Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1. RESULTS: Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities. CONCLUSION: Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

Low-dose trimetrexate glucuronate and protracted 5-fluorouracil infusion in previously untreated patients with advanced pancreatic cancer.

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-naïve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.

A phase II study of high dose ARA-C and mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia.

PURPOSE: The Southwest Oncology Group performed a Phase II study to investigate the effectiveness of an induction regimen of high dose cytosine arabinoside (ara-C) with high dose mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients at least 16-years-old with ALL that was in relapse after, or was refractory to, standard induction therapy including at least vincristine and prednisone were eligible, as long as they had no prior treatment with high dose ara-C. The induction regimen included high dose ara-C (3 g/m2 by 3-h i.v. days 1-5) and mitoxantrone (80 mg/m2 by 15-30 min i.v. 12-20 h after the first dose of ara-C). The study design called for a maximum of 55 patients, with early termination if less than nine of the first 30 achieved complete remission. RESULTS: Thirty-three patients entered the study, and 31 were included in the analysis. All 31 completed one course of induction therapy. Four patients died of infection and a fifth of cardiomyopathy with possible sepsis. Seven patients achieved complete remission (23%; 95% confidence interval 10-41%). One of the seven received syngeneic bone marrow transplantation while in remission, and the other six all relapsed within 10 months. All 31 patients died within 25 months after entering the study. CONCLUSIONS: The regimen of high dose ara-C and mitoxantrone was found to be insufficiently effective to warrant further investigation.

A phase II trial of irinotecan in hormone-refractory prostate cancer.

Irinotecan is a DNA topoisomerase I inhibitor that has a wide spectrum of activity against human tumors in both preclinical and clinical studies. To evaluate the efficacy of irinotecan in hormone-refractory prostate cancer, we conducted a phase II study in 15 men with metastatic, PSA-progressive disease after primary androgen deprivation. Irinotecan was administered at a dose of 125 mg/m2 weekly for four weeks followed by a two-week rest period; cycles were repeated every six weeks. Response was assessed by evaluation of serial changes in the serum PSA. None of fifteen patients had a decline in PSA of greater than 50%; eight patients had stable disease as a best response. None of three patients with measurable disease had a partial or complete response. Toxicity was primarily hematologic and gastrointestinal, with 40% of patients requiring dose modification due to granulocytopenia and 20% requiring intravenous fluid supplementation after development of diarrhea. There were no treatment-related deaths. We conclude that irinotecan in the dose and schedule used in this trial does not have significant activity against hormone-refractory prostate cancer.

Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria.

Seven patients with paroxysmal nocturnal haemoglobinuria (PNH) were treated with antithymocyte globulin (ATG). Each patient received ATG (20 mg/kg/d) for 8 d and prednisone to prevent or control serum sickness. Three patients experienced a sustained improvement in at least one peripheral blood cytopenia, including one patient who had a complete trilineage response. Several pretreatment clinical features appeared to be associated with response to ATG. All responding patients had hypoproliferative features including depressed platelet counts (< 30 x 10(9)/l), and a minor degree of chronic haemolysis as indicated by relatively low reticulocyte counts (< 100 x 10(9)/l), lactate dehydrogenase (< 1000 U/l) and total bilirubin (< 17 mumol/l) levels. Responding patients continued to have chronic low-grade haemolysis after their response to immunosuppression that was similar to that observed prior to treatment. The non-responding patients had a classic haemolytic form of PNH characterized by elevated reticulocyte counts (> 100 x 10(9)/l), lactate dehydrogenase (> 2000 U/l) and total bilirubin (> 17 mumol/l) levels. The impaired haemopoiesis that occurs in hypoproliferative PNH may respond to ATG treatment, but the haemolytic component of the disease, and hence the PNH clone, is not altered by immunosuppressive therapy.

Suramin in hormone-refractory metastatic prostate cancer: a drug with limited efficacy.

