Fluctuation of serum phenytoin concentrations during autologous bone marrow transplant for primary central nervous system tumors.

We reviewed our experience for adult patients receiving oral anticonvulsant therapy during high-dose chemotherapy and autologous bone marrow re-infusion for primary malignant tumors of the central nervous system. Nineteen patients received either iv carmustine (BCNU) 900-1050 mg/m2 and 6120 cGy cranial irradiation (N = 10), iv carmustine 900-1050 mg/m2 and iv cisplatin 200 mg/m2 (N = 8), or iv carmustine 600 mg/m2, iv cisplatin 200 mg/m2, and iv etoposide 2400 mg/m2 (N = 1). Anticonvulsant therapy consisted of phenytoin alone (N = 8), phenobarbital alone (N = 4), carbamazepine alone (N = 2), phenytoin and carbamazepine (N = 2), carbamazepine and phenobarbital (N = 1), and no anticonvulsant therapy (N = 2). Serum anticonvulsant concentrations were monitored frequently and doses adjusted to keep values in the therapeutic range. While phenobarbital and carbamazepine doses remained relatively stable, all patients required increased doses of phenytoin anticonvulsant therapy after beginning chemotherapy (mean onset 3.7 days after initiation of chemotherapy). The increase in phenytoin dose ranged from 50% to 300% above baseline (mean 134%). By the time of discharge from the hospital (approximately 3-4 weeks after the start of chemotherapy) anticonvulsant dose was decreased to near pre-therapy levels. These swings coincided with the initiation of dexamethasone therapy for antiemetic effect and were more pronounced in patients also receiving cisplatin therapy. Due to close monitoring of serum phenytoin concentrations, no instances of toxicity due to excessive drug concentration, or seizures due to subtherapeutic doses, were noted in patients with primary CNS malignancies. Serum phenytoin concentrations fluctuate markedly during high-dose chemotherapy and must be analyzed frequently during the course of therapy.

Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission.

To test whether variables at diagnosis can identify patients with acute nonlymphoblastic leukemia (ANL) for whom bone marrow transplantation (BMT) is more likely to be of benefit and those for whom continued chemotherapy is a better approach, the association of 15 clinical and laboratory factors with outcome was investigated among 220 patients (ages 1 to 53 years) treated with cyclophosphamide and total body irradiation (TBI) followed by allogeneic BMT, and among 392 patients (ages 13 to 50) administered intensive chemotherapy. In the BMT group, female sex, younger age, the absence of hepatitis during induction, a larger percentage of circulating blasts, and a shorter duration of symptoms were associated with longer survival, whereas only female sex and younger age favorably influenced disease-free survival (DFS). In the chemotherapy group, younger age, lower WBC at diagnosis, a single successful induction course, and the absence of circulating promyelocytes were associated with longer survival, whereas only a lower WBC and a lower percentage of peripheral neutrophils were associated with longer DFS. Estimated regression coefficients for treatment-by-prognostic-factor interactions were used to characterize subgroups of patients in which one treatment or the other produced better outcomes. BMT and chemotherapy produced similar durations of survival in a subset of patients characterized by many or all of the following: older age, male sex, achievement of complete remission (CR) after one induction, and absence of circulating blast cells at presentation. These data suggest that, using pretreatment variables, subgroups of patients can be identified for whom either BMT or continued chemotherapy is most likely to be beneficial.

High rate of long-term survival in adult acute leukemia following ten-day chemotherapy (OAP) induction. Maintenance with chemotherapy or chemotherapy plus BCG vaccine.

In this Southwest Oncology Group (SWOG) study, 216 adults with acute leukemia were treated with ten-day chemotherapy consisting of vincristine sulfate (Oncovin), cytarabine (ara-C) (100 mg per square meter of body area per day by 24-hour infusion), and prednisone (ten-day OAP). The results were compared with those of a previous SWOG study in which cytarabine (200 mg per square meter of body area per day) was given for five days (five-day OAP). Patients entering complete remission (CR) were given three consolidation courses of five-day OAP and randomized to maintenance chemotherapy alone (32 patients) or combined with BCG vaccine (24 patients). For 160 previously untreated patients with acute myelogenous leukemia, there was no difference in remission rates (53% vs 43%) or median survival times (48 vs 47 weeks) between ten-day and five-day OAP. The difference in duration of CR (74 vs 54 weeks, respectively) between the two maintenance arms was not statistically significant. However, 14% of evaluable patients with acute myelogenous leukemia and 26% of those achieving CR were alive and in remission more than five years.

Hepatic artery infusion of 5-fluorouracil and mitomycin C in cholangiocarcinoma and gallbladder carcinoma.

