Central nervous system toxicity with high-dose cytosine arabinoside.
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Acute Disease↗
Biomedical subjects
S N Wolff
Publications and source records attributed to S N Wolff.
High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study.
High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.
Acute Disease↗
Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow.
Twenty-seven patients with malignant lymphoma in whom primary chemotherapy had failed and the prognosis was poor were treated with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow. The median time to recovery of more than 500 neutrophils per microliter and more than 10,000 platelets per microliter was 18 and 24 days, respectively. Complete remission was achieved in 15 patients (56 per cent), five of whom were in continuous remission at this writing 19 to 71 months after transplantation without further therapy and one of whom was alive in a subsequent remission at 20 months. Fifteen patients died of lymphoma, three of interstitial pneumonitis, two of sepsis, and one of congestive heart failure. This experience shows that intensive therapy and autologous-marrow transplantation can produce prolonged remissions in patients with malignant lymphoma in whom conventional chemotherapy has failed.
Adolescent↗
The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation.
Forty patients with limited-stage small cell carcinoma of the lung were prospectively evaluated for adjuvant surgery after intensive chemotherapy to determine resectability. All patients giving informed consent and having a Karnofsky performance status greater than or equal to 50% were included in the study, which ran from May, 1980, to September, 1982. Ages ranged from 40 to 70 years (median, 59 years). One patient was lost to follow-up. Thirty-nine patients were evaluated for operation 9 to 15 weeks after diagnosis and after having received two to four cycles of chemotherapy intravenously every 3 weeks (cyclophosphamide, 1,000 mg/m2; doxorubicin, 50 mg/m2; vincristine, 1 mg/m2; VP-16, 300 mg/m2). Two patients had clinical Stage I tumors; 12 patients, Stage II; and 25 patients, Stage III. At the time of reevaluation there were 13 (33%) complete responders, 21 (54%) partial responders, and 5 (13%) with stable disease. Eleven (28%) of the 39 patients underwent thoracotomy using standard resection criteria for non-small cell carcinoma. Eight of these 11 had resectable lesions (2, Stage I; 3, Stage II; 3, Stage III); five pneumonectomies and three lobectomies were performed. Tumor was present in six of eight specimens. Twenty-eight patients were not candidates for operation for various reasons: poor pulmonary function, 5; unresectable tumors, 10; refusal, 6; very poor medical condition, 6; and primary site not identified, 1. Median survival for complete responders was 17 months and for partial responders, 11 months. We have prospectively identified suitable candidates for adjuvant surgery among the total group (denominator population) of patients with limited-stage small cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
High-dose VP-16-213 monotherapy for refractory germinal malignancies: a phase II study.
VP-16-213 at standard dose is one of the more active agents for the treatment of germ cell tumors. In previous phase I studies, VP-16-213 has been investigated in suprastandard dose when hematopoietic reconstitution was assured by autologous bone marrow transplantation (ABMT). This phase II study was performed to explore the possibility that an augmented dose of VP-16-213 may be more active than standard dose against germ cell tumors. Eleven patients with progressive refractory germ cell tumors were treated with high-dose VP-16-213: 2,400 mg/m2 with ABMT every three to four weeks followed by 1,200 mg/m2 without ABMT. Seven patients had received VP-16-213 at standard dose prior to high-dose VP-16-213. Toxicity to high-dose VP-16-213 included severe myelosuppression, nausea, vomiting, alopecia, mucositis, and hepatitis. Of 10 evaluable patients, two complete responses and four partial responses, all of short duration, were obtained. However, some patients unresponsive to standard-dose VP-16-213 exhibited responses to the augmented-dose VP-16-213. Therefore, although more myelosuppressive, VP-16-213 may have increased activity against germ cell tumors when administered at augmented dose. High-dose VP-16-213 may be considered in designing new approaches for initial management of patients with germ cell tumors not expected to be cured with standard chemotherapy.
Adolescent↗
Pharmacokinetics of high-dose etoposide (VP-16-213) administered to cancer patients.
