Laszlo Boros

A Randomized Phase II Trial of Two Schedules of Docetaxel in Elderly or Poor Performance Status Patients with Advanced Non-small Cell Lung Cancer

Background: We conducted a multicenter randomized phase II trial to evaluate two schedules of single-agent docetaxel in the first-line treatment of elderly and performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients 70 years of age and older with a PS 0–1 or patients of any age and PS 2 were randomly assigned to docetaxel 75 mg/m2 on day 1 every 3 weeks or 30 mg/m2 on days 1, 8, and 15 every 28 days. The primary end point was frequency of grade 3/4 toxicities. Health-related quality of life, response, and survival were secondary end points. Results: Fifty-five patients were randomized to received docetaxel every 3 weeks and 56 to receive docetaxel weekly. Hematologic toxicity, primarily grade 3/4 neutropenia, was significantly lower in the weekly schedule (0% versus 44%; p < 0.001). Health-related quality of life was similar between the two arms. Efficacy parameters were not significantly different, with a trend toward better survival in the weekly schedule group (6.7 versus 3.5 months). Patients with PS 0–1 had a significantly longer survival compared with PS 2 patients (7.8 versus 2.9 months; p < 0.001). A subset analysis of 30 octogenarian patients revealed similar outcomes as in 70- to 79-year-old patients. Conclusion: Weekly docetaxel is associated with less neutropenia and a trend toward improved survival in elderly or PS 2 patients. PS rather than age is the primary determinant of outcome in this population. Octogenarians benefited from weekly docetaxel. Future studies should separate elderly patients from PS 2 patients.

Leukemia in rochester (NY) a 17-year experience with an analysis of the role of cooperative group (ECOG) participation

Every adult acute nonlymphocytic leukemia patient in Rochester, New York seen from January 1975 to January 1982 was studied. Fifty percent of the patients did not receive combination chemotherapy. Among those who did, there was a significant selection bias toward placing patients with better prognostic features on protocol. Protocol patients were also treated with higher doses of chemotherapy than nonprotocol patients. However, these factors did not completely explain the significantly better complete response (CR) rate and survival among protocol patients. Eastern Cooperative Oncology Group (ECOG) participation remained an independent variable associated with a better outcome. An improvement in CR rate was seen during the 7‐year period studied as compared to that seen between 1965 and 1974. The study provided evidence that the availability and use of ECOG protocols was a positive factor in the improvement of leukemia treatment in Rochester.

Trisomy 5 as sole anomaly in acute lymphoblastic leukemia

We present a case of B-cell acute lymphoblastic leukemia (ALL) in whose leukemic cells trisomy 5 (+5) was the only cytogenetic anomaly observed. This is the first report of +5 as the sole cytogenetic abnormality in ALL; two cases (one questionable) of acute nonlymphocytic leukemia with such a change have been reported. The findings are presented in relation to other cases with +5 as part of a more complicated cytogenetic picture in hematologic disorders.

Ifosfamide, carboplatin and etoposide (ICE) in metastatic and refractory breast cancer.

Abstract Twenty-five patients with metastatic breast cancer were treated with ICE after failure of previous chemotherapy. Their median age was 50 years (range 36–73). All but 1 patient had multiple sites of metastases. Nineteen (76%) patients had undergone two or more chemotherapy regimens for metastatic disease prior to ICE. The performance status (PS) of the patients was Eastern Cooperative Oncology Group (ECOG) 0:6; 1:12; 2:5; 3:2. Ifosfamide 1.25 g/m2 over 3 h D1-3 along with mesna, etoposide 80 mg/m2 D1-3 and carboplatin 300 mg/m2 D1 were given every 3 weeks. We observed a partial response in 10 patients (40%, 95% confidence interval 21–62%). The response duration ranged from 1 to 15 months with a median duration of 4.5 months. The survival of all 25 patients ranged from 10 days to 25 months, with a median of 9 months. All 25 patients were evaluable for toxicity. Thirteen patients (52%) experienced grade 4 hematological toxicity, which improved after growth factor support. Four patients had leukopenic fever, 1 had gram-negative sepsis, while 2 had Clostridium difficile enterocolitis and another had herpes zoster reactivation. Four patients (16%) experienced grade 3–4 gastrointestinal (G-I) toxicity. No hepatic or renal toxicity was observed (1 patient had microscopic hematuria). One patient died of G-I bleed, and another patient died at home of undetermined cause. We conclude that ICE is an effective salvage regimen in metastatic and refractory breast cancer, even in heavily pretreated patients, and is a tolerable treatment when used with growth factor.

