Tandem and triple high-dose chemotherapy with autologous stem cell rescue in metastatic breast cancer

The purpose of this phase II study was to evaluate the therapeutic efficacy and toxicity of a tandem or triple high-dose chemotherapy (HDC) with autologous peripheral blood stem cell transplantation (PBSCT) in patients with metastatic breast cancer (MBC) as first line chemotherapy. Conventional chemotherapy consisted of two cycles of epirubicin 120 mg/m² and ifosfamide 7500 mg/m² in the case of tandem HDC and one cycle of paclitaxel 135 mg/m², epirubicin 90 mg/m² and ifosfamide 6000 mg/m² in the case of triple HDC. Tandem HDC was composed of two cycles of epirubicin 180 mg/m², ifosfamide 12000 mg/m² and carboplatin 900 mg/m². In the case of triple HDC, paclitaxel 180 mg/m², etoposide 1500 mg/m² and thiotepa 600 mg/m² was added as the third cycle. Patients with tandem HDC (n = 20) were evaluable for both survival and toxicity, and patients with triple HDC (n = 21) only for toxicity because of short-term follow-up. Both tandem and triple HDC were well tolerated and could be safely administered. Non-hematological WHO grade 3 or 4 toxicities were mucositis (8), temporary renal insufficiency (1), myocardial infarction (1), and neuropathy (1). No toxic death occurred. The Kaplan-Meier estimates for 44-months without progression and the overall survival were 12% and 38% respectively. The median survival was 22 months (95% CI: 7.4–51.7 months) and the median progression-free interval 14 months (95% CI: 5.1–43.7 months). In a population with an unfavorable prognosis, tandem HDC showed similar efficacy as to that described in other phase II studies. Triple HDC seems not to improve patient outcome compared to tandem HDC, but a long-term follow up is required. Received: 20 April 1998 / Accepted: 6 August 1998     

Outpatient reduced-intensity allogeneic stem cell transplantation for patients with refractory or relapsed lymphomas compared with autologous stem cell transplantation using a simplified method

The effectiveness of reduced-intensity conditioning allogeneic stem cell transplantation (allo- RIC) compared with high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) in Hodgkin’s disease (HD) and in non-Hodgkin’s lymphoma (NHL) patients remains poorly defined. The purpose of the study was to demonstrate the usefulness of auto-SCT or allo-SCT, employing a RIC regimen in refractory or relapsed NHL or HD patients. We analyzed the outcome of 71 patients with advanced disease. Twenty-three NHL and 14 HD patients received an allo-RIC using fludarabine, cyclophosphamide, and low-dose busulfan as the conditioning regimen. Sixteen NHL and 18 HD patients received auto-SCT using cyclophosphamide and etoposide as conditioning regimen. All hematopoietic stem cells products were not cryopreserved and the majority of grafts were done on an outpatient basis, including conditioning and post-stem cell infusion care (auto-SCT, 62% and allo-RIC procedure, 91%). The median OS was 45.5 months for the allo-RIC recipients and 53.3 months for auto-SCT recipients. Acute/chronic GVHD incidence in NHL and HL groups was 38%/31% and 14%/7%, respectively. We found no significant difference in overall survival between allo-RIC group and auto-SCT group for NHL patients (P = 0.43) but better OS was observed for auto-SCT group than for allo-SCT group in HL patients (P < 0.001). The relapse rate was higher in autografted patients, both in NHL and HD. Both auto-SCT and allo-RIC appear to be valid treatments for poor-risk patients with relapsed or refractory lymphoma who could not otherwise be cured with conventional salvage regimens.     

Correlation between granulocyte/macrophage-colony-forming units and CD34+ cells in apheresis products from patients treated with different chemotherapy regimens and granulocyte-colony-stimulating factor to mobilize peripheral blood progenitor cells

