Lung cancer treatment with high cyclophosphamide doses versus high cyclophosphamide doses plus radiotherapy.

Sixty-six evaluable male patients with a histologically proved inoperable lung cancer, with a Karnofsky's score ≥30, were considered for study. The mean age was 57.2 (range 20–74) years. Tumor cell types were of epidermoid carcinoma 50, adenocarcinoma 6, undifferentiated small cell carcinoma 5, and undifferentiated large cell carcinoma 5. Fifty patients had limited disease and 15 had extensive disease. They were treated with combined modality therapy Cyclophosphamide (CY) 50 mg/kg body weight, administered into the tubing of a freely running intravenous infusion of 5% dextrose every 10–12 days, followed by radiation therapy with ⁶⁰Co, 6000 rad and then, with CY 17 mg/kg body weight every 15 days until progression (ChRCh group). The control group (Ch) of 31 patients was treated with CY 50 mg/kg body every 10/12 days. Complete response was achieved in $\text{3}\text{35}$ patients and partial response in $\text{15}\text{35}$ patients of the ChRCh group. In the control group, $\text{12}\text{31}$ patients achieved partial response. Total dose of CY was higher in responders achieving a significantly longer survival (median 12+ months) in comparison to non-responders (median 7 months) and the control group (median 6 months). Less toxic reactions were seen in patients responding to ChRCh regimen.Bone marrow depletion did not affect the patient's survival, but cystitis and alopecia, it appeared, decreased life expectancy. It is concluded that combined modality therapy is better than chemotherapy alone, with less cytotoxicity in responders.     

The pharmacokinetics of high dose cyclophosphamide and high dose etoposide

We have studied the pharmacokinetics of single agent high dose cyclophosphamide (HDC) (160-240 mg kg-1) given as repeated intravenous (i.v.) infusions to six patients with small cell lung cancer (SCLC), and HDC (180 mg kg-1) combined with etoposide (750-1000 mg m-2) as repeated i.v. infusions to five patients with SCLC and two patients with teratoma. HDC has a similar pharmacokinetic profile to low dose cyclophosphamide, with a half-life of 4.83 +/- 1.3 h. Repeated administration of HDC produced a small but significant shortening of the half life (P = 0.02). The terminal half-life of high dose etoposide was 7.7 +/- 2 h which is similar to our previous results with low dose etoposide (50-300 mg m-2), but the volume of distribution which was 35.5 +/- 11.6 1. was significantly increased (P less than 0.001). Plasma steady state concentrations of 26.2 +/- 11.7 micrograms ml-1 were achieved. The possible mechanism for the alteration of volume of distribution of etoposide will be discussed.     

Phase I-II study of escalating doses of amifostine combined with high-dose cyclophosphamide

PURPOSE: To evaluate the feasibility and clinical effects of increasing doses of amifostine administered four times in 1 day with high-dose (HD) cyclophosphamide (CTX). METHODS: A group of 16 patients with a diagnosis of lymphoma were treated with HD-CTX given at a total dose of 7 g/m2 subdivided into four doses, each preceded by increasing doses of amifostine. A group of 12 lymphoma patients previously treated with the same HD-CTX regimen was used as historical controls. RESULTS: The dose of amifostine was escalated in cohorts of three patients each from 4x570 mg/m2 to 4x910 mg/m2 without severe toxic effects. Further patients were treated at the highest dose level. Side effects included a fall in blood pressure (always less than 20% of baseline value), asymptomatic hypocalcemia (from a median value of 2.4 to 1.7 mmol/l) and a decrease in creatinine clearance (from a median value of 102 to 85 ml/min). The parameters of hematotoxicity for patients treated in the study were not significantly different from those of the historical control patients. CONCLUSIONS: Amifostine can be given safely at a dose of 910 mg/m2 four times in 1 day in combination with HD-CTX. With this schedule amifostine did not show a myeloprotective effect.     

