Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors.

BACKGROUND: Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. PATIENTS AND METHODS: Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. RESULTS: Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. CONCLUSION: Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986.

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952.

PURPOSE: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. PATIENTS AND METHODS: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. RESULTS: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. CONCLUSION: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.

Sequential immunochemotherapy and edrecolomab in the adjuvant therapy of breast cancer: reduction of 17-1A-positive disseminated tumour cells.

BACKGROUND: The aim of our study was to evaluate the efficacy of the monoclonal antibody edrecolomab after chemo- and radiotherapy in the elimination of disseminated tumour cells in bone marrow in the adjuvant therapy of breast cancer. PATIENTS AND METHODS: The bone marrow of 25 patients with breast cancer was tested for the presence of disseminated tumour cells using the pancytoceratine antibody and the alkaline phosphatase-anti-alkaline-phosphatase (APAAP) technique. To characterize tumour cells simultaneously, immunofluorescent double labelling of pancytoceratine and epithelial cell adhesion molecule (antibody 17-1A) was performed on tumour cells after magneto bead enrichment. Patients positive for the 17-1A antigen in bone marrow after chemotherapy were treated with edrecolomab (500 mg Panorex) initially, then 100 mg/month over 4 months) and investigated for the presence of micrometastases 6 weeks after the last treatment. RESULTS: Of the 17 patients showing bone marrow micrometastases (BM-MM), 14 tested 17-1A positive before adjuvant chemotherapy. After chemotherapy, nine patients remained positive for the 17-1A antigen and were treated with edrecolomab. The final investigation after immunotherapy showed a complete elimination of the 17-1A-positive BM-MM in seven patients and a significant reduction of these cells in two patients. CONCLUSIONS: Sequential treatment of breast cancer with edrecolomab after adjuvant chemotherapy can reduce disseminated tumour cells in the bone marrow and eliminate 17-1A-positive micrometastases.

Transformation of Hodgkin's disease to high-grade B-cell lymphoma: remission after Rituximab monotherapy.

PURPOSE: We demonstrate the usefulness of immunotherapy with the CD20 antibody Rituximab in a case of transformation of Hodgkin's disease (HD) to high-grade non-Hodgkin's lymphoma (NHL). CASE REPORT: A 45-year-old women suffering from lymphocyte predominant HD of paragranuloma type (stage IVb) since 1995 showed mediastinal relapse despite of 6 cycles of chemotherapy following the COPP/ABVD-protocol in 1998. Again complete remission could be achieved after escalated BEA-COPP II therapy in May 1998. Six months later chest radiograph and CT depicted pulmonary nodules. The non-typical resection of the lung revealed pulmonary involvement of a high-grade T-cell rich large B-cell lymphoma with 100% of the tumoral cells CD20 positive. Since the symptoms occurred shortly after the BEA-COPP-escalated protocol chemotherapy resistance had to be assumed. Because of this problems and supported by the refusal of a high-dose chemotherapy with stem-cell transplantation by the patient we decided to perform a mono-immunotherapy with the monoclonal CD20 antibody Rituximab. Today, 14 months later, the patient is still in complete remission including the absence of B symptoms. CONCLUSIONS: Immunotherapy against CD20 positive cells in cases of sequential HD and NHL seems to be an effective therapy in chemotherapy resistant cases because of the suspected clonally relation of both diseases.

[Use of alternative medicine in oncology patients]. / Anwendung alternativmedizinischer Methoden durch onkologische Patienten.

