Spinal cord penetration of intrathecally administered cytarabine and methotrexate: a quantitative autoradiographic study.

Carcinomatous meningitis is an increasingly common complication of systemic cancer. Treatment usually involves the use of intrathecal methotrexate or cytarabine, which have been reported to be toxic to the spinal cord. This study was performed to determine the penetration and distribution of intrathecally administered chemotherapy within the spinal cord. Tritiated methotrexate and cytarabine were administered intraventricularly and by lumbar puncture to New Zealand White rabbits. The extent and pattern of penetration of drug into the spinal cord were determined using quantitative autoradiographic techniques. The results demonstrate that 1 hour after administration 67%-99% of the total area of the spinal cord sections were exposed to these intrathecally administered agents. The pattern of distribution of the labeled drugs was inhomogeneous and was not dependent on the agent or the route of administration. High drug levels were seen in the area of the substantia gelatinosa and peripheral white matter which correspond to the location of pathological changes seen in the spinal cords of patients with neurotoxicity from intrathecal chemotherapy. This rapid and extensive penetration of intrathecally administered chemotherapy may offer insight into the myelopathy observed with these treatments.

Favorable outcome of invasive aspergillosis in patients with acute leukemia.

During a 2-year period, 15 of 110 patients (14%) admitted for intensive therapy of acute leukemia associated with prolonged deep granulocytopenia developed documented invasive aspergillosis (IA). Antemortem diagnosis was accomplished in 14, and 13 of 15 (87%) survived the infection. Because of the high success rate, we reviewed the courses of the 15 patients to assess factors associated with this favorable outcome. Eleven presented with pulmonary IA; early symptoms occurred at a mean 21.6 days of granulocytopenia (less than 100/muL) and included refractory fever in 14 and pulmonary signs or symptoms in 11. Primary necrotic chest wall lesions associated with Hickman catheters developed in four at a mean 11 days of granulocytopenia, followed by pulmonary involvement. All 15 patients had chest radiographs during granulocytopenia, with 14 (93%) demonstrating pulmonary infiltrates and/or nodules at a mean 20.6 days of aplasia. Nine patients had lung computerized tomography (CT) scans, revealing nodular infiltrates in one patient and a characteristic zone of low attenuation surrounding a mass-like infiltrate in seven other patients, which was found to be diagnostic of IA. Subsequent CT scans performed during and following bone marrow recovery showed progression to cavitation followed by either complete resolution or minimal pulmonary scarring. Eleven patients developed IA during empiric amphotericin B (Amp-B) therapy (0.5 mg/kg/d) for fever refractory to antibacterial antibiotics. Fourteen patients received high-dose Amp-B (1.0 to 1.5 mg/kg/d), which was started within a mean of 2.2 days of first clinical findings; 13 survived. Ten patients received 5-fluorocytosine in addition to high dose amp-B. Survival was similar regardless of presentation, as 91% with primary pulmonary IA and 75% presenting with chest wall lesions survived. All 13 surviving patients had complete granulocyte recovery at a mean 33.8 days. Nephrotoxicity (creatinine greater than 2.0 mg/dL) was observed in seven patients during therapy for IA, but was transient in all seven. We conclude IA can be successfully treated in the deeply granulocytopenic patient provided that it is recognized and treated early, and provided that antifungal therapy is aggressive and is continued until granulocyte recovery occurs.

Early evaluation of combined fluorouracil and leucovorin as a radiation enhancer for locally unresectable, residual, or recurrent gastrointestinal carcinoma. The North Central Cancer Treatment Group.