Plasma urine, and cerebrospinal fluid etoposide concentrations have been measured in 12 adult patients after administration of high-dose (400 to 800 mg/sq m) etoposide in order to determine the pharmacokinetics of this drug at these elevated dosages. Increasing the drug dosage produced proportionally higher peak plasma etoposide concentrations (27 to 114 micrograms/ml) and total areas under the concentration-time curve (9,200 to 48,000 micrograms/ml X min). The etoposide mean (+/- S.D.) terminal half-life of 8.05 +/- 4.3 hr and plasma clearance of 28.0 +/- 9.7 ml/min/sq m, however, were independent of the dosage given. The mean etoposide renal clearance in 5 patients was 10.0 +/- 4.3 ml/min/sq m, representing from 35 to 40% of the total clearance of this drug from plasma. Cerebrospinal fluid etoposide concentrations ranged from 0.1 to 1.4 micrograms/ml, as measured in 6 patients at 1 to 8 hr after high-dose etoposide therapy, and were 1.8 +/- 1.7% of the simultaneously measured plasma levels. Pleural fluid removed from one patient at 18 hr posttherapy contained etoposide at 1.8 micrograms/ml. Our data, combined with data published previously, indicate that the pharmacokinetics of high-dose etoposide is linear within the dosage range tested and similar to that seen with lower drug doses. They also suggest that etoposide penetrates poorly into the cerebrospinal fluid.
Etoposide↗
Intensive 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), NSC #4366650 and cryopreserved autologous marrow transplantation for refractory cancer. A phase I-II study.
One hundred forty-three patients with refractory cancer were treated with intensive BCNU (600-2850 mg/m2) and autologous marrow transplantation to determine the maximum tolerated dose and antitumor effects of this regimen. Recovery from severe pancytopenia in less than 4 weeks after transplantation occurred in 92.8% of evaluable patients, suggesting the efficacy of the autologous marrow in limiting the prolonged myelosuppression anticipated with intensive BCNU. Serious extramedullary toxicity was encountered at BCNU 1200 mg/m2, where a 9.5% incidence of fatal interstitial pneumonitis and a 3.0% incidence of fatal hepatic necrosis was observed. Higher BCNU doses, 1500 to 2850 mg/m2, were associated with a 35.3% incidence of fatal hepatotoxicity. Fatal encephalomyelopathy was encountered in two patients given BCNU 2250 and 2850 mg/m2. One patient who received the highest cumulative dose of BCNU (3450 mg/m2 in 2 courses) died of cardiac necrosis. Other serious extramedullary toxicities were not encountered, even in the 14 patients who survived from 1 to nearly 5 years after BCNU therapy. Antitumor responses occurred in 40.0% of evaluable patients; a dose effect could not be evaluated due to patient heterogeneity. The BCNU doses associated with acceptable toxicity, 600 to 1200 mg/m2, produced a 37.5% total and an 11.3% complete response (CR) rate, including five patients with prolonged CRs of 1 to nearly 5 years. Notable among the CRs was the 25.0% CR rate in previously untreated metastatic melanoma, and the production of CRs in malignant disease in the central nervous system (CNS) including melanoma, lung cancer, adenocarcinoma of unknown primary, acute leukemia and glioblastoma multiforme. It is concluded that augmented doses of BCNU can be given when autologous marrow transplantation is used to limit myelosuppression. Lung and liver toxicity prevent the use of BCNU doses greater than 1200 mg/m2; neurotoxicity, and perhaps cardiotoxicity, are manifestations of the highest doses used in this study. The antitumor activity of BCNU 600 to 1200 mg/m2 remains to be determined for most neoplasms; these results suggest improved results in melanoma and CNS malignancy compared to conventional-dose BCNU therapy.
Adolescent↗
Antigens in chromatin associated with proliferating and nonproliferating cells.
Xenoantisera were raised to total chromatin from the leukemia cell line K562, or materials released through limited deoxyribonuclease I digestion of nuclei or during the control incubation of nuclei without enzyme. The peroxidase-antiperoxidase method of antibody-antigen detection was employed to visualize individual antigens resolved on one-dimensional polyacrylamide gels following transfer to sheets of nitrocellulose (immunotransfers). Each antiserum contained multiple antigen specificities as evidenced by the diverse patterns of reactive bands displayed on the immunotransfers. The most striking difference in antigens recognized between the antisera was observed in the molecular weight region below 50,000, where two highly reactive bands were seen mainly with antiserum to nuclear materials released by deoxyribonuclease I digestion. The antigens detected with all of the antisera were present in chromatins prepared from proliferating cells, while the levels of antigens present in chromatin from non-proliferating peripheral blood lymphocytes were greatly reduced or not detected. Antigens in chromatin from proliferating cells that migrated with apparent molecular weights of 37,000 and 100,000 were not lost once the activities to antigens in lymphocyte chromatin were absorbed out. These two activities were absorbed from antisera with the same amount of chromatins from proliferating cells. Two antigens migrating at molecular weight 52,000 and 76,000 appeared more active in the chromatin from unstimulated lymphocytes than in chromatin from proliferating cells.
