Treatment of relapsed and refractory acute leukaemia with high-dose cytosine arabinoside and etoposide

Summary A total of 65 patients under the age of 55 with acute leukaemia received high-dose cytosine arabinoside (Ara-C) in combination with high-dose etoposide without an anthracycline. Complete remission rates for patients with relapsed or refractory acute myelogenous leukaemia (AML) were 15/25 (60%) and 11/16 (69%), respectively. The complete remission rate for patients with refractory or relapsed acute lymphoblastic leukaemia (ALL) was 10/18 (56%). The treatment-related mortality was 17%. Nine patients whose leukaemia relapsed after matched allogeneic, sibling bone-marrow transplantation (BMT) were also treated in this way; the treatment-related mortality in this group was high (7/9) and the duration of remission in the two patients who responded, too short to justify this intensive treatment in such patients. Similarly, patients who underwent BMT after achieving a complete remission with high-dose Ara-C and etoposide did very poorly, only one patient surviving well and disease-free at 8 months. The important finding in this study was the high complete remission rate rapidly obtained in patients with relapsed or refractory AML without using an anthracycline.     

Antiemetic therapy in patients treated with high-dose cytosine arabinoside

The antiemetic efficacy of metoclopramide (MCP) was evaluated in 33 consecutive patients treated with high-dose cytosine arabinoside (HiDAC), greater than or equal to 3 g/m2, a highly emetogenic agent increasingly used in patients with hematologic malignancies for which no previous formal antiemetic trials have been reported. Administration of MCP in conjunction with prophylactic diphenhydramine resulted in major antiemetic responses (0-2 episodes of emesis in the 24 h after therapy) in 23 of 33 (70%) patients. The addition of lorazepam (LZP) to MCP resulted in major antiemetic response in 7 or 8 (88%) patients who failed to respond to MCP alone. Major side effects were extrapyramidal reactions (5%) and moderate diarrhea (18%). MCP alone or in conjunction with LZP is effective antiemetic therapy in patients treated with HiDAC.     

Cerebellar toxicity with high-dose cytosine arabinoside

CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of high-dose cytosine arabinoside, administered to 62 patients, did not increase the incidence of severe cerebellar toxicity, which occurred in five (8%) of these patients. Two of the five patients had severe toxicity with the initial course. Of the 60 patients with no antecedent cerebellar dysfunction, three (5%) had severe toxicity with the second course: one of 41 patients were less than 50 years old; two of 19 patients were greater than or equal to 50 years. Since the occurrence of severe cerebellar dysfunction is greatly affected by age, reduced doses of high-dose cytosine arabinoside should be given to patients greater than 50 years old, and methods for reducing the cerebellar toxicity should be investigated in these patients.     

Phase I study of weekly high-dose cisplatin combined with long-term oral etoposide in advanced solid tumors

BACKGROUND: In a previous phase I study we showed that single-agent cisplatincan be given weekly for six weeks at a dose of 80 mg/m²/wk.It has been suggested that etoposide has synergistic activitywith cisplatin and the drug can be given orally continuously.We therefore performed a phase I study with weekly cisplatincombined with oral etoposide. PATIENTS AND METHODS: Nineteen patients with metastases of a solid tumor were enteredin the study. Cisplatin was administered in hypertonic saline(NaCl 3%). Etoposide was administered as 50-mg capsules. RESULTS: The starting dose was cisplatin weekly at a dose of 70 mg/m²for six weeks combined with daily oral etoposide at a dose of50 mg. At the maximum tolerable dose of cisplatin 75 mg/m²/wkand etoposide 50 mg/m² daily, leukocytopenia and thrombocytopeniawere dose-limiting toxic effects which resulted in frequenttreatment delays. Other toxicities were mild. Finally, a doseof cisplatin 70 mg/m²/wk weeks 1–2–3 and weeks 5–6–7in combination with etoposide 50 mg orally days 1–15 anddays 29–43 combined a high median cisplatin dose intensityof 52.5 mg/m²/wk with a good patient tolerance. CONCLUSION: It is feasible to administer frequently dosed cisplatin in combinationwith oral etoposide. Leuko-cytopenia and thrombocytopenia aredose-limiting toxicities. The schedule will be explored furtherin phase n studies. phase I, cisplatin, etoposide, dose intensity     

