months, 30% of the patients being alive and disease-free at 3 years. The disease-free survival rate at three years was 25% for the SIC group, 30% for the allo-BMT group and 40% for the ABMT group (P = 0.45). Our study shows no benefit for bone marrow transplantation over intensive consolidation treatment. However, large randomized trials are required to define the real value of these treatment modalities.

Respiratory failure elicited by streptococcal septicaemia in patients treated with cytosine arabinoside, and its prevention by penicillin.

In order to prevent septicaemia with streptococci, 20 consecutive selectively decontaminated patients on intermediate high-dose Ara-C treatment for malignant haematological diseases were given penicillin G. The incidence of infection with streptococci decreased from 0.76 per episode (14 patients, 17 episodes) for controls who did not receive penicillin G to 0.11 per episode in the prophylaxis group (20 patients, 26 episodes). Simultaneously, a decrease in the incidence of respiratory failure was observed, i.e. 0.52 per episode for controls and 0.19 per episode for patients on penicillin G. The results suggest that septicaemia with streptococci triggers the development of noncardiogenic pulmonary oedema in patients with pre-existing damage of the lung due to aggressive cytotoxic treatment. This suggestion is supported by the sequence of events, regarding the occurrence of infection and respiratory failure and the results of measurements of antileukoprotease serum concentrations, a parameter for pulmonary capillary leakage. Taking into account the data in the literature and the results of the present study, the conclusion is drawn that in patients treated with (intermediate) high dose Ara-C, prevention of streptococcal septicaemia is associated with a decrease in the incidence of respiratory failure.

Cell kinetics after high dose cytosine arabinoside in patients with acute myelocytic leukemia.

In this study 10 patients with acute myelocytic leukemia (AML) each received a rapid intravenous injection of high dose cytosine arabinoside (HD Ara-C; 1 g/m2). Bone marrow aspirates were obtained before and after Ara-C administration to determine the percentage of cells in S-phase measured by flow cytometry. In 5 out of 10 cases synchronization of the leukemic cells in S-phase of the cell cycle was observed. However, the time of maximum synchronization turned out to be difficult to predict. Therefore, the strong correlation between percentage of cells in S-phase at diagnosis and the time of maximal accumulation of S-phase cells after Ara-C administration, as observed by others in childhood AML, could not be confirmed for adult AML patients. Although synchronization of AML cells after in vivo Ara-C administration could be demonstrated in at least half of the patients, the practical consequences are such that clinical application was hampered.

Paravertebral abscess due to nondiphtheria coryneform bacteria as a complication of ingrown toenails.

A patient developed a paravertebral abscess due to nondiphtheria coryneform bacteria following infected ingrown toenails. Both the causative role of this uncommon pathogen and the unusual origin were established by cultures of tissue from the toes, blood and an aspirate of the paravertebral abscess. The microorganism was tentatively identified as an atypical variant of Arcanobacterium haemolyticum.

Short-term intensive treatment (V.A.A.P.) of adult acute lymphoblastic leukemia and lymphoblastic lymphoma.

Increased dosages of cytosine arabinoside (Ara-C) have been shown to be active in remission induction and consolidation treatment of patients with primary refractory acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin's lymphoma (lyNHL). From August 1983 to December 1986 we treated 25 patients with ALL (9) and lyNHL, stage III and IV (16), median age 22 (range 15-48 yr) with a protocol consisting of remission induction with vincristine, prednisone, adriamycine and Ara-C (1 g/m2 twice daily as 2-h infusion d1-6) and intrathecal methotrexate, followed by consolidation courses with vincristine, prednisone, adriamycine and Ara-C (3 g/m2, twice daily as 2-h infusion d1-4) and intrathecal methotrexate. Some patients received CNS and/or mediastinal irradiation. No maintenance was given. 18 patients (72%) achieved complete remission (5 of the 11 previously treated and 13 of the 14 previously untreated patients). Consolidation courses were given to 17 patients. 5 of them relapsed in the bone marrow (3), skin (1) and CNS plus bone marrow (1) at 5, 5, 6, 6 and 24 months. The duration of complete remission ranged from 5 to 51+ months; the median could not yet be calculated. Short-term intensive treatment might be a worthwhile approach for ALL and lyNHL.

Day-6 bone marrow aspirate for the prediction of response to remission induction therapy for acute myelogenous leukaemia.

Seventy-two adults were treated for acute myelogenous leukaemia (AML). Forty-two had previously untreated AML and 30 had AML after a preleukaemic phase, refractory AML or relapsed AML. The previously untreated patients received a 7-day course of cytosine arabinoside (100 or 200 mg/m2 daily), daunorubicin and vincristine while the remaining patients received a 7-day course of cytosine-arabinoside (1 g/m2 q 12h for 6 days) and amsacrine (on day 7). The percentage of malignant cells and the reduction in the percentage of malignant cells were determined by means of bone marrow aspirates taken on day 6 of the chemotherapy course and at the time of diagnosis. Both variables correlated significantly with the ultimate treatment outcome; the reduction in the percentage of malignant cells correlated even more significantly than the absolute percentage malignant cells in the day-6 bone marrow. By means of multiple regression analysis it became possible to calculate the probability of achieving complete remission for the individual patient; this is given by the equation: probability = 1.9-0.009X (% malignant cell reduction). In addition, the mean percentage of malignant cells in the day-6 bone marrow was significantly higher for patients who failed to achieve than those who entered complete remission. Eighty-six per cent of the patients with less than 20% malignant cells on day 6 entered remission, while 75% of the patients with more than 21% malignant cells failed to achieve complete remission (p less than 0.001). Although all of these calculations support the predictive value of the day-6 bone marrow aspirate, the 95% confidence intervals are too large to allow reliable and safe predictions; therefore more patients must be studied to demonstrate the reliability of this test.