Wolfgang Fiebiger

Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer

BACKGROUND Patients with advanced biliary tract carcinoma face a dismal prognosis as no effective palliative therapy has been defined. The aim of the present phase II investigation was to evaluate the therapeutic efficacy and tolerance of a two-weekly high-dose gemcitabine regimen in this patient population. PATIENTS AND METHODS Thirty-two consecutive patients with locally unresectable or metastatic biliary tract cancer were enrolled in this multicenter phase II trial. Treatment consisted of gemcitabine 2200 mg/m2 given as a 30-min intravenous infusion every two weeks for a duration of six months unless there was prior evidence of progressive disease. RESULTS After a median number of 12 treatment courses, 7 of 32 (22%) patients had a partial response that lasted for a median duration of 6.0 months (range 3.5-10.0). Fourteen additional patients (44%) had stable disease, whereas eleven patients (34%) progressed despite therapy. The median time to progression was 5.6 months (range 1.8-13.0); median survival time was 11.5 months (range 3.0-24.0), and the probability of surviving beyond 12 months was 44%. The tolerance of treatment was remarkable with only two patients each experiencing grade 3 leukocytopenia, granulocytopenia and/or thrombocytopenia, and one patient had grade 3 anaemia. Similarly, nonhaematologic side effects were infrequent, and generally mild to moderate. CONCLUSIONS Two-weekly high-dose gemcitabine seems to represent a potentially effective, safe and well-tolerated regimen for the palliative treatment of patients with advanced biliary tract cancer.

Treatment of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type With Cladribine: A Phase II Study

PURPOSE As chemotherapy has not been extensively studied in patients with lymphoma of the mucosa-associated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease. PATIENTS AND METHODS Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion. Cycles were repeated every 4 weeks for a maximum of six cycles. RESULTS Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients (median number of cycles per patient, four). All 25 assessable patients responded to treatment: 21 patients (84%) achieved complete remission (CR) and four patients achieved partial remission. All patients (100%) with gastric presentation, but only three patients (43%) with extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and required dose reduction and/or premature discontinuation of therapy in only three cases. Two patients died from vascular events, one shortly after the first cycle because of myocardial infarction and the other from stroke 3 months after the second course. Three patients relapsed after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At present, 24 patients are alive at a median follow-up time of 32 months. CONCLUSION Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with MALT-type lymphoma.

Health-related quality of life outcomes after kidney transplantation

With the improvements in short and long term graft and patient survival after renal transplantation over the last two decades Health-Related Quality of Life (HRQL) is becoming an important additional outcome parameter. Global and disease specific instruments are available to evaluate objective and subjective QOL. Among the most popular global tools is the SF-36, examples of disease specific instruments are the Kidney Transplant Questionnaire (KTQ), the Kidney Disease Questionnaire (KDQ) and the Kidney Disease-Quality of Life (KDQOL). It is generally accepted that HRQL improves dramatically after successful renal transplantation compared to patients maintained on dialysis treatment but listed for a transplant. It is less clear however which immunosuppressive regimen confers the best QOL. Only few studies compared the different regimens in terms of QOL outcomes. Although limited in number, these studies seem to favour non-cyclosporine based protocols. The main differences that could be observed between patients on cyclosporine versus tacrolimus or sirolimus therapy concern the domains of appearance and fatigue. This may be explained by two common adverse effects occurring under cyclosporine therapy, gingival hyperplasia and hair growth. Another more frequently occurring side effect under calcineurin inhibitor therapy is tremor, which may favour CNI free protocols. This hypothesis, however, has not been formally evaluated in a randomised trial using HRQL measurements.In summary HRQL is becoming more of an issue after renal transplantation. Whether a specific immunosuppressive protocol is superior to others in terms of HRQL remains to be determined.

Rituximab for treatment of advanced extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue lymphoma.

