Clinical diversity and treatment approaches to blastic plasmacytoid dendritic cell neoplasm: a retrospective multicentre study.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive type of haematologic precursor malignancy primarily often manifesting in the skin. We sought to provide a thorough clinical characterization and report our experience on therapeutic approaches to BPDCN. METHODS: In the present multicentric retrospective study, we collected all BPDCN cases occurring between 05/1999 and 03/2018 in 10 secondary care centres of the German-Swiss-Austrian cutaneous lymphoma working group. RESULTS: A total of 37 BPDCN cases were identified and included. Almost 90% of the patients had systemic manifestations (bone marrow, lymph nodes, peripheral blood) in addition to skin involvement. The latter presented with various types of cutaneous lesions: nodular (in more than 2/3) and bruise-like (in 1/3) skin lesions, but also maculopapular exanthema (in circa 1/6). Therapeutically, 22 patients received diverse combinations of chemotherapeutic regimens and/or radiotherapy. Despite initial responses, all of them ultimately relapsed and died from progressive disease. Eleven patients underwent haematopoietic stem cell transplantation (HSCT; autologous HSCT n = 3, allo-HSCT n = 8). The mortality rate among HSCT patients was only 33.33% with a median survival time of 60.5 months. CONCLUSION: Our study demonstrates the clinical diversity of cutaneous BPDCN manifestations and the positive development observed after the introduction of HSCT.

Dermal infiltrates of cutaneous T-cell lymphomas with epidermotropism but not other cutaneous lymphomas are abundant with langerin⁺ dendritic cells.

BACKGROUND: The Langerhans cell (LC) hypothesis suggests that cutaneous T-cell lymphomas (CTCL) are diseases of chronic T-cell stimulation by LC-mediated antigen presentation. OBJECTIVE: To investigate a broad panel of CTCL and cutaneous B-cell lymphomas (CBCL) for the spatial association of langerin(+) dendritic cells (DC) with T and B cells in the skin, respectively. METHODS: Fifty-five specimens of CTCL and 10 of CBCL were double-stained with monoclonal antibodies against langerin and CD3 or CD20, respectively, and evaluated by confocal laser scan microscopy. RESULTS: Dermal infiltrates in mycosis fungoides (n = 38), primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (n = 3) and primary cutaneous peripheral T-cell lymphoma, unspecified (n = 3) were characterized by a high frequency of dermal langerin(+) DCs. These cells were exclusively present in the malignant infiltrates. No direct co-localization of CD3 and langerin could be resolved. Dermal langerin(+) cells were detected only in one of six primary cutaneous anaplastic large cell lymphomas (C-ALCL), characterized by epidermotropism. In other C-ALCL cases (five of six), in lymphomatoid papulosis (n = 3), subcutaneous panniculitis-like T-cell lymphoma (n = 2), and all variants of CBCL no dermal langerin(+) DCs could be found. CONCLUSIONS: Langerin(+) DCs are abundant in the dermal infiltrates of T-cell lymphomas with specific involvement of the epidermis. This might indicate that immature LC and neoplastic T cells interact and gives rise to further studies to characterize the phenotype of the langerin(+) cell population described here and its role in the pathology of CTCL.

Somatostatin receptor scintigraphy in primary cutaneous T- and B-cell lymphomas.

