Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.

Cancer-related fatigue is the most disabling symptom experienced by breast cancer patients following the cancer treatment. The positive effects of physical activity in the rehabilitation of breast cancer patients are documented in several studies. In a randomized controlled study the effects of a structured physical training program on fatigue and health-related quality of life were evaluated. Patients and Methods: 63 breast cancer patients with cancer-related chronic fatigue were randomized at the beginning of the inpatient rehabilitation. The control group received the standard complex rehabilitation program, the intervention group a structured physical training program and additional muscle strength and aerobic exercises. The effects of the treatment were evaluated by questionnaires at the start of rehabilitation (t1), end of rehabilitation (t2), and 3 months after t2 (t3). Isometric muscle strength and aerobic capacity were evaluated at t1 and t2. Results: There was an improvement of muscle strength at the end of rehabilitation for both groups. The increase from t1 to t2 was significantly higher for the training group. The scores for global quality of life, physical well-being, and functionality increased from t1 to t2, but further improvement in the follow-up (t3) was only observed in the training group. The cancer-related fatigue was significantly reduced in the training group from t1 to t3, however, not in the control group. Conclusions: Structured physical training programs initiated during inpatient rehabilitation and continuously practiced in the time thereafter can improve symptoms of chronic fatigue and quality of life in breast cancer patients.

Tumor necrosis factor (TNF) is a cytokine produced in vivo by activated macrophages and monocytes with pleiotropic effects on normal and malignant cells. TNF is cytotoxic to several tumor cell lines in vitro and in vivo. Phase I and phase II trials have been conducted to determine toxicity to humans and to evaluate responses. Recent investigations will be reviewed. Despite promising results in vitro and in vivo, data from systemic administration in the treatment of malignancies have been disappointing. Local administration has been successful. Therefore, we suggest that future efforts concerning TNF administration in the treatment of malignancies should aim at local treatment.

The purpose of this paper was to define the histologic distrito the endemic (African) and sporadic forms of Burkitt lymbution, clinical features, and treatment response of childhood phoma, which differ in their clinical presentation, regional non-Hodgkin lymphoma (NHL) in northeastern Brazil. We incidence, association with Epstein-Barr virus, and biologic Patients and methodsThere was a striking predominance of the small noncleaved cell (Burkitt) subtype, which occurred in 92 of the 98 children and adolescents diagnosed with NHL. Subsequent analyses Between January 1980 and October 1987, a total of 98 chilfocused on these patients. The majority (n = 84) had advanced dren were diagnosed with non-Hodgkin lymphoma at the parental refusal/abandonment of therapy (10%). Epstein-BarrDiagnostic imaging studies were performed as indicated. virus (EBV) was detected in tumor cells from eight of the 11The pathologic diagnosis was established by histologic Of the 98 patients evaluated during the study period, 92 had small noncleaved cell histology. There were only five cases of lymphoblastic lymphoma and one of large cell histology. Having confirmed the predominance of Burkitt lymIntroduction phoma among the pediatric patients with NHL, we then focused on these 92 cases. Records were reviewed to evaluate The non-Hodgkin lymphomas of childhood are predominantly clinical and biological features, type of treatment, and outhigh-grade extranodal tumors that include the lymphoblastic, come. When sufficient paraffin-embedded tumor tissue was large cell, and small noncleaved cell subtypes. 1 The relative available, in situ RNA/RNA cytohybridization using plasmids frequency of these subtypes varies with geographic location.containing EBV-encoded small nuclear RNA was performed In the United States, the distribution is almost equal, 2 whereas at St Jude Children's Research Hospital to detect the presence small noncleaved cell tumors (Burkitt lymphoma) account for of Epstein-Barr virus DNA. 6 In these cases, the histologic diagthe majority of childhood NHLs in equatorial Africa. 3,4 In nosis was also reviewed and confirmed by a pediatric hematonortheastern Brazil -an area in which we have established a pathologist at St Jude (CWB). cooperative clinical program -anecdotal evidence suggests an increased overall incidence of lymphoma. However, to our knowledge, there have been no reports focusing on pediatric Hodgkin or non-Hodgkin lymphomas in this region. TreatmentWe noted an apparent predominance of the small noncleaved cell histology among children treated for NHL at a There were two distinct treatment periods. From 1980 to major pediatric cancer center in Recife, Brazil. In the present 1983, all consenting patients were treated with induction study, we evaluated the accuracy of this clinical impression chemotherapy similar to that used in the LSA 2 L 2 regimen and assessed long-term treatment outcome. We also sought to described by Wollner et al, 7 followed by maintenance therapy determine the relationship of the small noncleaved...