We examined the efficiency of disease-specific “standard” chemotherapies epirubicin, cyclophosphamide (EC); cyclophosphamide, vincristine, doxorubicin, etoposide, prednisolone (CHOEP); epirubicin, ifosfamide (EPI/IFOS) for peripheral blood progenitor cell (PBPC) mobilization in comparison to well-characterized mobilization protocols, i.e. etoposide, ifosfamide, cisplatin, epirubicin (VIPE) and dexamethasone, carmustine, etoposide, cytarabine, melphalan (DexaBEAM). Twenty-seven patients with various malignancies underwent 75 apheresis procedures for PBPC collection. Median cell yields from all 75 aphereses were 1.18 × 10⁵ mononuclear cells/kg [range (0.28–3.7) × 10⁸], 1.4 × 10⁵ granulocyte/macrophage-colony-forming units (CFU-GM)/kg [range (0.2–11) × 10⁵] and 3.3 × 10⁶ CD34⁺cells/kg [range (0.35–17.7) × 10⁶. CD34⁺/CD90⁺ cells could be mobilized by all mobilization regimens used. The difference observed in the mobilization of CD34⁺ cells was only of low significance when the mobilization regimens were compared, whereas the mobilizations of MNC and CFU-GM were significantly different between the groups. Breast cancer patients treated with the VIPE regimen (including pretreated women) had a significantly higher CFU-GM rate than patients treated with EC (P = 0.0005). Mobilized CD34⁺ PBPC were correlated with CFU-GM in all apheresis products. The linear correlation coefficients differed for the various mobilization groups: DexaBEAM (r=0.9, P < 0.0001), VIPE (r = 0.68, P = 0.0024), CHOEP (r = 0.52, P = 0.022), EPI/IFOS (r=0.34, P=0.11) and EC (r=0.23, P=0.2). We conclude that clonogenic assays can provide additional information about the autotransplant quality, particularly when alternative or new mobilization regimens are being investigated. Received: 7 January 1998 / Accepted: 24 February 1998     

Antitumoral activity of oxaliplatin/cisplatin-based combination therapy in cisplatin-refractory germ cell cancer patients

Purpose: Only 20–30% of patient with advanced germ cell tumors, relapsing after standard first-line therapy, are curable with current second-line cisplatin-based regimens. New salvage combinations incorporating new active agents are needed. We report the toxicity/tolerance of a new salvage regimen based on the oxaliplatin (Eloxatin)/cisplatin combination, evaluated in patients with recurrent, mostly cisplatin-refractory germ cell tumors. Patients and methods: Thirteen patients were enrolled in this study. All except one had received cisplatin-based chemotherapy. Eight had progressive disease as the best response on their last platinum-based chemotherapy, and three had potentially sensitive tumors. The median interval since the last platinum-based chemotherapy was 6 months (range: 1–36 months). One untreated patient with poor prognosis was also enrolled. Twelve patients had pathological markers [median α-fetoprotein 14 800 ng/ml (58–10⁶), median human chorionic gonadotrophin β subunit 7000 IU/ml (37–723 700)]. Patients received either oxaliplatin (130 mg/m²) and cisplatin (100 mg/m²) every 3–4 weeks (Bi regimen, four patients), or the same regimen combined with one to four of the following cytotoxic agents: ifosfamide, epirubicin, vinorelbine, methotrexate, dactinomycin, etoposide and bleomycin (BiC regimen, 9 patients). Treatment was individualized according to each individual patient's pretreatment and clinical characteristics. Results: Seven objective responses were obtained (overall response rate = 54%), all with the BiC regimens (two complete and five partial responses). Two patients with recurrent disease achieved a long-term complete response lasting over 5 years. Four partial responders were seen in the eight cisplatin-refractory tumors, lasting 4–8 months. All objective responses had a corroborating major decrease in tumor marker blood levels (median decrease: 99.7%). The median survival for the whole group was 8 months. The commonest severe toxicity was hematological (grade 4 neutropenia in 78% and thrombopenia in 74% of the BiC cycles). Conclusion: Our combined salvage regimen induced significant antitumoral activity in recurrent, cisplatin-refractory germ cell tumors. Oxaliplatin merits further evaluation as a component of combination therapy for this disease. Received: 12 February 1999 / Accepted: 28 June 1999     

Phase I / II trial of human recombinant granulocyte-colony-stimulating factor (filgrastim) and escalating doses of cyclophosphamide, mitoxantrone, and 5-FU in the treatment of advanced breast cancer