BACKGROUND: Monitoring and repeated staging is of substantial importance in many patients with primary cutaneous T-cell lymphomas (CTCL). For primary cutaneous B-cell lymphomas (CBCL), extensive initial staging is the mainstay for correct diagnosis. AIM: To evaluate the value of somatostatin receptor scintigraphy using the radiolabeled somatostatin analog (111)In-pentetreotide in comparison to conventional imaging methods for the staging of patients with primary CTCL and primary CBCL. METHODS: Twenty-two patients (15 patients with histologically verified CTCL and 7 patients with histologically verified CBCL) were included. Stage of disease was established by physical examination, laboratory screening, skin inspection, palpation of superficial lymph nodes, sonography and computed tomography (CT) in patients with advanced clinical stage. Focally elevated tracer uptake of (111)In-pentetreotide was compared to common imaging modalities, physical aspect and digital photographs of the respective skin lesions. RESULTS: Of the 15 patients with CTCL, only 4 (27%) showed positive scintigraphic results, but not in all sites of lymphomatous involvement. None of the five patients with mycosis fungoides in stage I, nor any of the four patients with Sézary syndrome, had a positive (111)In- pentetreotide scan. Of the seven patients with CBCL three positive scintigraphic results (43%) could be obtained: in two patients with a follicular center lymphoma and one patient with a diffuse large B-cell lymphoma - leg type, but again not in all apparent sites of lymphoma. CONCLUSIONS: Based on our results, we do not recommend the use of somatostatin receptor scintigraphy for routine staging of patients with CTCL and CBCL. As our series includes only 22 patients, and the number of patients with rarer variants of CTCL was rather small, it might be too premature to abandon SST-R in the staging of patients with cutaneous lymphomas.

Prognostic relevance of hypoxia inducible factor-1alpha expression in patients with melanoma.

Overexpression of hypoxia inducible factor (HIF)-1alpha has been found in several human cancers and is thought to correlate with aggressive disease and poor response. A retrospective analysis was carried out on 89 patients with primary cutaneous melanoma. HIF-1alpha expression was assessed by immunohistochemistry in formalin-fixed, paraffin wax-embedded tumour sections. Overall survival (OS) and disease-free survival (DFS) were determined using univariate and multivariate analyses. Of the 89 patients, 78 (87.6%) expressed HIF-1alpha, and the remaining 11 patients (12.4%) did not. HIF-1alpha expression correlated with age (P = 0.002), but not with the main predictive factors in melanoma. Survival analysis disclosed no difference between the groups for OS and DFS. In multivariate analysis, only Breslow Index and ulceration were significantly associated with poor OS. Our results indicate that HIF-1alpha overexpression is present in most primary melanomas, but is not associated with clinicopathological variables, patient prognosis or survival.

Rituximab monotherapy for primary cutaneous B-cell lymphoma: response and follow-up in 16 patients.

BACKGROUND: We have carried out a retrospective analysis to evaluate the therapeutic value of the anti-CD20 antibody rituximab in 16 consecutive patients with primary cutaneous CD20+ B-cell lymphomas. PATIENTS AND METHODS: Sixteen patients (4 females, 12 males) with a median age of 54 years received systemic therapy with rituximab 375 mg/m(2) once weekly for four or six consecutive weeks. Eleven patients had primary cutaneous follicle center cell lymphoma and five patients had a primary cutaneous marginal zone B-cell lymphoma. RESULTS: Of the 16 patients with PCBCL, 14 patients (87.5%) achieved complete remission (CR). In two patients, partial remission was obtained and additional focal radiotherapy was applied, which resulted in final CR. Five to 14 (35%) patients with CR relapsed, in an interval between 6 and 37 months. There were no severe side-effects. CONCLUSIONS: On the basis of our results, single-agent treatment with i.v. rituximab appears to be feasible and safe and results in a high rate of durable remissions. Judging from our data, it appears to be an attractive treatment option and should be directly compared with local radiotherapy.

Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma.

Few data on the influence of lymphatic microvessel density (LMVD) on survival in patients with melanoma are available. The aim of this study was to assess LMVD and blood microvessel density (MVD) in tissue samples from 120 patients with melanoma. LMVD was stained with an antibody staining for podoplanin, and blood MVD was assessed by CD31 (PECAM-1)-immunostaining. Survival was determined using univariate and multivariate analysis. A significant association between a high CD31 MVD (but not LMVD) and the presence of lymph node metastases (P=0.007) was observed. Patients with a high LMVD had a significant shorter overall (OS) (P=0.0436) and disease-free survival (DFS) (P=0.0249) in univariate analysis. The survival analysis showed CD31 MVD was a strong prognostic factor for OS and DFS in both uni-and multivariate analyses. Our results demonstrate LMVD as a prognostic factor in malignant melanoma, although its prognostic relevance is much smaller compared with blood MVD.