Phase I study of Doxil and vinorelbine in patients with advanced malignancies

Introduction. This study was designed to define the maximum tolerated dose of pegylated liposomal doxorubicin (Doxil®) and multiday vinorelbine (VNB), without and with prophylactic filgrastim, and to identify antineoplastic effect. Patients and Methods: Patients with resistant cancers were treated with Doxil 50 mg/m² every four weeks, and with VNB 15 mg/m² on the same day. The VNB dose escalations were accomplished in subsequent patient cohorts by adding VNB doses on consecutive days. When the maximum tolerated dose (MTD) of VNB with Doxil was defined, prophylactic filgrastim was added to define a second MTD. Results. Of 29 patients entered, two had early adverse events, and 27 received at least one full cycle with at least one month follow-up. The MTD of VNB, combined with Doxil 50 mg/m², was 15 mg/m² on day 1, with neutropenia as the dose-limiting toxicity. With prophylactic filgrastim, the MTD was15 mg/m² daily for two days, with neutropenia and stomatitis as dose-limiting toxicities. Palmar plantar erythrodysesthesia occurred frequently, usually after the third cycle. Objective responses were documented in six patients, all of whom received multiday VNB. Conclusion. Doxil 50 mg/m² on day 1 of a 28-day cycle can be safely combined with VNB 15 mg/m2 day 1, or with VNB 15 mg/m² days 1 and 2 with filgrastim prophylaxis. Antineoplastic activity was observed in this heavily pretreated population. Future studies of Doxil 35-40 mg/m² with multiday VNB may be worthwhile, especially in metastatic breast cancer.     

Results of therapy with high-dose cytosine arabinoside

Four patients with acute leukemias resistant to various ARA-C containing regimens and one patient with rapidly progressive malignant nonseminomatous tumor of the testis, who failed to conventional therapy were treated with HD ARA-C from december 1979 to september 1980. The drug was monitored by HPLC in plasma and in CSF. The first patient received only one course of HD ARA-C, developed fever and died of septicemia ten days later. The leucocyte count of her AML (FAB 2) decreased from 120,000/microliter to 30,000/microliter on the third day after HD ARA-C. Patient 2 reached CR criteria of the bone marrow for 23 days, then resistant AML (FAB 2) recurred. A male patient of 30 years was treated for recurrent acute undifferentiated leukemia (AUL) with a high cumulative dose of 176 gs of ARA-C. The repeated courses of treatment included a period of 50 days of CR. Toxicity was remarkable including pulmonal and cerebral dysfunction. A fourth patient with monocytic leukemia did not respond to HD ARA-C, neither did the patient with the malignant teratoma. Adverse reactions were tolerable. Only the third patient suffered from severe toxicity, pneumonitis, blurring vision, cerebral dysfunction and dermatitis. His pretreatment regimen had included X-ray prophylaxis to the skull. Since there was no possibility to prolong the remission duration in 1980, we decided not to treat further patients with HD ARA-C. Nowadays bone marrow transplantation offers some patients a capability of eradication of the leukemic disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurotoxicity associated with systemic high-dose cytosine arabinoside

High doses of cytosine arabinoside (ara-C) have been used in the treatment of refractory forms of acute nonlymphoblastic leukemia (ANLL) and ANLL occurring after previous antineoplastic therapy. In addition to the usual toxicities associated with antimetabolites, neurotoxicity, mainly in the form of cerebellar dysfunction, develops in a significant proportion of patients receiving high-dose cytosine arabinoside HDara-C. This study was performed to determine the incidence of cerebellar dysfunction in our patients and to determine any factors that predict its development. In this series of 30 consecutive patients receiving HDara-C, confusion with cerebellar signs and symptoms developed in seven (23%). Factors that appear to predispose patients to the development of neurotoxicity are (1) past history of neurologic dysfunction and (2) preexisting and progressive hepatic dysfunction. No peripheral neuropathy was seen. In contrast to previous reports, we did not find neurotoxicity to be dose related. Prophylactic use of pyridoxine does not prevent neurotoxicity.     