Eleven patients with histologically proven cholangiocarcinoma and gallbladder carcinoma were treated with hepatic artery infusion (HAI) of 5-fluorouracil (5-FU) and mitomycin C (Mito-C). Catheters were placed percutaneously through the femoral artery. The schedule used was 5-FU 1200/mg/m2/day given as a continuous infusion for 4 days, plus Mito-C 6 mg/m2 on days 1 and 4. Courses were repeated every 4 weeks. Complete responses (CR) occurred in one patient (9%), and partial response (PR) occurred in six patients (55%). Median survival for all patients from the start of the first treatment was 12.5+ months. Median duration of the response was 3.0 months. Median survival of the patients with gallbladder carcinoma was 12.5 months, and for patients with cholangiocarcinoma has not yet been reached. Drug toxicity was mild, and morbidity of the HAI was minimal. Further trials of chemotherapy in these two neoplasms are warranted.

Management of adult acute leukemia. A Southwest Oncology Group study.

Five hundred forty three adult patients with acute leukemia were entered on the study designed to: (1) test efficacy of vincristine and prednisone used as primary drug therapy in patients with good prognosis as judged by a circulating blast cell count less than 30,000 cm2; (2) investigate the use of either simultaneously or sequentially administered Adriamycin plus cytosine arabinoside plus vincristine and prednisone; and (3) to assess the use of bacillus Calmette-Guerin (BCG) in the maintenance phase on both the response and duration of response. Complete remissions were seen in 21% of patients with the vincristine and prednisone arm. Complete remission rates were similar in both the simultaneously and sequentially administered chemotherapy with overall complete remission rates of 55%. Median durations of complete remission and survival were 35 and 62 weeks, respectively, for patients with AML; and 47 and 75, respectively, for patients with ALL. Toxicity was within acceptable limits. BCG administered during the maintenance phase of therapy caused no differences in duration of complete remission and survival. These results demonstrate an improved response and duration of response over previous studies done by this group.

Randomized controlled trial of transfer factor in Stage II malignant melanoma.

Thirty-six patients with Stage II malignant melanoma were randomized to no further therapy or transfer factor (TF) following surgical removal of all evident disease. Eighteen patients received TF, and 18 were in the surgery only group. Median disease-free intervals were 12.0 and 10.0 months, and survival, 40.8 and 27.0 months, respectively. Nine TF patients and four control patients remain alive. These differences were not statistically significant, and no adjuvant effect of TF could be demonstrated.

High dose BCNU with autologous bone marrow rescue in the treatment of recurrent malignant gliomas.

Eleven patients with malignant gliomas recurring after surgery and radiation therapy, were treated with high dose BCNU 1 050-1 200 mg/M2 with autologous bone marrow rescue. Four patients also received concomitant 5-fluorouracil 1 000 mg/M2/24 hr daily for three days. Eight of ten evaluable patients demonstrated improvement on CAT scan as well as a decrease in steroid requirement. All patients surviving longer than two weeks after BCNU administration experienced full hematologic recovery. No delayed myelosuppression was seen after a single course of high dose therapy. Two patients died as a result of therapy, one following a second induction of BCNU for a total cumulative BCNU dose of 2 400 mg/M2 and one of infection while cytopenic. Additional toxicity includes one steroid-responsive interstitial pneumonitis, one centrilobular necrosis of the liver which spontaneously resolved and one episode of deep vein thrombosis. With limitation on the maximum BCNU dose and distribution of the total dose over three days, high dose BCNU can be administered with acceptable toxicity. This approach may offer a higher response rate than that expected for standard dose BCNU.

Treatment of severe aplastic anemia with antithymocyte globulin.

Eleven patients with acute-onset (less than 2 months), severe aplastic anemia were treated with antithymocyte globulin (ATG) at a total dose between 50 and 420 mg/kg. Median age was 27 (5-74) years. Two additional patients with chronic severe aplastic anemia received ATG but were excluded from analysis after development of bone marrow morphologic and cytogenetic abnormalities suggestive of acute leukemia. Of the 11 analyzed patients, 5 died within 6 months after initial ATG treatment. Six patients, or 54 percent, survived with a minimum follow-up of 24 months and the longest 48 months. Median survival is 42 months. All patients are transfusion-independent although none are completely normal, due to mild thrombocytopenia. The in vitro effect of ATG on pretreatment marrow CFUE was determined in 8 patients and concordance with clinical outcome was observed for only 3 patients. Three patients had no in vitro response and survived, and 2 patients had a positive in vitro response and died. Survival after ATG correlated with maximum percent decrease in absolute lymphocyte count during treatment. No significant correlation was determined for any other parameter. The mechanism of ATG action remains unknown but the clinical response suggests that immune dysfunction may play an important role in the development or prolongation of aplastic anemia, and that this abnormality may be reversible by ATG in some patients.