Complete remission of chronic plaque psoriasis and gastric marginal zone B-cell lymphoma of MALT type after treatment with 2-chlorodeoxyadenosine.

A 58-year-old woman with a 15-year history of chronic plaque psoriasis was diagnosed with gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. Topical treatment and ultraviolet radiation for therapy of psoriasis had been of limited efficacy. The patient received intravenous treatment with 0.12 mg/kg per day of 2-chlorodeoxyadenosine (2-CDA) over 5 days for management of MALT lymphoma, as it was resistant to eradication of Helicobacter pylori. A total of six cycles were administered from June 1999 until November 1999 (cumulative dose 244.8 mg 2-CDA). After 2 months of 2-CDA administration, psoriatic skin lesions improved significantly, and after 3 months, complete remission of skin lesions was observed. Ongoing complete remission of the MALT lymphoma could be achieved after six cycles of 2-CDA administration. After a follow-up period of 34 months, no recurrence of psoriatic lesions has occurred. The patient is at present free of psoriatic plaques and gastric MALT lymphoma. The course of disease in our patient provides evidence for sustained therapeutic efficacy of 2-CDA in chronic plaque psoriasis in the absence of severe side effects except asymptomatic lymphopenia.

Beta-2-microglobulin levels in patients with extranodal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type: a retrospective analysis.

BACKGROUND: Serum levels of beta-2 microglobulin (B2M) have been reported as a predictor of clinical outcome, prognosis and tumor burden in patients with various types of lymphomas. In case of lymphoma of the mucosa-associated lymphoid tissue (MALT)-type, no clear data exist to define the role of B2M in terms of staging or prognosis. In a retrospective analysis we investigated the serum B2M-levels in patients suffering from histologically verified MALT-type lymphoma in correlation to stage and response to treatment. PATIENTS AND METHODS: All patients admitted to our institution since 1996 with a diagnosis of MALT-type lymphoma were retrospectively evaluated for staging procedures and measurements of serum B2M levels. Patients with a staging work-up including otorhinolaryngologic evaluation, gastroscopy with multiple biopsies, endosonography of the upper GI-tract, enteroclysis, colonoscopy, CT of thorax and abdomen and bone marrow biopsy were analysed, while staging was performed according to the Ann Arbor system as modified by Musshoff. In addition, only patients with histologic samples amenable to re-assessment by a reference pathologist were included. RESULTS: A total of 68 patients with a diagnosis of MALT-type lymphoma were identified from our records. However, only in 32 patients exact staging according to our inclusion criteria had been performed and serum B2M-levels prior to the initiation of therapy were available in all these patients. Twenty-five patients; suffered from gastric lymphoma, while the remaining 7 patients had extragastric manifestations. In total, 13 out of 32 patients presented with stage I disease, 17 patients were rated as stage II and 2 patients suffered from stage III disease. Nineteen patients had elevated B2M-levels prior to therapy: 6 patients were rated as stage 1, II had stage II and two had stage III disease. Five patients still had elevated B2M-levels following treatment despite radiologically and histologically verified complete remission. CONCLUSION: In this series, no correlation between serum B2M levels, tumor burden and clinical outcome was apparent in patients with MALT-type lymphomas. While the number of patients with disseminated disease was small we could not demonstrate a difference for B2M-levels between stage I and stage II. While we cannot rule out that B2M might be different in patients with stage I/II disease as compared to more advanced disease, further investigations are necessary to determine the role of this marker in patients with MALT-type lymphoma.

Treatment of advanced, refractory breast cancer with alternating docetaxel and epirubicin/cyclophosphamide plus human granulocyte colony-stimulating factor.

