Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015.

BACKGROUND: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.). RESULTS: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). CONCLUSION: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

Prevalence and clinical significance of anticardiolipin and anti-beta2-glycoprotein-I antibodies in patients with non-Hodgkin's lymphoma.

The association of antiphospholipid antibodies (APA) has been reported in several cases of patients with non-Hodgkin's lymphoma (NHL) with or without thromboembolic complications. The purpose of this study was to analyse systematically the prevalence of APA and its clinical significance in lymphoma patients. Sera of 90 consecutive unselected patients with NHL were tested for the presence of anticardiolipin (aCL) antibodies and anti-beta2-glycoprotein-I (anti-beta2-GPI) antibodies. The patients were followed up over a median period of 14 months to note the occurrence of thromboembolism. We found APA in 24 out of 90 NHL patients (26.6%). Elevated APA were more often detected in women and in the elderly. The presence of elevated APA was not correlated with the histology and the stage of the lymphoma. None of the 24 patients with elevated APA developed a thromboembolic event in the follow-up period. Thromboembolic events were observed in 12 patients (13.3%), all with negative APA. High APA titres and the combination of positive aCL- and anti-beta2-GPI antibodies, features which are known to be more strongly correlated with thrombosis among patients with antiphospholipid syndrome and systemic lupus erythematous (SLE), were very uncommon in our cohort of NHL patients (3.3%). Vessel compression by lymphoma but not elevated APA remains the main cause of thrombosis in NHL patients.

Use of hematopoietic growth factors in elderly patients receiving cytotoxic chemotherapy.

Myelosuppression is a common side effect in elderly patients undergoing chemotherapy. Neutropenia and anemia cause considerable morbidity, may increase mortality, and can result in a worse outcome of treatment in elderly patients compared to younger patients with comparable type and stage of disease. The availability and proven efficacy of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) have had a considerable impact on supportive care in cancer patients: Several randomized trials have demonstrated a reduction of neutropenia and the frequency of severe infections in elderly patients treated with G-CSF following myelotoxic chemotherapy compared with patients without growth factor support. Both for G-CSF and for recombinant human erythropoietin (rHu-EPO) several studies have demonstrated the safety and effectiveness of these molecules in elderly patients with regard to increasing hemoglobin concentrations, improving quality of life (rHu-EPO), and neutrophil recovery. Although a positive effect of the use of growth factors on overall survival in elderly cancer patients is not yet proven, a reduction of chemotherapy-induced side effects could clearly be shown. The National Comprehensive Cancer Network (NCCN) of cancer centers has recommended that all patients aged 70 years and older treated with CHOP or cytotoxic chemotherapy of comparable intensity should receive prophylactic G-CSF administration, and that the hemoglobin concentration be maintained at >or=12 g/dl in elderly patients undergoing chemotherapy.

[Treatment of malignant non-Hodgkin's lymphomas in elderly patients]. / Behandlung maligner Non-Hodgkin-Lymphome bei älteren Patienten.

The number of elderly patients with non-Hodgkin's lymphomas (NHL) is continuously increasing. The diagnostic and staging procedures should be carried out in elderly patients as careful as in younger patients. Furthermore, for treatment decisions geriatric assessment and the patient's preferences concerning therapy are essential and have to be considered. The treatment of indolent NHL depends on the stage of the disease and the clinical status of the patient. Most of the patients with limited indolent NHL can be treated with curative intent using localized irradiation. Treatment of patients with advanced indolent NHL is palliative. In contrast, all stages of aggressive NHL can also be treated with curative intent in elderly patients. In limited aggressive NHL standard treatment consists of polychemotherapy followed by involved field irradiation. Standard treatment of advanced aggressive NHL is polychemotherapy with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP). The goal for the near future is to improve perspectives for elderly patients with NHL. One way is to treat as many of these patients as possible according to current standards. In the field of geriatric oncology, one of the questions we are often confronted with is the limitation of treatment, especially in frail patients. This issue is closely associated with ethical considerations which are discussed in another paper.

[Treatment of multiple myeloma in elderly patients: consensus of the Geriatric Oncology Working Group of the German Society of Hematologic Oncology and the German Society of Geriatrics]. / Behandlung des multiplen myeloms bei alteren patienten: konsensus der arbeitsgruppe geriatrische onkologie der DGHO und DGG.

Treatment of Multiple Myeloma in the Elderly: Consensus of the Cooperative Group of Geriatric Oncology of the DGHO and DGG Multiple myeloma is an illness of old age. Often, in elderly people the diagnosis is delayed by the fact that bone pain, which is the most frequently presenting symptom, is not correctly interpreted because this is a common complaint in the elderly. In contrast to younger patients with multiple myeloma, elderly patients often present with infections at diagnosis. After the diagnosis is established, careful observation is very important. This applies both to patients who require still no therapy and to patients under treatment. In order to optimize the care of older patients, apart from tumor-specific investigations multidimensional geriatric assessment is helpful. This specifically applies for multiple myeloma which predisposes the patient to 'instability' and 'immobility', both belonging to the typical geriatric symptoms. Geriatric assessment may also be helpful in the selection of those elderly patients who are candidates for a possible prognosis-improving experimental intense chemotherapy. For the majority of the elderly patients in need of treatment the standard is melphalan/prednisone accompanied by one of the biphosphonates. Nevertheless, in order to improve prospects also for this group of patients, as many elderly patients as possible should be included into studies. This is the only way to compile valid recommendations for the treatment of elderly patients with multiple myeloma.