Intermittent regional infusion of chemotherapy for pancreatic adenocarcinoma. Phase I and II pilot study.

Nineteen patients with unresectable and metastatic adenocarcinoma of the pancreas and ampulla of Vater were treated with intermittent regional infusion of the celiac axis (CAI) with the combination of 5-fluorouracil, adriamycin, mitomycin-C, and streptozotocin (FAM-S). Three schedules with escalating doses were investigated. The arterial infusion was repeated at 4 weeks, and in responding and stable patients, I.V. FAM-S was continued at monthly intervals. Twelve patients had measurable disease, and in this group one complete response and seven partial responses occurred. Median duration of response was 6+ months and median survival for all patients was 5.2 months. Four patients had catheter-related complications (emboli, three, sepsis, one). Hematologic and gastrointestinal toxicity was minimal. Celiac artery infusion with FAM-S in locally extensive and metastatic adenocarcinoma of the pancreas and ampulla of Vater is a relatively simple procedure associated with low incidence of serious complications and toxicity but a higher response rate than previously reported. Induction of response with CAI and subsequent maintenance therapy with intravenous chemotherapy is under investigation.

Phase II trial of 5-fluorouracil, adriamycin, mitomycin C, and streptozotocin (FAM-S) in pancreatic carcinoma.

Twenty-five patients with unresectable and metastatic pancreatic carcinoma were treated with the combination of 5-fluorouracil, Adriamycin, mitomycin C and streptozotocin (FAM-S). Twelve of 25 patients responded (48%) and four patients demonstrated stable disease. Median survival of all patients was 6.75 months, and seven of 25 patients survived more than 12 months. Hematologic toxicity was moderate, and the predominant side effect recorded was nausea and vomiting (80% patients). Combination chemotherapy in pancreatic carcinoma may provide palliation and randomized trials are warranted to confirm these results.

Hepatic artery infusion with 5-fluorouracil and mitomycin-C in metastatic colorectal carcinoma phase II study.

Thirty-two patients with hepatic metastases colorectal carcinoma were treated with hepatic artery infusion (HAI) employing 5-fluorouracil (5-FU) and mitomycin-C (mito-C). Catheters were placed percutaneously via the femoral artery. Two schedules were employed: (I) 5-FU 1,200 mg/m2 IA (D1-4) and mito-C 8 mg/m2 IA (D1 + D4); (2) 5-FU 1,200 mg/m2 IA (D1-6) and mito-C 8 mg/m2 IA (D1 + D4). Courses were repeated every 4 weeks. Thirty patients with measurable disease were evaluable, 22 received schedule I and 8 patients schedule II. Complete response occurred in two patients (6.7%) and partial response in 13 patients (43.3%). Five patients (16.7%) had minimal regression. The overall response rate as 66.7%. Median survival of all patients from start of treatment was 11.2 months. Median survival of responders and nonresponders was 12.4 months and 4.6 months, respectively (P less than 0.05). No differences in response rates, duration of response, or survival was seen between the two schedules. Drug toxicity was moderate to severe, but morbidity of HAI per se was minimal. Intermittent HAI of 5-FU and mito-C is a well-tolerated treatment modality associated with few serious complications. The response rate, duration of response, and the survival is comparable to continuous HAI infusion of 5-FU or floxuridine (FUDR). As given in this study, mito-C did not appear to provide added benefit.

Cisplatin hydration with and without mannitol diuresis in refractory disseminated malignant melanoma: a southwest oncology group study.

In a prospective phase II randomized trial, a dose of 100 mg/m2 iv cisplatin every 3 weeks plus forced hydration with or without mannitol diuresis was tested in patients with previously treated advanced malignant melanoma. A total of 67 patients were evaluated: 33 not given mannitol and 34 in the mannitol arm. Two partial remissions (of 2+ and 6.5 months) were achieved in the no-mannitol arm and one complete response and four partial responses (of 1, 2, 2.5, 5.5, and 8 months) were seen in the mannitol arm. Moderate, severe, and life-threatening renal toxicity was less in the mannitol arm, and patients tolerated more doses of cisplatin. The renal toxicity occurred mostly after the first dose of chemotherapy and did not seem to be cumulative. Other side effects were comparable in both arms. We concluded that renal toxicity is less severe in patients treated with cisplatin, hydration, and mannitol and that the use of cisplatin alone or in combination with other active agent(s) should be considered for further evaluation in previously untreated patients with malignant melanoma.

VP16-213, cisplatinum, and adriamycin salvage therapy of refractory and/or recurrent nonseminomatous germ cell neoplasms.