Purpose: We performed a phase I/II dose-escalation trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) in combination with human recombinant granulocyte-colony-stimulating factor (G-CSF, filgrastim) in patients with advanced breast cancer. The objectives of this trial were (1) to gain experience with filgrastim given to patients with advanced breast cancer and receiving standard-dose CNF, and (2) to determine the maximum tolerated dose of CNF that could be given with filgrastim support by incremental dose escalation of two components of the CNF regimen, cyclophosphamide and mitoxantrone. Methods: Four patients who had received prior therapy for advanced disease received standard-dose CNF with filgrastim support. Sequentially enrolled patients who had received no prior chemotherapy for advanced disease were treated with standard-dose CNF without filgrastim (5 patients), standard-dose CNF with filgrastim (15 patients), or were entered into sequential cohorts of 3–6 patients to be treated with increasing doses of CNF with filgrastim support (29 patients). Results: The maximum tolerated doses that could be given with filgrastim support were 1500 mg/m² cyclophosphamide, 20 mg/m² mitoxantrone, and 500 mg/m² 5-FU. Overall, 7 complete (14%) and 13 partial responses (26%) were observed. Despite the use of filgrastim, repeated cycles of CNF at doses of 2000 mg/m² cyclophosphamide, 25 mg/m² mitoxantrone, and 500 mg/m² 5-FU could not be given because of neutropenia and thrombopenia. Among 18 patients with bidimensionally measurable disease there were 3 complete (17%) and 5 partial (28%) responses. The median progression-free survival of all patients was 236 days (34 weeks). Conclusion: The use of filgrastim allows CNF to be given at approximately twice the dose intensity of “standard”-dose CNF. Because non-hematopoietic toxicity was not dose-limiting, further dose escalation of this regimen might be possible with more effective hematopoietic support. The response rate and survival of patients treated in this study were within the range expected with standard-dose chemotherapy. Received: 10 December 1998 / Accepted: 3 February 1999     

Salvage chemotherapy with mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in relapsing and refractory lymphoma

Purpose: The aim of the study was to evaluate the feasibility and efficacy of the combination of mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in patients with prognostically unfavorable recurrent and refractory Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Methods: Forty-six patients (median age 43 years, range 18–63) with relapsed (n=15) or refractory (n=31) malignant lymphoma were enrolled (HD, n=13; low-grade/transformed NHL, n=4; high-grade NHL, n=29). A total of 39 patients (85%) showed multiply relapsed diseases with a duration of prior remission of <12 months (n=8) or had lymphoma being resistant to prior chemotherapy (n=31). The MIFAP therapy consisted of fludarabine (15 mg/m², q. 12 h, day 1–4), cytarabine (50 mg/m² by continuous infusion (CI) over 22 h, day 1–4), cisplatin (25 or 30 mg/m² by CI over 24 h, day 1–4), and mitoxantrone (4 mg/m², day 2–5). Results: Thirteen patients (28%) achieved complete remission (CR) and 15 patients (33%) partial remission (PR), for an overall response (OR) rate of 61%. Twenty-two patients responding to MIFAP (10 CR, 12 PR) have been consolidated by high-dose therapy (HDT) with hematopoietic stem cell transplantation (SCT). After a median follow-up of 12 months, 16 patients are in continuous CR (CCR) (n=14) or CCRu (unconfirmed) (n=2). The median duration of event-free survival (EFS) and overall survival (OS) were 6.5 and 19.3 months, respectively. Probabilities of EFS and OS after 3 years were 19% and 40%. Responders consolidated by subsequent HDT showed rates for 3-year EFS and OS of 40% and 66%, respectively. Unfavorable prognostic factors for EFS by univariate analysis were refractory lymphoma and the presence of B-symptoms. Significant prognostic factors for OS were NHL, refractory lymphoma, B-symptoms, and bone marrow involvement. The major toxicities were leukocytopenia and thrombocytopenia of the World Health Organization (WHO) grade IV in nearly all courses (median duration 10 and 11 days). In contrast, non-hematological side effects were moderate, predominantly of WHO grades I and II. Treatment-related mortality with MIFAP was 4% (two patients with septicemia by Aspergillus fumigatus). Conclusions: MIFAP is an effective salvage protocol for patients with poor-risk recurrent or refractory HD and NHL. The observed toxicity seems to be acceptable considering the unfavorable prognosis and intensive pretreatment. The results in patients responding to MIFAP and afterwards undergoing HDT with autologous stem cell support are even comparable to those published in patients with prognostically more favorable diseases. Received: 12 October 2000 / Accepted: 8 November 2000     

Influence of conditioning regimens and stem cell sources on donor-type chimerism early after stem cell transplantation

