The use of prophylactic eye drops during high-dose cytosine arabinoside therapy

An ocular toxic reaction presenting as conjunctivitis or keratitis develops in a significant number of patients who are treated with high-dose cytosine arabinoside (ara-C). Although eye drops containing glucocorticoid reportedly decrease the incidence, they do not totally eliminate this side effect. In comparing this technique with artificial tears, both were found to be equally effective. The primary mechanism by which eye drops decrease ocular toxic reactions associated with high-dose ara-C is presumably due to dilution of intraocular concentrations of ara-C.     

Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology

Summary Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg×4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged <5 years (237 ng ml^–1) was lower than that observed in adults or older children (607 and 573 ng ml^–1, respectively). The AUC for the last dose was significantly lower in young children (2,315 h ng ml^–1) than in adults or older children (6,134 and 5,937 h ng ml^–1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min^–1 kg^–1) as compared with both older children and adults (3.02 and 2.7 ml min^–1 kg^–1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.Abbreviations AML acute myeloblastic leukemia - ALL acute lymphatic leukemia - AUL acute undifferentiated leukemia - ABMT autologous bone marrow transplantation - BMT allogeneic bone marrow transplantation This work was supported by grant 2805-B90-01X from the Swedish Cancer Society     

Effect of IV hydration with sodium bicarbonate on high-dose methotrexate disposition kinetics

Following two-compartment kinetic analysis, the effect of loading of transfusion with sodium bicarbonate on methotrexate disposition was investigated in 13 cases with malignant tumor, being treated with high-dose methotrexate. The mean values of total body clearance, when administered at doses 50 mg and 100 mg per kg body weight, were 0.369 and 0.402 (l/h) per kg, respectively. No significant relationship was observed between alpha value and total amount of transfusion, of urine or dosage of sodium bicarbonate. The other kinetic parameters on elimination, beta value, K10 and total body clearance, did not also correlate with those values described above. These results suggest that the elimination profile of methotrexate show linear kinetics, and that massive administration of transfusion with sodium bicarbonate be not necessary if pH value of urine exceeds 7.0.     

Studies on high-dose methotrexate with citrovorum factor rescue therapy in children: analysis of bone marrow cell kinetics by flow cytometry

Nine children in remission from hematologic malignancies received infusion of methotrexate (2,000-6,000 mg/m2) for 24 hours followed by citrovorum factor rescue (beginning 36 hours after the start of MTX infusion). Marrow cell kinetics of these patients were studied by flow cytometry with computer analysis. An accumulation of cells in the early-mid S phase and a decrease of cells in the G2/M phase were observed at 24-48 hours after exposure to MTX except for one infant case. By the 6th day after MTX infusion, the DNA histograms returned to pretreatment values. No kinetic perturbation was observed in the marrow cells of a 1-year, 5-month-old infant who showed high plasma MTX concentrations over the median values of the other eight children. These results show that profound but reversible changes are observed in marrow cell kinetics in most patients treated with our current high-dose MTX therapy with CF rescue and that a repeated course would be possible without cumulative marrow toxicity. More studies in young infants are needed to clarify the relationship between age and marrow toxicity of MTX so that treatment schedules with a higher therapeutic index can be designed.     

Influence of high-dose ketoconazole on the pharmacokinetics of docetaxel

OBJECTIVE: The pharmacokinetics (PK) of docetaxel are characterized by large inter-individual variability in systemic drug exposure (AUC) and drug clearance. The PK variability is thought to be largely related to differences in the catalytic function of CYP3A, involved in docetaxel metabolism and elimination. As variability in efficacy and toxicity is associated with variability in docetaxel AUC and clearance, reducing inter-individual PK variability may help improve the risk-benefit ratio of docetaxel therapy. We investigated if high-dose ketoconazole, a potent CYP3A inhibitor, could result in a uniform reduction of docetaxel clearance and reduce the inter-individual variability in docetaxel AUC and clearance. METHODS: Seven patients were treated in a randomized-cross over design with intravenous docetaxel (100 mg/m(2)) followed 3 weeks later by docetaxel (15 mg/m(2)) given in combination with orally administered ketoconazole (400 mg 3 times daily, up to 47 hours after docetaxel infusion) or vice versa. Docetaxel plasma concentration-time data were described by a three-compartment PK model. Ketoconazole plasma concentration-time data were described by a one-compartment PK model. RESULTS: Docetaxel clearance was reduced by 50% (P = .018) from 32.8 +/- 13.7 L/hr to 16.5 +/- 8.15 L/hr upon ketoconazole coadministration, albeit with large inter-individual variability (fractional change in clearance, range 0.31 - 0.66). In the presence of ketoconazole, inter-individual variability in clearance and AUC, expressed as coefficient of variation, was increased from 41.6 to 49.5% and from 28.0 to 35.1%, respectively, and not, as we had hypothesized, reduced. CONCLUSION: Inhibition of CYP3A by concomitant high-dose ketoconazole administration does not result in a uniform reduction of docetaxel clearance and does not reduce the inter-individual variability in docetaxel AUC or clearance. This approach is unsuitable as method to achieve a uniform docetaxel PK profile.     

