Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicin for acute myeloid leukemia in elderly patients.

Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA). Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone. Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33-45] versus 55% (95% CI: 49-61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513). Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.

Multimodality treatment including early high-dose chemotherapy with peripheral blood stem cell transplantation in limited-disease small cell lung cancer.

Combined-modality treatment for limited-disease small cell lung cancer using conventional chemotherapy and chest irradiation achieves high response rates, but most patients relapse over a period of 12 to 16 months. To improve current results, we performed a phase II trial including high-dose chemotherapy and peripheral blood progenitor cell transplantation (PBPCT) as part of an early intensification strategy after two cycles of induction therapy. Moreover, to reduce the risk of local recurrence, the protocol included surgical resection in stages I to IIIA patients as well as chest irradiation. Between January 1991 and July 1994, 16 consecutive patients (median age, 50 years; age range, 30 to 59 years) were treated in this single-center trial. The patients received two cycles of conventional chemotherapy consisting of etoposide 500 mg/m2, ifosfamide 4 g/m2, cisplatin 50 mg/m2, and epirubicin 50 mg/m2 plus granulocyte colony-stimulating factor 5 microg/kg at a 3-week interval, followed by PBPC collection and subsequent high-dose etoposide 1,500 mg/m2, ifosfamide 12 g/m2, carboplatin 750 mg/m2, and epirubicin 150 mg/m2 with PBPCT. The duration of the entire chemotherapy program was 9 weeks. Six of 10 patients in stages I to IIIA and one of six patients in stage IIIB received neoadjuvant or adjuvant surgery before high-dose chemotherapy, followed by thoracic (50 Gy) and prophylactic (30 Gy) cranial irradiation. Hematopoietic reconstitution after high-dose chemotherapy occurred within 11 days (range, 9 to 17 days) for both neutrophils (>0.5 x 10(9)/L) and platelets (>20 x 10(9)/L). Oral mucositis (World Health Organization grade 2 to 4) was the predominant nonhematologic toxicity, which was observed in 12 of 16 patients. One patient developed neutropenic septicemia with fatal multiorgan failure. At a median follow-up of 44 months (range, 32 to 77 months) after PBPCT, nine patients are alive and well, resulting in a disease-free and overall survival rate of 56.3% +/- 12.4%. The median overall survival has not yet been achieved. None of the patients who had surgery relapsed or died after therapy. All relapses occurred within the first 12 months after PBPCT. Patients in stages I to IIIA (10 patients) had a 70% +/- 14% overall survival rate at 4 years, while patients in stage IIIB (six patients) had a 33% +/- 19% survival rate at 4 years, with a median survival of 17 months posttransplant. These data demonstrate that a multimodality treatment including early high-dose chemotherapy with PBPCT may lead to a prolonged disease-free survival in the majority of patients. A randomized phase III study has now been initiated to prospectively investigate the role of high-dose chemotherapy, surgery, and chest irradiation in the multidisciplinary approach to limited-disease small cell lung cancer.

Secondary chronic myelogenous leukemia after chemotherapy followed by adjuvant radiotherapy for small cell lung cancer.

A 40-year old patient with small cell lung cancer (SCLC) was treated with combined modalities including high-dose chemotherapy with subsequent autologous peripheral blood progenitor cell transplantation plus adjuvant radiotherapy. He achieved complete remission with regards to the primary disease. After an interval of 28 months, he was diagnosed with chronic myelogenous leukemia (CML). Analysis of graft samples at time of primary treatment for SCLC using polymerase chain reaction (PCR) did not show the bcr-abl transcript characteristic for CML. This case supports the observation that CML can develop as a treatment-related malignancy and gives insight in the length of the preclinical phase of the disease.

An aerobic exercise program for patients with haematological malignancies after bone marrow transplantation.