We retrospectively analyzed very early chimerism before and ongoing neutrophil engraftment (days 7, 14, 21, 28) and investigated the influence of conditioning regimens and stem cell sources on donor-type chimerism in 59 Japanese patients who had received allogeneic hematopoietic stem cell transplantation. The percentage of donor-type chimerism increased before engraftment in all patients who achieved engraftment. The average percentage of donor-type chimerism in patients who had received reduced-intensity stem cell transplantation (RIST) with total body irradiation (TBI) was significantly higher than that in patients who had received RIST without TBI (98.8% vs 87.5% on day 21, P < 0.01; 99.3% vs 84.3% on day 28, P < 0.01). The average percentage of donor-type chimerism after peripheral blood stem cell transplantation was significantly higher than that after bone marrow transplantation on day 7 (81.5% vs 43.1%, P < 0.01), and the average percentage of donor-type chimerism after cord blood transplantation was significantly lower on day 14 (55.8% vs 84.8%, P < 0.05). Compared with the average percentage of donor-type chimerism in patients who achieved engraftment with each stem cell source, a notable decrease in donor-type chimerism was observed in patients who failed to achieve engraftment. This study suggests that differences in conditioning regimens and stem cell sources should be taken into account when considering donor-type chimerism.     

Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in locally advanced nasopharyngeal carcinoma: a phase II study

Purpose: The incidence of nasopharyngeal carcinoma in Germany is relatively low in comparison with certain regions in south-east Asia. However, standardised therapeutical regimes are required in the treatment of these tumours. Methods: Between August 1990 and December 1997, 25 patients with stage III and IV nasopharyngeal carcinoma received an accelerated and hyperfractionated radiotherapy with concurrent chemotherapy (5-FU and mitomycin C). The primary tumour and positive lymph nodes received a total dose of 72 Gy over a period of 6 weeks. In the first 3 weeks, irradiation fields were treated five times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving two daily fractions of 1.4 Gy. Salvage surgery was offered for residual lymph node disease after radiotherapy. Results: The overall response rate defined as complete and partial response of the primary was 100%. Sixteen of the 25 patients were still alive and were free of any evidence of tumour recurrence or distant metastases at a mean follow-up period of 34 months (range 7–95 months). Six patients received salvage surgery. Only one of these six patients had histologically proven evidence of vital tumour. No severe late complications such as blindness or temporal lobe necrosis were observed. Conclusions: The presented data are promising and show that the combination of hyperfractionated accelerated radiotherapy and chemotherapy is feasible and effective. Received: 10 January 2000 / Accepted: 22 January 2001     

Femoral head necrosis in three patients with relapsed ovarian cancer receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation

We report three patients with relapsed ovarian cancer who developed femoral head necrosis requiring endoprosthetic hip surgery 16-35 months after high-dose chemotherapy (HDC) with treosulfan (47 and 56 g/m(2) body-surface area (BSA)) given as 3-25 h infusions and followed by autologous peripheral blood stem cell (PBSC) transplantation. One woman received two courses of single agent treosulfan while the other two patients received one course of high-dose treosulfan either preceded or followed by high-dose carboplatin, etoposide and cyclophosphamide. A total of 30 women with ovarian cancer were treated with HDC at our unit and 21 of them received treosulfan-containing regimens. Femoral head necrosis was not observed in patients either receiving conditioning regimens without treosulfan (n=9) or when the total treosulfan dose was given over 3 consecutive days (n=3) or in patients with a diagnosis other than ovarian cancer and treated with high-dose treosulfan (n=10). We conclude that women with relapsed ovarian cancer receiving HDC with excessive single-dose treosulfan might be at an increased risk of developing bone necrosis.     

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel

Purpose: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. Methods: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. Results: The following single-point model was selected as optimal: AUC carboplatin (min mg⁻¹ ml⁻¹) = 418 · c _2.5 h(mg/ml) + 0.43 (min mg⁻¹ ml⁻¹), where c _2.5 h is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 ± 1.6%) and precise (root mean square error = 10.1 ± 1.5%). Conclusions: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualise treatment. Received: 19 June 1998 / Accepted: 7 May 1999     

Successful mobilization of peripheral blood stem cells in heavily pretreated myeloma patients with G-CSF alone