Eleven patients with recurrent and/or resistant nonseminomatous germinal cell neoplasms refractory to conventional chemotherapy were treated with the combination. VP16-213, cis-diamminedichloroplatinum, and adriamycin. One complete response, four partial responses which at surgery were benign teratomas, and six partial responses have been observed. Four patients are prolonged survivors (greater than 18 months). The possibility that this regimen may offer true salvage for refractory patients exists. Incorporation of VP16-213 into initial treatment regimens for germinal cell neoplasms is warranted.

Effect of schedule on activity and toxicity of 5-azacytidine in acute leukemia: a Southwest Oncology Group Study.

One-hundred-fifty-four patients with acute leukemia and extensive prior chemotherapy were treated with 5-Azacytidine and evaluated according to five different schedules. One-hundred-twenty patients received adequate trials; 34 patients died within 14 days of onset of treatment. Nine patients achieved a complete remission (CR) and two achieved a partial remission. Although two of the treatments have a higher remission rate, the data were not statistically significant. The median time to CR was 48 days (range 21-173). The median duration of CR was 65 days (range 39-369). There was no difference in response rate according to cell type. The median age of responders was 31 years, and 39 years for nonresponders. Proportionately there were more women among responders (5M/6F) and more men (70M/39F) among nonresponders. At onset of therapy the median leukocyte counts were similar between responding (5.4 X 10(3)) and nonresponding (5.7 X 10(3)) patients, but the proportion of leukemic cells was significantly higher among nonresponding patients (46% vs. 7%). Toxicities included nausea, vomiting, diarrhea, skin rash, myalgias, prolonged myelosuppression, hypotension, and central nervous system stupor and/or coma. Lower dose continuous infusion schedules of five-, seven-, and ten-days duration appear effective and were associated with less toxicity.

Simultaneous treatment with cisplatin and radiation therapy for advanced solid tumors: a pilot study.

To study the toxicity and efficacy of simultaneous cisplatin chemotherapy and radiation therapy, 13 patients with metastatic solid tumors were treated with cisplatin on a weekly, outpatient basis during palliative radiation therapy. The dose of cisplatin ranged from 20 to 50 mg/m2 weekly, with most patients receiving 40 mg/m2. Radiation therapy was administered in a variety of dose-fraction schedules. Toxic effects were moderate and consisted of emesis (12 patients), transient elevation off BUN (three patients), myelosuppression (three patients), and radiation reactions (two patients). Twelve of 13 irradiated lesions (91%) responded with at least a 50% reduction in biperpendicular diameter. Four of the six patients with metastatic melanoma had complete regression of treated lesions; another melanoma patient had a partial response. Responses were also seen in patients with mesothelioma, bladder cancer, squamous cell carcinoma of the head and neck, and oat cell lung cancer. Only one responding patient has had disease progression in the treated field after 2+ to 7+ months of followup; two other patients have died of disseminated disease. Weekly cisplatin administration during radiotherapy deserves further evaluation, especially in the primary management of unresectable tumors that are responsive to cisplatin alone.

Doxorubicin and ifosfamide combination chemotherapy in previously treated acute leukemia in adults: a Southwest Oncology Group pilot study.

The Southwest Oncology Group did a limited institutional pilot study of the combination of doxorubicin and ifosfamide in the treatment of previously treated adult patients with acute leukemia. Thirty-four patients received one or two courses of the combination. All patients had received prior chemotherapy and 32 had received prior anthracycline chemotherapy. Three patients died before their responses could be fully evaluated. Fourteen patients achieved complete remission (41%) and one patient achieved partial remission. The complete remission rate was 27% for patients with acute myeloblastic leukemia (myelomonoblastic leukemia, monoblastic leukemia, and erythroleukemia) and 89% for patients with acute lymphocytic and undifferentiated leukemia (ALL). Toxic effects included severe hematologic reactions in 33 of 34 patients, hematuria in six patients, altered sensorium in one patient, and congestive heart failure in one patient. The safety of the combination was established and toxic side effects of this therapy were tolerable. The 89% complete remission rate for previously treated patients with ALL suggests that the combination of doxorubicin and ifosfamide may be particularly effective in ALL.

Phase II trial of streptozotocin, mitomycin C, and 5-fluorouracil in adenocarcinoma of the pancreas.

A phase II study study employing 5-fluorouracil, mitomycin C, and streptozotocin in unresectable pancreatic carcinoma was performed. Seven of 22 patients (32%) responded and 4 of 22 (18%) had stable disease. Median survival of the entire group was 6 months, and of responders 9.5 months. In 13 patients with localized disease, five responses (38%) were seen and median survival was 7.5 months. Toxicity of the regimen was moderate, being predominantly gastrointestinal and renal. The usefulness of this regimen in localized pancreatic cancer should be explored further.