PURPOSE: To confirm the previously reported high response rates and prolonged survival in hormone-refractory prostate cancer treated with suramin. PATIENTS AND METHODS: Thirty-six eligible patients with hormone-refractory prostate cancer with either measurable disease or bone disease only and a prostate-specific antigen (PSA) level greater than 50 ng/mL were enrolled. Treatment consisted of two 8-week courses of outpatient-based therapy with an interposed rest period. A bayesian adaptive control strategy and a three-compartment pharmacokinetic model that accommodates clearance changes was used to guide individual dosing. A rapid infusion of 1,000 mg/m2 suramin was followed by five daily infusions that targeted 285 micrograms/mL peak plasma levels during the first week. All patients received concomitant hydrocortisone. For the next 7 weeks, patients received one to two doses per week that targeted levels in the 150 to 285 micrograms/mL range and integrated weekly averages of 200 ug/mL. RESULTS: Nine patients (28%) had a partial response to suramin based on a > or = 50% decrease in PSA levels coupled with either relief of bone pain or by a 50% decrease in measurable disease. The median overall survival time for all patients is 31 weeks (95% confidence interval [CI], 23 to 51). Treatment was generally well tolerated, with fatigue being the most common significant toxicity, but fatal idiosyncratic myelosuppression (grade V) was observed in one patient. CONCLUSION: Using this dosing schedule, suramin has limited activity against hormone-refractory metastatic prostate cancer. Recent data suggest that hydrocortisone administered with suramin may be partly responsible for the benefit attributed to the drug. Although a small cohort of patients appeared to benefit, we were unable to confirm the previously reported high rate of activity and durability of remission using this agent.

Autoimmune myelofibrosis. A steroid-responsive cause of bone marrow fibrosis associated with systemic lupus erythematosus.

Autoimmune myelofibrosis is an uncommon disorder in which patients present with anemia and thrombocytopenia in conjunction with limited clinical manifestations of autoimmune disease or an exacerbation of previously established SLE. The presence of leukoerythroblastosis in a patient with SLE may suggest the presence of myelofibrosis. Conversely, the absence of splenomegaly in a patient with presumed idiopathic myelofibrosis may suggest an autoimmune etiology. Patients with autoimmune myelofibrosis universally have a positive ANA test and frequently have either elevated anti-DNA titers or a positive LE cell preparation. Because physical manifestations of autoimmune disease may not be evident at presentation, all patients found to have myelofibrosis should have an ANA test. Peripheral blood cytopenias in autoimmune myelofibrosis frequently respond to glucocorticoids but regression of bone marrow fibrosis may be incomplete. Hematologic response to treatment parallels that of the associated autoimmune disease.

Fentanyl for epidural intravascular test dose in obstetrics.

BACKGROUND AND OBJECTIVES: Although dizziness and drowsiness may be produced with either intravenous or epidural fentanyl, their occurrence after an intravenous injection is more rapid and relatively more pronounced. The purpose of this study was to determine whether or not the difference between routes of administration would be a reliable method of detecting an accidental intravascular injection. METHODS: In part 1, using a double-blinded protocol, we prospectively assessed in laboring women the incidence of dizziness, drowsiness, or both associated with intravenous fentanyl (100 micrograms). In random order, subjects received two peripheral intravenous injections: 2 ml of fentanyl and 2 ml of saline, separated by a 3-minute observation period. RESULTS: In group 1 (18/18) and group 2 (22/22), all subjects reported a response to intravenous fentanyl within the one-minute assessment. In part 2, we evaluated in laboring patients the frequency of dizziness, drowsiness, or both to epidural fentanyl (100 micrograms). The study design was identical to part 1; however, the subjects received 2 ml of fentanyl and 2 ml of saline via a functional epidural catheter. In group 3 (1/18) and group 4 (1/22), one subject reported a response to epidural fentanyl within the 3-minute observation period. CONCLUSIONS: Overall, the responses to intravenous fentanyl (40/40) occurred in a remarkably more consistent fashion when compared to epidural fentanyl (2/40). Thus, the results suggest that in laboring patients, intravenous fentanyl produces predictable and easily detectable changes that may be useful in identifying an epidural catheter unintentionally placed intravascularly.

Prolonged continuous infusion of fluorouracil with weekly bolus leucovorin: a phase II study in patients with disseminated colorectal cancer.