BACKGROUND AND OBJECTIVE: Up to 60% of all oncological patients use methods of alternative medicine in the course of their illness. In earlier blinded studies demographic characteristics and the patients' motives of using alternative medicine had been recorded, but a correlation with individual illnesses had not been possible. PATIENTS AND METHODS: 142 patients of a oncological outpatient clinic gave their experience with alternative medicine in interviews and non-blinded questionnaires, 103 of them (72.5%; 46 men and 57 women; median age 58 years, range 18-91 years) returning questionnaires that could be evaluated. RESULTS: 46 patients stated that they had used alternative medicine. There was no difference between users and non-users regarding sex; age, profession, education, family status or religion. 58% of all patients with advanced disease used alternative medicine, compared with only 31% with partial remission or stable disease and 41% in complete remission (P = 0.042). Vitamins and mistletoe preparations were the most commonly used substances (50 and 45%, respectively). The predominant purpose was to stimulate the immune system (77%) and strengthen general physical capacity (64.5%). As main stimulus for using alternative medicine the patients came from their family doctor (56%), followed by family and friends (41%). Alternative medicine was used largely as complementary and not an alternative to conventional medicine. Health insurance met all or some of the costs of alternative treatment in 59% of patients. CONCLUSION: A large number of patients treated with conventional oncological regimens also use alternative medicine, most of them because of a polypragmatic attitude to tumor treatment. Family doctors and health insurance companies are playing a more important role than had hitherto been assumed in spreading the use of treatment options without providing scientifically based evidence of their efficacy.

Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study.

BACKGROUND: Anemia is a common side effect of anticancer chemotherapy. Blood transfusion, previously the only available treatment for chemotherapy-induced anemia, may result in some clinical or subclinical adverse effects in the recipients. Recombinant human erythropoietin (rhEPO) provides a new treatment modality for chemotherapy-induced anemia. PATIENTS AND METHODS: To evaluate the effect of rhEPO on the need for blood transfusions and on hemoglobin (Hb) concentrations, 227 patients with solid tumors and chemotherapy-induced anemia were enrolled in a randomized, controlled, clinical trial. Of 189 patients evaluable for efficacy, 101 received 5000 IU rhEPO daily s.c., while 88 patients received no treatment during the 12-week controlled phase of the study. RESULTS: The results demonstrate a statistically significant reduction in the need for blood transfusions (28% vs. 42%, P = 0.028) and in the mean volume of packed red blood cells transfused (152 ml vs. 190 ml, P = 0.044) in patients treated with rhEPO compared to untreated controls. This effect was even more pronounced in patients receiving platinum-based chemotherapy (26% vs. 45%, P = 0.038). During the controlled treatment phase, the median Hb values increased in the rhEPO patients while remaining unchanged in the control group. The response was seen in all tumor types. CONCLUSIONS: RhEPO administration at a dose of 5000 IU daily s.c. increases hemoglobin levels and reduces transfusion requirements in chemotherapy-induced anemia, especially during platinum-based chemotherapy.

Serum levels of soluble intercellular adhesion molecule-1 (ICAM-1, CD54) in patients with non-small-cell lung cancer: correlation with histological expression of ICAM-1 and tumour stage.

The expression of the intercellular adhesion molecule-1 (ICAM-1, CD54) seems to have an influence on the metastatic behaviour of tumour cells via immunological mechanisms. Recently, a soluble form of ICAM-1 was identified in physiological fluids. We analysed the serum levels of sICAM-1 in patients with non-small-cell lung cancer (NSCLC) and healthy individuals using a sandwich ELISA technique. Sera from 51 patients with NSCLC were tested for sICAM-1 (46 male, five female; age 38-81 years, median 64 years), 29 of whom presented with localized and 26 with metastatic disease. The control group consisted of 40 healthy individuals (20 smokers, 20 non-smokers). Immunohistochemical analysis of ICAM-1 in tumour cells was performed in 20 cases. Patients with NSCLC had significantly higher serum levels of sICAM-1 compared with healthy non-smokers (P = 0.00001) and smokers (P= 0.0328). Metastatic disease was associated with higher sICAM-1 than localized tumours (P = 0.0013). Only 11 out of 23 patients with localized NSCLC had sICAM-1 levels >300 ng ml(-1), compared with 25 out of 28 patients with metastatic disease. Histological expression of ICAM-1 was positively correlated with serum slCAM-1 (P = 0.0399). No difference was observed between histological tumour types with regard to sICAM-1 or NSCLC expression of ICAM-1. In sequential analysis (13 patients), rising sICAM-1 levels predicted a short-term fatal outcome (P = 0.0054) but, overall, sICAM-1 levels did not correlate with prognosis. In the control group, smokers showed significantly higher levels than non-smokers (P = 0.0016). In contrast to patients with NSCLC, sICAM-1 in the control group was correlated to the leucocyte count (r = 0.580, P = 0.003). In conclusion, serum levels of sICAM-1 seem to be associated with tumour burden and histological expression of ICAM-1 in patients with NSCLC. However, the (patho-) physiological role of ICAM-1 in NSCLC remains to be determined.