 We investigated the feasibility of mobilizing peripheral blood stem cells (PBSC) with G-CSF alone in 24 patients with multiple myeloma. The median age was 53 years (range 33–62). All patients had stage II/III disease and responded to standard first-line (n=6) or salvage chemotherapy (n=18). The median number of previous chemotherapy cycles was 7 (4–18) and the median number of prior melphalan-cycles was 6 (0–14). Nine (35%) patients had experienced prior radiation therapy. The patients received either 10 μg/kg G-CSF (n=18) or 24 μg/kg G-CSF (n=7, including one patient with previous 10 μg/kg G-CSF stimulation) daily s.c. for 5 or more consecutive days until completion of harvesting, starting apheresis on the fifth day. G-CSF treatment was well tolerated, with only slight bone pain in half of the patients (51%). After a median of three (range 1–7) apheresis procedures, medians of 3.8 (0.3–17)×10⁶ CD34+ cells/kg, 8.5 (4.5–24)×10⁸ MNC/kg, 2.9 (0.6–39.4)×10⁴ CFU-GM/kg, and 5.6 (0.9–49)×10⁴ BFU-E/kg were harvested. Three patients (12%) with extensive melphalan pretreatment failed the target collection of at least 2.0×10⁶ CD34+ cell/kg. Pretreatment with six or more cycles of melphalan yielded a smaller number of CD34+ cells than pretreatment with fewer than six cycles (2.5 vs 5.3×10⁶/kg;p=0.001). Nineteen patients underwent high-dose chemotherapy consisting of either total marrow irradiation (9 Gy)/busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) (n=10), or busulfan (14 mg/kg)/cyclophosphamide (120 mg/kg) (n=5), or tandem melphalan (200 mg/m²). The median time for granulocyte (>1.0/nl) and platelet (>50/nl) recovery was 10 and 14 days (ranges 7–12 and 8–40), respectively. G-CSF alone is a safe, alternative approach to mobilizing sufficient PBSC in patients with multiple myeloma and allows an exact prediction of harvest time. G-CSF-mobilized PBSCs ensure rapid engraftment after myeloablative therapy. Melphalan treatment should be avoided in patients who are candidates for high-dose chemotherapy. Received: February 5, 1998 / Accepted: April 14, 1998     

Pegylated doxorubicin for primary cutaneous T-cell lymphoma: a report on ten patients with follow-up

Purpose: Pegylated liposomal doxorubicin (PEG-DOXO) was found to be effective in primary cutaneous T-cell lymphomas (CTCL). The present observation reports on follow-up and relapse-free interval in patients with CTCL. Methods: Ten patients (one female, nine male) aged 50–78 years (mean 66.7 years) with relapsing or recalcitrant CTCL, stage I b (n=3), II a (2), II b (3), IV a (1), and IV b (1) were treated with PEG-DOXO 20 mg m⁻² once a month with an upper limit of 400 mg or eight infusions to induce a clinical response. There was one drop out after a single infusion because of a capillary leak syndrome. Results: In nine patients with PEG-DOXO the best response was a complete response (CR) in five patients and a partial response (PR) in four patients. The final outcome was CR in six, PR in two, stable disease (SD) in one, and progressive disease (PD) in another patient. The overall response rate (CR + PR) was 80% (of ten patients). The follow-up was 2–22 months (mean 12.8 ± 7.1 months). The overall survival was calculated as 19.8 ± 7.4 months with eight out of ten patients still alive. Response duration was 15.2 ± 3.9 months, disease-free survival 13.3 ± 6.1 months, event-free survival 16.7 ± 9.0 months, and progression-free survival 18.2 ± 6.5 months. Four patients (stage I b and II b) achieved 12–19 months of disease-free survival. The follow-up after the first course with PEG- DOXO was 2–22 months (mean 12.8 ± 7.1 months). The survival rate after 12 months of follow-up was 80% (n=5). One patient free of relapse died after 12 months because of pulmonary embolism not related to disease or treatment. Another patient died 1 month after a second course of PEG-DOXO in an advanced tumor stage of CTCL. The most frequent side effects of treatment were anemia and lymphopenia without the need of supportive treatment or dose-reduction. Only one patient developed toxicity of grade 4 (anemia). Conclusions: These results indicate that patients with relapsing or recalcitrant CTCL can achieve an 80% response rate with PEG-DOXO and long-term remissions. Received: 26 April 2000 / Accepted: 9 June 2000     

High-dose therapy with peripheral blood stem cell transplantation for patients with relapsed or refractory Hodgkin's disease: long-term outcome and prognostic factors