We describe the effects of an aerobic exercise program designed to improve the physical performance of patients undergoing bone marrow transplantation. Twenty patients entered the rehabilitation program, consisting of walking on a treadmill, and carried it out for 6 weeks. Patients started the training program 30 +/- 6 days (range 18-42) post-BMT. By the end of the program we observed a significant improvement in maximal physical performance and maximum walking distance, and a significant lowering of the heart rate with equivalent workloads (P for all significances < 0.001). All participants of the program reached a peak performance (calculated in metabolic equivalents, METs) more than sufficient for carrying out all basic activities of daily living. These results contrast with literature reports indicating that spontaneous recovery of physical functioning after BMT can take many months and that about 30% of patients experience long-lasting impairment of physical performance. We conclude that that fatigue and loss of physical performance in patients undergoing BMT can be corrected with adequate rehabilitative measures.

High-dose chemotherapy with autologous peripheral blood stem cell transplantation for metastatic gastric leiomyosarcoma.

We report a case of metastatic gastrointestinal leiomyosarcoma treated with high-dose combination chemotherapy and autologous peripheral blood stem cell transplantation. After incomplete surgical resection, enteral, peritoneal and hepatic involvement remained. Postoperatively, standard-dose chemotherapy with etoposide, ifosfamide, cisplatin and epirubicine, and high-dose chemotherapy with the same agents (carboplatin replacing cisplatin) was given. Treatment was well tolerated and the patient remains in complete remission at 36+ months. We conclude that high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation may be of use as treatment for inoperable residual disease after resection of the primary lesion in gastrointestinal and other soft tissue sarcomas.

Treatment of relapsed non-Hodgkin's lymphoma after BEAM chemotherapy and autologous transplantation by BU/CY chemotherapy and salvage transplantation.

We report a patient with centroblastic non-Hodgkin's MALT lymphoma of the stomach treated initially with surgery and post-operative chemotherapy and radiotherapy. First relapse was treated with high-dose BEAM chemotherapy and autologous peripheral blood stem cell transplantation (PBSCT). Second, systemic relapse was treated with high-dose BU/CY and second PBSCT. Today, the patient is in complete remission at 27+ months. The case indicates a curative potential for high-dose BU/CY chemotherapy as salvage therapy for relapsed high-grade lymphoma after BEAM and autologous PBSCT. This may have implications for the prevention as well as for the management of lymphoma relapse after high-dose chemotherapy (HDC) and autologous PBSCT.

Mobilization of peripheral blood progenitor cells for allogeneic transplantation: efficacy and toxicity of a high-dose rhG-CSF regimen.

Mobilization of PBPC was investigated in 19 healthy matched sibling donors using two different rhG-CSF regimens. Five donors (median age 39 years, range 17 to 57 years) received 10 micrograms rhG-CSF/kg bw once daily subcutaneously (s.c.), while 14 donors (median age 34 years, range 19 to 56 years) were treated with 10-12 micrograms rhG-CSF/kg bw twice daily s.c.. Leukapheresis was started on day 4 of rhG-CSF administration. Cytokine priming as well as collection of PBPCs were well tolerated. Application of twice daily rhG-CSF resulted in a higher yield of CD34+ cells in leukapheresis products than injection of once daily rhG-CSF. This high-dose twice daily rhG-CSF regimen is well tolerated and results in reliably high numbers of progenitor cells in the leukapheresis product in healthy donors, therefore collection as well as subsequent selection has been facilitated.

Acute myelomonocytic leukemia secondary to synchronous carcinomas of the breast and lung, and to metachronous renal cell carcinoma.

We describe a patient in whom synchronous breast cancer and small-cell lung cancer, and metachronous renal cell carcinoma were diagnosed within an 11 months period. All three tumors were treated surgically, followed by administration of tamoxifen, adjuvant chemotherapy with etoposide (2.8 g/m2 total) and vindesine, and administration of interferon alpha and flutamide. The patient developed acute myelomonocytic leukemia 26 months after discontinuation of etoposide-containing chemotherapy. This pattern of multiple neoplasms fits the wider disease spectrum associated with germline mutations of the p53 gene; however, analysis of p53 exons 5-8 did not disclose any sequence abnormalities in this patient. In conclusion, clustering of four (synchronous and metachronous) malignancies may on rare occasions occur in an individual patient and in the absence of a family history of cancer; the sequence during which treatment of primary malignancies may result in treatment-related acute myelocytic leukemia is discussed.

Cytogenetic and molecular characterization of simultaneous chronic and acute myelocytic leukemia.