Background: Extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) is a relatively common type of lymphoma. Owing to its B cell lineage, it appears to be a potential target for treatment with the CD20 antibody rituximab. We present an analysis of our experience with rituximab for treatment of patients with advanced MALT lymphoma. Patients and Methods: A retrospective analysis of patients with histologically verified MALT lymphoma undergoing treatment with rituximab was done. After reassessment of histological samples for the presence of MALT lymphoma, patients were evaluated as regards date of diagnosis, prior therapy for MALT lymphoma, sites of involvement upon treatment with rituximab, clinical response in terms of complete remission (CR), partial response (PR), stable disease (SD) and progressive disease as well as symptomatic response, duration of response and survival. Results: A total of 9 patients with advanced MALT lymphoma undergoing therapy with single-agent rituximab were identified. All patients received treatment at a dose of 375 mg/m2 once weekly ×4. One patient each had relapsed after chemotherapy and radiation, respectively, while none of the other 7 patients had received prior cytotoxic treatment or radiation. Three patients achieved a CR, 2 patients had PR for 6 and 14 months, while the remaining patients had SD between 8 and 18+ months. One patient died of progressive disease in spite of the initiation of chemotherapy and 1 patient succumbed to a cardiovascular event while having been in ongoing PR for 11 months. The other 7 patients are currently alive with disease 10–27 months after initiation of therapy. Follow-up biopsies for histological assessment were available in 5 patients with gastric lymphoma. In 1 patient with SD, however, persistence of CD20-positive cells within lymphoepithelial lesions was noted in spite of almost complete depletion of B lymphocytes from the normal gastric mucosa, suggesting either recirculation of MALT lymphoma cells to these lesions or defining lymphoepithelial lesions as a sanctuary site from rituximab penetration. Conclusion: Rituximab had only moderate activity in terms of inducing objective responses in our unselected and heterogeneous cohort of patients with disseminated MALT lymphoma. Long-term disease stabilization, however, along with a symptomatic benefit was seen in all patients. Our data nevertheless indicate that rituximab might not optimally penetrate into the gastric mucosa in all patients.

Subcutaneous administration of amifostine: a promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy.

Subcutaneous administration of amifostine: A promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Oxaliplatin, a third-generation platinum compound with a 1,2-diaminocyclohexane (DACH) carrier ligand, is a recently developed agent with a broad spectrum of antineoplastic activities [1]. Hallmarks of this novel agent include its lack of cross-resistance with cisplatin and carboplatin, synergistic activity with various other cytotoxic agents such as 5-fluorouracil-leucovorin, and an excellent safety profile with a specific and manageable set of toxicities. When given alone or in combination with other cytotoxic drugs at its recommended dose of 85 mg/m 2 every two weeks or 130 mg/m 2 every three weeks, haematological side effects are commonly seen, but are generally mild. The most frequently encountered nonhaematological adverse events include gastrointestinal symptoms and a peripheral neurosensory toxicity (PNP), characterised by pares-thesia and/or dysesthesia triggered or exacerbated by exposure to cold. This side effect, which is cumulative but reversible in most patients a few months after stopping treatment, does represent the principal dose-limiting toxicity in patients receiving oxaliplatin [1]. Amifostine (WR-2721; ethyol) is a thiophosphate cytoprotec-tant agent with the potential to abrogate many chemotherapy-induced toxicities [2], In preclinical studies, amifostine protected against the cytotoxic side effects of alkylating agents, platinum analogues, and radiation therapy in normal tissues, but preserved antineoplastic activity of these therapeutic modalities in tumour tissue. Most normal tissues were protected, including bone marrow, kidney, lung, and peripheral nerves. Usually amifostine is administered as a short intravenous (i.v.) infusion over 15 minutes. Recent pharmacokinetic studies, however, have shown acceptable plasma levels of its active metabolite (WR-1605) after subcutaneous (s.c.) injection [3], and Koukourakis et al. have subsequently established feasibility, efficacy as well as a superior tolerance of this simplified administration schedule in a randomised phase II trial involving 140 patients with head and neck, thoracic, and pelvic cancers undergoing radical radiotherapy [4]. In the present pilot study, we have investigated the therapeutic potential of an identical s.c. administration schedule of the cytoprotective agent amifostine to counteract oxaliplatin-related PNP. Nine patients with metastatic colorectal cancer receiving chemotherapy with raltitrexed 3 mg/m 2 plus oxali-platin 130 mg/m 2 every three weeks and six patients receiving irinotecan 175 mg/m 2 plus oxaliplatin 85 mg/m 2 both given i.v. on days 1 and 14 every four weeks were enrolled onto this study until today. All patients gave written informed consent according to institutional regulations. Their pretreatment characteristics are summarised in Table …