PURPOSE: To develop a tolerable regimen of fluorouracil (5-FU), low-dose leucovorin, and radiation, and to obtain an early estimate of therapeutic effectiveness. PATIENTS AND METHODS: Forty patients with locally unresectable or recurrent gastrointestinal carcinoma were studied (pancreas, n = 22; rectum and sigmoid, n = 10; gastric, n = 6; other, n = 2). Irradiation therapy was administered in 1.8-Gy fractions 5 days per week, with total doses ranging from 45 to 54 Gy. 5-FU 400 mg/m2/d plus leucovorin 20 mg/m2/d, both by rapid intravenous injection, were administered for 3 or 4 days during the first and fifth weeks of radiation. 5-FU 425 mg/m2/d plus leucovorin 20 mg/m2/d were administered for 4 days at 4 weeks following radiation and for 5 days at 9 weeks. RESULTS: Major toxicities with upper abdominal treatment were nausea, vomiting, weight loss, and leukopenia. A tolerable dosage regimen was radiation at 45 Gy with 4 days of 5-FU plus leucovorin during the first week and 3 days during the last week with postradiation chemotherapy. Major toxicities with pelvic radiation were diarrhea and leukopenia. A tolerable regimen was 54 Gy with 4 days of 5-FU plus leucovorin during the first and fifth week followed by the postradiation chemotherapy. Median survival durations for pancreatic and rectal/sigmoid carcinomas are 13 months and 31 months, respectively. Five patients have no evidence of disease from 38 to 50 months after the onset of therapy (rectal, n = 2; stomach, n = 2; pancreas, n = 1). CONCLUSION: We have developed patient-tolerable regimens for combined 5-FU plus leucovorin followed by radiation to the abdomen and to the pelvis. The favorable results observed in locally unresectable disease allow cautious optimism for possible effectiveness in the surgical adjuvant setting, a possibility currently being tested in national trials of rectal and gastric carcinoma.

Phase II trial of nitrogen mustard, vincristine, and procarbazine in patients with recurrent glioma: North Central Cancer Treatment Group results.

PURPOSE: Previous investigators have reported responses in 52% of patients treated with mechlorethamine (nitrogen mustard), vincristine, and procarbazine (MOP) for recurrent glioma. To confirm these promising results, we conducted a phase II prospective study. PATIENTS AND METHODS: Sixty-three patients with histologic confirmation of recurrent glioma were treated with the MOP regimen. Patients with or without prior chemotherapy received nitrogen mustard 3 mg/m2 or 6 mg/m2, respectively, intravenously on days 1 and 8 plus vincristine 2 mg/m2 intravenously on days 1 and 8, and procarbazine 100 mg/m2 orally on days 1 to 14. Cycles were repeated every 28 days. RESULTS: Of 61 patients assessable for response, eight responded (13%), with one complete response (CR). Responses were as follows: low-grade gliomas, 19%; anaplastic astrocytomas, 11%; anaplastic oligodendrogliomas or oligoastrocytomas, 25%; and glioblastomas, 4.3%. The most common toxicity was myelosuppression with leukocyte nadirs less than 1,000/microL in 23% and platelet nadirs less than 25,000/microL in 13% of patients. Two patients died of infection in the setting of neutropenia. Nonhematologic toxicity included neurosensory changes in 21% of patients (severe in 3%) and severe dermatologic reactions in 8%. In multivariate analysis, Eastern Cooperative Oncology group (ECOG) performance status (PS) was the best predictor for response to chemotherapy (P=.01) and time to progression (P=.008), while PS and grade were the most important predictors of survival (P=.002 and .05, respectively). CONCLUSION: This study did not confirm the high response rate previously reported in recurrent gliomas. Patients with recurrent anaplastic oligodendrogliomas or oligoastrocytomas and recurrent low-grade gliomas had the highest response rates (25% and 19%, respectively). In multivariate analysis, ECOG PS was the best predictor of response, while PS and tumor grade were the most important predictors of survival.

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer.

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.

Phase III evaluation of octreotide versus chemotherapy with 5-fluorouracil or 5-fluorouracil plus leucovorin in advanced exocrine pancreatic cancer: a North Central Cancer Treatment Group study.

