A randomised phase II/III study was conducted in patients with advanced breast cancer to determine the dose intensity achievable through an acceleration of administration of chemotherapy with epidoxorubicin and cyclophosphamide (EC) alone, as compared with the combination of this regimen with two different schedules of granulocyte-macrophage colony stimulating factor (GM-CSF). 73 patients received EC intravenous (i.v.) (epidoxorubicin 100 mg/m2, cyclophosphamide 600 mg/m2) on day 1 (group A), or the same chemotherapy plus sub-cutaneous (s.c.) GM-CSF (5 micrograms/kg/day) either from days 3 to 12 (group B) or from days -6 to -3 (group C). The primary objective of the study was the investigation of dose intensity delivered in the three treatment arms, whereas the secondary objective was response rate. A significant increase (P = 0.006) in dose intensity of 21% was observed for treatment group B, whereas the increase in dose intensity achieved in group C (7%) was not significant (P = 0.086). Response rates (complete response (CR) + partial response (PR)) of 56% were observed in group A, 65% in group B, and 57% in group C, respectively. This difference in response rates did not reach statistical significance (P = 0.271). We thus conclude that an acceleration of the EC regimen over the standard schedule could be accomplished with postchemotherapeutic GM-CSF support, leading to an increase in dose intensity, whereas pretherapeutic short-term GM-CSF administration did not reach this goal.

The use of bolus 5-fluorouracil (5-FU) as a short-term infusion over 10-30 min is increasing at the cost of a push injection, mainly due to practical advantages. Since even a short prolongation of the administration time results in lower 5-FU peak and area under the curve (AUC) levels, there might be a risk of decreased efficacy. The aim of this study was to compare a rapid intravenous (i.v.) 5-FU injection and a short-term 5-FU infusion with respect to objective responses and toxicity in patients with advanced colorectal cancer. 203 patients with measurable advanced colorectal cancer were randomised to bolus 5-FU either as an injection for 2-4 min or as a short-term infusion lasting 10-20 min. In both groups, the 5-FU dose was 500 mg/m2 and leucovorin 60 mg/m2 was given 40 min after the start of 5-FU. Treatment was given on two successive days every other week until progression. Objective tumour regression was seen in 27/100 (27%) in the injection group and in 13/103 (13%) in the infusion group (P = 0.02). Severe toxicity was rare and did not differ significantly between the groups. Progression-free survival tended to be longer in the injection group (P = 0.07), but overall survival did not differ between the groups. Bolus 5-FU should be administered as a rapid i.v. injection rather than as a short-term infusion, since the former rate of administration results in a higher response rate without being significantly more toxic.

We performed a randomized clinical trial to assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with advanced Hodgkin's disease in complete remission (CR) after conventional chemotherapy. One hundred and thirty-five patients (stage IIIB-IV B) were initially treated with EBVD (epirubicin, bleomycin, vinblastine, dacarbazine). IF CR was achieved they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU three times a week for one year or no further treatment (control group). Clinical and laboratory characteristics at diagnosis were quite similar in both groups. After a median follow-up of 74.3 months (range 49 to 108), 61 out of 68 patients (91%; 95% confidence interval (CI): 76% to 97%) remain in first complete remission in the IFN-treated group compared to 38 out of 67 (58%; 95% CI: 49% to 71%) in the control group (p<.01). Overall survival was also better in the IFN treated group: 62 patients (92%; 95% CI: 82% to 97%) are alive free of disease at 7-years compared to 40 patients (67%, 95%: 55% to 76%) in the control group (p<.01). Toxicity secondary to IFN administration was mild and no dose modification was necessary during treatment. All patients received the planned dose of IFN. This was not an intent-to treat analysis. IFN administration as maintenance therapy was appears to be the only cause of improvement in outcome in these patients. We feel that IFN should be considered as maintenance therapy in patients with advanced Hodgkin's disease because this treatment improves the final outcome without the excessive toxicities of more aggressive therapeutic approaches such as bone marrow transplantation during first CR. We hope that IFN will be considered in future randomized clinical trials in order to define it's role in the treatment of Hodgkin's disease.