Impaired response of gastric MALT-lymphoma to Helicobacter pylori eradication in patients with autoimmune disease

BACKGROUND AND AIMS Gastric MALT-lymphoma is thought to be related to chronic antigenic stimulation provided by Helicobacter pylori (HP). As clonal expansion of gastric B cells not related to HP has been demonstrated in patients with autoimmune disease (AD), we have analysed whether AD adversely influences response of MALT-lymphoma following HP-eradication. PATIENTS AND METHODS Retrospective analysis of all patients with early stage gastric MALT-lymphoma treated with HP-eradication was performed. The presence of AD was evaluated by personal questioning for specific symptoms and serologically by analysis of rheumatoid factor, antinuclear antibodies and thyroid autoantibodies. RESULTS A total of 22 patients were identified receiving only antibiotic treatment for initial management, and six presented with an autoimmune condition: three had Sjögrens syndrome, one polymyalgia rheumatica, one autoimmune thyroiditis along with psoriasis, and one patient had only autoimmune thyroiditis. Successful eradication of HP was achieved in all patients, and 15 of 22 patients (68%) achieved complete response of the lymphoma, while none out of the six patients with an autoimmune disorder responded to HP-eradication. CONCLUSION Apart from questioning the role of HP in the development of lymphoma in such patients, these results suggest that patients with autoimmune disease might not be optimal candidates for HP-eradication even in case of early stage lymphoma.

Randomized Multicenter Phase II Trial of Oxaliplatin Plus Irinotecan Versus Raltitrexed as First-Line Treatment in Advanced Colorectal Cancer

PURPOSE Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.

CD5 expression in a lymphoma of the mucosa-associated lymphoid tissue (MALT)-type as a marker for early dissemination and aggressive clinical behaviour.

Mucosa associated lymphoid tissue (MALT) developing in response to chronic infection or autoimmune stimuli has been recognized as a possible site of origin for a distinct type of B-cell lymphoma. While preferentially occurring in the stomach, MALT-type lymphomas can be found in virtually all organs. MALT-type lymphomas normally follow an indolent course, with a tendency to remain localized at their site of origin for a prolonged period of time. His-tologically, MALT-type lymphomas are heterogeneous covering a cytological spectrum ranging from centrocyte-like cells to smaller lymphoid cells or monocytoid B-cells. Usually a small number of transformed blasts are also present. Immunohistochemically, the malignant cells express markers of B-cell lineage, but are distinct from follicular lymphomas (which express CD 10), mantle cell lymphomas (expressing cyclin Dl and CD5) and small lym-phocytic lymphoma, which express CD5 and CD23. In contrast to the usual phenotype CD20+CD10-CD5-Cyclin Dl-, scattered reports in the literature have documented expression of CD5 in marginal zone B-cell lymphomas of MALT-type. However, these cases are rare, and aberrant CD5-expression has been thought to be a marker for early dissemination and aggressive behavior in some patients, while other reports have also found CD5 expression in localized indolent MALT-type lymphomas. We report a patient with a CD5+ MALT-type lymphoma following an aggressive clinical course without histological progression who relapsed only 18 months after local radiotherapy at the initial localizations (conjunctiva of the right upper eye lid and hypopharynx), and showed a rapid generalization to the contralateral conjunctiva, mediastinal lymph nodes and the esophagogastric junction. Our case lends further support to the notion that CD5+ MALT-lymphomas arising in the head-and-neck area and/or the ocular adnexa might be characterised by an aggressive clinical course.