BACKGROUND: Biochemical modulation of bolus fluorouracil (5-FU) by addition of leucovorin to the treatment regimen has increased response in patients with disseminated colorectal cancer from fewer than 20% to more than 40%. In view of the short half-life of 5-FU and its cell cycle specificity, it may be that infusion rather than intravenous bolus injection would increase efficacy. Furthermore, the advent of safer indwelling intravenous catheters and pump technology, allowing home and ambulatory treatment, has made protracted infusion clinically feasible. To examine these questions, we conducted a phase I trial using protracted infusion of 5-FU by indwelling catheter and pump, with leucovorin given by bolus injection, and reported 40% partial response. PURPOSE: We have now initiated a phase II study of 5-FU given by prolonged continuous infusion with weekly bolus injections of leucovorin in previously untreated patients with measurable, disseminated colorectal cancer. METHODS: Forty-one patients were treated. The regimen consisted of treatment for 4 weeks with 5-FU at a dose of 200 mg/m2 daily as a continuous infusion by indwelling intravenous catheter and pump, followed by a 2-week rest and then by monthly cycles of 3 weeks of treatment and 1-week rest until disease progression. Leucovorin was given as a bolus injection of 20 mg/m2 at the beginning of each week of treatment with 5-FU. RESULTS: Nineteen (46%) of 41 patients had objective response: Three complete responses and 16 partial responses were seen. Overall, the median duration of response was 8 months. The median duration of survival was 16 months: 18 months for responders and 10 months for nonresponders. In general, toxic effects were mild and consisted primarily of stomatitis and palmar-plantar erythrodysesthesia (hand-foot syndrome). Neither grade 4 toxic effects nor treatment-related deaths were observed. The only serious side effects were catheter thrombosis (three patients) and catheter sepsis (one patient). CONCLUSION: We conclude that this safe regimen is one of the most effective for the treatment of disseminated colorectal cancer. IMPLICATIONS: The regimen should be tested prospectively against other regimens in use for this disease. It is currently included in a phase III study of the Southwest Oncology Group for this purpose. That study will assess quality of life as well as response rates and survival duration.

Bleeding problems in the cancer patient.

Bleeding problems in the cancer patient may result from the effects of the tumor on hemostatic mechanisms or from the treatment of the tumor by cytotoxic and other agents. Among the tumor-related bleeding problems are disseminated intravascular coagulation, primary fibrinolysis, thrombocytopenia, acquired platelet dysfunction, and circulating inhibitors or anticoagulants. Disseminated intravascular coagulation in most solid tumors is associated with hypercoagulability, whereas in acute promyelocytic leukemia bleeding is the most common presentation. Treatment-related bleeding disorders include the common problem of thrombocytopenia secondary to myelosuppressive chemotherapy as well as the interesting microangiopathic hemolytic anemia syndrome associated with mitomycin C and other agents.

A phase II trial of CI-921 in advanced malignancies.

CI-921, (9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino]- N,5-dimethyl-4-acridinecarboxamide 2-hydroxyethanesulfonate (1:1)), an anilinoacridine derivative with activity in experimental solid tumors was studied in a multicenter phase II trial in patients with solid tumors. Eligible tumor types included cancers of the breast, stomach, pancreas, nonsmall cell lung, small cell lung, colon, head and neck area, and melanoma. Prestudy requirements included an ECOG performance status of < or = 2, no CNS metastases, and measurable disease. CI-921 was administered intravenously over 1-2 hours on days 1, 8, and 15 of a 35-day course at an initial dose of 270 mg/M2, with modification in subsequent courses based upon tolerance. Principal toxicities included leukopenia, marked phlebitis, and mild nausea and vomiting. One hundred fifty patients were entered of whom 132 were evaluable for response. There was one complete and one partial response among 19 patients with breast cancer, and two partial responses, one each among 14 head and neck and 36 nonsmall cell lung cancer patients.

Biological modification of protracted infusion of 5-fluorouracil with weekly leucovorin. A dose seeking clinical trial for patients with disseminated gastrointestinal cancers.