Tolerability of the cytoprotective agent amifostine in elderly patients receiving chemotherapy: a comparative study.

In order to determine if age and comorbidity influence the tolerability of the cytoprotective agent amifostine, we compared side effects related to amifostine in patients > or = 70 years (group I) with patients < 70 years (group II). We evaluated 268 consecutive administrations of amifostine (119 in group I and 149 in group II, respectively), given i.v. at a dose of 740 mg/m(2) just before platinum-, taxol- or cyclophosphamide-based chemotherapy. Transient hypotension was the most common side effect occurring in association with amifostine. Decreases in systolic blood pressure > 20 mmHg were of similar frequency in both groups (27.1 versus 28.8% of amifostine infusions in group I and II, respectively). Hypotension did not result in medical sequelae in any of the patients. The amifostine infusion was interrupted 16 times in group I and 8 times in group II, respectively, mainly due to hypotension, but could be restarted after a few minutes in all patients except for three cases in group I. Patients in group II more often suffered from nausea/vomiting than in group II (20.8 versus 10.0% in group I). Other subjective symptoms (e.g. warmed, flushed sensation, sneezing, metallic taste, mouth dryness, dizziness and sleepiness) and hypocalcemia occurred with a similar frequency in both groups. Adverse effects associated with amifostine were not observed more frequently in elderly patients than in younger ones, although more elderly patients had a comorbidity than the younger ones.

Patients with malignant lymphomas experience a higher rate of documented infections than patients with breast cancer after high-dose chemotherapy with autologous peripheral stem cell transplantation.

The influence of underlying disease on documented infections has rarely been addressed in patients treated with high-dose chemotherapy (HDCT) and subsequent autologous peripheral blood stem cell transplantation (PBSCT). Because autografting has been used most frequently for malignant lymphomas and breast cancer, we analyzed in a retrospective study the data of 100 consecutive adult patients with either malignant lymphomas (group A, n = 50) or breast cancer (group B, n = 50) treated with HDCT at a single institution. The number of autografted CD34+ cells was not statistically different in either group. In this paper, we show for the first time that there is a significant difference in clinically or microbiologically documented infections in these groups of patients: documented infections occurred in 30% of malignant lymphoma patients but only in 4% of breast cancer patients (P=0.001). Of all isolated microorganisms, 78% were gram-positive. Because most of the documented infections were due to staphylococci, further studies should prospectively evaluate preventive measures to reduce the high incidence of these infections. This is especially important for lymphoma patients, who can be regarded as a high-risk group concerning gram-positive bacteremia.

Arterial thrombosis associated with anticardiolipin and anti-beta2-glycoprotein-I antibodies in patients with non-Hodgkin's lymphoma: a report of two cases.

Autoimmune phenomena in lymphoid malignancies are often observed. However, clinical manifestations such as a secondary antiphospholipid syndrome in the presence of antiphospholipid antibodies are rarely reported. Furthermore, in the few cases of lymphomas so far reported with thrombosis associated with elevated antiphospholipid antibodies, the anti-beta2-glycoprotein-I antibodies have not been studied. We report on two cases of arterial thrombosis occuring in patients with B-cell lymphoma who presented with positive anticardiolipin and anti-beta2-glycoprotein-I antibodies. Our observation suggests that patients with non-Hodgkin's lymphoma and both anticardiolipin and anti-beta2-glycoprotein-I antibodies may be, similar to lupus patients, at considerable risk towards thrombosis, especially towards arterial thrombosis.

Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas.

Because of the low number of active cytotoxic drugs and their limited activity, the evaluation of new anti-cancer agents for their activity in soft tissue sarcomas is a continuing need. The objectives of this prospective phase II trial of gemcitabine were to estimate the response rate and to define the toxicities of prolonged infusions of low-dose gemcitabine in patients with pretreated advanced soft tissue sarcomas. Patients were eligible if they had a histologic diagnosis of unresectable, recurrent or metastatic, progressive soft tissue sarcoma, and if they had been treated with at least one prior chemotherapy consisting of an anthracycline- and/or ifosfamide-containing regimen. Gemcitabine was administered as a 360 min infusion on days 1, 8 and 15 of a 28 day cycle. The initial dose of gemcitabine was 200 mg/m2 in all patients. Dose escalation to 250 mg/m2 was allowed in the case of stable disease and good tolerability of the drug. All 18 patients (median age 58 years) who enrolled were treated with gemcitabine, and all were assessable for toxicity, response and survival. Only two of these 18 patients had an objective response to a previous palliative chemotherapy. A median of 3 cycles (range 1-7) of gemcitabicin were administered. Two (11%) of the patients had a partial response lasting 5 and 6 months, respectively. Both of these patients had only lung metastases. Whereas one of these patients had a transient partial response to the foregoing chemotherapy (consisting of ifosfamide and doxorubicin), the other patient has been progressive on these drugs. One additional patient, progressive on ifosfamide and doxorubicin, had an objective response of greater than 50% confined to the lungs and stable local recurrence for 6 months. Six patients had stable disease for 3-6 months and nine patients had disease progression. The median survival was 8 months. Treatment generally was well tolerated with six patients having transient grade 3 non-hematologic toxicity, four having grade 3 neutropenia, and one having grade 4 neutropenia and thrombocytopenia. Gemcitabine, given as a prolonged infusion at a low dose level, has a favorable toxicity profile and displays antitumor activity in patients with intensively pretreated, advanced soft tissue sarcomas.