Retinal toxicity after high-dose cisplatin therapy

Because of increasing complaints of visual dysfunction, 13 patients with refractory or recently diagnosed ovarian carcinoma were evaluated for possible cisplatin-induced ophthalmologic toxicity. All patients had received high-dose cisplatin (200 mg/m2 in five divided daily doses) over two to four cycles. Eight patients (62%) developed symptoms of blurred vision and three (23%) also developed altered color perception. Retinal toxicity in the form of cone dysfunction was documented by electroretinography and color vision testing in 11 patients. Three patients were studied prospectively. Two patients who developed cone dysfunction had normal ophthalmologic exams before the initiation of chemotherapy or after one cycle of cisplatin, suggesting a causal relationship between cisplatin therapy and subsequent retinal abnormalities. Though visual acuity improved off therapy, color vision abnormalities persisted as long as 16 months beyond therapy.     

Non-hematologic toxicity in high-dose cytarabine therapy

The hence reported non-haematologic toxicity in high-dose cytarabin mainly concerned CNS (cerebellar dysfunction), eyes (keratitis and conjunctivitis), skin (erythema), and gastrointestinal tract (vomiting, diarrhea). It partly depends on dosage and partly on duration of treatment. A dose of 48 g/sq m within one cycle apparently represents a critical upper limit as hence especially the risk of irreversible brain damage increases. Considering the fact that the indication for high-dose cytarabin is given mainly for poor prognostic failures and relapses in acute leukemias toxicity seems to be acceptable.     

Increased teniposide clearance with concomitant anticonvulsant therapy.

PURPOSE: A possible pharmacokinetic interaction between teniposide and anticonvulsant medications was evaluated in pediatric patients. PATIENTS AND METHODS: The systemic clearance of teniposide was determined in six pediatric patients with acute lymphocytic leukemia receiving concomitant therapy with anticonvulsants. Clearance was then compared with a control group of patients treated with the same protocol therapy and matched for age at diagnosis, sex, and race but not receiving anticonvulsants or other agents known to induce hepatic metabolism or alter protein binding of drugs. Eight blood samples were obtained during and after 4-hour infusions of teniposide, and plasma concentrations were measured by a specific high-performance liquid chromatography (HPLC) assay. A two-compartment model was fitted to each subject's data. RESULTS: The mean systemic clearance (range) for the six anticonvulsant-treated patients studied during 22 courses of therapy was 32 mL/min/m2 (range, 21 to 54 mL/min/m2), significantly higher (P less than .001) than the mean value of 13 mL/min/m2 (range, 7 to 17 mL/min/m2) for the control patients studied during 26 courses of therapy. Clearance estimates for control patients were similar to previously published values for pediatric patients. CONCLUSION: These data indicate that the systemic clearance of teniposide is consistently increased two- to three-fold by concomitant phenobarbital or phenytoin therapy. The consequent substantial reduction in systemic exposure may reduce teniposide's efficacy.     

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)     

Effect of granisetron on performance status during high-dose interferon therapy

Two case reports demonstrating the new complete amelioration of the toxicity of alpha-2b recombinant interferon using granisetron i.v. or p.o. Copyright Copyright 1999 S. Karger AG, Basel     

乳腺癌预防性治疗研究进展

一系列化学干预试验显示,雌激素受体调节剂（三苯氧胺、雷诺昔芬）等药物能够显著降低高危人群乳腺癌的发病率。针对BRCA基因突变携带者开展的预防性双侧乳腺切除术和预防性双侧卵巢切除也取得了明显的疗效,特别是预防性双侧乳腺切除术被充分汪明是一个有效的治疗手段,既能显著降低高危妇女乳腺癌风险也显著降低乳腺癌相关死亡。     

Acute cerebellar dysfunction with high-dose ARA-C therapy

The authors report a patient with clinical and morphologic evidence of acute cerebellar toxicity after receiving high-dose cytosine arabinoside (ARA-C) (3000 mg/m2/12 hours) for refractory AML. Damage of Purkinje cells and dentate nucleus was demonstrated. Reversible cerebellar toxicity has previously been noted in patients on an identical regimen. Signs of cerebellar dysfunction mandate immediate cessation of high-dose ARA-C therapy.     

Peripheral neuropathy associated with high-dose Ara-C therapy

Central nervous system toxicity associated with high-dose cytosine arabinoside (Ara-C) therapy (HD Ara-C) is well known. The authors report the case of a severe isolated peripheral polyneuropathy due to HD Ara-C. Electrophysiologic changes and histologic observations were consistent with axonal degeneration and scattered destruction of myelin sheaths. This observation emphasizes the need for careful complete neurologic evaluation for patients receiving HD Ara-C treatment.     