Phase I study of rubitecan and gemcitabine in patients with advanced malignancies.

BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.     

Phase I trial of high-dose tamoxifen in combination with cisplatin in patients with lung cancer and other advanced malignancies

BACKGROUND: Tamoxifen has been reported to enhance the antitumor activity of cisplatin in preclinical models by modulation of protein kinase C signal transduction and apoptosis-related pathways. METHODS: We conducted a phase I study of high-dose oral tamoxifen in combination with intravenous cisplatin, with two objectives: 1) to determine tolerability, and 2) to determine the daily tamoxifen dose required to achieve serum levels equivalent to in vitro concentrations reported to enhance cisplatin cytotoxicity in preclinical models. Tamoxifen was administered days one through seven at escalating daily doses of 160 mg/m2 (n = 5), 200 mg/m2 (n = 6), and 250 mg/m2 (n = 4) by patient cohort, followed by cisplatin at 100 mg/m2 on day eight. Serum concentrations of tamoxifen and its hydroxylated metabolite N-desmethyltamoxifen were determined by high-performance liquid chromatography (HPLC) on day eight of the first treatment cycle in seven patients. RESULTS: Fifteen patients with advanced malignancies received treatment with tamoxifen at 160 mg/m2, 200 mg/m2, and 250 mg/m2 per cycle, respectively. Serum concentrations of tamoxifen and N-desmethyltamoxifen on day eight of the first cycle ranged from 1.75-8.22 microM (mean 4.72 microM) and 3.62-10.85 microM (mean 3.87 microM), respectively. Toxicity analysis demonstrated that grade 3/4 nonhematological toxicity occurred in 0/5 at a tamoxifen dose of 160 mg/m2, 1/6 at a tamoxifen dose of 200 mg/m2, and in 1/4 patients at the 250 mg/m2 dose level. No grade 4 hematological toxicity occurred. Classic dose-limiting toxicity was not observed; the trial was closed to further accrual after documentation that targeted tamoxifen levels (around 5 microM) were achieved with daily tamoxifen doses > or = 160 mg/m2 in combination with cisplatin. CONCLUSIONS: This regimen of high-dose tamoxifen in combination with cisplatin can be safely administered. Serum tamoxifen levels comparable to concentrations required for enhancement of cisplatin sensitivity in vitro are clinically achievable with acceptable toxicity. The level of antitumor activity in nonsmall cell lung cancer NSCLC is encouraging (partial response in 4/10 patients). Based on these data, a Phase II study of high-dose tamoxifen in combination with cisplatin in patients with metastatic NSCLC is being conducted through the Southwest Oncology Group.     

Phase I study of doxil-cisplatin combination chemotherapy in patients with advanced malignancies.