Previous studies have demonstrated a beneficial effect of intraperitoneally applied mitomycin bound to activated carbon particles (M-CH) in preventing intraabdominal recurrence following curative surgery for gastric cancer. The Austrian Working Group for Stomach Cancer, a subgroup of the Austrian Working Group for Surgical Oncology, initiated a multicentric phase III trial to evaluate the safety and efficacy of this treatment regimen.

This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy.

High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 x 10(6) units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140-200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multicentre studies in the setting of minimal residual disease following autologous transplantation.

Oral mucositis is a frequent complication of radiochemotherapy. The origin of radiation-induced mucosal lesions is iatrogenic in nature, although further development of mucositis is essentially influenced by infection. It can be assumed that disinfection measures should decrease the severity of mucositis induced by radiochemotherapy. Therefore, in a prospective randomised study the efficacy of prophylactic oral rinsing with a disinfection agent was investigated. A randomised, prospective comparative trial was conducted with 40 patients undergoing radiochemotherapy of the head and neck region because of malignant disease. The treatment scheme consisted of irradiation to the tumour region and adjacent lymph nodes, with a total dose of 71.3 Gy, and simultaneous chemotherapy with carboplatin (60 mg/m2) on days 1-5 and 29-34. In all patients mucositis prophylaxis with nystatin, rutosides, panthenol and immunoglobulin was undertaken. In addition, 20 patients rinsed the oral cavity 4 times daily with povidone-iodine solution, while the group for comparison rinsed with sterile water. Clinical examination of the oral mucosa was performed weekly. Onset, grading and duration of mucositis were used as the main variables. Clinically manifest oral mucositis was observed in 14 patients in the iodine group (mean grading: 1.0) and in all 20 patients in the control group (mean grading: 3.0). The total duration (mean) of clinically observed mucositis was 2.75 weeks in treatment patients and 9.25 weeks in control patients. Median AUC (area under curve for grade vs duration) was 2.5 in the iodine rinsing patients and 15.75 in control patients. All differences found between the two groups were statistically significant. Increased iodine incorporation was not observed. A pathologic rise in thyroid hormone levels was not found in the iodine group. The results obtained indicate that incidence, severity and duration of radiochemotherapy-induced mucositis can be significantly reduced by oral rinsing with povidone-iodine in addition to the standard prophylaxis scheme. It can be concluded that rinsing with povidone-iodine is an easy, cheap and safe prophylactic method and can be recommended as a supportive treatment during antineoplastic treatment of the head and neck region.

This study evaluated whether relapse of acute promyelocytic leukemia (APL) patients from clinical remissions achieved and/or maintained with all-trans retinoic acid (RA) in combination with intensive chemotherapy is associated with leukemic cellular resistance to RA and with alterations in the PML-RARalpha fusion gene. We studied matched pretreatment and relapse specimens from 12 patients who received variable amounts of RA, primarily in nonconcurrent combination with daunorubicin and cytarabine (DA) on Eastern Cooperative Oncology Group (ECOG) protocol E2491, and from 8 patients who received DA only on protocol E2491. Of 10 RA-treated patients evaluable for a change in APL cell sensitivity to RA-induced differentiation in vitro, 8 showed diminished sensitivity at relapse, whereas, of 6 evaluable patients treated with DA alone, only 1 had marginally reduced sensitivity. From analysis of sequences encoding the principal functional domains of the PML and RARalpha portions of PML-RARalpha, we found missense mutations in relapse specimens from 3 of 12 RA-treated patients and 0 of 8 DA-treated patients. All 3 mutations were located in the ligand binding domain (LBD) of the RARalpha region of PML-RARalpha. Relative to normal RARalpha1, the mutations were Leu290Val, Arg394Trp, and Met413Thr. All pretreatment analyses were normal except for a C to T base change in the 3'-untranslated (UT) region of 1 patient that was also present after relapse from DA therapy. No mutations were detected in the corresponding sequences of the normal RARalpha or PML (partial) alleles. Minor additional PML-RARalpha isoforms encoding truncated PML proteins were detected in 2 cases. We conclude that APL cellular resistance occurs with high incidence after relapse from RA + DA therapy administered in a nonconcurrent manner and that mutations in the RARalpha region of the PML-RARalpha gene are present in and likely mechanistically involved in RA resistance in a subset of these cases.