Advanced breast-cancer - a randomized study of different doses of epirubicin associated with fixed doses of cyclophosphamide and 5-Fluorouracil

A moderate increase in the dose of anthracycline could be feasible and of clinical benefit in advanced breast cancer. Between April 1991 and April 1994, 69 consecutive patients with recurrent or metastatic breast cancer were randomly treated with two regimens, including different dosages of epirubicin (75 versus 100 mg/m(2)) associated with the same dosage (600 mg/m(2)) of cyclophosphamide and 5-fluoruracil (75-FEC vs 100-FEC). Patients were planned to receive 6 courses at 21 day-intervals. Thirty-six patients received the 75-FEC regimen and 33 received the 100-FEC regimen. The two groups were comparable for age, menopausal status, disease-free interval, previous therapy, performance status and sites of disease: Over the whole study, the 100-FEC regimen has allowed a 18% actual increase in the epirubicin dosage over the 75-FEC regimen. Overall response rate was 56% for the 100-FEC and 51% for the 75-FEC, with the 100-FEC inducing some more complete responses than the 75-FEC (38% vs 23%). Survival (but not time to progression) tended to be longer with the 100- than with the 75-FEC (median: 20 vs 13 mos, p<0.09). Nonhematologic side effects Were similar. Hematologic toxicity was slightly higher with 100- than with 75-FEC, with granulocyte colony stimulating factors used to recycle in the scheduled time in the 15 and 4% of courses, respectively.     

Late intensification in small-cell lung cancer: a phase I study of high doses of cyclophosphamide and etoposide with autologous bone marrow transplantation

We conducted a late dose intensification pilot study of small-cell lung cancer (SCLC) treated with high doses of cyclophosphamide (200 mg/kg) and etoposide (1.0 to 3.5 g/m2), administered during a period of 48 hours, as well as autologous bone marrow infusion. We have been able to administer safely 3 g/m2 of etoposide with the autologous bone marrow infusion and 1.5 g/m2 without it. Limiting extrahematopoietic toxicity appeared to take the form of irreversible cardiac failure. Complete responses have been obtained with our regimen for late dose intensification, but the duration of the responses and the survival rates of the patients were poor. This suggests that late dose intensification in incomplete responders is not superior to the usually reported results obtained with standard regimens for the treatment of SCLC.     

Pilot study of escalating doses of carboplatin and cyclophosphamide in patients with advanced cancer

Summary In all, 18 patients with histologically proven advanced cancer received 400 mg/m² carboplatin (CBDCA) plus 800 mg/m² cyclophosphamide (level 1), and 14 others received 550 mg/m² CBDCA plus 1100 mg/m² cyclophosphamide (level 2). A maximum of six cycles was given if a response occurred. The dose-limiting toxicity was myelosuppression, with neutropenia being more marked than thrombocytopenia. At level 2, patients experiencing a fibrile-neutropenic event showed a mean 24-h urinary creatinine clearance value of 1.1 ml/s (95% confidence limits 0.8–1.4 ml/s), whereas in those who remained afebrile it was 1.7 ml/s (95% confidence limits, 1.3–2.0 ml/s). This difference was significant (P<0.01). Other toxicities were only mild. Creatinine clearance is a predictor of febrile episodes after treatment with high doses of CBDCA and cyclophosphamide. We are now conducting a study using human granulocyte colony-stimulating factor to reduce the incidence of neutropenia with escalating doses of these drugs in an attempt to prevent febrile events.     

The gross and cellular response of a rat mammary tumour to single doses of cyclophosphamide

The response of a transplanted mammary carcinoma of Wistar rats, to single intraperitoneal doses of cyclophosphamide (25–250 mg kg⁻¹) has been assayed by measurement of; delay in growth of the tumour between 9 and 25 mm; cell survival in vitro, 3 and 24 hr after in situ treatment; tritiated thymidine autoradiography and Feulgen microdensitometry of histological material. All three methods of assay indicate that at 9 mm diameter the tumour contains a subpopulation of malignant cells relatively resistant to cyclophosphamide doses in excess of 50 mg kg⁻¹. The in vitro cell survival assay suggests that these cells comprise 40–50% of the clonogenic population and are capable of considerable in situ repair of potentially lethal damage within 24 hr of treatment. Cellular repopulation from this resistant component, after 150 mg kg⁻¹ of drug, is delayed for 6 or more days and restoration to near pre-treatment status only achieved by 10 days, in this rapidly-growing tumour.     

