Phase I chemotherapy study of biochemical modulation of folinic acid and fluorouracil by gemcitabine in patients with solid tumor malignancies.

PURPOSE: This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest. RESULTS: The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months. CONCLUSION: The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.

Randomized study of cyclophosphamide, doxorubicin, and etoposide (VP16-213) with or without cisplatinum in non-small cell lung cancer.

Sixty-eight patients with non-small cell lung cancer were treated in a prospectively randomized study with cyclophosphamide, doxorubicin (Adriamycin), and etoposide (VP16-213) with cisplatinum (CAE +/- P). Response rate, time to progression, and survival of CAE-P treated patients were each superior compared to those of patients who received CAE therapy. Of 36 patients, 10 (4 complete remissions, 6 partial remissions) responded to CAE-P and of 29 patients 3 (1 complete remission, 2 partial remissions) responded to CAE (p = 0.073). The median time to treatment failure was 22.9 wk for the CAE-P regimen and 15.0 wk for CAE (p = 0.032). The median survival for patients treated on the regimen with and without cisplatinum was 34.5 and 22.5 wk, respectively (p = 0.04). There were two CAE-P and one CAE drug-related deaths. Toxic effects were more severe in the CAE-P regimen. The addition of cisplatinum to the CAE combination produced an increase in response rate with significant prolongation in both time to progression and survival, but did add morbidity. These results suggest that the combined use of cisplatinum with at least one of the chemotherapeutic agents in the CAE regimen is synergistic.

Therapeutic efficacy and pharmacokinetics of vindesine and vindesine-cisplatin in previously treated patients with non-small cell lung carcinoma.

Twenty-nine patients with non-small cell lung cancer refractory to prior therapy were treated with either vindesine (VDS) alone (3 mg/m2 every week) or the combination of VDS plus cisplatin (DDP) (100 mg/m2 every 28 days). Serial blood and urine samples were collected to assess the pharmacokinetics of VDS and DDP. All patients were evaluable for toxicity and 27 were evaluable for response. No objective antitumor responses were observed. Peripheral neuropathy manifested by paresthesias, muscle weakness, and constipation were observed in 20 treated patients, and hematologic toxicity consisting of thrombocytopenia and/or leukopenia occurred in 18 patients. The plasma and urinary pharmacokinetics of VDS and DDP measured in this study indicate that VDS and DDP do not interfere with each other and that the pharmacokinetics in previously treated and untreated patients are similar. The antitumor responses and degree of toxicity observed in this trial compare unfavorably with previously reported VDS and VDS-DDP trials in previously untreated patients with this disease and suggest that prior exposure to chemotherapy might both decrease antitumor activity and enhance toxicity of these chemotherapeutic agents.

Cyclophosphamide and dimethylsulfoxide in the treatment of squamous carcinoma of the lung. Therapeutic efficacy, toxicity, and pharmacokinetics.

To determine whether dimethylsulfoxide (DMSO) can potentiate antitumor activity of cyclophosphamide (CYC) in patients with squamous cell carcinoma of the lung, 14 patients were treated with 5 l of a 5% or 6% DMSO solution PO over 3 days and 1,500 mg CYC/m2 IV as a 60-min infusion on the third day of treatment. Serial blood, CSF, and urine samples were collected to assess the pharmacokinetics of CYC. Courses were repeated every 3-4 weeks. No antitumor responses were observed. Toxicity was mainly hematologic and similar to that of CYC alone. There was one death from infection during granulocytopenia. Nonhematologic toxicity was moderate to severe and included nausea (14 patients) and vomiting (five patients). The plasma pharmacokinetics of CYC in this study are similar to previously reported results for CYC alone, but the 24-h urinary excretion of CYC in our study is much lower than previously reported. Further studies in tumors more responsive to CYC may be warranted.

A phase II trail of vindesine in patients with refractory small-cell carcinoma of the lung.

A phase II study of vindesine at a dose of 3 mg/m2 I.V. for 6 weeks and every other week thereafter was carried out in 18 patients with small-cell carcinoma of the lung. All patients were refractory to conventional therapy and all had been treated previously with spindle inhibitors, vincristine, or VP 16-213. All patients were evaluable for response and toxicity. No objective responses were observed. Leukopenia, the only hematologic toxicity, occurred in 13 patients (72%). Neurotoxicity occurred in five patients (28%). Vindesine appears to have limited activity in patients with small-cell carcinoma of the lung previously treated with spindle inhibitors.

The management of nonseminomatous testicular cancer: current therapy and future directions.

