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.

Percutanous and intraoperative ultrasound-guided radiofrequency ablation of hepatic tumours.

PURPOSE: Ultrasonography (US)-guided Radiofrequency ablation (RFA) is increasingly used to treat liver tumours. The aim of this study was to evaluate the impact of multidisciplinary patient selection on clinical results. MATERIALS AND METHODS: From January 2002 to December 2004, 69 consecutive patients with malignant hepatic tumours were presented to our clinic for RFA-treatment. After a multidisciplinary tumour board decision, 33 patients (47.8%) with 70 liver tumours underwent RFA using a 14-gauge needle electrode via a percutaneous (26) or surgical (7) approach, either alone or combined with resection (3) or chemoembolisation (3). 36 patients (52.2%) were excluded from RFA treatment, mainly because of extensive disease or failure of prior chemotherapy. With a median of 20 months (range 6 - 42 months), all 69 patients were followed clinically to assess survival, and the 33 patients who received additional treatment were examined by contrast-enhanced CT to assess local success. RESULTS: Complete necrosis was obtained in 64/70 of ablated tumours (91.4%).The corresponding mean sizes (ranges) of lesion vs. necrosis achieved were 2.3 cm (0.9 - 5.0) vs. 3.7 cm (2.1 - 5.7). Two complications (6.6%) occurred, including one liver abscess and one postablational syndrome. At the time of the tumour board decision, the RFA (33) and non-RFA (36) group differed in mean sizes of tumours (2.3 vs. 3.5 cm), average tumours per patient (2.1 vs. 3.8), and failure of prior chemotherapy (2/33 vs. 22/36). From 36 patients judged to be ineligible for RFA, 24 (66.6%) underwent RFA at another institution. When comparing survival of patients who underwent RFA at our institution (33) vs. those who underwent RFA outside (24) vs. those who underwent no RFA (12), 1/33 (3%) vs. 9/24 (37.5%) vs. 8/12 (66.6%) died within 6 month and 27/33 (81.2%) vs. 5/24 (29.2%) vs. 2/12 (16.7%) were alive after 20 months median follow up. CONCLUSION: US-guided RFA offers a safe local treatment option to destroy small liver tumours (< 3 cm). Carefully and multidisciplinary selected patients may derive benefit, but uncritical application leads to unsatisfying clinical results.

[Mucocele of the appendix. Incidental sonographic discovery and laparoscopic resection]. / Mukozele der Appendix. Sonographischer Zufallsbefund und laparoskopische Resektion.

HISTORY AND ADMISSION FINDINGS: A 76-year-old currently asymptomatic man was admitted for routine sonography of the abdomen. 15 years he had had intermittently symptomatic cholecystolithiasis. 25 years before a colon contrast showed a normal coecum but no filling of the appendix. SUBSEQUENT INVESTIGATION: Sonographic examination showed the known cholecystolithisasis but additionally revealed as an incidental finding a tubular-cystic structure with a thin, echogenic wall and a hypoechogenic lumen. The lesion was located in the right upper quadrant, not compressible and arising from the coecum. Computed tomography confirmed a mucocele of the appendix without ascites and no inflammatory changes, peritoneal thickening or nodules. TREATMENT AND COURSE: Laparoscopic resection of the unruptured appendiceal mucocele together with cholestectomy was performed. On gross examination, the resected mucocele proved to be macroscopally an intact mass with a thin wall and full of white gelatinous material measuring 3 cm in diameter and 8 cm long. The histologic diagnosis was mucinous cystadenoma. The patient was discharged on the second postoperative day and recovered uneventfully. Because of the clear association of appendiceal cystadenoma with colorectal tumor a colonoscopy was performed which showed a normal colon. CONCLUSION: The differential diagnosis of a cystic mass in the right lower quadrant without previous appendectomy should include an appendiceal mucocele. If preoperatively there are no signs of malignancy, laparoscopic resection can be performed. In patients with histologic diagnosis of appendiceal cystadenoma: the colon should be examined to exclude synchronous colon tumors.

Ultrasound-guided radiofrequency ablation: a new treatment option after failure to stop severe acute upper gastrointestinal tumor bleeding using endoscopic techniques.