Autologous and allogeneic high-dose therapy for melanoma

Opportunities for the treatment of melanoma with high-dose chemotherapy have been inadequately explored because of the failure of early studies to demonstrate an advantage for high doses of those agents with disease activity that could also be safely dose-escalated without excessive extramedullary toxicities. However, emerging concepts of tumor and transplantation immunology have recently coincided, providing the rationale for new strategies that exploit principles of allogeneic transplant to overcome immunologic tolerance and escape mechanisms in the tumor-bearing individual. It is hoped that this setting will provide an improved milieu for donor-derived immunotherapeutic intervention that takes advantage of shared tumor antigens with therapeutic potential shown in a variety of tumor vaccination studies.     

The impact of conventional and high-dose therapy for lymphoma on fertility

The impact of chemotherapy on gonadal function is an important issue for younger patients surviving lymphoma. This article reviews the effects on fertility of conventional and intensive-dose chemotherapy regimens with or without radiation therapy. In general, conventional dose regimens such as ABVD (doxorubicin/bleomycin/vinblastine/decarbazine) and CHOP21 (cyclophosphamide/doxorubicin/vincristine/prednisone) are not sterilizing, but data are limited on the effects of newer aggressive regimens such as BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone), CHOP14, and CHOP/etoposide. Infertility after myeloablative transplant conditioning is common but not invariable. The role of prechemotherapy gonadotrophin-releasing hormone agonists and antagonists for the prevention of gonadal damage is under evaluation. In addition, new techniques for sperm and oocyte retrieval offer the prospect of improved fertility after sterilizing treatment. Management guidelines for patients undergoing nonmyeloblative and myeloablative therapy are presented, addressing additional issues such as contraception during and after the administration of cytotoxics and the importance of gynecologic and endocrine follow-up in determining the need for short- and long-term hormone replacement therapy.     

Results of high-dose cytarabine therapy. A review

Of the many high-dose Ara-C regimens that have been proposed, the one published by Herzig [24] has been applied most widely. Every 12 h patients receive 3 g/m2 Ara-C for 75-90 minutes for a total of 12 doses. Using that regimen, 25% of patients with refractory acute myelogenous leukemia (AML) and 60% of patients in untreated relapse achieve a complete remission (CR). With few exceptions, complete remissions are obtained after one cycle, median remission duration is between 4 and 6 months. Consolidation or maintenance therapy was not usually given. Currently, numerous modifications of that regimen are under investigation: combinations with other cytostatic agents like anthracyclins, m-AMSA, vincristine; the Capizzi-regimen and intermediate dose Ara-C. Preliminary results of those trials are promising but need to be confirmed by other groups. This survey does not comment on Ara-C toxicity and on Ara-C treatment of CNS leukemia, which are both reviewed in two further articles of this issue.     

Kinetics of 7-hydroxy-methotrexate after high-dose methotrexate therapy

Summary Kinetics of 7-hydroxy-methotrexate (7-OH-MTX) excretion after high-dose methotrexate (MTX) (12 g/m²) therapy were monitored in 93 consecutive drug cycles of 19 adolescent patients with osteosarcoma. A reversed-phase HPLC method was used. Serum elimination was found to be monophasic with a mean half-life of 5.5 h. Shortly after the 4-h MTX infusion period 7-OH-MTX levels exceeded those of the parent compound. By 12 h after MTX infusion 7-OH-MTX levels were 16.5 times higher than those of MTX itself.Autostimulation of MTX metabolism leading to enhanced 7-OH-MTX production after repeated drug cycles was not observed. The production of 7-OH-MTX decreased significantly from the first to the last high-dose MTX cycle of the adjuvant chemotherapy protocol.     

The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate

The pharmacokinetics of high-dose methotrexate (MTX, 5-15 g/m2) were evaluated in 11 children and adolescents who had previously received two to eight doses of cisplatin (90 mg/m2) in the treatment of malignant solid tumors. The half-life for disappearance of MTX from serum during the first 24 hours after infusion was determined from serum samples obtained at the end of a six-hour infusion and six, 12, and 24 hours after infusion. These values were compared to a mean half-life of 2.83 (+/- 0.34) hours following 489 courses administered to 71 patients who had not received cisplatin. Stepwise multiple linear regression analysis of patient variables revealed cumulative cisplatin dosage and time from last cisplatin dose as the best predictors of MTX half-life (r2 = 65.4%, p less than 0.001). The best predictors of 24-hour serum concentration were cumulative cisplatin dosage and MTX dosage (r2 = 54.2%, p less than 0.001) in the multiple linear regression model. Patients with delayed MTX clearance received additional leucovorin and experienced no severe toxicity. Patients receiving up to 270 mg/m2 of cisplatin appear to have minimal increases in MTX half-life, while the likelihood of delayed clearance increases in patients who have received 360 mg/m2 or more of cisplatin. All patients who have previously received cisplatin should be treated cautiously with high-dose MTX and prospective pharmacokinetic monitoring should be routinely performed.