5-Fluorouracil and high-dose folic acid treatment for metastatic colon cancer

Twenty-two patients with metastatic colorectal cancer were treated with a regimen of 5-fluorouracil 600 mg/m2 (maximum, 1.0 g) i.v./week and folic acid 140 mg/m2 i.v. given 1 h prior to the 5-FU. This study was undertaken in an attempt to confirm the in vitro finding that inhibition of thymidylate synthetase by 5-fluorouracil is prolonged by the presence of folates. There were four partial responses (18%) with mean duration 4 months. Dose-limiting toxicity was enteritis, seen in 12 patients (58%), and causing hospitalization in seven patients. Enteritis was shown to be due to the folic acid in most patients. Two patients died from leukopenia, enteritis, and sepsis. Mean serum folate levels at the time of 5-FU injection were 36 μM. This regimen is no more effective than 5-FU alone and has significantly more serious toxicity. Further investigation of this regimen is not recommended.

Pharmacokinetics of very high-dose oral melphalan in cancer patients

The pharmacokinetics and systemic availability of melphalan after high-dose oral administration with and without 1,3− bis(2-Chloroethyl)-l-nitrosourea (BCNU) or etoposide were examined in three patients undergoing autologous bone marrow transplantation. Patient 1 (advanced melanoma) received melphalan at 80 mg/m2/day p.o. on days −6, —5, and −4, followed by BCNU at 300 mg/m2/day i.v. on days −3, —2, and —1 prior to bone marrow transplantation. Patient 2 (advanced colon carcinoma) received melphalan at 75 mg/ m2/day p.o. on days −3, —2, and — 1. Patient 3 (advanced refractory lymphoma) received etoposide at 800 mg/m2/day i.v. on days —7, —5, and —3, followed by melphalan at 157 mg/m2/day p.o. on days −2 and −1. Melphalan was administered as a bolus oral dose, using 2-mg tablets. Blood samples were collected at 0, 5, 10, 15, 30, and 45 min and 1, 2, 3, 4, 6, 8, 12, and 24 h after each dose of melphalan. Peak plasma melphalan concentrations in the three patients ranged from 0.354 (patient 2) to 1.768 μg/ml (patient 1). Plasma melphalan concentration × time products (C × Ts) showed extreme variability in one patient (patient 2), ranging from 0.76 to 4.48 μg · h/ml. To determine the relative systemic availability of orally administered melphalan, i.v. C × Ts proportional to the p.o. doses were extrapolated from previously reported i.v. bolus pharmacokinetic data. The p.o.:i.v. plasma C × T ratios for high-dose melphalan ranged between 0.09 (patient 3) and 0.58 (patient 2). Although these C × T data suggest a dose-response for orally administered melphalan, the systemic availability of these high p.o. melphalan doses was extremely variable, both within and between study patients. Thus, we cannot recommend the use of high-dose p.o. melphalan regimens in patients undergoing autologous bone marrow transplantation.

13-cis-retinoic acid in the treatment of elderly patients with acute myeloid leukemia. A phase II pilot study of the Eastern Cooperative Oncology Group.

The management of acute myeloid leukemia in the elderly (65 years and older) is unsatisfactory because of poor patient tolerance of standard myeloablative chemotherapy. The authors conducted a Phase II study to evaluate the effectiveness and toxicity of 13‐cis‐retinoic acid (CRA) in the therapy of elderly patients with acute myeloid leukemia (AML). Patients presenting with leukocyte counts less than 20,000/μ1 were treated with CRA alone. Those with leukocyte counts of 20,000/μ1 or greater were pretreated with hydroxyurea, followed by CRA. Twelve of 18 patients received at least 4 weeks of CRA and were thus considered evaluable for toxicity and response. No objective responses were observed. Cis‐retinoic acid administration was well tolerated; only modest dermatologic, musculoskeletal, and gastrointestinal toxicity was observed. Alternative therapeutic strategies should be investigated in this subpopulation of AML patients.