We describe a patient initially diagnosed with a chronic myeloproliferative disorder in the accelerated phase. Cytogenetic analysis showed the presence of two independent clones. One clone contained a typical Philadelphia (Ph) chromosome due to t(9;22)(q34;q11), as the sole abnormality which was proven molecularly to result in the b2a2-BCR/ABL fusion. The other clone displayed a complex karyotype with several structural and numerical aberrations including trisomy 11 and 22 but lacking a t(9;22) or any other structural abnormalities involving chromosomes 9 and 22. Fluorescence in situ hybridization demonstrated that the t(9;22) was present only in cells with two copies of chromosomes 11 and 22. In contrast, cells with trisomies 11 and 22 lacked evidence for a BCR/ABL fusion. Based on the genetic findings, simultaneous chronic and acute myelocytic leukemias were diagnosed rather than a blastic phase of a chronic myelocytic leukemia.

The clinical role of growth factors in the treatment of breast cancer.

Growth factors have had an increasingly strong impact in breast cancer management in recent years. The main role of growth factors, particularly hematopoietic growth factors, in this setting has been to promote better tolerance of standard-doses, and for the implementation of high-dose chemotherapy in innovative protocols. After a brief overview of growth factor biology, the current clinical guidelines for their use in cancer management is reviewed. Finally, the role growth factors in palliative and curative chemotherapy of breast cancer and methods to reduce tumor cell contamination of peripheral stem cell harvests will be discussed.

[New medical care models in the USA and their effect on the therapeutic freedom of the American physician]. / Die neuen medizinischen Versorgungsmodelle in den USA und ihre Auswirkungen auf die Therapiefreiheit des amerikanischen Arztes.

Managed care and quality control have markedly changed American medicine. After describing some of the more important features of the recent activities in the American health care reform, this article describes the methods used by managed care corporations in improving pharmaceutical treatment quality and pharmaceutical treatment costs. The advantages of newer methods to improve pharmacotherapy (eg. pharmaceutical benefits management) are then balanced against their potential dangers (eg. loss of physician autonomy or manipulation of drug prescription and consumption by health care corporations).

Supportive care in hematologic malignancies: hematopoietic growth factors, infections, transfusion therapy.

A number of recent developments in the supportive care of hematological malignancies have been selected for critical discussion. The first section focuses on the role of evidence-based guidelines in influencing the use of hematopoietic growth factors in medical practice. The next section updates the current clinical status of amifostine (Ethyol, Alza Corp., Palo Alto CA, USA, and US Bioscience, West Conshohocken, PA, USA) the first broad-spectrum cytoprotective agent available. The management of invasive fungal infections and the use of liposomal antifungal agents are reviewed next. Finally, the current status of transfusion support is presented.

Supportive care in hematologic malignancies, including hematopoietic growth factors, transfusions, and infectious complications.

This review focuses on some of the recent developments in the field of supportive care in hematologic malignancies. The increasingly important role of hematopoietic growth factors in modern treatment modalities for hematologic disorders is clear. Newer developments in transfusional therapy and in the management of infectious complications are also discussed.

Supportive care in hematological malignancies: hematopoietic growth factors, infections, transfusion therapy.

This article focuses on a selected number of topics among recent developments in the supportive care of hematological malignancies. The first section focuses on the role of hematopoietic growth factors, such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin, interleukin-11, and keratinocyte growth factor. The following sections discuss the management of fungal and viral infections as well as changes in the current policies of platelet transfusion. The focus of this review is on the clinical utility and economic feasibility of the published findings.

Supportive care in hematologic malignancies.

Supportive care in hematologic malignancies includes a wide range of topics. We have selected the following issues for a review of recently published developments: new insights into the benefits and risks of established hematopoietic growth factors (HGF), such as granulocyte- or granulocyte-macrophage colony-stimulating factor (G-CSF, GM-CSF); the emerging role of newly introduced HGFs such as keratinocyte-growth factor (KGF) and thrombopoietin; the prophylactic and therapeutic use of amifostine, a cytoprotective agent; the role of hematopoietic growth factors and the demethylating agent decitabine in myelodysplastic syndromes (MDS); infectious complications of anticancer therapy; and, recent improvements in and complications of transfusional therapy, including the renewed interest in granulocyte transfusions.