Cell Division↗
Neoplastic meningitis. Marked variations of cerebrospinal fluid composition in the absence of extradural block.
Cerebrospinal fluid levels of protein, glucose, and malignant cells may differ markedly at different levels of the neuraxis in patients with neoplastic meningitis, even in the absence of an extradural blockage to cerebrospinal fluid flow. The pathogenesis of these differences is unclear, but is probably related to focal disruption of the blood-cerebrospinal fluid barrier produced by neoplastic involvement of the meninges. The clinical implications of this new observation are important. When the diagnosis of neoplastic meningitis is strongly suspected, but malignant cells cannot be demonstrated by repeated examination of lumbar cerebrospinal fluid, samples should be obtained by cisternal tap if the neurologic deficits are manifestations from involvement of the cranial nerves or cerebrum. Similarly, response to intrathecal chemotherapy should be monitored with serial examinations of cerebrospinal fluid obtained from the site of most marked pretreatment abnormality.
Adult↗
Aspiration does not influence interpretation of bone marrow biopsy cellularity.
Alterations of hematopoietic cellularity have been described in preaspirated marrow biopsy specimens. In this study, the extent of aspiration-induced artifacts was evaluated by comparing preaspirated and nonaspirated marrow biopsy specimens obtained from individual patients. Fourteen patients (28 specimens) were studied. One specimen, containing only cortical bone, was not evaluable. Of the remaining specimens, estimation of hematopoietic cellularity was not disturbed by preaspiration. Provided an adequate sized biopsy specimen is obtained, this study demonstrates that aspiration can be performed immediately before biopsy without altering the interpretation of hematopoietic cellularity. This makes a simple one-step aspiration-biopsy technic possible, without loss in diagnostic accuracy. In addition, without the need for repositioning to a different site on the iliac crest, patient tolerance should be improved.
Biopsy, Needle↗
High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study.
VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.
Adolescent↗
Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer.
Thirty-three adult and pediatric patients with refractory malignancies were treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days) followed by reinfusion of previously harvested and cryopreserved autologous marrow. The hematological and nonhematological toxicities and the therapeutic effects of this regimen were evaluated. Increasing doses of melphalan did not alter the rate of decline nor the recovery of peripheral blood counts. Granulocyte (greater than 500/microL) and platelet count (greater than 20,000/microL) recovery occurred in a median of 19 (range 12-54) and 24 (range: 12-54) days after bone marrow transplantation, respectively. Five patients experienced severe infection, three of which were fatal, and one patient died due to thrombocytopenic hemorrhage. Toxicity to the gastrointestinal system was dose limiting. The maximum tolerated dose of melphalan was 180 mg/m2; only three of 24 patients experienced severe stomatitis, esophagitis, and diarrhea at this level or less, while eight of nine patients at 225 mg/m2 were affected (p less than 0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before melphalan therapy did not reduce the incidence of severe gastrointestinal toxicity. Plasma melphalan concentration peaked 30-60 min after infusion (4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid concentration was 10% of the corresponding plasma concentration and was undetectable at 3 hours. Antitumor responses occurred in nine of 13 patients with malignant melanoma (five complete and four partial remissions), and ranged 2-12+ months with a median of 5 months. Four of six neuroblastomas demonstrated responses (three complete and one partial remission( lasting a median of 7.5 (range: 5-10) months. Other tumors in which this regimen had activity included breast cancer and Ewing's sarcoma. The overall response rate for the 33 patients was 30% complete remissions (10 patients) and 21% partial remissions (seven patients). High dose melphalan and autologous bone marrow transplantation is a promising therapy for patients with malignancies for which no effective treatment is known or for patients whose cancer is refractory to conventional therapeutic agents.
Adolescent↗
High-dose cytosine arabinoside therapy for refractory leukemia.