There continues to be a need for new systemic approaches for the treatment of advanced pancreatic cancer. The purpose of this study was to compare the antitumor activity of the somatostatin analogue octreotide to 5-fluorouracil chemotherapy in a Phase III setting. Eighty-four patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and limited tumor volume were randomized to receive octreotide 200 microg three times daily or 5-fluorouracil with or without leucovorin. After the first 12 patients had been randomized to octreotide, we increased the dose in the remaining patients to 500 microg three times daily. This change was based on early reports in other studies, suggesting that our original dose may not have been effective and that higher doses of octreotide were well tolerated. A planned interim analysis performed after 84 patients were enrolled demonstrated inferior time to progression and survival for the patients randomized to octreotide. Further accrual to the octreotide arm of this protocol was therefore terminated. Octreotide in doses of 200-500 microg three times daily does not delay progression or extend survival in patients with advanced pancreatic cancer compared with treatment with 5-fluorouracil with or without leucovorin.

Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer.

We attempted to induce therapeutic immunity against prostate-derived tissues in patients suffering from progressive hormone-refractory metastatic prostate carcinoma. Thirteen patients were treated with two infusions, 1 month apart, of autologous dendritic cells (APC8015) preexposed ex vivo to PA2024, a fusion protein consisting of human granulocyte/macrophage-colony stimulating factor (GM-CSF) and human prostatic acid phosphatase (PAP). The infusions were followed by three s.c. monthly doses of PA2024 without cells. Three groups of patients each received PA2024 at 0.3, 0.6, or 1.0 mg/injection. All Ps were two-sided. Treatment was well tolerated. After infusions of APC8015, patients experienced only mild (grade 1-2) short-lived fever and/or chills, myalgia, pain, and fatigue. One patient developed grade 3 fatigue. Four patients developed mild local reactions to s.c. PA2024. Twelve patients were evaluable for response to treatment. Circulating prostate-specific antigen levels dropped in three patients. T cells, drawn from patients after infusions of APC8015, but not before, could be stimulated in vitro by GM-CSF (P = 0.0004) and PAP (P = 0.0001), demonstrating broken immune tolerance against these two normal proteins. Injections of PA2024 did not influence the reactivity of T cells against PAP and GM-CSF. However, antibodies to GM-CSF and, to a much lesser extent, to PAP reached maximum titers only after two or even three injections of PA2024, showing that directly injected PA2024 was involved in stimulation of humoral immunity. Dendritic cells exposed to antigen ex vivo can induce antigen-specific cellular immunity in prostate cancer patients, warranting further studies of this mode of immunotherapy.

Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy.

A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 +/- 1.8 h, 13.0 +/- 3.8 liters/h/m2, 234 +/- 83 liters/m2, and 123 +/- 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (p = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.

Alleviation of cancer anorexia and cachexia: studies of the Mayo Clinic and the North Central Cancer Treatment Group.

Anorexia and cachexia are common clinical problems of many patients with advanced cancer. Approximately 20 years ago, a controlled, clinical study demonstrated that dexamethasone could stimulate appetites of patients with advanced gastrointestinal cancer without causing any apparent effect on patient weight or survival. More recently, two double-blind, placebo-controlled trials investigated cyproheptadine and megestrol acetate in patients with cancer anorexia/cachexia. The first of these studies suggested that cyproheptadine could mildly stimulate appetite without causing any discernible effect on patient weight. Megestrol acetate, on the other hand, can clearly cause an increase in patient-perceived appetite and food intake and can also lead to substantial nonfluid weight gain in a proportion of patients with cancer anorexia/cachexia. Ongoing studies have been designed to better study the appetite-enhancing effects of megestrol acetate. In addition, current studies are evaluating the effect of the drug hydrazine sulfate on the appetite and weight status of patients with advanced lung or colon cancer.

Treatment of epidural cord compressions from Hodgkin's disease with chemotherapy. A report of two cases and a review of the literature.

Epidural cord compressions are a frequent and serious problem for patients with cancer. Standard treatment for these lesions includes local irradiation with or without surgery. Herein are reported two cases of epidural cord compression from Hodgkin's disease that responded dramatically to systemic chemotherapy. A review of the literature reveals reports of successful chemotherapy in the treatment of seven patients with epidural metastases secondary to lymphomas and 15 secondary to a variety of other tumors. The use of systemic chemotherapy is an increasingly important therapeutic option for treatment of epidural cord compressions in carefully selected patients.