PURPOSE: Our first objective was to evaluate the feasibility of administering a combination of Doxil, a pegylated liposome formulation of doxorubicin, and cisplatin and to determine the maximum tolerated dose of the combination. A secondary objective was to examine Doxil peak and 7-day postinjection plasma levels at the various dose levels tested. METHODS: Patients with advanced solid tumors were treated every 4 weeks with cisplatin on day 1 and Doxil on day 2. In the first three dose levels, the dose of Doxil was fixed at 40 mg/m(2), whereas the dose of cisplatin was escalated from 40 to 50 and 60 mg/m(2). At the fourth and fifth dose levels, the dose of cisplatin was fixed at 60 mg/m(2), whereas the dose of Doxil was escalated to 50 and to 60 mg/m(2). Plasma Doxil (doxorubicin-equivalent) levels were measured by a high-performance liquid chromatography assay with fluorescence detection at 1 h and 7 days after infusion of Doxil. RESULTS: Twenty-six patients entered the study. Twenty-four patients completed a minimum of 2 courses and were fully assessable for toxicity and efficacy. Eighteen patients had received prior chemotherapy, 11 of them with anthracycline-containing regimens. A total of 177 courses were administered within the study. In 12 patients, cisplatin was discontinued after 1 to 13 courses, and Doxil was continued alone for 1-22 courses. All other patients received both drugs until discontinuation of therapy. The dose-limiting toxicities were neutropenia and mucositis. Grade 4 neutropenia was seen in 3 patients (one with neutropenic fever) at dose levels 4 and 5. Grade 3 mucositis was observed in 4 patients at dose levels 3, 4, and 5. In contrast, the most severe palmar-plantar erythrodysesthesia manifestation was grade 2 seen in 1 patient only. Tumor responses included seven partial responses, of which three were in ovarian cancer patients. In four of seven responders, the time to disease progression exceeded 1 year. Doxil 1-h (C(max) equivalent) levels were assessed in 20 patients. The mean Doxil C(max) (mg/l plasma) increased gradually with dose escalation from 14.7 +/- 1.9 for 40 mg/m(2), to 17.3 +/- 3.0 for 50 mg/m(2), and 23.3 +/- 5.5 for 60 mg/m(2). The 60 mg/m(2) C(max) was similar to data obtained in parallel clinical studies at our institution with single-agent Doxil at 60 mg/m(2). However, the 7-day Doxil postinfusion levels were significantly lower in patients receiving the Doxil-cisplatin combination than in those receiving single-agent Doxil. CONCLUSION: Doxil can be administered at full maximum tolerated dose (50 mg/m(2) every 4 weeks) in combination with 60 mg/m(2) cisplatin, with no evidence of major overlapping toxicities. Palmar-plantar erythrodysesthesia incidence and severity appears to be diminished, in comparison with data available for single-agent Doxil. Plasma concentration data point to an accelerated clearance of Doxil when administered after cisplatin.     

Phase I study of high-dose cisplatin,ifosfamide, and etoposide

To test the feasibility of a regimen of high-dose cisplatin, ifosfamide, and etoposide (VP-16; VIPP regimen), we registered 15 patients with advanced non-small-cell lung cancer in a phase I trial of the Northern California Oncology Group. One cycle of treatment consisted of high-dose cisplatin given at 100 mg/m² i.v. on days 1 and 8, VP-16 given at 60–75 mg/m² i.v. on days 1–3, plus ifosfamide given at 1.0–1.2 g/m² i.v. on days 1–3; cycles were repeated every 28 days. There were 13 men and 2 women; the median age was 59 years (range, 47–72 years). The median Karnofsky performance status (KPS) was 90 (range, 70–100). All patients were assessable for toxicity and response. The median number of cycles delivered per patient was two (range, one to four). Hematologic toxicity was dose-limiting and required de-escalation of the ifosfamide and VP-16 doses. Ten patients developed a white blood count of <1000/mm³ and seven patients developed a platelet count of <50,000/mm³. The duration of cytopenia increased progressively with each subsequent cycle of therapy. Two patients required antibiotics for neutropenic fever with documented infections (pneumonia, bacteremia). Seven patients received red blood cell transfusions for a hemoglobin level of <8 gm/dl. Grade III or IV non-hematologic toxicities were uncommon and involved one patient each with grade 3 ototoxicity and grade 3 neurotoxicity. Five patients developed laboratory evidence of renal salt wasting. The overall response rate was 33% (5/15) with a complete response being achieved by two patients (13%) and a partial response being attained by three (20%). The overall median survival was 44 weeks. We conclude that although this regimen demonstrated activity, hematologic toxicity limited its use in the palliative treatment of non-small-cell lung cancer. Using hemopoietic growth-factor support to permit dose escalation, this schedule of VIPP may be of interest in a number of different chemotherapy-sensitive tumor types.     