Fifty-seven patients with refractory acute leukemia were treated with high-dose cytosine arabinoside to establish the maximum tolerated dose and duration and to determine the antileukemic activity. The maximum tolerated regimen was found to be 3 g/sq m every 12 hr for 6 days. At this dose, nonhematologic toxicity was limited to conjunctivitis in approximately half of the patients, and liver toxicity (transient elevations in transaminase, alkaline phosphatase, or bilirubin) was frequently observed, but neither was dose-limiting. Extending the duration of treatment to 8 days resulted in excessive diarrhea and skin toxicity (painful erythema with bullae), while increasing the dose to 4.5 g/sq m q. 12 hr for 6 days resulted in severe cerebellar toxicity. Myelosuppression was severe, but was not related to the intensity of treatment; granulocyte recovery occurred a median of 28 days (range 22-40 days) after initiating therapy, and platelet recovery occurred after a median of 25 days (range 16-41 days). Antileukemic activity was evaluable in the 46 patients who survived at least 3 wk. Complete remissions were obtained in 1 of 6 patients with chronic myelogenous leukemia (CML) in accelerated phase and 1 of 3 acute lymphoblastic leukemia (ALL) patients. A more detailed analysis of response was possible for the 37 evaluable patients with acute nonlymphoblastic leukemia: 70% of these patients responded, with 51% complete remissions. The median unmaintained response was 4 mo (range 2-26+ mo). The complete response rate was higher in patients who received at least 12 doses of high-dose cytosine arabinoside compared to shorter regimens [17/28 (61%) versus 2/9 (22%), p less than 0.05]. Resistance to cytosine arabinoside in conventional doses was documented in 11 patients, 5 of whom responded (2 complete remissions) to high-dose regimens. We conclude that high-dose cytosine arabinoside in the maximally tolerated regimen of 3 g/sq m every 12 hr for 6 days has substantial antileukemic activity in patients refractory to standard therapy. Durable unmaintained remissions can be achieved, even in patients who fail to respond to cytosine arabinoside in conventional doses.
Acute Disease↗
High-dose etoposide as single-agent chemotherapy for small cell carcinoma of the lung.
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Adult↗
Etoposide-induced hepatic injury: a potential complication of high-dose therapy.
Two cases of toxic hepatitis developing in patients receiving high-dose etoposide (VP-16-213) for refractory germinal neoplasms are described. Each patient received a total cumulative dose of at least 6800 mg/m2. Liver function abnormalities, including hyperbilirubinemia, elevated transaminases, and elevated alkaline phosphatase, became clinically apparent approximately 3 weeks following the last dose of VP-16-213. These abnormalities resolved spontaneously without sequelae over 12 weeks. High-dose VP-16-213 may be associated with hepatic injury.
Adult↗
Veno-occlusive disease of the liver after high-dose mitomycin C therapy and autologous bone marrow transplantation.
Twenty-nine patients with refractory malignancies underwent intensive therapy with mitomycin C (60, 75, or 90 mg/m2 IV) and autologous marrow transplantation. Six patients developed the clinical syndrome of hepatic veno-occlusive disease (VOD) characterized by progressive abnormalities in liver function, abdominal pain, and ascites 15-70 days after mitomycin C therapy. Postmortem material was available in 16 patients, including four patients who had the clinical syndrome. VOD of the central and sublobular hepatic veins was noted in these four patients. VOD was discovered incidentally at autopsy in one of 12 patients without antemortem clinical evidence of disease. Two patients with abnormalities of liver function but without ascites or right upper quadrant pain had no evidence of VOD at autopsy. Although not statistically significant, there was a greater incidence of VOD with increasing doses of mitomycin C. When bone marrow toxicity of mitomycin C was overcome by autologous bone marrow transplantation, the development of VOD appeared to be the limiting factor in dose escalation.
Adult↗
Effects of high-dose cytarabine.
Plasma, urine, cerebrospinal fluid, and tear concentrations of cytarabine (ara-C) were measured in 15 patients receiving 3 gm/m2 IV ara-C given as a 1 hr infusion every 12 hr for 6 days. The two assay methods used for measuring ara-C concentrations (high-pressure liquid chromatography and radioimmunoassay) gave much the same results. Peak plasma ara-C concentrations (2.0 microM) after high-dose therapy were 50 times those achieved with more conventional (100 to 300 mg/m2) doses. High doses of ara-C were not sufficient to saturate cytidine deaminase; plasma ara-C half-lifes (t1/2) after high-dose therapy (distribution t1/2 = 6.2 min; elimination t1/2 = 154 min) were much the same as those after conventional ara-C doses. Kinetics of ara-C were not altered by repeated dosing over a 6-day period. Cerebrospinal fluid ara-C concentrations after high-doses (mean = 7.8 microM) were 10 times those after conventional intravenous dosing, bot were 0.5% to 1.0% those achieved by intrathecal ara-C doses. Tear concentrations of 22 and 38 micro M were measured in two patients who developed conjunctivitis after high-dose therapy so that the presence of ara-C in tears may be a cause of the conjunctivitis seen in some patients.
Adult↗
Oncology Grand Rounds: recent trends in the treatment of acute leukemia in adults.
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Adult↗