An approach to intensive antileukemia therapy in patients with previous invasive aspergillosis.

PURPOSE: In an attempt to decrease the risk for reactivation of life-threatening invasive aspergillosis (IA) during subsequent myelosuppression in patients with previously diagnosed IA who were receiving antileukemic treatment, we evaluated the role of intensive antifungal therapy with amphotericin B and 5-fluorocytosine administered prophylactically throughout the antileukemic regimen and induced granulocytopenia to prevent IA reactivation without compromising the intensive chemotherapy. PATIENTS AND METHODS: During a 30-month period, 10 patients with acute myelogenous leukemia and primary IA developing during initial antileukemia induction therapy and severe granulocytopenia (less than 100/mm3) underwent 14 subsequent courses of intensive marrow aplasia-producing chemotherapy during early complete remission or at leukemia relapse. All patients had evidence of ongoing IA healing by lung computerized tomography (CT) prior to reinstitution of intensive chemotherapy. Nine patients receiving 13 chemotherapy courses also received aggressive prophylactic anti-IA therapy with amphotericin B (1.0 mg/kg/day) and 5-fluorocytosine beginning at least 48 hours prior to antileukemia therapy institution and continued until the time of granulocyte recovery. RESULTS: All nine patients receiving aggressive antifungal therapy survived without clinical evidence of IA reactivation. Transient radiographic evidence of IA reactivation during granulocytopenia was detected by lung CT during two of the 13 chemotherapy courses. In contrast, the patient who did not receive anti-IA prophylaxis had both clinical and radiographic evidence of IA reactivation during severe granulocytopenia and died. Anti-IA prophylaxis was achieved without irreversible nephrotoxicity, prolonged marrow suppression, alteration of antileukemia treatment, or negative impact on clinical outcome relative to acute leukemia. CONCLUSION: This approach of antifungal prophylaxis in adults with acute leukemia and documented primary IA occurring during initial induction chemotherapy has been successful in preventing clinically significant IA reactivation during subsequent granulocytopenic courses, and allows for administration of additional intensive antileukemia therapy.

Results of irradiation or chemoirradiation for primary unresectable, locally recurrent, or grossly incomplete resection of gastric adenocarcinoma.

OBJECTIVE: To evaluate the results of irradiation +/- chemotherapy for patients with unresectable gastric carcinoma. MATERIALS AND METHODS: The records of 60 patients with a gastric or gastroesophageal junction adenocarcinoma and a locally advanced unresectable primary (n = 28), a local or regional recurrence (n = 21), or gross residual disease following incomplete resection (n = 11) were retrospectively reviewed. Patients were treated with external beam irradiation (EBRT) alone or external beam plus intraoperative irradiation (IOERT), and 55 of the 60 (92%) patients received 5-FU based chemotherapy. RESULTS: The median survival for the entire cohort was 11.6 months. There was no significant difference in median survival between each of the three treatment groups. In examining the extent of disease there was a significant difference in survival based on the number of sites involved. Nine patients with disease limited to a single non-nodal site appeared to represent a favorable subgroup compared to the rest of the patients (median survival of 21.8 months vs. 10.2 months,p = 0.03). In the patients with recurrent disease, the number of sites involved (p = 0.05), and total dose adding external beam dose to IOERT dose (> 54 Gy vs. < or =54 Gy, p = 0.06) were of borderline significance in regard to survival. CONCLUSIONS: In patients with either primary unresectable, locally or regionally recurrent, or incompletely resected gastric carcinoma, the overall survival is similar, and related to the extent of disease based on the number of regional sites involved. The patients with a single non-nodal site of disease represent a favorable subgroup and patients with recurrent disease may benefit from total irradiation doses > 54 Gy.

Results of irradiation or chemoirradiation following resection of gastric adenocarcinoma.