Carcinoma of the testes is the fourth leading cause of death in males between the ages of 15-54, and its incidence may be increasing. Nonseminomatous testicular cancer represents 50% of all testicular tumors. There have been recent advances in diagnosis, staging and therapy of these tumors. Currently, there is a high success rate with platinum containing combination chemotherapy regimens in patients with advanced stages of disease. The article reviews the evolution of successful chemotherapy and the issues of adjuvant therapy for early stage disease, radiation therapy and the role of retroperitoneal lymphadenectomy and surgery following chemotherapy.

Meningeal carcinomatosis from small cell carcinoma of the lung. Consequence of improved survival.

The cells of oat cell carcinoma of the lung can be identified in sputum because of their characteristic morphologic appearance. The cells from oat cell carcinomas can also be identified in other body fluids but are seen there less often. Spinal fluid involvement with oat cell carcinoma has been seen very infrequently, presumably because of a poor survival rate. Aggressive systemic chemotherapy has improved survival, and meningeal involvement is now being recognized as a complication. Of 62 patients treated by aggressive chemotherapy protocols, six (10%) were found to have leptomeningeal involvement by cytologic evaluation of cerebrospinal fluid (CSF). Involvement was found 6 to 13 months after the initiation of therapy. Two of the six patients had no evidence of CNS metastases by CAT brain scan. Necropsy was performed in three of the six cases and showed excellent histologic correlation with the cytologic findings. Because of most therapeutic drugs' poor penetration into the CSF, and because the spinal cord is not routinely irradiated, cytologic examination of the CSF from patients with oat cell carcinoma is necessary when there are new neurologic signs or symptoms to ensure proper, specific therapy.

Peripheral neuropathy after cis-platinum (II) (DDP) therapy.

A 56-year-old man developed a malignant fibrous histiocytoma in the left antecubital space in THE LEFT ANTECUBITAL SPACE IN September 1974. He underwent local resection, local radiation therapy, and chemotherapy with Adriamycin and Levamisole with resolution of the disease. In January 1977, a recurrent mass developed in the left antecubital space and electrophysiologic studies revealed segmental demyelination of the left median nerve across the tumor site. In July 1977, a Cis-diamminedichloplatinum (II) (DDP) therapy was instituted and 5 months later the patient developed paresthesias in both hands and both feet. Repeat nerve conduction studies revealed abnormalities in all 4 extremities consistent with a mixed sensorimotor peripheral neuropathy. Serial studies at 2-month intervals during DDP therapy showed further deterioration in nerve conduction. Following completion of DDP therapy, the patient's symptoms improved and subsequent nerve conduction studies done over an 11-month period showed improvement in nerve conduction with values approaching normal.

Leptomeningeal carcinomatosis in small cell carcinoma of the lung.

Among 137 patients with small cell carcinoma of the lung (SCCL) treated on two consecutive protocols, leptomeningeal metastases were documented in 12 patients (9%), 10 antemortem by cerebrospinal fluid (CSF) cytology, one by myelogram, and one only at necropsy. Signs and symptoms included confusion in seven, limb weakness in six, paresthesias in three, headache in two, urinary incontinence in two, and nausea and vomiting, diplopia and neck pain in one patient each. Nine of the 12 patients had evidence of other metastases while three patients relapsed first in the CSF and one had disease only in the leptomeninges. Treatment for this complication including irradiation, intrathecal chemotherapy, or systemic chemotherapy was generally ineffective with a median duration of survival of 50 days (range 5 to 130) after diagnosis of leptomeningeal. Necropsies showed thick tumor deposits along cord, distal nerve roots, cauda equina, and in Virchow--Robbins spaces with deep invasion into adjacent neural substance in six of the seven. Leptomeningeal involvement appears to have become manifest as median survival has increased. CSF cytology should therefore be examined in patients who develop unusual neurological findings during the course of this disease and methods of prevention may need to be considered in future studies.

Nodular lymphoma. Prolongation of survival by complete remission.

Forty previously untreated patients with either nodular poorly differentiated lymphocytic or nodular mixed lymphocytic/histiocytic non-Hodgkin's lymphoma were evaluated for length of survival from the onset of combination chemotherapy. Complete remissions from initial therapy were achieved in 27/40 patients (67.5%). Actuarial analysis of survival shows that 83% of the complete responders from initial treatment are expected to be living at 7 years in contrast to a less than 2-year median survival of those who failed to reach complete remission with initial therapy when deaths from nonlymphomatous causes are excluded. Wilcoxon comparison of these curves shows a significant (p = 0.0001) advantage for those who are able to attain a complete remission. Treatment was not implicated in any death. Of those patients not reaching complete remission from initial therapy, 80% of the survivors attained a complete response from other therapy. It is concluded that complete remission attainment from initial chemotherapy significantly prolongs survival for patients with nodular lymphoma. Therefore, since combination chemotherapy has given higher complete remission rates than have single agents, such therapy offers the patient with nodular lymphoma the greatest chance for prolonged survival.