Phase I study of pegylated liposomal doxorubicin and gemcitabine in patients with advanced malignancies

BACKGROUND: Pegylated liposomal doxorubicin (PEG-LD) and gemcitabine have single-agent activity in breast and ovarian carcinoma patients. We conducted a Phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in patients with advanced malignancies. METHODS: Twenty-six patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of PEG-LD 20 mg/m(2) and gemcitabine 1000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. RESULTS: The MTD was PEG-LD 20 mg/m(2) and gemcitabine 2000 mg/m(2) administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicity, a Grade 3 rash, was observed in one patient during Cycle 1 and Grade 3 stomatitis and a rash were observed in a second patient during Cycle 2 after administration of PEG-LD 25 mg/m(2) and gemcitabine 2000 mg/m(2). Other side effects included palmar-plantar erythrodysesthesia, nausea, and fatigue. One complete and two partial responses were observed. CONCLUSIONS: The recommended Phase II dose is PEG-LD 20 mg/m(2) with gemcitabine 2000 mg/m(2) on Days 1 and 15 of a 28-day cycle. A trial with this combination is currently ongoing at this institution comprising patients with refractory ovarian carcinoma.     

Phase I toxicity and pharmacology study of trimethylcolchicinic acid in patients with advanced malignancies

Summary A phase I study of trimethylcolchicinic acid (TMCA) given orally once daily for 5 days every 3rd week was performed in 19 patients with advanced malignancies. Myelosuppression and mucositis were the major toxicities observed. Serum TMCA levels were monitored and appear to be useful in predicting toxicities. A partial response was seen in one lymphoma patient and stabilization of disease was noted in one patient each with prostatic and ovarian cancer. Supported in part by NIH DRR GCRC grant MOI RR-43     

Cutaneous toxicity associated with high-dose cytosine arabinoside.

High-dose cytosine arabinoside (HDAC) is used to treat adults with acute and chronic leukemia and non-Hodgkin's lymphoma. Although HDAC is associated with various toxicities, cutaneous toxicity in particular leads to alterations in comfort, interference with daily living activities, and increased risk of infection. The incidence of cutaneous toxicity ranges from 3%-72%. A review of the literature revealed a variety of terms describing this toxicity, which begins as erythema and progresses to painful swelling, bullae formation, and desquamation. The etiology is unclear, and the severity is related to the number of consecutive doses. Interventions specific to prevention and treatment of this toxicity were found to be minimal, with no interventions scientifically examined. The challenge for nurses is to explore measures that will minimize the complications, treat the manifestations, and document the impact of these problems on quality of life.     

Phase I clinical and pharmacokinetic study of thiotepa administered intraperitoneally in patients with advanced malignancies