PURPOSE: A phase II study was performed to investigate the efficacy and tolerance of alternating docetaxel and epirubicin/cyclophosphamide plus recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with advanced breast cancer who failed previous non-anthracycline/taxane-containing palliative chemotherapy. PATIENTS AND METHODS: Between November 96 and June 98, a total of 45 patients participated in this trial. Chemotherapy consisted of docetaxel 100 mg/m2 given as a 1-h infusion on day 1, and epirubicin 100 mg/m2 plus cyclophosphamide 800 mg/m2 both administered on day 21. G-CSF 5 microg/kg/day was given subcutaneously from days 22-28 during each cycle. Treatment courses were repeated every 42 days for a total of three courses unless prior evidence of progressive disease. RESULTS: The overall response rate was 57.8% (95% confidence interval, 42.1-72.3%), including seven complete (15.5%) and 19 partial remissions (42.3%); nine patients (20%) had stabilization of disease and 10 (22.3%) progressed. The median time to treatment failure was 7.0 months (range 1.5-26.0), and the median overall survival time 15.0 months (range 2.0-37.0+) with 12 patients (27%) currently still alive with metastatic disease. Myelosuppression was commonly observed with WHO grade 3/4 neutropenia in 20 patients (44%) complicated by septicemia in five (11%). Severe nonhematologic toxicity included stomatitis in five patients (11%), skin and peripheral neurotoxicity each in one patient; alopecia was seen in all 45 patients with complete hair loss in 26 (58%). CONCLUSIONS: Our data suggest that alternating docetaxel and epirubicin/cyclo-phosphamide plus G-CSF is an effective and tolerable second-line combination regimen for the treatment of advanced breast cancer.

Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma.

Lymphoma of the mucosa-associated lymphoid tissue (MALT) type usually arises in MALT acquired through chronic antigenic stimulation triggered by persistent infection and/or autoimmune processes. Due to specific ligand-receptor interactions between lymphoid cells and high-endothelial venules of MALT, both normal and neoplastic lymphoid cells display a pronounced homing tendency to MALT throughout the body. In the case of neoplastic disease these homing properties may be responsible for lymphoma dissemination among various MALT-sites. According to this concept, we have standardized staging procedures in all patients diagnosed with MALT-type lymphoma. All patients with MALT-type lymphoma underwent standardized staging procedures before treatment. Staging included ophthalmologic examination, otolaryngologic investigation, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen and bone marrow biopsy. Biopsy was performed in all lesions suggestive for lymphomatous involvement, and evaluation of all biopsy specimens was performed by a reference pathologist. 35 consecutive patients with histologically verified MALT-type lymphoma were admitted to our department. Twenty-four patients (68%) had primary involvement of the stomach, five (15%) had lymphoma of the ocular adnexa, three (8.5%) had lymphoma of the parotid, and three (8,5%) of the lung. Lymph-node involvement corresponding to stage EII disease was found in 13 patients (37%), only one patient with primary gastric lymphoma had local and supradiaphragmatic lymph-node involvement (stage EIII). Bone marrow biopsies were negative in all patients. Overall, eight of 35 patients (23%) had simultaneous biopsy-proven involvement of two MALT-sites: one patient each had lymphoma of parotid and lacrimal gland, conjunctiva and hypopharynx, conjunctiva and skin, lacrimal gland and lung, stomach and colon, and stomach and lung. The remaining two patients had bilateral parotideal lymphoma. Staging work-up was negative for lymph-node involvement in all of these eight patients. The importance of extensive staging in MALT-type lymphoma is emphasized by the demonstration of multiorgan involvement in almost a quarter of patients. In addition, our data suggest that extra-gastrointestinal MALT-type lymphoma more frequently occurs simultaneously at different anatomic sites than MALT-type lymphoma involving the GI-tract.

Chemotherapy for the treatment of patients with primary high grade gastric B-cell lymphoma of modified Ann Arbor Stages IE and IIE.

