Subcutaneous infusion of bleomycin--a practical alternative to intravenous infusion.

The phase specificity and short half-life of bleomycin make it likely that it would be more effective when administered by continuous infusion. This is supported by studies using cell lines, as well as by animal studies and clinical experience in humans. This study was conducted to compare the pharmacokinetics of intravenous (IV) and subcutaneous infusions of bleomycin. The serum concentrations of bleomycin were measured using a sensitive and specific radioimmunoassay. The results demonstrate similar plasma concentrations and area under the curve for both routes. The subcutaneous infusions were well tolerated, without local discomfort or excoriation. Subcutaneous infusion of bleomycin may thus offer a practical alternative to IV infusions and can be administered to patients who are ambulatory and out of hospital.

The treatment of stage IIIA Hodgkin's disease.

Sixty consecutive previously untreated adults with surgically confirmed stage IIIA Hodgkin's disease (39 stage IIIA1, 21 stage IIIA2) began therapy at St. Bartholomew's Hospital between 1969 and 1981. Prior to 1973, treatment consisted of total nodal irradiation (TNI). From 1973 until 1978 patients were randomly allocated to receive either TNI or cyclic combination chemotherapy of mustine, vinblastine, prednisolone, and procarbazine (MVPP) as part of a Medical Research Council Trial. Since 1978 treatment has been allocated according to substage, those with stage IIIA1 receiving TNI and those with stage IIIA2 receiving MVPP. Seven patients received "non protocol" therapy (extended mantle radiotherapy in three patients, mantle and MVPP in four patients), and have been excluded from the study. Complete remission was achieved in 48 of 53 patients regardless of substage or therapy. Seven have relapsed, one after MVPP and six after TNI. The predicted freedom-from-relapse after MVPP was 96% compared with 60% after TNI, both at 10 years (p less than 0.01). The relapse pattern was the same for both substages in the group receiving TNI. Although overall survival of patients receiving TNI was identical to that of those receiving MVPP, TNI must be considered inappropriate therapy for stage IIIA Hodgkin's disease if permanent freedom-from-recurrence is the goal.

A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity.

PURPOSE: Etoposide is a schedule-dependent drug, as demonstrated by the superiority of 5 consecutive daily infusions over a continuous 24-hour infusion in patients with small-cell lung cancer. A randomized trial has therefore been conducted to compare an extended 8-day regimen with the 5-day schedule. PATIENTS AND METHODS: Ninety-four patients with small-cell lung cancer (35 limited disease, 59 extensive disease) were randomized to receive single-agent etoposide 500 mg/m2, either as 5 daily 2-hour infusions of 100 mg/m2 or as 8 daily 75-minute infusions of 62.5 mg/m2, both repeated every 3 weeks for six cycles. Single-agent carboplatin was administered at relapse in both arms of the study. Patients were stratified at randomization according to extent of disease and Karnofsky performance status (KPS). RESULTS: The overall response rate was 81% in the 5-day arm and 87% in the 8-day arm, with median survival durations of 7.1 and 9.4 months, respectively (no significant differences). The time over which plasma etoposide exceeded low plasma concentrations was significantly longer in patients who responded compared with patients who did not respond. This was most significant for time at concentrations greater than 1, 1.5, and 2 micrograms/mL. Hematologic toxicity was significantly worse in the 5-day arm of the study (cycle no. 1 nadir neutrophil count, 0.8 x 10(9)/L v 1.7 x 10(9)/L). Stepwise regression analysis found duration of exposure to plasma etoposide greater than 3 micrograms/mL to be predictive of nadir neutrophil count and duration of exposure to plasma etoposide greater than 2 micrograms/mL to be predictive of nadir WBC count. CONCLUSION: The 5-day and 8-day regimens had equivalent activity in small-cell lung cancer. A pharmacokinetic association between concentrations of etoposide and response and toxicity was found. Antitumor activity was associated with the maintenance of lower levels of etoposide than found to be associated with hematologic toxicity. This supports the hypothesis that the schedule of etoposide administration may affect efficacy and toxicity, and that prolonged exposure to low concentrations of etoposide may improve the therapeutic ratio for this drug.