An important subset of malignancies arising in the ovary or digestive organs remains confined to the peritoneal cavity throughout its natural course. These tumors constitute appropriate targets for loco-regional therapy. With this rationale a clinical phase I and pharmacokinetic study of intraperitoneally administered N, N', N' triethylenethiophosphoramide (thiotepa), an alkylating agent with activity against ovarian carcinoma, was initiated with the objectives of determining the systemic and local toxicities, maximum-tolerated dose, and pharmacokinetic advantage associated with using the drug in this manner. A total of 13 patients received 15 courses of intraperitoneal thiotepa at doses ranging from 30 mg/m2 to 60 mg/m2. The only important systemic toxicity observed was myelosuppression. At 50 mg/m2 two patients developed Eastern Cooperative Oncology Group (ECOG) grade III myelosuppression. At 60 mg/m2, the maximum-tolerated dose, the mean nadir WBC and platelet counts were 2.7 X 10(3)/microliter and 110 X 10(3)/microliter, respectively. There were no instances of vomiting, stomatitis, or alopecia. Pharmacokinetic studies performed in nine patients revealed that thiotepa was rapidly lost from the peritoneal cavity in a biexponential fashion with a mean t1/2 alpha of 0.26 +/- 0.08 hour and a mean t1/2 beta of 2.13 +/- 0.52 hour. Concomitant with the rapid loss of drug from the peritoneal cavity was the rapid rise in drug levels in the plasma, with peak plasma values approaching those associated with intravenous administration. Peritoneal exposure to thiotepa expressed as the area under the curve (AUC)peritoneal fluid was 7 to 34 micrograms/mL X hour. Systemic exposure expressed as the AUCplasma ranged between 0.95 and 7.71 micrograms/mL X hour. The observed pharmacokinetic advantage of intraperitoneal administration calculated as AUCperitoneal fluid/AUCplasma was 4.3 +/- 0.6. This relatively small advantage, combined with our observation of rapid appearance of the active metabolite, tepa, into the plasma argue against an important role for intraperitoneal administration of thiotepa.     

A phase I, II study of high-dose 5-fluorouracil and high-dose leucovorin with low-dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.     

Phase II study of etoposide (NK 171) in advanced hematological malignancies

A clinical study of a new semisynthetic podophyllotoxin etoposide (NK 171) was performed in patients with various hematological malignancies refractory to standard chemotherapies. The drug was given intravenously in a dose of 100-130 mg/m2/day for five days or orally in a dose of 130-170 mg/m2/day for five days. Out of 9 patients with non-Hodgkin's lymphoma, 2 CR and 4 PR were obtained; out of 4 acute nonlymphoblastic leukemias, 1 CR, and out of 4 chronic myerogenous leukemias 2 CR and 1 PR, were obtained. The dose limiting factor was leukopenia, and alopecia was frequent while other hematologic and gastrointestinal toxicities were mild. Etoposide (NK 171) had no clinical cross resistance to other antitumor agents, thus warranting further clinical trials, in combination chemotherapy against NHL, ANLL and CML-BC.     

Hepatic dysfunction and jaundice following high-dose cytosine arabinoside

Two patients with poor-prognosis leukemia were treated with high-dose cytosine arabinoside (Ara-C), 3 g/m2, for induction. Both patients developed serious jaundice in the second posttreatment week. Clinically, the jaundice was characterized by conjugated hyperbilirubinemia, normal amino transferase levels, significant elevation of alkaline phosphatase, and no evidence of obstruction. Microscopic examination of the liver showed only passive congestion with blood, and no bile lakes or plugs. This was believed to be most consistent with drug-induced intrahepatic cholestasis, possibly as a result of injury to the hepatocyte transport system.     

A pilot study of short-course, high-dose cytosine arabinoside, etoposide, and cisplatin in refractory, aggressive-histology, non-Hodgkin's lymphomas

Twenty-three patients with refractory, aggressive-histology, non-Hodgkin's lymphomas were treated with cytosine arabinoside (2.0 g/m2 i.v. every 12 h on days 1 and 2), etoposide (100 mg/m2 i.v. on days 1 and 2), and cisplatin (35 mg/m2 i.v. on days 1 and 2) every 3 weeks. All patients had received one or two prior chemotherapy regimens. Five of 19 (26%) evaluable patients responded, with a median duration of response of 9 weeks (90% confidence interval: 11-48%). One patient with a complete response remains free of disease over 31 months after completing six cycles of therapy. Six transient responses of less than 1-month duration were also observed. Hematological toxicity was significant: 73% of patients experienced grade 4 neutropenia, and 52% experienced grade 4 thrombocytopenia. Twenty patients (87%) underwent dose reductions following their first cycle of therapy for grade 3 or 4 myelosuppression. We conclude that this combination of drugs, when administered by this schedule, has limited antitumor activity; however, administering the regimen with a dose-intense schedule appears warranted.