Leukemic dermal infiltrates as a complication of central venous catheter placement

A leukemic dermal infiltrate at the site of a central venous catheter placement was the first manifestation of relapse in a 58‐year‐old woman in clinical remission of acute myelomonocytic leukemia. The patient developed a large hematoma around the site of an unsuccessful attempt to place a central venous (CV) catheter. Although the hematoma resolved completely by the time that complete remission was achieved, an indurated, erythematous mass subsequently developed, which when biopsied revealed leukemic cells in the dermis. The patient had a relapse in her peripheral blood shortly thereafter. The authors reviewed recent literature and their own experience with CV catheters and report on localized dermal relapse as a previously unpublished risk of CV catheter placement. They also speculate on the role of the dermis as a sanctuary for leukemic cells and a potential source for relapsing disease.

Phase II study of ifosfamide, carboplatin, and etoposide in patients with advanced non-small cell lung cancer

This study was to define the efficacy of ifosfamide, mesna, carboplatin, and etoposide (ICE) in patients with metastatic non-small cell lung cancer (NSCLC). From September 1990 to October 1991, 33 patients were treated with ifosfamide/mesna 1.25 g/m2/day and etoposide 80 mg/m2/day intravenously from days 1 to 3, and carboplatin 300 mg/m2 on day 1 every 4 weeks. There were 20 male patients and 13 females. The median age was 65 (range: 38–79). Seventeen patients had a performance status (PS) of 0 or 1, and 16 had a PS of 2 or 3. All had measurable diseases. Nine had initial treatment for localized disease with concurrent radiation, 5-fluorouracil, and interferon-α2b and four had radiation only. None had received chemotherapy for metastatic disease. There were nine partial responses (PR) (27.3%, 9/33) with a median response duration of 8 months (range: 2–16 months). Five patients had stable diseases (SD), which lasted for 3, 6+, 7+, 10+, or 13.4 months. The median survival was 8 months for PR and SD and 4 months for the entire group. Patients with PS of 2 or 3 were less likely to respond (18.8% vs 35.3%) and had a shorter median survival (2.7 months vs 6 months) than patients with better PS. Dose-limiting toxicity was myelo-suppression. Seventeen (51.5%, 17/33) patients developed grade III-IV leukopenia with four septic episodes and three septic deaths. Grade III or IV thrombocytopenia was seen in five patients. Patients with prior radiation were significantly more prone to develop leukopenia (P < .005). Gastrointestinal toxicity was mostly mild. No neurologic or genitourinary toxicity was observed. In conclusion, ICE is active in patients with advanced NSCLC and good PS. Besides myelosuppression, it is well tolerated. Further study is indicated to evaluate if granulocyte-colony stimulating factor can reduce myelo-suppression from ICE in good PS patients.

Distribution characteristics of mitoxantrone in a patient undergoing hemodialysis

SummaryThe pharmacokinetic profile of mitoxantrone in a patient undergoing hemodialysis is described. Significant characteristics of our patient included lymphoma with liver involvement, tumor lysis syndrome, renal and hepatic failure. Combination chemotherapy consisted of mitoxantrone, vincristine, and cyclophosphamide. Mitoxantrone plasma samples were obtained prior to dosing and at 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.5, 7.0, and 12 h after the intravenous infusion of a 17-mg dose over 20 min. Serum concentrations were determined by high-performance liquid chromatography. The serum concentration versus time curve was consistent with a three-compartment model. However, rebounds in serum drug concentrations were detected during the last portion of dialysis and after its completion. The gamma elimination half-life could not be determined due to the continued detection of rebounds in drug concentrations throughout the postdialysis sampling period. The alpha and beta distribution phases did not appear to be affected by hemodialysis. The peak mitoxantrone concentration fell within the reported range. Mitoxantrone does not appear to be eliminated by hemodialysis, and dose adjustments are not needed in patients undergoing this procedure.