A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer.

Etoposide is an increasingly used and well-tolerated drug in cancer medicine. Its cytotoxic action is phase-specific and it has demonstrated schedule dependency in both in vitro and animal studies, but clinical evidence of the importance of drug scheduling is uncertain. The two administration schedules of etoposide that have been compared in this randomized study of 39 patients with previously untreated extensive small-cell lung cancer treated with single-agent etoposide were 500 mg/m2 as a continuous intravenous (IV) infusion over 24 hours or five consecutive daily 2-hour infusions each of 100 mg/m2. Both regimens were repeated every 3 weeks, for a maximum of six cycles. Patients received combination chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAC) or radiotherapy on failure to respond or at relapse, depending on their Karnofsky performance status. The same therapy was used in both arms of the study. All patients are evaluable for response to etoposide. In the 24-hour arm, two patients achieved a partial remission, resulting in an overall response rate of 10%. In the 5-day schedule, 16 patients had a partial response and one had a complete remission, producing an overall response rate of 89%, which was significantly superior to that in the 24-hour arm (P less than .001). The median duration of remission to etoposide in the 5-day arm was 4.5 months. Bone marrow toxicity was similar in both schedules. Etoposide pharmacokinetics were measured in all patients, and total areas under the concentration versus time curves (AUCs) were equivalent in both regimens. This study has clearly demonstrated the importance of etoposide scheduling in humans, and the superiority of five daily infusions over a 24-hour continuous infusion. The response rate to single-agent etoposide using an efficacious schedule in extensive small-cell lung cancer has been determined to be in excess of 80%.

The effect of dose on the bioavailability of oral etoposide.

The bioavailability of orally administered etoposide varies considerably. The effect of dose on bioavailability has not previously been investigated. In this study six patients were each treated with oral etoposide at doses of 200, 400, and 600 mg, and the pharmacokinetics determined. Each patient acted as his own control. The area under the plasma concentration-time curve (AUC) was proportionately greatest at the lowest dose. Doubling the dose from 200 mg to 400 mg increased AUC by only 50%, and a further increase of only 2.2% occurred at a dose of 600 mg. These data show nonlinear bioavailability of etoposide within the range in clinical use and may explain the variable results of reported studies. The data may have important implications for chemotherapy regimens with oral etoposide.

Adriamycin, bleomycin, vinblastine and imidazole carboxamide (ABVD) therapy for advanced Hodgkin's disease resistant to mustine, vinblastine, procarbazine and prednisolone (MVPP).

Forty-one previously treated patients with advanced Hodgkin's disease were treated with a combination chemotherapy regimen -- ABVD (adriamycin, bleomycin, velbe/vincristine, imidazole carboxamide). Complete remission was achieved in three patients (7%), partial remission in 23 (56%), and no response in 15 patients (37%). The median survival of the group was 12 months from the start of therapy. Survival correlated with response to treatment. No apparent benefit resulted from giving more than six courses of therapy (3 months' treatment time). There was no serious haematological toxicity in patients without bone marrow disease, and bleomycin and adriamycin toxicity was not apparent clinically or at autopsy in the dosages employed in the regime. Alopoecia was very frequent. The role for ABVD, other than as a primary induction regimen, appears to be in conjunction with other regimens in the induction of patients with adverse features at presentation or during induction; or in the salvage and palliation of patients who demonstrate a response but fail to achieve remission, either initially or at relapse, with MOPP (mustine, vincristine rpocarbazine, and prednisolone) or MVPP (mustine, vinblastine, procarbazine and prednisolone.

EVA treatment for recurrent or unresponsive Hodgkin's disease.