Endoscopy is well established as the primary approach in cases of severe acute upper gastrointestinal bleeding. Although endoscopic techniques can achieve hemostasis in up to 95% of instances, not all sources of bleeding seen at endoscopy can be managed endoscopically. Massive and diffuse bleeding from locally advanced gastric adenocarcinoma is not usually self-limit-ing and is often refractory to endoscopic treatment. If surgery or endovascular tumor embolization are not possible after failure of endoscopic hemostasis, the situation may become life-threaten-ing. We present a new option for the treatment of patients in this rare but potentially fatal situation, which involves radiofrequency ablation using a needle electrode placed percutaneously un-der ultrasound guidance.

[Progressive paralysis caused by radiation-induced cervical malignant peripheral nerve sheath tumor]. / Progrediente Lähmungen infolge eines strahleninduzierten zervikalen malignen peripheren Nervenscheidentumors.

HISTORY AND DIAGNOSIS: A 59-year old engineer was admitted to the hospital because of pain in his right collar region and the onset of incomplete paresis of the right arm. Magnetic resonance tomography displayed an advanced tumour arising from the right paravertebral soft tissue. Histological examination revealed a malignant peripheral nerve sheath tumor (MPNST). Thirteen years before admission, the patient had a right-sided tumor-tonsillectomy of a squamous cell carcinoma and local radiation of a cystic squamous cell carcinoma in the ipsilateral cervical soft tissue. CLINICAL COURSE AND THERAPY: In the following course, progressive neurological symptoms occurred including beginning paraplegia, right phrenic paralysis and a severe concomitant pain syndrome. Due to the location and advanced tumor state, surgical treatment was not performed and palliative chemotherapy remained ineffective. Three months later the patient died due to rapidly progressive neurological failure. CONCLUSION: MPNST represents a rare entity which has been related to postoperative radiation. Unusual neurological symptoms in anatomical regions of former radiation should therefore include neurogenic secondary malignancies in the differential diagnosis for early surgical intervention.

Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia.

To evaluate the efficacy and toxicity of two different etoposide (VP-16) dosages (30 or 45 mg/kg) in combination with busulfan/cyclophosphamide as conditioning therapy followed by stem cell transplantation in acute myeloid leukemia (AML), 90 patients with AML received either 30 mg/kg (n = 60) or 45 mg/kg (n = 30) etoposide in combination with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). The stem cell source was allogeneic related bone marrow (BM) (n = 53), allogeneic unrelated BM (n = 5), allogeneic unrelated peripheral blood (PBSC) (n = 2), syngeneic BM (n = 2), autologous BM purged (n = 9) or unpurged (n = 9), autologous PBSC (n = 10). Fifty-six patients (62%) were in first CR, 26 (29%) were > first CR, and eight (9%) were transplanted in relapse. Principal toxicities in both groups were mucositis and hepatotoxicity. Forty-five mg/kg etoposide resulted in greater hepatic toxicity (P = 0.03), and a higher incidence of VOD (23 vs 12%, P = 0.04) and acute GVHD grade III/IV (13 vs 5%, NS). The treatment-related mortality was 17% in the 30 mg/kg group and 33% in the 45 mg/kg group, mainly due to infections, intestinal pneumonia and GVHD. Hematological recovery of leukocytes 1/nl was comparable in both groups (17 vs 16 days). After a median follow-up of 16 months 19% in the 30 mg/kg group and 23% in the 45 mg/kg group relapsed. In patients who had undergone allogeneic related bone marrow transplantation in first CR no relapses occurred after a median follow-up of 3 years. For all patients the 3-year estimated disease-free survival was 62% in the 30 mg/kg group and 40% in the 45 mg/kg group (P = 0.03). For patients in first CR who underwent allogeneic related stem cell transplantation the 3 year disease-free survivals were 80% and 66%, respectively (P = 0.4). We conclude that etoposide 30 mg/kg or 45 mg/kg in combination with busulfan/cyclophosphamide is a highly active regimen for bone marrow transplantation of patients with AML with a low relapse rate. However, conditioning with 30 mg/kg rather than 45 mg/kg etoposide resulted in less toxicity and a better overall survival due to a lower transplant-related mortality. Bone Marrow Transplantation (2000) 26, 711-716.

ASHAP--an effective salvage therapy for recurrent and refractory malignant lymphomas.