 From March 1986 to March 1998, 82 patients with relapsed or refractory Hodgkin's disease underwent high-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) transplantation in our center. This is a retrospective analysis of the long-term clinical outcome. There were 52 males and 30 females with a median age of 32 years (range 18–59 years). Prior to transplantation, 36 patients were in complete remission (CR), 34 in partial remission (PR), and 12 had refractory disease after salvage therapy. For HDCT, 78 patients were treated with CBV (cyclophosphamide, 6.0–6.8 g/m²; etoposide, 1.0–1.6 g/m²; carmustine, 0.45–0.8 g/m²), while four patients received different regimens. Probability of freedom from progression (FFP), overall survival (OS), and event-free survival (EFS) at 5 years of the entire group was 63%, 61%, and 54%, respectively. Early mortality rate (≤100 days) declined from 17% to 6% after 1992. Five patients died of late transplant-related complications (>100 days), including secondary lymphoma and leukemia in two patients. None of the refractory patients survived beyond 3.5 years. Multivariate analyses identified extranodal sites of disease at relapse and refractory disease status prior to transplantation as significant prognostic factors for FFP, EFS, and OS. As we have shown in our study, remarkable progress was achieved in reducing early morbidity and mortality over time, but this was associated with only a slight, not significant improvement of long-term outcome (OS 66% vs 57% at 5 years for patients undergoing PBSC transplantation before and after 1992, P=0.26). Although the results as a whole are encouraging for chemosensitive patients, new therapeutic strategies are needed to reduce toxicity and improve the clinical outcome of patients, especially of those with a less favorable prognosis. Received: 12 October 1999 / Accepted: 29 February 2000     

Pentoxyphylline in association with vitamin E reduces cutaneous fibrosis in systemic sclerosis

Systemic sclerosis (SSc) is a disorder characterized by skin thickness and vasculopathy. The objective of the study was to evaluate the therapeutic effect and safety of the association of pentoxyphylline and vitamin E in SSc patients. Twelve SSc patients (American College of Rheumatology criteria) enrolled this 24-week open-label study. Patients received daily 800 mg of pentoxyphylline and 800 UI of vitamin E and were evaluated at 4-week interval. The primary efficacy endpoint was the change in Modified Rodnan Skin Score (MRSS) at week 24. Nine diffuse SSc patients treated 6 months with cyclophosphamide were used as a historical control group. The mean age of the treated group was 43.6 years, and ten of 12 (84%) patients were women. Their mean MRSS reduced from 25.7 to 18.7 (p = 0.03) at 16th week and remained significantly reduced throughout the study. In contrast, only a trend of MRSS reduction was observed in the historical control group (p = 0.06). Two patients started the study with active ischemic ulcers and ended with a complete healing of them. No serious side effects were reported. Pentoxyphylline and vitamin E might be an alternative therapeutic approach in SSc patients.     

A phase II study of weekly high-dose 5-fluorouracil and leucovorin plus biweekly alternating doxorubicin and cisplatin for advanced gastric carcinoma

On the basis of recent clinical data suggesting that high-dose continuous 5-fluorouracil (5-FU) is able to overcome resistance to 5-FU bolus application in gastric carcinoma, a phase II study was performed to evaluate the activity and toxicity of weekly high-dose 5-FU and leucovorin plus biweekly alternating doxorubicin and cisplatin as the first-line treatment in patients with advanced gastric carcinoma. Between October 1995 and September 1997, 24 consecutive patients with locally advanced (n = 4) or metastatic (n = 20) gastric carcinomas were treated with a combination of 500 mg/m² leucovorin as a 2-h infusion, followed by 2.0 g/m² 5-FU as a 24-h continuous infusion once weekly for 6 weeks, plus 20 mg/m² doxorubicin as a bolus application and 50 mg/m² cisplatin as a 1-h infusion, week 1, 3 and 5 (FLAP regimen). Response, toxicity and survival data were evaluated. A total of 20 patients were evaluable for response and 24 for toxicity. Objective responses were observed in 11 patients (55%) with no complete remission. Four patients (20%) showed stabilization and 5 patients (25%) experienced progressive disease. The median time to disease progression was 8 months and the overall duration of survival was 14 months. Myelosuppression was significant. In 2 patients, grade 4 WHO thrombocytopenia and leukopenia/anaemia respectively were registered, but there were no treatment-related deaths. We conclude that the weekly alternating FLAP regimen is effective in advanced gastric carcinoma with tolerable toxicity. However, significant myelotoxicity and frequent hospitalization suggest that FLAP should not be preferred to other regimens used in metastatic disease. Currently we intend to establish this regimen in the neoadjuvant setting in patients with primary unresectable localized gastric carcinomas. Received: 15 January 1998 / Accepted: 28 January 1998     

Increased angiogenin expression in gastric cancer correlated with cancer progression