PURPOSE: To evaluate the results of postoperative irradiation +/- chemotherapy for carcinoma of the stomach and gastroesophageal junction. METHODS AND MATERIALS: The records of 63 patients who underwent resection for stomach cancer were retrospectively reviewed. Twenty-five patients had complete resection with no residual disease but with high-risk factors for relapse. Twenty-eight had microscopic residual and 10 had gross residual disease. Doses of irradiation ranged from 39.6 to 59.4 Gy with a median dose of 50.4 Gy in 1.8 Gy fractions. Fifty-three of the 63 (84%) patients received 5-fluorouracil (5-FU)-based chemotherapy. RESULTS: The median duration of survival was 19.3 months for patients with no residual disease, 16.7 months for those with microscopic residual disease, and 9.2 months for those with gross residual disease (p = 0.01). The amount of residual disease also significantly impacted locoregional control (p = 0.04). Patients with linitis plastica did significantly worse in terms of survival, locoregional control, and distant control than those without linitis plastica. The use of 4 or more irradiation fields was associated with a significant decrease in the rate of Grade 4 or 5 toxicity when compared to the patients treated with 2 fields (p = 0.05). CONCLUSIONS: There was a significant association between survival and extent of residual disease after resection as well as the presence of linitis plastica. Distant failures are common and effective systemic therapy will be necessary to improve outcome. The toxicity of combined modality treatment appears to be reduced by using greater than 2 irradiation fields.

Phase I evaluation of radiation combined with recombinant interferon alpha-2a and BCNU for patients with high-grade glioma.

PURPOSE: A Phase I study to determine the safety, toxicity, and maximum tolerated dose (MTD) of carmustine (BCNU) and interferon alpha-2a (IFN-a) when combined with radiation as initial therapy in high-grade glioma. METHODS AND MATERIALS: Patients with newly diagnosed Grade 3 or 4 astrocytoma, oligoastrocytoma, or gliosarcoma were enrolled after surgery. All received radiation therapy to the brain (64.8 Gy/36 fractions), combined with a single dose of BCNU (200 mg/m2) at the start of radiation. Chemotherapy after completing radiation consisted of BCNU 150 mg/m2 once every 7 weeks, and IFN-a 12 x 10(6) units/m2 subcutaneously Days 1-3 each week of a 7-week cycle. Subsequent dose modification was based on constitutional symptoms for IFN-a and on myelosuppression for BCNU. RESULTS: Fifteen patients were entered on the study. Four were excluded because they did not receive IFN-a (3 refused treatment and 1 patient left the study due to multiple medical problems). Eleven were evaluable for toxicity and efficacy. Nonhematological toxicity, mainly lethargy and flu-like symptoms, were dose-limiting for IFN-a. After the first 6 patients were treated per the initial protocol, the frequency of IFN-a administration was decreased to Days 1-3 on weeks 1, 3, and 5 of the 7-week cycle for 5 additional patients. Lethargy, fever, chills, myalgias, alopecia, and anorexia occurred in all patients. Other toxicities included nausea and vomiting (91%), central-nervous-system depression or mood changes (64%), headaches (55%), and elevation of liver enzymes (36%). Grade 3-4 leukopenia occurred in 4 (45%) of 11 patients, and Grade 3-4 thrombocytopenia in 3 (27%) of 11 patients. Due to myelosuppressive effects, BCNU dose was not escalated. Median survival of the cohort was 44 months. Objective responses occurred in 5 (56%) of 9 patients and median duration of response was 33 months. The MTD of this combination after radiation therapy is IFN-a 12 x 10(6) units/m2 Days 1-3, on Weeks 1, 3, and 5 of a 7-week cycle and BCNU 150 mg/m2 Day 1, every 7 weeks. CONCLUSIONS: Treatment with radiation, IFN-a, and BCNU is feasible and effective in patients with high-grade gliomas, although constitutional symptoms from IFN-a are substantial.

Pilot study of continuous-infusion 5-fluorouracil, oral leucovorin, and upper-abdominal radiation therapy in patients with locally advanced residual or recurrent upper gastrointestinal or extrapelvic colon cancer.