BACKGROUND: Surgical intervention and combined modality treatment including radiation and chemotherapy have been studied widely in patients with high grade gastric B-cell lymphoma, whereas to the authors' knowledge the role of chemotherapy alone in patients with localized disease has not been investigated extensively. METHODS: Twenty-five consecutive patients with primary high grade gastric B-cell lymphoma of localized modified Ann Arbor Stages IE and IIE were studied prospectively at the study institution. Patients age < 75 years (n = 17; age range, 41-75 years) were given a standard regimen comprised of doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP), whereas patients age > 75 years (n = 8; age range, 82-93 years) were treated at a reduced dose. Restaging was performed after 3 and 6 cycles, followed by every 3 months for the first 2 years, and every 6 months thereafter. RESULTS: A total of 123 cycles were administered to the study patients, with the median number of 6 cycles per patient (range, 1-9 cycles). At a median follow-up of 24 months (range, 1.5-87+ months), 22 patients were alive without evidence of disease and 3 patients had died (1 patient death was treatment-related). Twenty-four patients who were considered evaluable achieved a complete remission, 21 patients after 3 cycles and the remaining 3 patients after 6 cycles of treatment. Side effects generally were manageable, with only one patient requiring premature discontinuation of treatment due to protracted thrombocytopenia after three courses of therapy, and tolerance was not different between the two age groups. No recurrences were observed at last follow-up. CONCLUSIONS: The authors believe that chemotherapy using the CHOP regimen is highly effective in the treatment of patients with localized primary high grade gastric lymphoma.

Evidence of therapeutic efficacy of CCNU in recurrent choroid plexus papilloma.

A pregnant 33-year old woman developed nystagmus and cerebellar ataxia. A tumor in the roof of the fourth ventricle was diagnosed. The tumor was subtotally removed using microneurosurgical techniques. The histopathological diagnosis was choroid plexus papilloma (CPP). Twenty-one months later, the tumor recurred and was reoperated. Histologically the tumor displayed now increased mitotic activity and pleomorphism. Radiation therapy of the neuroaxis was performed. Within 59 months, the CPP recurred 3 more times with neuroradiological evidence of extensive spinal seeding. After several palliative irradiations, including 2 gamma-knife boosts, the patient was referred to chemotherapy. She was treated with CCNU (Lomustin) 100 mg/m2 orally (12 cycles, cumulative dosis 1440 mg/m2). Within 42 months, there was no new local recurrence and spinal seeding showed significant regression. Clinically the patient improved and stabilized, but needs continuous support because of persisting severe gait ataxia. The course of disease in our patient provides evidence for therapeutic efficacy of CCNU in recurrent CPP.

Regression of colonic low grade B cell lymphoma of the mucosa associated lymphoid tissue type after eradication of Helicobacter pylori.

BACKGROUND: Lymphoma of the mucosa associated lymphoid tissue (MALT) arising in the stomach has been shown to be related to Helicobacter pylori infection, and total regression of gastric lymphoma after successful eradication of H pylori has consistently been reported. MALT-type lymphoma at other localisations, however, has to our knowledge not been linked to H pylori, and eradication of the bacteria has not been studied for management of such lymphomas. PATIENT/METHOD: A 67 year old man was diagnosed with MALT-type lymphoma simultaneously involving the stomach and the colon descendens. In addition to the presence of MALT-type lymphoma, H pylori associated chronic gastritis was diagnosed, and treatment with clarithromycin, metronidazole, and omeprazole was initiated, resulting in its successful eradication. RESULTS: Follow up performed four months later showed regression of the colonic manifestation, whereas the gastric lymphoma did not respond to antibiotic treatment, as assessed by regular follow up for 14 months, in spite of its restriction to mucosa and submucosa. The patient was therefore treated with oral cyclophosphamide (100 mg a day) resulting in partial remission after seven months of continuous treatment. Because of the presence of residual lymphoma, additional irradiation was performed, which led to complete remission of the gastric lymphoma. The patient remains in complete remission 40 months after diagnosis and 26 months after initiation of treatment. CONCLUSION: In the case of concurrent gastric and intestinal low grade MALT-type lymphoma, H pylori eradication may cause regression of the intestinal lesion.