BACKGROUND: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. PATIENTS AND METHODS: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n = 51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m2 by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1-5), Ara-C (2 g/m2 as a 2-h infusion on day 5), and CDDP (100 mg/m2 by CI over 96 h). RESULTS: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0-70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. CONCLUSIONS: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification.

Intensified conditioning regimen in bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

We investigated an intensified conditioning regimen including fractionated total body irradiation (12 Gy), etoposide (30-45 mg/kg) and cyclophosphamide (120 mg/kg), followed by autologous (n = 5), allo-related (n = 13) or allo-unrelated (n = 6) bone marrow (n = 22) or peripheral stem cell (n = 2) transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. One patient received busulfan (16 mg/kg) instead of TBI. Nineteen patients were transplanted in 1CR, two in 2CR, one in 1PR and two in relapse. Major toxicity was mucositis grade II according to the Bearman scale in all patients. The treatment-related mortality was 25%, mainly due to infection or GVHD after allogeneic transplantation. After a median follow-up of 45 months (range 2-93), nine patients (37.5%) remain alive in CR. Nine patients (37.5%) relapsed and eight (33.3%) of these subsequently died. After autologous transplantation, four of five patients (80%) relapsed and died. Late relapse was seen after allogeneic, as well as autologous transplantation, at 33 and 59 months, respectively. The Kaplan-Meier estimate of leukemia-free survival for all patients is 38% at 3 years (95% CI: 18-58%) and 35% at 5 years (95% CI: 15-55%). For allogeneic transplants in first CR (n = 15) the estimate of disease-free survival was 46% at 3 years (95% CI: 19-73%) and 34% at 5 years (95% CI: 17-51%). Patients aged below 30 years had a better estimated overall survival at 3 years (61% vs 11%, P < 0.001). The bcr-abl fusion transcript (p210 vs p190 vs p210/190) did not affect disease-free or overall survival. In our experience, an intensified conditioning regimen seems to improve the results of bone marrow transplantation in patients with Ph+ acute lymphoblastic leukemia. However, the high relapse rate warrants novel approaches to enhance anti-leukemic efficacy.

High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission.

We explored the combination of busulfan/cyclophosphamide/etoposide as conditioning regimen prior to bone marrow transplantation in 31 patients with acute myeloid leukemia (AML) in first complete remission. The preparative regimen consisted of 16 mg/kg busulfan, 30-60 mg/kg VP-16, and 120 mg/kg cyclophosphamide. With a median follow-up of 30.5 months (range, 5-60 months), 25 patients are alive in continuous complete remission. Estimated disease-free survival at 5 years is 80.5%. Death was due to transplant-related toxicity (graft-versus-host disease and cytomegalovirus infection, graft-versus-host disease and pneumonia, sepsis and mucositis, respectively). None of the patients have relapsed. As demonstrated by the results of this analysis, the conditioning regimen busulfan/cyclophosphamide/etoposide is effective and well tolerated in patients with AML in first complete remission. Main nonhematological toxicities were mucositis and hepatotoxicity. The low mortality and relapse rate appears to justify allogeneic bone marrow transplantation for patients with AML in first complete remission who have an HLA-identical donor. Whether this regimen offers a substantial improvement in disease-free and overall survival over presently used regimens warrants further investigation.

Treatment of metastatic colorectal carcinoma with a combination of fluorouracil and recombinant interferon alfa-2b: preliminary data of a phase II study.

From March 1990 to January 1991 52 previously untreated patients with metastatic colorectal carcinoma were enrolled in a phase II study with the combination of interferon alfa-2b and fluorouracil (5-FU). 5-FU 750 mg/m2 per day was administered as continuous infusion for 5 days, then weekly in a dose of 750 mg/m2 as IV push injection starting on day 15. Interferon alfa-2b (Intron A, ESSEX Pharma) 9 x 10(6) units was given subcutaneously three times per week. Response to therapy was evaluated after 3 and 6 months. So far, data on response rates and toxicity are available in 32 patients: partial remission, 10 patients (31%); stable disease, nine patients (28%); progressive disease, 12 patients (37%); toxic deaths, two patients (6%). Projected median survival has not been reached after 11 months. In about one third of the patients severe side effects occurred with leukopenia grade 3 and 4, diarrhea, mucositis and septic complications being the clinically most important. We think that this combination is an effective but toxic regimen in advanced colorectal carcinoma. Further studies must reevaluate both the schedule and the doses of the drugs administered.