Treatment-related chronic myelogenous leukemia.

Treatment-related (Tr) AML and MDS after chemotherapy, radiotherapy, or the combination of both have been well characterized. However, tr-CML seems to differ from these better-known entities in frequency, clinical course, and prognosis. Tr-CML cannot be distinguished from de novo CML cytogenetically, and, in contrast to tr-AML and tr-MDS, typical chromosomal aberrations related to tr-CML have not been described. Treatment-related CML is a late effect of cytotoxic or immunosuppressive therapy which might be increasingly recognized due to a higher number of patients treated with intensive therapy regimens. We review here the available data on incidence of tr-CML as well as the affected individual's characteristics with regard to different treatment options in malignant and nonmalignant diseases.

Elevation of CA 19-9 in giant hydronephrosis induced by a renal calculus.

CA 19-9 is a tumor marker of pancreatic and gastrointestinal cancer. Elevation in nonmalignant disease is rare. The case of a patient with a partial staghorn calculus, giant hydronephrosis, and elevated CA 19-9 serum levels is presented. Open transperitoneal right-sided nephrectomy was performed. In immunohistochemical analysis, CA 19-9 was expressed in the renal tubular epithelium and the renal pelvis. During postoperative follow-up, the CA 19-9 levels returned to normal. Hydronephrosis might cause false-positive results when CA 19-9 measurement is used to screen for malignant disease. Posttreatment CA 19-9 levels of patients with hydronephrosis have to be monitored closely to safely exclude malignant disease.

Sepsis with bullous necrotizing skin lesions due to vibrio vulnificus acquired through recreational activities in the Baltic Sea.

This report describes the case of a 59-year-old woman with a history of non-Hodgkin's lymphoma who developed bacteremia with Vibrio vulnificus. The patient had been swimming in the unusually warm Baltic Sea in the summer of 2002. She presented with symptoms of septicemia and severe bullous necrotizing skin lesions of the extremities. Blood culture revealed Vibrio vulnificus as the pathogenic organism. Under treatment with cefotaxime and gentamicin, she recovered slowly without further complications. Vibrio vulnificus is a marine bacterium that is present in aquatic ecosystems worldwide, especially when water temperatures exceed 20 degrees C. Infections with Vibrio vulnificus are uncommon in Europe, and most cases are reported from subtropical or tropical regions.

Long-term follow-up after high-dose chemotherapy and autologous stem-cell transplantation for high-grade B-cell lymphoma suggests an improved outcome for high-risk patients with respect to the age-adjusted International Prognostic Index.

BACKGROUND: To evaluate the long-term benefit from high-dose chemotherapy (HDCT) with autologous stem-cell transplantation (ASCT), as part of the initial treatment for patients with chemosensitive, high-grade B non-Hodgkin's lymphoma (hg B-NHL), stratified according to the age-adjusted International Prognostic Index (aaIPI). PATIENTS AND METHODS: Eligible patients were 33 consecutive hg B-NHL patients responding to first-line chemotherapy and fulfilling at least one of the following criteria: stage III or IV, bulky disease, elevated lactate dehydrogenase or failure to achieve complete remission (CR). Twenty-two of 33 patients (67%) had two or three risk factors with respect to the aaIPI. All patients received HDCT with ASCT after a minimum of 6 weeks of VACOP-B standard therapy and VIP-E for mobilization. RESULTS: After ASCT, 31 patients (94%) achieved CR. No treatment-related death occurred. The cumulative incidence of relapse at a medium follow-up of 10 years is 16% for 31 of 33 patients achieving CR. Twenty-five of 33 patients are in sustained CR with a disease-free survival of 76% [95% confidence interval (CI) 67% to 86%]. The overall survival at a median follow-up of 122 months (range 86-148) is 79% (95% CI 68% to 89%). CONCLUSIONS: The results suggest that up-front HDCT with ASCT may improve long-term outcome in high-risk patients with chemotherapy-sensitive hg B-NHL when compared to historic populations treated solely with dose-intense chemotherapy. We observed that long-term survival of high-risk (two to three risk factors) patients is comparable to low-risk (zero to one risk factor) patients after HDCT and ASCT with a low incidence of late relapse.