Induction of rat intestinal carcinogenesis with single doses, low and high repeated doses of 1,2-dimethyihydrazine

We investigated seven different procedures for chemical inductionof rat chemical induction of rat colonic carcinogenesis using:repeated high doses (i) weekly 10 x 15 mg/kg, (ii) quarterly8 x 15 mg/kg; repeated low doses (iii) weekly 27 x 1.5 mg/kg,(iv) quarterly 8 x 5 mg/kg, (v) quarterly 8 x 1 mg/kg; and singleinjections of 1,2-dimethylhydrazine (DMH) at (vi) 1 x 40 mg/kgor (vii) 1 x 20 mg/kg. Rats had typical histological precancerouslesions of the colon (dysplasia) and intestinal carcinomas inthe six groups receiving a total dose of more than 8 mg/kg DMH.With doses of > 120 mg/kg, rats had more cancers, particularlyintestinal carcinomas and significantly reduced survival. Ratsreceiving a single injection of 20 or 40 mg/kg also had histologicallesions and colonic carcinomas. The group receiving a 40 mg/kgtotal dose in a single injection had a significantly higherfrequency of colonic lesions per rat and a higher incidenceof rats with colonic lesions than groups receiving the sametotal dose but fractionated. Control rats and groups injectedwith an 8 mg/kg total dose had no cancers, nor pre-canceroushistological lesions. Thus the carcinogenesis is dose-related,but for the same final dose a single injection gives more histologicalcolonic lesions than several recurrent injections; however,the number of colonic carcinomas and the survival did not vary.This lack of correlation between the number of dysplasia andthe number of adenocarcinomas may indicate that dysplasia isnot always the precursor lesion of adenocarcinoma. With repeatedlow doses, we obtained colonic adenocarcinomas after a longperiod of latency in old rats, thus producing an experimentalmodel with characteristics similar to those found in humans.     

High-dose cyclophosphamide or melphalan with escalating doses of mitoxantrone and autologous bone marrow transplantation for refractory solid tumors

As the dose-limiting toxicity of mitoxantrone is hematological, the drug is suitable for dose escalation and use in intensive chemotherapy followed by autologous bone marrow rescue. Adult patients with therapy-resistant solid tumors received a regimen of high-dose cyclophosphamide (7 g/m2) and escalating doses of mitoxantrone in dose steps of 30, 45, 60, and 75 mg/m2. Both drugs were given i.v. on 3 consecutive days. Despite the addition of mesnum (3.5 to 7 g/m2), hemorrhagic cystitis occurred on the second day in four of eight patients, irrespective of the mesnum or mitoxantrone dose. Therefore, the cyclophosphamide in the combination regimen was replaced by high-dose melphalan (180 mg/m2). Mucositis was dose limiting at 75 mg/m2 of mitoxantrone. Responses were seen in eight of ten evaluable patients with four complete responses. Three responders received, after the autologous bone marrow transplantation program, radiotherapy or surgery on pretreatment bulky tumor localizations. Five patients still have disease-free survival after 9 to 36 mo. Pharmacokinetic studies of mitoxantrone were performed by high-performance liquid chromatography with UV detection. The plasma disappearance of mitoxantrone fitted into a three-compartment model with a mean t1/2 alpha of 10 min, a mean t1/2 beta of 96 min, and a slow elimination phase of 172 h. The mean distribution volume was 4294 +/- 3836 liters. We conclude that the high-dose cyclophosphamide-mitoxantrone regimen led to unexpected bladder toxicity, but the combination of melphalan (180 mg/m2) and mitoxantrone (60 mg/m2) can probably be given without major extramedullary toxicity. However, more patients should be evaluated at this dose before definite conclusions can be drawn about toxicity.