An unusual case of leukemic non-Hodgkin's lymphoma with blastic transformation.

We report on a patient who was diagnosed as having B-cell chronic lymphocytic leukemia (CLL) with atypical morphology. Flow cytometry disclosed CD5, CD19, and CD23 positivity, an immunophenotype seen mostly in B-CLL. Histology of the spleen and bone marrow suggested a diagnosis of small lymphocytic lymphoma. Upon blastic transformation, only 3 years after the diagnosis had been made, unusual clinical and laboratory features emerged. Lymphoid blasts appeared in the peripheral blood, and the patient developed nodular infiltrates consisting of these blasts at recent venous puncture sites. The patient did not respond to chemotherapy and died. The lymphoid blasts in the peripheral blood were CD5-, CD19+, and CD23+ and harbored t(11;14) (q13;q32) and t(11;21)(p11;q21) translocations. To account for the possibility of two independent lymphoid malignancies, molecular genetic analyses were performed on samples from the spleen, bone marrow and a lymph node with the large-cell lymphoma, which showed identical clones in these tissues. This unusual case supports the idea that in leukemic non-Hodgkin's lymphoma, in addition to morphology, an accurate diagnostic workup requires immunophenotypic, cytogenetic, and molecular studies.

Interferon-alpha acutely impairs sleep in healthy humans.

We investigated the effects of two low doses of interferon-alpha (IFN-alpha) on nocturnal sleep in 18 healthy men by means of polysomnographic sleep recordings. At 1900h, human recombinant IFN-alpha (1000 or 10000 U/kg body weight) or placebo was administered subcutaneously. Between 2300h and 0700h subjects were allowed to sleep. In general effects were stronger at the dose of 10000 than 1000 U/kg body weight of IFN-alpha. Although, after IFN-alpha subjects experienced increased fatigue, the cytokine impaired the quality of nocturnal sleep. The higher dose of IFN-alpha suppressed slow wave sleep (17.8 +/- 2.0% vs 25.2 +/- 2.6% following placebo, P<0.003) but increased time spent in shallow sleep (P<0.05) during the first half of sleep time. Rapid eye movement (REM) sleep latency was postponed (P<0.02) and time spent in REM sleep was significantly decreased after IFN-alpha (P<0.04). The impairing influence of IFN-alpha on sleep in humans is in contrast with findings of sleep promoting effects of this cytokine in animals. Our data suggest that endogenous IFN-alpha may be a factor responsible for alterations of sleep, e.g. in the course of viral infections.

[Primary cerebral highly-malignant B-cell lymphoma of the Burkitt type]. / Primäres zerebrales hochmalignes B-Zell-Lymphom vom Burkitt-Typ.

HISTORY AND CLINICAL FINDINGS: A 40-year-old man was admitted with acute onset of positional vertigo, nausea and vomiting. Neurological examination revealed a fatigable nystagmus to the upward ear in positional testing, to the right more than to the left, as well as latent paresis and rigidity of the left arm. INVESTIGATIONS: Magnetic resonance imaging of the brain revealed two space-occupying lesions in the cerebellum and pons. Open biopsy showed a highly malignant B-cell lymphoma of Burkitt type. There was no evidence of acquired or congenital immunodeficiency. As there were no significant abnormalities outside of the CNS, a primary lymphoma in this location was diagnosed. TREATMENT AND COURSE: Chemotherapy with a combination of drugs including methotrexate achieved only partial remission. Subsequent radiotherapy brought about full remission, which has now lasted for over a year. CONCLUSIONS: Treatment of first choice of a primary cerebral lymphoma in an immunocompetent patient is chemotherapy with cerebrospinal fluid-permeable cytostatics. Partial remission should be followed by radiotherapy.

Subacute encephalopathy after combination chemotherapy including moderate-dose methotrexate in a patient with gastric cancer.

An episode of subacute encephalopathy after the infusion of a moderate dose of methotrexate (1500 mg/m2) (MTX) is reported in a young adult with metastastic gastric cancer. Weakness of the right arm, focal seizures, lethargy and confusion appeared on day 10. High signal intensity in periventricular white matter was observed on T2-weighted magnetic resonance imaging. Symptoms resolved spontaneously and completely after 48 h. We believe that this represents an unusual case of moderate-dose MTX-induced neurotoxicity in a patient with gastric cancer, which has not previously been reported.