Treatment of Advanced Hepatocellular Carcinoma with Biweekly High-Dose Gemcitabine

Introduction: Until today, an optimal palliative treatment regimen has not been defined for patients with advanced hepatocellular carcinoma. Since the novel cytidine analog gemcitabine has shown strong antitumor effects in vitro in a human hepatoma cell line and its therapeutic potential seems well established in several different tumors including gastrointestinal adenocarcinomas, the present phase II trial using a dose-intensified biweekly administration schedule was initiated. Patients and Methods: 17 patients with histologically confirmed unresectable advanced or metastatic hepatoma were treated with gemcitabine 2,200 mg/m2 given as a 30-min intravenous infusion on days 1 and 15. Treatment courses were repeated every 4 weeks. Results: All patients were evaluable for response and toxicity assessment. No objective response was achieved, stable disease occurred in 8 patients (47%), and 9 progressed while on chemotherapy. The median time to progression was 4 months (range 1.5–14 months), and the median survival time was 8.5 months (range 2.5–16.0+ months). Treatment was well tolerated with mild or moderate leukopenia, thrombocytopenia and anemia representing the most common side effects. Gastrointestinal and other subjective toxicities were infrequent and also generally mild. Conclusions: In view of the disappointing treatment results, gemcitabine using this particular dose regimen should not be considered for further investigation in patients with advanced hepatocellular carcinoma.

Randomized Phase II Study of Irinotecan Plus Mitomycin C vs. Oxaliplatin Plus Mitomycin C in Patients with Advanced Fluoropyrimidine/Leucovorin-Pretreated Colorectal Cancer

Introduction: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs might act synergistically with mitomycin C, a randomized study using a ‘pick the winner’ design was undertaken to determine the effectiveness and tolerance of these two combination schedules in patients with fluoropyrimidine/leucovorin-pretreated advanced colorectal cancer. Patients and Methods: Sixty-four patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin were enrolled onto this study. They were randomly assigned to treatment with irinotecan 120 mg/m2 on days 1+15 plus mitomycin C 8 mg/m2 on day 1 (arm A) or oxaliplatin 85 mg/m2 on days 1+15 plus mitomycin C 8 mg/m2 on day 1 (arm B). In both treatment arms, courses were repeated every 4 weeks. Results: The objective response rate in arm A is 7/33 (21.2%; 95% confidence interval, 9.0–38.9%) as compared to 5/31 in arm B (16.1%; 95% CI, 5.5–34.7%). Stable disease was noted in 48.5 vs. 45.2%, whereas the tumor progressed in 30.3 vs. 38.7%, respectively. Similar to the recorded response activities, the difference of the two combination regimens in terms of median time to progression (7.0 vs. 5.2 months) and overall survival (12.0 vs. 11.2 months) was only minor and clincally insignificant. The tolerance of treatment was acceptable in both arms, though severe adverse reactions requiring dose reductions (30 vs.16%) and treatment delays (22 vs. 13% of courses) were more commonly noted with irinotecan/mitomycin C. The most common toxicities in arm A were neutropenia (85%; WHO grade 3/4 in 33%), thrombocytopenia (52%), diarrhea (45%), emesis (52%) and alopecia (92%). In arm B, common toxicities included neutropenia (68%; grade 3/4 in 13%), thrombocytopenia (81%), emesis (52%), and peripheral neutropathy (48%). Conclusions: Both mitomycin C combination regimens seem to provide an acceptable therapeutic index in patients with fluoropyrimidine/leucovorin-pretreated metastatic colorectal cancer. In view of the increasing need for a broader chemotherapeutic armentarium for second-line therapy of this common malignant disease, both regimens may be worthwhile to undergo further clinical investigation.