Fear of risks of cure in the treatment of a giant germ cell tumour. A case report.

A delay of treatment of a giant germ cell tumour because of fear of therapy and lacking knowledge of prognosis is presented. Based on this case, the possible pitfalls and limitations of self-detection programmes are discussed and recommendations for the improvement of general knowledge of testicular tumours are given.

[Bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the anus and vulva in congenital intestinal lymphangiectasis]. / Bowenoide Papulose, Morbus Bowen und Plattenepithelkarzinom von Anus und Vulva bei kongenitaler intestinaler Lymphangiektasie.

A 32-year-old woman with congenital intestinal lymphangiectasia (CIL) and warts (condylomata acuminata) was found to have bowenoid papulosis, Bowen's disease and squamous-cell carcinoma, at first in the anus, later also in the vulva. Limited surgical measures and laser vaporization with systemic and topical administration of interferon controlled the tumour development for some time. But after 7 years the squamous-cell carcinoma recurred with infiltration of the outer anogenital region. The patient then had an episode of thrombotic cerebral ischemia, which prevented a planned abdominoperineal resection with radical vulvectomy. Instead she received chemotherapy with bleomycin, mitomycin and cisplatin. But she died 8 weeks later, from tumour cachexia. Occurrence of a squamous-cell carcinoma of the anus and vulva in this young patient suggests a high oncogenic potential of the papilloma virus (HPV) infection. The latent period was probably shortened by a cellular immune deficiency as part of CIL. Treatment of the various carcinomatous manifestations should as long as possible be by local measures and interferon administration.

Cerebrospinal fluid cytology in granulocytic sarcoma with meningeal extension but without bone marrow involvement.

Granulocytic sarcoma (GS) is a localized tumour of immature granulocytes that is usually associated with myelogenous leukaemia. We report an unusual case of mastoid GS with meningeal extension but no bone marrow involvement on presentation. Histological examination of the surgical specimen and the characteristic cerebrospinal fluid (CSF) cytology showing cytoplasmic granulations and Auer bodies led to the diagnosis of GS. Positive cytochemical staining of the immature CSF cells for naphthol-ASD chloroacetate esterase and myeloperoxidase confirmed their myeloid origin. Immunophenotyping did not reveal common acute lymphoblastic leukaemia antigen, cytokeratin, T- or B-cell antigens. The patient underwent surgical resection of the localized tumour, followed by radiation therapy, intrathecal and systemic chemotherapy, as if he had acute myelogenous leukaemia (AML). He did not develop AML in the 21 months after the tumour resection. This case emphasizes the value of CSF cytological examination of tumour cells and the use of an immunocytochemical marker for differentiating GS from malignant lymphoma.

[Clodronate in treatment of tumor osteopathy. Evaluation in tumor patients with bone metastases or hypercalcemia]. / Clodronat in der Behandlung der Tumorosteopathie. Anwendungsbeobachtung bei Tumorpatienten mit Knochenmetastasen oder Hyperkalzämien.