Nineteen patients with recurrent or unresponsive Hodgkin's disease who had previously received combination chemotherapy comprising mustine or chlorambucil with vinblastine, prednisolone and procarbazine (MVPP or ChlVPP), were treated with a combination of etoposide, vincristine and adriamycin (EVA). Clinical remission (complete, CR + good partial, GPR) was achieved in eleven of the nineteen patients (58%). The remission rate was similar for patients who had previously responded well to chemotherapy and for those who had previously been poorly responsive. Six patients have relapsed between 3 and 5 months after completion of therapy. The remainder continue in remission, two without further therapy at 7 and 8 months, respectively, and three having had additional radiotherapy while in remission. Myelosuppression was the most important toxicity, but in general this was manageable. These results suggest that EVA may be non-cross-resistant with MVPP and ChlVPP and that it is of potential value in combination chemotherapy for previously untreated patients, even though it is unlikely to be curative when treatment with either MVPP or ChlVPP has failed.

Failure to preserve fertility in patients with Hodgkin's disease.

The hypothesis that the "down-regulated" gonad is less vulnerable to the effects of cytotoxic chemotherapy for advanced Hodgkin's disease has been investigated. Thirty men and eighteen women were randomly allocated to receive an agonist analogue of gonadotrophin-releasing hormone prior to, and for the duration of, cytotoxic chemotherapy. Buserelin (d-Ser-[TBU]6 LHRH ethylamide) was prescribed in two different dosage schedules to twenty men, and in a single dosage schedule to eight women. A standard gonadotrophin-releasing hormone test (GnRH 100 micrograms) was performed 1 week prior to and on day 1 of each cycle of chemotherapy. In all patients peak luteinizing hormone responses to GnRH were suppressed throughout treatment. The higher of the two dosage schedules used in the men caused more effective suppression of luteinizing hormone, and both regimens led to an initial suppression of peak follicle-stimulating hormone responses to GnRH, which was not maintained. At follow-up assessment up to 3 years from the completion of treatment, all men treated with buserelin were profoundly oligospermic and four of the eight women were amenorrhoeic. All ten male controls were profoundly oligospermic, and six of nine female controls were amenorrhoeic. In the dosages and schedules investigated, buserelin was ineffective in conserving fertility.

Delayed-release bleomycin. Comparative pharmacology of bleomycin oil suspension and bleomycin in saline.

Experimental and clinical evidence indicates that bleomycin by continuous infusion is superior to intermittent administration. Continuous infusion is less convenient, however. It has been suggested that a suspension of bleomycin in sesame oil, given by IM injection, simulates a continuous infusion. The pharmacokinetics of this formulation have been compared with those of bleomycin in saline following IM injection, in six patients. The pharmacokinetic profiles of the two formulations were similar. The only difference between the profiles was the long terminal half-life at very low concentrations between 12 and 48 h after injection of the oil suspension. This difference is of unknown, but doubtful, clinical significance.

The bioavailability of oral intermediate-dose methotrexate. Effect of dose subdivision, formulation, and timing in the chemotherapy cycle.

The oral bioavailability of methotrexate is variable and may be dose-dependent. The absorption of 'interval' oral methotrexate, which is given between cycles of chemotherapy, is unknown. The bioavailability of oral methotrexate has been studied in eight patients, acting as their own controls, to assess the effect of subdivision of the dose, the formulation, and the timing of the methotrexate within the chemotherapy cycle. The mean bioavailability for all the oral methods of administration was 28.2% +/- 3.7% compared with the same dose given IV. Absorption was uninfluenced by subdivision of the dose, liquid or tablet formulation, or administration on day 1 or day 10 of the chemotherapy cycle.

The effect of dose on the bioavailability of oral etoposide: confirmation of a clinically relevant observation.

The effect of dose on the bioavailability of oral etoposide was investigated in ten patients with malignant mesothelioma who received single-agent etoposide as part of a phase II study. Etoposide pharmacokinetics were studied in each patient at oral dose levels of 100, 200, 300, 400 and 600 mg. At doses above 200 mg, the AUC and peak concentrations of etoposide were substantially lower than predictions based on the 100-mg dose. This study confirms previous observations that etoposide absorption is dose-dependent and that a mean bioavailability of approximately 50% cannot be assumed at total oral doses greater than 200 mg.