Purpose: The purpose of this study is to elucidate the expression of angiogenin and its previously undemonstrated clinical significance in gastric cancer (GC). Methods: Angiogenin expression was examined immunohistochemically in 21 GC tissues and 21 corresponding normal gastric tissues. The serum concentration was determined by enzyme-linked immunosorbent assay (ELISA) in GC patients preoperatively (n=48) and postoperatively (n=41), in nonneoplastic patients preoperatively (n=23) and postoperatively (n=19), and in 32 healthy volunteers. The amount of angiogenin in the tissue of 21 GC patients was also determined by ELISA. Results: Angiogenin expression was observed in GC cells as well as in some fundic glandular cells and some inflammatory cells. The mean serum concentration in GC patients (407.8 ± 105.2 ng/ml) was significantly higher than that in the nonneoplastic patients (345.7 ± 58.3 ng/ml; P < 0.003) and in the healthy volunteers (333.0 ± 59.3 ng/ml; P < 0.0002). The mean serum angiogenin concentrations were progressively higher in the order T1+T2 (P < 0.04) < T3+T4 (P < 0.0001) < recurrent GC (P < 0.05) subgroups, in the order node-negative (P < 0.05) < node-positive (P < 0.0002) subgroups, and in the order stage I+II (P < 0.02) < stage III and over (P < 0.0005) subgroups as compared with those in the healthy volunteers. These elevated serum angiogenin concentrations in each subgroup were significantly (P < 0.0003) reduced after cancer resection. The amounts of angiogenin in GC tissues correlated significantly with the serum angiogenin concentration (P < 0.01). Conclusions: These results suggest that angiogenin expression is increased in GC and that the increased serum concentration in GC patients correlates with cancer progression. Received: 15 December 1999 / Accepted: 14 February 2000     

Additive cytotoxic effect of cisplatin and X-irradiation on human glioma cell cultures derived from biopsy-tissue

Purpose: Investigation of the in vitro cytotoxic effect of X-rays, either alone or combined with cisplatin on early passage cell cultures derived from human glioblastoma multiforme biopsy tissue. Materials and methods: Fresh tumour specimens from four patients were processed to cell cultures. The U373 glioma cell line was used as a reference. Early passage cell cultures were X-irradiated (0–8 Gy) either alone or in combination with cisplatin (0.5–1 μg/ml). Cell survival was determined by either clonogenic assay or the colorimetric MTT assay. Survival curves were generated and mathematically analysed using the linear quadratic model, to obtain the radiosensitivity parameters α, β, and SF2, i.e., the Surviving Fraction after 2 Gy. Results: Two patient-derived glioma cell cultures and the U373 cell line showed rather high SF2 values of 0.61–0.72 in the clonogenic assay, indicating relative high radiation resistance. Cisplatin alone (1 μg/ml) reduced cell survival by 10–30% (n=4). When combined with irradiation, a clear additive cytotoxic effect of cisplatin was demonstrated by the unaltered value of the α-parameter for reproductive cell death. Conclusion: Cisplatin exerted an additive rather than radiosensitising cytotoxic effect in uncharacterised patient derived glioma cell cultures. Received: 5 November 1999 / Accepted: 10 May 2000     

Severe non-haematological toxicity after treatment with gemcitabine

The authors report that 4 out of a series of 56 patients (7.1%) treated with gemcitabine developed an unexplained non-cardiogenic pulmonary distress syndrome most likely related to gemcitabine. One further patient developed ventricular arrhythmia immediately after gemcitabine exposure, leading to cardiac arrest. Between 1995 and 1998 56 patients with locally advanced or metastatic carcinoma were treated with gemcitabine. The patients suffered from breast cancer (n = 17), pancreatic cancer (n = 17), lung cancer (n = 12), cancer of unknown primary (n = 5), ovarian cancer (n = 2), oral cavity cancer (n = 2) and cancer of the bladder (n = 1). Their median age was 55 years, and there were 33 female and 23 male patients. Fifteen patients had been pretreated with radiation therapy: 2 had received radiation therapy involving the mediastinum as treatment for non-small-cell lung cancer and cancer of unknown origin respectively, 11 patients had had prior neoadjuvant or adjuvant radiation therapy of the chest wall for breast cancer and 2 patients had received radiation therapy for head/neck cancer. All patients received gemcitabine on days 1, 8 and 15 and this was repeated on day 29 at a dose of 1000 mg/m² as a 30-min infusion in 250 ml isotonic NaCl. In 4 patients gemcitabine treatment was combined with cisplatinum, in 7 patients with a somatostatin analogue and in 1 patient with epirubicin. All other patients received gemcitabine as a single agent. We assume that the pulmonary or cardiac toxicity of 5 patients was related to gemcitabine. In 3 patients re-exposure resulted in repeated toxicity. One patient did not receive gemcitabine again because of the life-threatening nature of the primary response. Two patients had received prior radiation to the mediastinum with 62 Gy and 50 Gy respectively, 3 years and 1 year before gemcitabine application. In our experience pulmonary toxicity after gemcitabine treatment is more common than initially anticipated. Gemcitabine should be used with caution in patients who have received prior radiation to the mediastinum. Received: 5 May 1999 / Accepted: 2 June 1999     