Nodular poorly differentiated lymphocytic lymphoma: changes in histology and survival.

Lymphoma patients with a nodular pattern have a better prognosis than those with a diffuse pattern. Histologic evolution from nodular to diffuse may occur during the course of the disease in the same patient. This change in pattern may be of prognostic significance. We reviewed 56 patients with an initial diagnosis of nodular poorly differentiated lymphoma seen over a 12-year period (1966-1978). Thirty-five patients had biopsies after initial diagnosis, and 28 of the cases could be classified as nodular or diffuse. Eleven of the 56 cases evolved from a nodular to a diffuse pattern. Forty-four of the 56 patients achieved a complete remission and were evaluated for survival. The median survival (66+ months) for patients who have never relapsed is similar to that for patients who relapsed with a nodular pattern (70 months) and patients who relapsed with a diffuse pattern (73 months). Relapse with a nodular pattern occurred at a median of 27 months after initial diagnosis and relapse with a diffuse pattern (73 months). Relapse with a nodular pattern occurred at a median of 27 months after initial diagnosis and relapse with a diffuse pattern occurred at a median of 49 months. Although overall survival in patients relapsing with nodular or diffuse disease is similar, median survival from relapse with nodular disease is longer (32+ months) than median survival with diffuse disease (17 months) (P = 0.068).

Physiologic response and toxicity in patients undergoing whole-body hyperthermia for the treatment of cancer.

Seven patients with advanced cancer underwent whole-body hyperthermia using a nylon and vinyl mesh, water-perfused suit. Treatments were given at 41.8 degrees C for 4 hours. Five patients received concomitant cyclophosphamide with hyperthermia. Compared to baseline (37 degrees C) conditions, there was a significant rise in pulse rate (P less than 0.001), a fall in diastolic pressure (P less than 0.02), and an increase in respiratory rate (P less than 0.001). Toxic effects included fatigue, extremity edema, diarrhea, nausea and vomiting, and respiratory depression in a patient with cerebral metastases. Compared to baseline values, there was a significant increase in serum glucose (P less than 0.02) and decreases in serum calcium (P less than 0.01) and phosphorus (P less than 0.01). Significant elevations in serum LDH and SGOT values occurred 24 hours following hyperthermia, suggesting hepatic sensitivity to heat. The methods used to induce whole-body hyperthermia, as described in this paper, are feasible, permit relatively easy access to the patient, and are potentially applicable in diverse hospital settings such as intensive care units, radiation therapy areas, and conventional rooms. The physiologic alterations that were observed and the toxic effects that were documented indicate that careful monitoring of patients is necessary.

High-dose cis-diamminedichloro-platinum therapy in patients with advanced breast cancer: pharmacokinetics, toxicity, and therapeutic efficacy.

Seventeen patients with advanced breast cancer were treated with cis-diamminedichloroplatinum (DDP) 100 mg per m2 every 21--28 days. Hydration and mannitol or furosemide diuresis was given. Responses were seen in two patients (one complete, one objective) with soft-tissue metastases. There was no difference in peak plasma platinum concentration (3.91 micrograms/ml +/- 1.41 micrograms/ml), terminal plasma half-life (116--288 hours), peak concentration of unbound platinum (0.7 micrograms/ml), or 24-hour urinary platinum excretion (6.7--17.2% of administered dose) between the objective responder and the nonresponders. Toxicities included severe nausea and vomiting, renal insufficiency, high-frequency hearing loss, and peripheral neuropathies. Hematologic toxicity was mild in most patients. DDP has limited activity when used as a single agent in this dose and schedule in patients with metastatic breast cancer.

Ophthalmologic toxicity after cis-dichlorodiammineplatinum(II) therapy.

Two cases of apparent ophthalmologic toxicity which occurred during treatment with cis-dichlorodiammineplatinum(II) (DDP) are described. In the first case, a patient with testicular carcinoma developed papilledema after three courses of DDP and adriamycin therapy. In the second case, a patient with breast cancer developed retrobulbar neuritis after three courses of DDP therapy. The differential diagnosis and possible explanation for these toxic effects are discussed.

Causes of death in patients with non-Hodgkin's lymphoma.

The causes of death and postmortem findings in patients treated for non-Hodgkin's lymphoma at a single institution over a 13-year period were reviewed. Postmortem examination (70% of the entire sample) revealed evidence of lymphoma in 67 of 80 patients. The most frequent extranodal sites of involvement were the respiratory tract, bone marrow, liver, kidney, and gastrointestinal tract in that order. The most common cause of death was infection (33% of cases). Predisposing factors for infection included the underlying disease, (i.e., lymphomatous infiltration of organ systems) and granulocytopenia secondary to combination chemotherapy. Other causes of death included hemorrhage and respiratory failure secondary to lymphomatous infiltration of the lung. Despite advances in therapy and supportive care of patients with non-Hodgkin's lymphoma, many patients still die of this disease or of sequelae related to its treatment.