Background: Major endpoint for the assessment of a complex inpatient rehabilitation program is the health-related quality of life. In a prospective longitudinal study we evaluated the subjective well-being of breast cancer patients by different methods. Patients and Methods: 183 breast cancer patients were asked to complete six different questionnaires at three different time points: t1: start of treatment, t2: end of treatment, t3: 3 months after t2. Results: In the Hospital Anxiety and Depression Scale (HADS-D) we observed high mean scores for anxiety (8.73) and depression (5.55), as compared to a healthy control population (5.8 and 3.34, respectively). There was a significant improvement for both scores at t2 (6.84 and 4.77, respectively) and for anxiety at t3 (7.68). This was confirmed by the FBK questionnaire showing a significant decrease of the psychological distress in the t1/t2 and t1/t3 time periods as well. The global health score of the QLQ-C30 instrument increased significantly at the end of the rehabilitation and was maintained at the 3-month follow-up. This was true for most of the functional subscales as well. Older widowed women with 3–4 accompanying diseases had the most profit from the program. Using the Perceived Adjustment to Chronic Illness Scale (PACIS), we observed significantly less effort of coping with the illness at t2 and t3. Conclusions: At the end of a complex rehabilitation program for breast cancer patients, the health-related quality of life improved in several domains. While after a 3-month follow-up the scores were still better than before the treatment, anxiety and depression increased again. Therefore, the good results of the rehabilitation program should be maintained by continuous ambulatory treatment.

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A total of 144 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin/etoposide (PE) or ifosfamide/etoposide (IE) combination chemotherapy. PE consisted of cisplatin, 80 mg/m2, intravenously (IV) on day 1, and etoposide, 150 mg/m2, IV on days 3 through 5. IE consisted of ifosfamide, 1,500 mg/m2, IV on days 1 through 5, and etoposide, 120 mg/m2, IV on days 3 through 5. Six cycles were administered in 3-week intervals. Nonresponders were switched immediately to CAV, consisting of cyclophosphamide, 600 mg/m2, IV on days 1 and 2, Adriamycin (Adria Laboratories, Columbus, OH), 50 mg/m2, IV on day 1, and vincristine, 2 mg, IV on day 1. Patients obtaining complete remission (CR) received prophylactic cranial irradiation with 30 Gy. After completion of chemotherapy, patients with limited disease received chest irradiation with 45 Gy. No maintenance therapy was given to patients in CR. Minimum follow-up was 2 years. Of the 141 patients evaluable, the overall response rate was 65% in PE therapy and 68% in IE therapy. The CR rate was 32% v 20% for all patients, 50% v 24% for limited disease, and 22% v 18% for extensive disease, all in favor of PE therapy. Median survival for all patients was 11.6 months v 9.4 months, for limited disease 14.8 months v 11.0 months, and for extensive disease 8.9 months v 7.5 months, all preferring PE therapy. The 2-year survival rate was higher in PE therapy than in IE therapy for all patients (12% v 9%) and for limited disease (23% v 10%), but not for extensive disease (5% v 9%). Median progression-free survival was 7.5 months v 6.0 months for all patients, 12.2 months v 8.8 months for limited disease, and 5.9 months v 4.4 months for extensive disease, all in favor of PE. Relapse in the area of the primary tumor was found less often after PE than after IE therapy (25% v 38%). Response to second-line CAV was seen in 30% of patients with prior PE and 43% with prior IE therapy, but was usually short lasting, and only one patient achieved CR. Toxicity included three lethal complications. Nausea, vomiting, diarrhea, and skin lesions occurred more often after PE than after IE therapy. These results suggest that PE is superior to IE chemotherapy in limited-stage, but not in extensive-stage SCLC, and that CAV is cross-resistant to PE, as well as to IE in the majority of patients.

Background: Characteristic features of multiple myeloma are bone resorption, osteoporosis and osteolytic lesions. Bisphosphonates can inhibit osteoclast activity and bone resorption. In this controlled randomized multicenter trial the effect of the bisphosphonate clodronate on the progression of bone involvement in multiple myeloma was evaluated. Patients and Methods: 170 patients with multiple myeloma requiring treatment and with bone involvement were recruited and randomized. All patients received 15 mg/m² i.v. melphalan on day 1 and 60 mg/m2 p.o. predisone on days 1-4 every 4 weeks. Patients randomized to the bisphosphonate arm received 1,600 mg clodronate p.o./day for 1 year. Bone response was evaluated on the basis of X-ray controls of the skeleton at baseline, 6, and 12 months staging. In addition chemotherapy response, blood chemistry, cytology, pain, and analgesic drug consumption were documented. Results: After one year of treatment there was a higher bone response in the clodronate group (13%) when compared to the control group (6%, n.s.). The difference was mainly due to the change of the osteolytic lesions. Hypercalcemia was observed more often in the control group. The number of progressive sites was lower in the clodronate group (mean 0.49 vs. 0.66, result after one year, p = 0.09). The bone resorption index was significantly reduced in the clodronate group, but not in the control group. A reduction of pain and analgesic consumption was observed under clodronate treatment.