PURPOSE: The purpose of this study was to develop a satisfactorily tolerated regimen of radiation therapy, continuous infusion 5-fluorouracil, and leucovorin in patients with locally advanced upper-abdominal gastrointestinal cancer. METHODS AND MATERIALS: Patients with locally advanced or locally recurrent gastric, pancreatic, or extrapelvic colon cancer were eligible for this study. Radiation therapy consisted of 45 Gy in 25 fractions to the tumor and regional lymph nodes, followed by 5.4-9 Gy in three to five fractions to the tumor. Treatment with leucovorin, 10 mg orally daily, and continuous infusion 5-fluorouracil was initiated on the first day of radiation therapy. 5-Fluorouracil was administered at an initial daily dose of 125 mg/m2, with dose escalation planned in 25-mg increments, depending on patient tolerance. RESULTS: Twenty-one evaluable patients participated in this study. Six were treated at the initial daily 5-fluorouracil dose of 125 mg/m2. One patient experienced Grade 4 anorexia and nausea. No other Grade > or = 3 toxicity was observed at this dose. Fifteen evaluable patients were entered at a planned 5-fluorouracil dose of 150 mg/m2 daily; 6 of them experienced Grade 3 toxicity, and none experienced Grade > or = 4 toxicity. Grade 3 toxicities and the number of patients who developed each were: vomiting (three patients); nausea (two patients); diarrhea (two patients); and skin toxicity, hand-foot syndrome, catheter-related infection, and stomatitis in one patient each. Four of the six patients who experienced Grade 3 toxicity developed more than one type of Grade 3 toxicity. CONCLUSIONS: In patients with upper-abdominal gastrointestinal cancer, continuous infusion 5-fluorouracil (150 mg/m2 daily), leucovorin (10 mg orally daily), and radiation therapy (50-54 Gy) resulted in a 40% rate of severe toxicity but no life-threatening toxicity. This clinical trial excludes, with 90% confidence, a 20% risk of Grade 4 toxicity with this combination. The 40% rate of severe toxicity suggests that this combination of agents is near the maximal tolerated dose.

Renal cell carcinoma metastatic to the pancreas: clinical and radiological features.

OBJECTIVE: To review the clinical features, computed tomographic (CT) appearance, and treatment outcomes in a case series of patients with renal cell carcinoma (RCC) metastatic to the pancreas. PATIENTS AND METHODS: We retrospectively reviewed the records of 23 patients (15 men and 8 women) with RCC metastatic to the pancreas, detected by CT examination between 1986 and 1996. All patients had undergone a previous nephrectomy for RCC. RESULTS: Isolated mild elevation in liver function test results (in 5 patients) or in serum amylase level (in 8 patients) was observed. New-onset diabetes was detected in 3 patients. The CT characteristics of the pancreatic metastases generally resembled those of primary RCC with well-defined margins and greater enhancement than normal pancreas with a central area of low attenuation. The mean interval between resection of the primary RCC and detection of the pancreatic metastases was 116 months (range, 1-295 months). In 18 patients (78%), the pancreatic metastases were diagnosed more than 5 years after nephrectomy. The pancreas was the initial metastatic site in 12 patients (52%). Survival was shortened with higher tumor grade (mean survival time of 41 months and 10 months in patients with grade 2 and 3, respectively). Surgical resection was carried out in 11 patients (7 distal and 3 total pancreatectomies and 1 distal pancreatectomy followed 4 years later by total pancreatectomy), with 8 patients alive at a mean follow-up of 4 years, 6 of whom remained free of recurrence. Overall, 12 patients (52%) were alive at a mean of 42 months after diagnosis of metastatic disease. CONCLUSIONS: The appearance of metastatic RCC lesions in the pancreas closely resembles the appearance of primary RCC on CT images. Pancreatic metastases from RCC are frequently detected many years after nephrectomy. Patient survival correlates with tumor grade. Histologic analysis of pancreatic masses in patients with a history of resected primary RCC is important since the prognosis for RCC metastatic to the pancreas is much better than that for primary pancreatic adenocarcinoma.

Invasive pulmonary aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management.