METHOD: In an observational study involving 398 tumor patients with bone metastases or related hypercalcemia, the effect of treatment with clodronate over a period of 12 months was investigated. Bone pain, analgesic requirements, quality of life and laboratory parameters were recorded at monthly intervals. RESULTS: Some 71.4% of all patients indicated an improvement in quality of life. Bone pain, experienced by 91.4% of the patients at the start of treatment, regressed (from 2.0 +/- 1.2 to 1.3 +/- 1.0). After the 12-month treatment period, 36% of the patients did without analgesics completely (prior to treatment the corresponding figure was 24%). The most common side effects attributed to clodronate were gastrointestinal disorders (10%). CONCLUSION: Clodronate would appear to be a useful supportive drug in the management of tumor-related bone disease.

Evaluation and limitations of the lipid-associated sialic acid test for the detection of human cancer.

Previous studies and those of the authors have reported about raised levels of lipid-bound sialic acid (LSA) in sera of patients with various neoplasms. Most authors have used the method of Katopodis and Stock for isolating serum LSA. Because of the discrepancy of the amount of extracted LSA with the content of pure gangliosides in sera reported by other groups the authors analyzed the composition of the extracted LSA by immunochemical approaches. They were able to isolate considerable amounts of glycoproteins containing sialic acid as acid alpha-1-glycoprotein, antitrypsin, haptoglobin, antichymotrypsin, and immunoglobulins from the so-called "LSA" fraction. There is a very strong correlation between the raised LSA levels and the content of acid-alpha-1-glycoprotein in the sera of patients with malignancy. Therefore the term lipid-bound sialic acid applied to this test is misleading, since glycoproteins containing sialic acid are mostly responsible for the high "LSA" levels.

[Bone marrow necrosis in a patient with metastatic breast cancer in chemotherapy with chlorambucil, methotrexate and prednisone]. / Knochenmarksnekrose bei einer Patientin mit metastasierendem Mammakarzinom unter Chemotherapie mit Chlorambucil, Methotrexat und Prednison.

In this case report the clinical course of a female patient with metastatic breast cancer receiving a mild cytostatic regimen with chlorambucil, methotrexate and prednisone is described. She developed an unusual clinico-pathological syndrome with pancytopenia, fever and bone pain resulting from a bone marrow necrosis. The clinical course illustrates the great diagnostic difficulties and the potential benefit from rapid identification of this prognostically very poor event. Leading symptoms such as fever, bone pain, pancytopenia, an increase in the sedimentation rate, in lactate dehydrogenase and alkaline phosphatase in serum are often misinterpretated as tumor progression with bone or hepatic metastases and bone marrow carcinomatosis. An iliac crest aspirate and biopsy detects the diagnosis of a marrow necrosis. These symptoms should be kept in mind in order to avoid a diagnostic pitfall resulting from a misinterpretation of the morphological picture as necrotic metastasis in bone marrow or as an artefact. It is assumed that, in addition to the underlying malignant disease, cytostatic therapy with chlorambucil, methotrexate and prednisone triggers this event.

[Follow-up of combined radiotherapy and chemotherapy of advanced bladder cancer using magnetic resonance tomography. Initial results]. / Verlaufskontrolle bei der kombinierten Strahlen- und Chemotherapie fortgeschrittener Harnblasenkarzinome mittels Kernspintomographie. Erste Ergebnisse.

A combination of cis-platinum and radiotherapy was applied in five patients with advanced bladder carcinomas. The patients were examined by nuclear magnetic resonance imaging prior to and following therapy. Corresponding to cell-kinetic considerations regarding tissues with slow cell turnover, a maximum therapy effect is shown about nine months after the end of local therapy. Smaller control intervals are recommended in case of bladder carcinomas with lymph node metastases. Due to the possibility of multiple slice imaging, the nuclear magnetic resonance technique is particularly suited for the monitoring of bladder carcinomas. Sagittal and coronary slices show a better image of tumoral extension at the roof and floor of the bladder than axial computed tomography. Lymph node metastases are represented relatively late by both methods.