Advanced breast cancer: a phase II trial with gemcitabine.

PURPOSE: In this phase II study, the efficacy and tolerability of gemcitabine were studied in 44 patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by a 1-week rest every 4 weeks. The mean number of completed cycles administered was 2.7 and the mean dosage delivered was 725 mg/m2 per injection. Eighty-one percent of doses were delivered as scheduled. RESULTS: There were three complete responses and seven partial responses, for an overall response rate of 25.0% (95% confidence interval [CI], 12.7% to 41.2%). Four patients were not assessable for efficacy (one had insufficient therapy, two had no bidimensionally measurable disease, and one had neither). All responses were independently validated by an external oncology review board. Responses were observed early in treatment, with a median time to response of 1.9 months. The median survival duration for all 40 assessable patients was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization (WHO) grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.3% and 7.0%, of patients, respectively. The only other grade 4 toxicities were infection and nausea and vomiting in one patient each. One patient was withdrawn due to shortness of breath, possibly drug-related. Flu-like symptoms, which were mild, transient, and treatable with acetominophen, were reported in 6.8% of patients. Only one patient developed alopecia of severity greater than WHO grade 2. CONCLUSION: In view of the single-agent activity seen in advanced breast cancer, modest toxicity profile, and novel mechanism of action, gemcitabine deserves evaluation in breast cancer and is an ideal candidate for combination therapy.

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin's disease (HD). PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Anagrelide for treatment of patients with chronic myelogenous leukemia and a high platelet count.

Chronic myelogenous leukemia (CML) is usually treated with hydroxyurea or interferon-alpha. In some patients high platelet counts develop although leukocyte counts are well controlled with these drugs. If in such a situation cytoreductive therapy has to be intensified by a increase of the dosage, anemia and leukocytopenia as well as adverse effects of the drugs are likely to occur. In twelve CML patients we have therefore combined the basic CML treatment with anagrelide. This drug which selectively reduces platelet counts has been shown to be efficacious in the control of thrombocytosis in essential thrombocythemia. The diagnosis had been confirmed in all CML patients by cytogenetic and/or molecular biological analysis. The median age of our group was 58 years. Five were women and seven men. All patients were on treatment with hydroxyurea, some of them had previously received treatment with interferon-alpha (alone or in combination with hydroxyurea), busulfan or melphalan. Prior to the initiation of anagrelide treatment the platelet count was between 970,000 and 3,600, 000/microl (median about 2,000,000/microl). Seven patients had thrombohemorrhagic complications. All twelve patients, experienced hematologic responses, since their platelet counts decreased to less than 600,000/microl. The median platelet count after reduction was 343,000/microl. The median dosage required to achieve these responses and to maintain them for a period of at least four weeks was 1.9 mg/day. Thrombohemorrhagic complications disappeared or did not recur in all symptomatic patients. Adverse effects were seen in 3/12 patients: headache (1), tachycardia (1), palpitation (1) and fluid retention (1). Whereas these symptoms were mild and transitory they caused one patient to request discontinuation of treatment. Currently five patients are still on treatment with anagrelide (median duration of treatment 11 months) while therapy had to be discontinued in the seven others because of bone marrow transplantation, development of osteomyelofibrosis, blast crisis or on patient request. In our experience anagrelide is a useful therapeutic adjunct when thrombocytosis in patients with CML cannot properly controlled alone with traditional drugs.

Anagrelide, a novel platelet lowering option in essential thrombocythaemia: treatment experience in 48 patients in Germany.

We report on our treatment experience in Germany with anagrelide, a novel platelet lowering agent, in 48 patients (27 females, 21 males) with essential thrombocythaemia. Their age was between 19 and 79 yr when anagrelide therapy was initiated. Sixteen patients were previously untreated, 15 pretreated with hydroxyurea and 17 had multiple pretreatments. Forty-one of the 48 patients had either microvascular, thromboembolic or bleeding complications. About 50% received low dose acetylsalicylic acid as an adjunct. Their platelet count prior to therapy ranged from 850,000/microl to 3,100,000/microl. Eighty-seven per cent of the patients treated with anagrelide were complete hematological responders, while 13% responded only partially or failed to respond. Twelve of our patients (25%) developed short-term (from a few days to a maximum of 4 wk) side effects including headache (most frequent), palpitations, tachycardia or nausea. Eight patients reported long-term (more than 1 month) adverse effects. However, in only 5 of all 48 patients (10%) were these side effects not acceptable so that treatment had to be discontinued. We have now treated patients for up to 7 yr (median maintenance dose 2.5 mg/d). Preliminary evidence suggests that anagrelide mediated platelet count reduction also prevents recurrence of thromboembolic complications. Hence, anagrelide has the potential to become the first-line platelet-lowering treatment in myeloproliferative disorders with high platelet counts.

Chemotherapy dose and survival in advanced Hodgkin's disease.

We analysed the effect of chemotherapy dose reductions on survival in 35 patients with Hodgkin's disease stage IIIB or IV treated at our institution by three double courses of C-MOPP/ABVD chemotherapy followed by either one further course or by involved-field radiotherapy. Patients receiving reduced doses of alkylating agents had markedly slower responses and worse survival than those not requiring dose reductions. This experience with a very limited number of cases suggests that dose intensity may be an important prognostic factor in advanced Hodgkin's lymphoma, although dose reductions might have been necessary in patients with an intrinsically poor prognosis. Prospective randomized trials comparing standard chemotherapy with intensified protocols supported by hematopoietic growth factors are needed and are being conducted to determine the role of total chemotherapy dose and delivery time in the cure of Hodgkin's disease.

Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer.

BACKGROUND: To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. PATIENTS AND METHODS: Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2). RESULTS: Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). CONCLUSIONS: The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.