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 microg/kg G-CSF (n = 18) or 24 microg/kg G-CSF (n = 7, including one patient with previous 10 microg/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) x 10(6) CD34+ cells/kg, 8.5 (4.5-24) x 10(8) MNC/kg, 2.9 (0.6-39.4) x 10(4) CFU-GM/kg, and 5.6 (0.9-49) x 10(4) BFU-E/kg were harvested. Three patients (12%) with extensive melphalan pretreatment failed the target collection of at least 2.0 x 10(6) 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 x 10(6)/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.

The efficacies of granisetron plus dexamethasone and dexamethasone alone in controlling delayed nausea and vomiting after cisplatin chemotherapy (> or = 69 mg/m2) were compared in a multicentre, double-blind, placebo-controlled comparative study.

The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens.

A combination of irinotecan hydrochloride (CPT-11; 160 mg/m2, intravenous infusion, day 1) and cisplatin (5-day continuous intravenous infusion; 20 mg/m2/day) was administrated to advanced non-small cell lung cancer patients. They were given Hangeshashin-to (TJ-14), a Kampo medicine, to prevent the occurrence of irinotecan-induced diarrhea. The authors studied the Kampo medicine's clinical usefulness in a randomised comparative trial. Subjects in the study comprised 41 non-resectable and untreated non-small cell lung cancer patients. A daily dosage of 7.5 g Hange shashin-to was divided into three portions, each of which was given to the subjects orally before each meal. The subjects began taking the medicine three or more days before the start of chemotherapy, and continued taking it more than 21 days after starting chemotherapy. A total of 18 patients received TJ-14, and 23 did not. Compared with the latter, those given the Kampo medicine reported a significant (p = 0.044) improvement in the grade of diarrhea, and had a lower incidence of diarrhea grade 3 and above (p = 0.018). However, no differences were seen among the two groups in terms of the frequency of diarrhea and the duration of the diarrhea. As side effects, two patients developed grade 1 constipation. These findings showed that TJ-14 was effective in preventing and alleviating the incidence of diarrhea induced by CPT-11.

In this preliminary study the efficacy of high-dose methylprednisolone (HDMP) during remission-induction chemotherapy was evaluated on 166 children with acute lymphoblastic leukemia (ALL). The St. Jude Total Therapy Study XI protocol with minor modifications was used in this trial. Patients were randomized into two groups. Group A received conventional-dose (2 mg/kg/day orally) prednisolone, and group B received high-dose methylprednisolone (HDMP, Prednol-L, 900-600 mg/m2 orally) during remission-induction chemotherapy. Complete remission was achieved in 97% of the children. For the 80 patients who were followed up for 3 years, median follow-up was 44 (range 5-60) months and the 3-year event-free survival (EFS) rate was 68.5%) overall, 58.6% in group A and 78.4% in group B. The EFS among patients in group B was significantly higher than in group A (p=0.05). When we compared the 3-year EFS of groups A and B in the high-risk groups and high-risk subgroups with white blood cell (WBC) counts > or = 50 x 10(9)/l and age > or = 10 years, the survival rates were 45% versus 77.2%, 33% versus 78% and 45% versus 89%, respectively. During the follow-up of 162 patients, relapses were significantly higher in group A. Bone marrow relapses in 162 patients, and also in a subgroup of patients > or = 10 years of age were significantly higher in group A. These results suggest that HDMP during remission-induction chemotherapy improves long-term EFS, particularly for high-risk patients.

The aim of this study was to investigate whether tamoxifen toxicity and treatment discontinuations differed in the adjuvant versus chemopreventive setting.

Tamoxifen, a drug with antioestrogenic effects, is predicted to prevent the occurrence of breast cancer. We have undertaken a trial of tamoxifen in healthy women who are at increased risk of breast cancer because of family history. We report a planned interim analysis.

Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive.

We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy.

To assess the efficacy and maximum dose-intensity of a new topoisomerase I (topo I)-targeting agent, 9-aminocamptothecin (9-AC), in patients with relapsed or refractory lymphomas.

To compare progression-free survival (PFS), overall survival (OS), and toxicity of a doxorubicin-containing regimen administered alone or in combination with interferon alfa-2b (IFNalpha) in patients with low-grade follicular lymphoma (FL) and poor prognostic factors.