Over 80 percent of patients with invasive pulmonary aspergillosis (IPA) undergoing intensive antileukemic chemotherapy in a recent two-year period survived the pulmonary infection as a result of early diagnosis and aggressive therapy with high-dose amphotericin B and 5-fluorocytosine. CT played an important role in establishing the early diagnosis of IPA and affected management. Since our original communication describing the CT findings of IPA, we have added ten new cases, each subsequently substantiated by lung biopsy (two), autopsy (two), and/or positive cultures of sputum or extrapulmonary sites (seven). The CT halo sign, or zone of lower attenuation surrounding a pulmonary mass, was present in eight of nine patients with early CT scans obtained during bone marrow aplasia. Characteristic CT progression from multiple fluffy masses to cavitation or air crescent formation suggested IPA in five of seven patients with serial CT scans. CT directly affected patient management in seven of ten cases. Scan findings were one criterion for increasing to high-dose amphotericin B or for adding 5-fluorocytosine. CT characteristics of healing IPA lesions were similar to resolving pulmonary infarcts and were used to monitor disease activity in patients on long-term amphotericin B and prior to retreatment chemotherapy.

North Central Cancer Treatment Group Phase II study of 5-fluorouracil and high-dose levamisole for gastric and gastroesophageal cancer using survival as the primary endpoint of efficacy.

At present there is no established standard chemotherapy for advanced gastric cancer. Combination regimens have yielded response rates at times exceeding 50% but with no improvement in survival compared to single agents. This study examined the role of 5-fluorouracil and high-dose levamisole in a phase II setting using survival as the main endpoint. Patients with advanced carcinomas of the stomach or gastroesophageal junction were treated with 5-fluorouracil, 450 mg/m2 IV days 1 to 5, and levamisole, 100 mg/m2 orally three times daily on days 1 to 3, and 50 mg/m2 tid days 4 to 5 every 5 weeks. To allow more rapid accrual and to study a population that more accurately reflects the makeup of patients treated in clinical practice, patients with both measurable and nonmeasurable disease were entered in this study. Two of fifteen (13%) patients with measurable disease experienced a partial response to treatment. The adjusted 1-year survival rate for the 44 patients entered was 29.6%, which is similar to the historical 1-year survival of 30% observed in a group of nearly 400 patients treated in prior North Central Cancer Treatment Group studies. This regimen offers no improvement in therapeutic activity for advanced gastric cancer. This study design, however, allows rapid screening of phase II regimens in patients who would usually be candidates for phase III trials.

Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial.

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11-36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (> or =grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand-foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.

A phase II study of high-dose cimetidine and the combination 5-fluorouracil, interferon alpha-2A, and leucovorin in advanced renal cell adenocarcinoma.

Cimetidine is an H2-receptor antagonist used in the management of peptic ulcer disease and other hypersecretory gastrointestinal disorders. This agent has intriguing immunomodulatory characteristics. A phase II trial of cimetidine in 19 patients with advanced malignant melanoma yielded an objective response rate of 16%. Having demonstrated that cimetidine is active in malignant melanoma, the authors conducted a phase II trial of cimetidine, 800 mg twice daily by mouth, in patients with advanced renal cell cancer. Among the 31 eligible patients, only one (3.2%) achieved a regression. It was a partial regression lasting 93 days. Median time to treatment failure was 83 days. The combination of interferon alpha-2A (IFL-RA) and 5-fluorouracil (5-FU) has been shown to be synergistic against experimental cell lines in vitro. Citrovorum factor (CF) added to 5-FU has been shown to improve objective tumor response compared with single-agent 5-FU in patients with advanced colorectal cancer. Fluorinated pyrimidines have shown some activity against renal cell cancer. We conducted a phase II trial of the combination of CF at 20 mg/m2 intravenous push followed by 5-FU at 325 mg/m2 intravenously daily for 5 days every week with interferon alpha-2A 5 x 10(6) units/m2 subcutaneously on days 1, 3, 5 in patients with advanced renal cell cancer. Among the 31 eligible patients, only two (6.5%) achieved a regression. Both were partial regressions. Median time to treatment failure was 84 days. Neither regimen is recommended for further testing in patients with advanced renal cell adenocarcinoma.