The treatment of postmenopausal women with advanced breast cancer with buserelin.

Repeated administration of long-acting analogues of gonadotrophin-releasing hormone down-regulates the pituitary gonadotrophins and gonadal hormones. The activity of these compounds in premenopausal women with breast cancer has been previously noted. In an attempt to cause a highly selective medical hypophysectomy 18 consecutive postmenopausal women with symptomatic advanced breast cancer were treated with intranasal buserelin in divided dosages of either 600 or 1000 micrograms daily. The pituitary gonadotrophins were suppressed in all patients, without objective evidence of response. This is in contrast with an earlier finding that the long-acting analogues of gonadotrophin-releasing hormone were effective in postmenopausal patients with breast cancer.

Combination chemotherapy for advanced non-Hodgkin's lymphoma of unfavourable histology.

Thirty previously untreated adults with diffuse histiocytic and diffuse undifferentiated lymphoma were treated with a combination of adriamycin, vincristine, prednisolone, and L-asparaginase. Complete remission was achieved in 11 out of 12 cases with stage III and 7 out of 18 cases with stage IV disease (P less than 0.005). Bone marrow infiltration, clinical central nervous system involvement, and massive intra-abdominal disease all influenced the prognosis adversely. Complete remission was followed by cranial irradiation and intrathecal methotrexate, and maintained with weekly cyclophosphamide and methotrexate and daily 6-mercaptopurine. The duration of remission was significantly longer for patients with stage III disease (the median of which has not been reached), than for patients with stage IV disease (P = 0.007). Survival was significantly longer for patients in whom complete remission was achieved than for those in whom it was not (P = 0.001), and also for patients with stage III than for those with stage IV disease (P = 0.02).

Protein binding of indomethacin, methotrexate and morphine in patients with cancer.

The in vitro protein binding of indomethacin, morphine and methotrexate has been studied in two groups of ten patients each suffering from different types of cancers and compared with twenty normal adult subjects. One group of patients had active disease and the other group was in complete clinical remission. Serum samples were obtained from each subject and the concentrations of albumin and alpha-1 acid glycoprotein (AGP) were measured. Protein binding of drugs was determined using equilibrium dialysis. Alpha-1 acid glycoprotein levels were increased in patients and this effect was more pronounced in active disease (1802 +/- 1025 mg/l) than in remission (931 +/- 273 mg/l). Albumin levels were reduced in active disease (47.67 +/- 15.91 milligrams), but not in remission (61.86 +/- 6.62 milligrams), as compared to control values (58.98 +/- 9.9 milligrams). The protein binding of methotrexate and indomethacin were both reduced in active disease (34.17 +/- 7.12% and 96.26 +/- 0.93% respectively) in comparison with normal subjects (39.33 +/- 4.68% and 96.89 +/- 0.47% respectively), but that of morphine was not changed. In patients there was a strong negative correlation between albumin and alpha-1 acid glycoprotein levels (r = -0.75, p < 0.01) but the correlation in controls was not significant. This study found only weak association between the binding of the drugs studied and the protein levels. It is concluded that reduction in methotrexate dose levels may reduce toxicity in patients with active cancer.

Indomethacin and protein binding of methotrexate.

Indomethacin, a non-steroidal anti-inflammatory drug is known to increase the efficacy and toxicity of methotrexate, the widely used anti-cancer drug in man. The mechanism for this interaction has not been clearly established. However, since these drugs bind with albumin, a possible displacement of methotrexate by indomethacin from albumin might explain this interaction. To investigate the possible interaction an in-vitro protein-binding displacement study was carried out in 17 normal volunteers and in two groups of eight cancer patients. One group of patients had active disease and the other was in complete clinical remission. Serum samples were obtained and protein levels estimated. The protein binding of methotrexate was measured alone and with indomethacin using equilibrium dialysis. Statistical analysis of results suggested that the binding of methotrexate is not influenced by indomethacin, confirming that methotrexate is not displaced by indomethacin.