The nerve of Henle: an anatomic and immunohistochemical study.

The topography of the nerve of Henle was reviewed. Fifty-two human cadaveric upper extremities were studied. In 30 (58%) the nerve was well defined; in 22 (42%) its origin from the ulnar nerve was unidentifiable. The palmar cutaneous branch of the ulnar nerve separated from the ulnar nerve 5 to 11 cm distal to the medial epicondyle of the humerus to divide into its terminal branches in the distal forearm. Four patterns were detected: ulnar, radioulnar, vessel-related, and radial. These shared a consistent vascular branch, which sent 2 branches to the ulnar artery just proximal to the distal ulnar tunnel. Using a tyrosine hydroxylase antibody-based immunohistochemistry technique the nerve was shown to carry sympathetic fibers. Motor fibers were ruled out with Karnovsky's stain, which was used in combination with the tyrosine hydroxylase method in 10 specimens.

Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony-stimulating factor.

PURPOSE: A phase II trial was performed to investigate the efficacy and tolerance of gemcitabine, vinorelbine, and recombinant human granulocyte colony-stimulating factor (G-CSF) in advanced breast cancer. PATIENTS AND METHODS: Between April 96 and August 97, 60 patients entered this trial. Forty-five patients were previously untreated and 15 patients had failed previous palliative chemotherapy with (n = 10) or without anthracyclines (n = 5). Therapy consisted of gemcitabine 1000 mg/m2 on days 1 + 15 + 21 and vinorelbine 40 mg/m2 on days 1 + 21, both diluted in 250 ml saline and infused over 30 min. G-CSF was administered at 5 microg/kg/day subcutaneously from days 2-6 and 22-26. Courses were repeated every 5 weeks. Treatment was continued in case of response or stable disease until a total of six courses. RESULTS: The overall response rate was 55.5% for patients who had not received prior palliative chemotherapy (95% confidence interval, 40%-70.3%), including 5 CR (11.1%) and 20 PR (44.4%); 12 patients (27%) had stable disease (SD), and 8 (18%) progressed. Second-line treatment with this regimen resulted in 6/15 (40%) objective remissions, 5 had SD, and 4 PD. The median time to progression was 9.5 months (range, 1.5-28) in previously untreated patients, and 7.0 months (range, 2-23) in those who had failed prior chemotherapy. After a median follow-up time of 15 months, 44 patients (73%) are still alive with metastatic disease. Myelosuppression was commonly observed, though WHO 3 and 4 neutropenia occured in only 9 (15%) and 2 patients (3%), and was never complicated by septicaemia; grade 3 anemia was noted in 2 patients. Severe (WHO grade 3) nonhematologic toxicity was rarely observed, and included nausea/emesis in 3 and constipation in 2 patients. CONCLUSIONS: Our data suggest that gemcitabine and vinorelbine plus G-CSF is an effective and tolerable first- as well as second-line combination regimen for treatment of advanced breast cancer.

Phase II trial of gemcitabine, epirubicin and granulocyte colony-stimulating factor in patients with advanced pancreatic adenocarcinoma.