Cis-Dichlorodiammine platinum and adriamycin therapy for advanced gynecological and genitourinary neoplasms.

Cis-Dichlorodiammine platinum (DDP) 75 mg/m2 on days 1 and 8 and Adriamycin (ADR) 60 mg/m2 on day 1 were used in 31 patients with advanced gynecological and genitourinary neoplasms. The DDP was given by 6 hours intravenous infusion with 2 liters of 5% Dextrose and 0.5 normal saline using Mannitol and/or furosemide diuresis. Courses were repeated every 21 to 28 days. Responses were seen in 7 of 8 patients with germinal cell neoplasms (5 complete, 2 partial) with a median duration of eight months. A partial response was obtained in 3 of 7 patients with bladder carcinoma with a median duration of three months. There were four partial responses obtained in 9 patients with ovarian carcinoma with a median duration of five months. Toxicities included nausea and vomiting in all 31 patients, nephrotoxicity (serum creatinine > 2 g/100 ml) in patients, tinnitus and/or high frequency hearing loss in 10 patients, and neurotoxicity (peripheral neuropathy, normal pressure hydrocephalus, papilledema) in 8 patients. Severe leukopenia (WBC < 2000/cu mm) and thrombocytopenia (< 100,000/cu mm) occurred in 25% and 45% of evaluable courses, respectively and necessitated dosage reduction in all and delay of therapy in some patients. Peak plasma Pt levels were 2.61 +/- .18 microgram/cc on day 1 and 3.52 +/- .39 microgram/cc on day 8 with a longer terminal half-life on day 8 (252 hours) compared to day 1 (156 hours). Peak plasma ADR levels ranged from .53 to 1.67 N moles/cc with an average terminal half-life of 22.8 hours. This agrees with values of ADR when given alone. This dose and schedule of DDP-ADR is active against advanced gynecological and genitourinary neoplasms, but the amount of toxicity seen indicates that modifications will have to be made.

High-dose cisplatin therapy using mannitol versus furosemide diuresis: comparative pharmacokinetics and toxicity.

The dose-limiting toxic effect of high-dose (100 mg/m2) cisplatin is renal insufficiency. Hydration with furosemide- or mannitol-induced diuresis has been reported to ameliorate this toxicity. Animal studies suggest that mannitol may be superior to furosemide in this regard. Twenty-two patients with advanced neoplasms refractory to conventional therapy were treated with cisplatin at a dose of 100 mg/m2 every 21--28 days. Patients were randomized to receive 37.5 g of mannitol by 6-hour infusion with cisplatin or 40 mg of furosemide prior to cisplatin therapy. Hydration with at least 1 liter of normal saline was given prior to cisplatin. Nephrotoxicity (creatinine greater than 2 mg/100 ml, creatinine clearance greater than 50 ml/minute) occurred in 19% of courses in the furosemide-treated group and in 28% of courses in the mannitol-treated group. Peak plasma platinum concentration, terminal half-life, urinary excretion, and percent protein-bound plasma platinum were similar in both groups. The use of cisplatin at this dose schedule resulted in similar toxicity and pharmacokinetics when using hydration with either furosemide or mannitol.

Doxorubicin, cyclophosphamide, and whole body hyperthermia for treatment of advanced soft tissue sarcoma.

Eleven patients with advanced soft tissue sarcoma were treated with whole body hyperthermia (41.8 degrees C-43.0 degrees C) for 2 hours, doxorubicin (45 mg/m2) at the beginning of peak temperature and cyclophosphamide (1000 mg/m2) 6 hours after doxorubicin. Warming was accomplished with a nylon and vinyl mesh water perfused suit and heating blankets under barbiturate anesthesia. Thirty-five thermochemotherapy treatments were administered after an initial baseline euthermic course. There were two complete and two partial responses including three of three liposarcomas and one of two leiomyosarcomas, and there were two disease stabilizations . Morbidity included anasarca, nausea and vomiting, diarrhea, myalgias, mild surface burns, perioral herpes simplex, reversible neuropathy, hypotension, and cardiac arrythmias . Hyperglycemia and hypophosphatemia were found during heating, and normalized at 24 hours. Liver enzyme elevations occurred 24 hours after heating and normalized within 1 week. A uniform platelet decrease (mean, 107,000/microliter) was found at 24 hours. Thermochemotherapy was found to be a feasible approach for selected patients with advanced soft tissue sarcoma for the subset of liposarcomas and leiomyosarcomas.