Solomon Zimm

Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered

Induction therapy is now successful in producing a complete remission in more than 90 per cent of patients with acute lymphoblastic leukemia.1 , 2 However, maintenance of remission remains a major ...

Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy.

Ninety ovarian carcinoma patients failing primary intravenous (IV) combination chemotherapy were treated with cisplatin-based combination intraperitoneal therapy. Sixty-five patients had residual disease greater than 2 cm at the start of intraperitoneal therapy. Their median survival was 8 months. Twenty-five patients had disease less than 2 cm; their median survival was greater than 49 months, and the survival curve has an apparent plateau at 69%, with no relapses having occurred after 32 months. The median survival for all 90 patients was 15 months. The median duration of follow-up for all patients was 37 months. These results confirm the critical role of tumor bulk in determining the effectiveness of intraperitoneal therapy, and suggest a role for intraperitoneal salvage treatment in patients with small-volume disease.

Inhibition of first-pass metabolism in cancer chemotherapy : interaction of 6-mercaptopurine and allopurinol

Earlier studies suggested that the dose of 6‐mercaptopurine (6‐MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6‐MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6‐MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6‐MP in monkeys (from a mean of 0.54 μM to a mean of 2.1 μM) and a 500% increase in man (0.74 μM to 3.7 μM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6‐MP (from a mean of 121 μM/min to a mean of 391 μM/min) and a 500% increase in AUC in man (from a mean of 142 μM/min to a mean of 716 μM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6‐MP. This difference was found to be due to inhibition of first‐pass metabolism of oral 6‐MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6‐MP given in conjunction with allopurinol is appropriate, it is not necessary when 6‐MP is injected intravenously.

Cytosine arabinoside cerebrospinal fluid kinetics

To better characterize the disposition of cytosine arabinoside (Ara‐C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara‐C, CSF and plasma samples were obtained over a 24‐hr period. Ara‐C levels were measured by a reverse‐phase HPLC assay (with a sensitivity of 0.5µM in CSF and 1.0 µM in plasma) that readily separated Ara‐C from its major metabolite uracil arabinoside (Ara‐U). Elimination of Ara‐C from CSF followed a biphasic pattern, with an initial t½ of 1 hr and a terminal t½ of 3.4 hr. Ara‐C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara‐U to the AUC of Ara‐C was 0.08, indicating only minor metabolism of Ara‐C to Ara‐U in CSF, in contrast to that after systemic Ara‐C. Despite initial CSF Ara‐C concentrations exceeding 2 mM, Ara‐C was not detectable in plasma in any patient. Intraventricular Ara‐C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara‐C.

The effect of methotrexate on the bioavailability of oral 6-mercaptopurine.

Fourteen children (aged 3 to 14 years) with average‐risk acute lymphoblastic leukemia were studied after an oral dose of 6‐mercaptopurine (6‐MP) (75 mg/m2) administered alone and, on the next day, concurrently with oral methotrexate (20 mg/m2). When 6‐MP was administered alone, both the peak plasma concentration (15 to 150 ng · ml−1) and the AUC (36 to 340 ng ml−1 · hr) were highly variable. Concurrent methotrexate resulted in a 31% increase in the AUC (P < 0.01) and a 26% increase in peak plasma levels (P < 0.05) of 6‐MP. The AUC of methotrexate correlated with the degree of increase in 6‐MP plasma concentrations. These findings are consistent with previous in vitro studies demonstrating that methotrexate is an inhibitor of xanthine oxidase, the enzyme that catabolizes 6‐MP to the inactive metabolite thiouric acid. Although the increases in 6‐MP AUC and peak plasma concentrations resulting from concurrent methotrexate administration were statistically significant, this interaction is probably not clinically significant at standard low oral doses of methotrexate in light of the wide interpatient variability in these pharmacokinetic parameters of 6‐MP.

A phase II trial of intraperitoneal cisplatin and etoposide for primary treatment of ovarian epithelial cancer.