Although the novel cytidin analogue gemcitabine has shown superior anti-tumour activity than 5-fluorouracil in advanced pancreatic cancer, further improvements of therapeutic results are warranted. This goal might be achieved by combining gemcitabine with other active drugs. This trial evaluated the efficacy and tolerance of such a combination regimen with epirubicin and granulocyte colony-stimulating factor (G-CSF) in patients with metastatic disease. Seventy patients with metastatic pancreatic adenocarcinoma were enrolled in this multicentre trial. Patients received 4-weekly courses of a combination regimen consisting of epirubicin 60 mg m(-2) given as intravenous bolus injection on day 1, gemcitabine 1000 mg m(-2) infused over 30 min on days 1, 8 and 15, and G-CSF administered at 5 microg kg(-1) day(-1) subcutaneously from days 2-6 during each cycle. The efficacy of treatment was assessed by conventional measures, i.e. objective response, progression-free and overall survival, as well as by analysis of clinical benefit response (defined as > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, and/or > or = 20-point improvement in Karnofsky performance status that was sustained for > or = 4 consecutive weeks). Of 66 patients evaluable for objective response, one achieved complete and 13 partial remissions, for an overall response rate of 21% (95% confidence interval (CI), 12-33%); 27 additional patients (41%) had stable and 25 (38%) increasing disease. The median time to progression was 3.8 months. Median survival was 7.8 months, and the probability of surviving beyond 12 months was 21.2%. Out of 60 patients with tumour-related symptoms, who were considered evaluable for clinical benefit response, 26 (43%) experienced significant palliation. The median time to achieve a clinical benefit response was 7 weeks, and its median duration was 22 weeks. Chemotherapy was well-tolerated with leukopenia/granulocytopenia representing the most common and dose-limiting side-effect. Gastrointestinal and other subjective toxicities were infrequent and generally rated minor. We conclude that the combination of gemcitabine, epirubicin and G-CSF seems to be an effective palliative treatment with only moderate toxic effects in patients with metastatic pancreatic adenocarcinoma. Our results in terms of objective and clinical benefit response, as well as survival seem to suggest an advantage over gemcitabine-monotherapy, though this remains to be confirmed in a randomized trial.

Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer.

INTRODUCTION: Carcinoma of the biliary system is a rare tumor entity, and patients with advanced disease face a dismal prognosis. Because of the absence of standard chemotherapy for advanced biliary carcinoma, we have performed two consecutive studies to evaluate the clinical potential of 5-fluorouracil, leucovorin and mitomycin C as well as the novel antimetabolite gemcitabine in this disease. PATIENTS AND METHODS: A total of 39 consecutive patients suffering from locally inoperable or metastatic biliary cancer were enrolled in the study between March 1994 and October 1997. Twenty patients were treated with leucovorin 200 mg/m2 and 5-FU 400 mg/m2, both given as intravenous bolus on days 1-4, and mitomycin C 8 mg/m2 on day 1 (group A). Treatment cycles were repeated every 28 days. The second cohort included 19 patients, who received gemcitabine 1200 mg/m2 on days 1, 8 and 15 with a 2-week interval before the next treatment cycle (group B). Treatment was continued for a maximum of 6 cycles in the absence of progressive disease in both groups, and endpoints of the study were responses rates, survival and toxicity. RESULTS: In group A, 5 patients (25%) had a partial response (PR), 6 additional patients (30%) had stable disease (SD) and 9 patients (45%) progressed during treatment. The median survival was 9.5 months (range, 3-14.5) with the median time to progression being 4 months (range, 3-9). In group B, 3 patients achieved a PR (16%), 4 showed SD (21%), while the remaining 12 patients had progressive disease. A median survival of 6.5 months (range, 2-11.5) was obtained, and the median time to progression was 2.5 months (range, 1-6+). Toxicity was generally mild in both treatment arms, 6 patients in group A required dose reductions, while no dose adaptation had to be performed for gemcitabine. CONCLUSION: Our data suggest that treatment of advanced biliary cancer is feasible and can be safely performed with both regimens applied in our study. While administration of gemcitabine has resulted in only mild toxicities, its exact impact on the management of advanced biliary cancer should be evaluated in a controlled trial.

Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.

PURPOSE: To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS: Thirty-six 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. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. RESULTS: The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION: Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.

Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide.

Treatment options for hepatocellular cancer apart from surgical resection are limited because of the drug-refractory nature of this disease. Little is known about the role of somatostatin-receptors in hepatocellular cancer, and somatostatin analogs have not been investigated for treatment of this malignancy. We present the case of a 68-yr-old male, who was successfully treated with the long-acting somatostatin analog lanreotide.