Heat shock protein 72 expression in chondrosarcoma correlates with differentiation

Purpose: Heat shock proteins (hsp) are involved in tumor immunity, and a correlation with survival, occurrence of metastases, and drug resistance has been reported. It was the aim of this study to investigate the expression of heat shock proteins in chondrosarcomas and chondromas. Methods: Hsp expression was investigated immunohistochemically on paraffin-embedded sections of 37 consecutive patients (24 male and 13 female, mean age 48 years) with chondrosarcoma and of ten patients (six male, four female, mean age 36 years) with chondroma. Results: Chondromas showed a positive staining for hsp27 in 100%, for hsp60 in 30%, for hsp72 in 80%, for hsp73 in 80%, and for hsp90 in 90%. In chondrosarcoma a decreased expression was found for hsp27 (62% positive, P < 0.05) and hsp72 (43% positive, P < 0.05), whereas no significant difference to chondromas was detected in the expression of hsp60 (49% positive), hsp73 and hsp90 (73% and 81% positive, respectively). In addition, hsp72 expression showed a correlation with differentiation of the tumors (P < 0.05); the lowest hsp72 expression was found in G3 chondrosarcomas (only 13% positive). No correlation with respect to differentiation was found for the expression of the other hsps. Conclusions: This study shows a different expression of hsps in chondrosarcomas and chondromas. Together with the correlation of hsp72 expression with low differentiation, this finding could lead to new experimental and diagnostic strategies. Received: 18 February 2000 / Accepted: 9 May 2000     

Intestinal permeability in patients with chemotherapy-induced stomatitis

Purpose: Mucositis represents one of the most common side effects of chemotherapy, and may affect any part of the gastrointestinal tract, resulting in stomatitis, dysphagia, dyspepsia, or diarrhea. The aim of the present study was to evaluate intestinal permeability in patients with stomatitis during treatment with oral granulocyte-monocyte colony-stimulating factor (GM-CSF, Leucomax). Methods: Ten patients with chemotherapy-induced stomatitis and 21 control cancer patients were included in the study. Intestinal permeability in patients with stomatitis was evaluated before and after the treatment with oral GM-CSF (200 μg for 4 consecutive days) by measuring urinary lactulose, D-xylose, and mannitol after oral challenge in collected urine using capillary gas chromatography. Results: Mean grade of stomatitis (3, range 2–3) improved during treatment by a mean of 1 grade (range 0–2, sign test P < 0.05) with an improvement observed in eight of ten patients. Lactulose excretion, lactulose/mannitol, and lactulose/xylose ratios were markedly elevated in the patients with mucositis compared with 21 control cancer patients (1.60 ± 1.04%, 0.2446 ± 0.2937, and 0.3877 ± 0.6808 vs 0.35 ± 0.20%, 0.0332 ± 0.0148, and 0.0255 ± 0.0086, respectively, Mann Whitney U-test, P < 0.001). After treatment, lactulose excretion, lactulose/mannitol, and lactulose/xylose ratio decreased significantly (1.60 ± 1.04 vs 0.63 ± 0.42%; 0.2446 ± 0.2937 vs 0.1303 ± 0.1149; and 0.3877 ± 0.6808 vs 0.1126 ± 0.1146, respectively, P < 0.05). Conclusions: Lactulose excretion after oral challenge, lactulose/mannitol, or lactulose/xylose ratio may be useful markers for intestinal involvement in chemotherapy-induced mucositis. Improvement of oral mucositis was associated with a significant decrease of intestinal permeability to lactulose. Testing of intestinal permeability by the present method may be useful to evaluate the effect of therapeutic interventions in patients with chemotherapy-induced mucositis. Received: 13 July 2000 / Accepted: 29 August 2000