Phase II trial of 5-fluorouracil and recombinant interferon alfa-2B in metastatic colorectal carcinoma.

Between February 1990 and April 1991, 59 previously untreated patients with progressive and/or symptomatic metastatic colorectal carcinoma were enrolled in a phase II study of 5-fluorouracil (5-FU) and interferon alfa-2b (IFN-alpha). 5-FU 750 mg/m2/day was administered as continuous infusion for 5 days, then weekly in a dose of 750 mg/m2 as intravenous push injection starting on day 15. IFN-alpha 9 MU was given subcutaneously three times a week. Treatment was given for a maximum of 6 months. 55 patients are evaluable for response and 51 for toxicity. 17 patients (31%) achieved a partial remission, 15 (27%) had stable disease and 21 patients (38%) had progressive disease. Median duration of remission was 5 months and median survival for all patients 10 months. Toxicity was important with two treatment-related deaths and severe leukopenia, fever, diarrhoea and mucositis in about one third of the patients. In our opinion, this regimen is effective but rather toxic in metastatic colorectal carcinoma.

[The manifestations of extrapulmonary tuberculosis]. / Erscheinungsformen der extrapulmonalen Tuberkulose.

Seven weeks after a generalized cerebral seizure a 27-year-old woman from Ghana developed nausea, vomiting and weight loss, gradually increasing over two weeks. Cranial computed tomography revealed several hyperdense formations with extensive associated oedema and a midline shift. Among extensive biochemical tests only a raised erythrocyte sedimentation rate of 24/50 mm and leukopenia of 2,600/microliters (with normal differential count) were notable. Diagnostic laparotomy was performed because of sonographic and computed tomographic evidence of enlarged abdominal lymph nodes. Histological examination of representative lymph nodes and of tiny nodules deposited on the peritoneum revealed caseous granulomatous inflammation. Mycobacterium tuberculosis was cultured from these specimens. Antituberculosis treatment was started with 0.3 g/d isoniazid, 0.6 g/d rifampicin, 2 g/d pyrazinamide and 1 g/d streptomycin, plus dexamethasone, 4 mg four times daily. After eight weeks treatment an intracerebral focus, removed to exclude neoplasm, proved histologically to be a tuberculoma. Only after four months was it possible to reduce the glucocorticoid dosage to prednisone, 20 mg/d. The antituberculosis treatment was continued for 18 months, with only isoniazid and rifampicin taken during the last 14 months. Final clinical and biochemical examinations were unremarkable. Computed tomography demonstrated regression of the abdominal lymph nodes and the cerebral foci. The patient was without any symptoms.

[Myocardial infarcts within the scope of 5-fluorouracil therapy]. / Myokardinfarkte im Rahmen einer 5-Fluorouracil-Therapie.

A young man without heart disease with a metastatic carcinoma of the pancreas received a 5-Fluorouracil therapy (25 mg per kilogram body weight/24 h by continuous infusion over a period of 5 days). Approximately 56 h after beginning of the first cycle of therapy (after 36 h of the second cycle) he complained of severe chest pain, which did not respond to nitrates, improved after application of opioids, and subsided definitely after termination of the 5-FU infusion. During the periods of pain, the ECG and the creatine kinase were normal. At a later time, finally, a scar in the posterior wall of the myocardium was detectable in the ECG. When repeating the 5-FU infusion, similar problems arose with less intensity. The patient died as a consequence of the progress of the tumor disease. At autopsy, two myocardial infarctions were detectable. There was no demonstrable stenosis of the coronary arteries. Spasms of the coronary arteries are discussed as a cause of this side effect of 5-FU-therapy.

IgE myelomatosis. Presentation of a new case and summary of literature.

This paper describes a case of IgE (kappa) myeloma in a 39 year old female patient who has been observed for a period of eight years to the present. The findings and the course of disease in this patient were compared with 18 other case reports published since the discovery of IgE in 1966. In contrast to myelomas of other immunoglobulin classes, patients with IgE myelomas are somewhat younger and anaemia and hyperproteinaemia are more pronounced. A plasma cell leukaemia is more frequent and the ratio of light chains has shifted in favour of the kappa chains.