We conducted a phase II trial of intraperitoneal (IP) cisplatin (DDP) and etoposide (VP-16) in stage III and IV newly diagnosed ovarian carcinoma patients with residual disease of any size. Twenty-three patients were entered, 19 had stage III and four stage IV disease. DDP 200 mg/m2 and VP-16 350 mg/m2 were given in 2 L saline IP via a Port-A-Cath (Pharmacia-Deltec, St Paul, MN). Sodium thiosulfate 4 g/m2 was given intravenously (IV) just before the start of IP instillation, and continued as a constant IV infusion of 2 g/m2/hr IV for a total of 6 hours. Treatment was given once every 4 weeks; six cycles of therapy were planned. Thirteen patients (56%) were in complete clinical remission at the end of treatment (normal physical exam, computed tomographic [CT] scan, CA-125, and peritoneal cytology). Seven of these 13 underwent a second-look laparotomy: three (13%) were in pathologic complete remission and four (17%) had microscopic disease only. Projected survival is 68% at 27 months, with 10 patients being alive and continuously free of disease. There was a very rapid fall in mean CA-125 to within normal limits at the end of the second course of treatment. The major toxicity was myelosuppression with median nadir WBC, granulocyte, and platelet counts of 2,600, 896, and 205,000/microL, respectively. There was no cumulative renal damage, anemia, hypomagnesemia, or chemical peritonitis. Neurotoxicity was similar to that observed with IV dosing. We conclude that therapy with the IP DDP/VP-16/IV thiosulfate regimen, in which all cytotoxic drugs are given only by the IP route, produces less anemia and renal damage than standard IV DDP-containing regimens, and that survival with this regimen appears to be at least as good as that produced by IV programs.

The pharmacology of orally administered chemotherapy: A reappraisal

Rational treatment of pediatric malignancies requires a detailed knowledge of the clinical pharmacology of those antineoplastic agents used therapeutically. A number of different agents are administered by the oral route. Recently, the clinical pharmacology of 6‐mercaptopurine (6‐MP) and methotrexate (MTX), the two agents that are the mainstay of maintenance chemotherapy in acute lymphoblastic leukemia (ALL), were investigated. Studies of oral 6‐MP indicate that, contrary to previous information, the bio‐ availability of this drug is relatively poor after oral administration, and that plasma 6‐MP concentrations achieved after uniform oral dosing are highly variable. Similarly, study of the pharmacology of orally administered MTX indicates that there is little correlation between MTX dose and the peak serum level achieved. These findings suggest that some patients may not be exposed to adequate systemic concentrations of 6‐MP and/or MTX after oral administration, and raise the possibility that the development of relapse in some patients with ALL may be the result of a pharmacologic failure of oral maintenance therapy. A comprehensive prospective study of the clinical pharmacology of MTX and 6‐MP in patients with ALL undergoing maintenance chemotherapy is currently in progress. Cancer 58:473‐480, 1986.

A phase II trial of continuous-infusion 6-mercaptopurine for childhood solid tumors.

SummaryA phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was >95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing’s sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.

Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole.

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.

A phase II trial of continuous-infusion 6-mercaptopurine for childhood leukemia

SummaryA phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6MP) in patients with refractory leukemia was performed. The dosing schedule, 50 mg m−2 h−1 for 48 h, was based on the results of a previous phase I trial of this approach. Among the 40 children treated for acute lymphoblastic leukemia (ALL), all of whom had received prior therapy with oral 6MP, 1 complete and 1 partial response were achieved. No response was observed in 17 patients with refractory acute nonlymphocytic leukemia (ANLL). Reversible hepatotoxicity, the primary dose-limiting toxicity, was observed in approximately 50% of cases. Mucositis was encountered infrequently and was usually not severe. 6MP given on the present continuous intravenous infusion schedule overcomes the limited and variable bioavailability of oral 6MP but shows limited activity as induction agent in children with recurrent ALL.