A clinical trial was designed to find the maximally tolerated dose of weekly leucovorin (LV) that could be combined with 4 weeks of protracted infusion (PI) of 5-fluorouracil (5FU) at a fixed dose of 200 mg/m2. A total of 36 patients with disseminated gastrointestinal malignancies were treated; 9 either progressed or died before receiving 4 weeks of treatment leaving 27 patients evaluable for toxicity and response. 5FU was given as a protracted infusion using an ambulatory infusion pump and indwelling venous access. LV doses included 20, 25, 50, and 75 mg/m2 given as an i.v. push at the time of weekly pump fill with 5FU. In all, 72% of the patients tolerated LV at 20 mg/m2 for 4 continuous weeks, whereas the higher doses required treatment rests prior to 4 weeks. The dose-limiting toxicity at all doses was stomatitis. No significant myelosuppression was seen; diarrhea was infrequent. Overall, 40% of the patients with measurable cancer had partial responses. In view of evidence of biologic and therapeutic effects of these weekly doses of 20 mg/m2 LV with 200 mg/m2 5FU per day given as a protracted infusion over 4 weeks, phase II trials and multimodality studies for patients with gastrointestinal malignancies are being initiated at our institution using this dose and schedule.

Acute lymphocytic leukemia manifesting as splenic rupture.

Pathologic rupture of the spleen is a rare phenomenon in acute lymphocytic leukemia, and its mechanism is unknown. This complication has been seen almost exclusively in men, and at ages much older than those of the majority of patients who have this leukemia; these unusual features are also unexplained. A case of acute lymphoctyic leukemia with pathologic rupture of the spleen in which the pathologic findings suggest that the splenic rupture was due to infiltration and destruction of the splenic capsule by leukemic cells is reported.

Tamoxifen flare in advanced breast cancer.

The antiestrogen tamoxifen citrate is an effective antitumor agent in postmenopausal women with advanced breast cancer. The drug has produced relatively few and generally mild side effects. However, a not uncommon clinical phenomenon that may falsely suggest premature discontinuation of tamoxifen therapy has become evident to us and has not yet been sufficiently emphasized in the literature. We have designated this phenomenon as the tamoxifen flare. It consists of transient, at times severe, increase in pain with an apparent worsening of the patient's clinical status occurring within the first few weeks of therapy. In each of six patients experiencing this flare (45 patients treated) pain subsided despite continuation of tamoxifen therapy, followed by a partial remission lasting from six to 20 months.

Convoluted lymphocytic lymphoma in adults: a clinicopathologic entity.

Twelve adults had a distinct clinicopathologic type of malignant lymphoma that closely resembles the mediastinal lymphomas of childhood. Nine patients presented with mediastinal masses, and seven had symptoms related to intrathoracic compression. Seven patients presented with or developed leukemia, and in four of these patients the central nervous system (CNS) became involved. Structurally, the tumor cells had a distinctive stippled chromatin pattern, in addition to the characteristic nuclear convolutions. Tumor cells from five patients were studied immunologically, and, in each case, the tumor cells formed rosettes with sheep erythrocytes. The response to combination chemotherapy was rapid and dramatic, but usually transient, with relapse in the CNS or previously involved sites. The above data strongly suggest that these cases represent a distinct clinicopathologic entity that should be treated similarly to childhood leukemia and lymphoma, with intensive multiple agent induction, CNS prophylaxis, possibly radiation therapy to initially involved sites, and prolonged maintenance.

Study of leukocyte kinetics in acute myelocytic leukemia utilizing chromium-51.

Leukocyte kinetic studies using chromium-51 were performed in four patients with acute myelocytic leukemia (AML). Intravascular leukocyte survival was prolonged in comparision with granulocyte survival in normal subjects. Significant splenic pooling occurred in three patients, none of whom had splenomegaly. In one patient studied, circulating leukemic cells were shown to return to the bone marrow. The prolongation of intravascular leukocyte survival in AML in relapse, as in chronic myelocytic leukemia, probably depends on several factors including the presence of immature leukemic cells and the recycling of these cells from the spleen and bone marrow.