PubMed Health⌕ Search

Biomedical subjects

P G Harper

Publications and source records attributed to P G Harper.

At least 19 recordsLinked to original sources
PubMed1995

Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry.

We studied the variability in doxorubicin pharmacokinetics in 27 patients, all of whom had normal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography (HPLC). The relationship of doxorubicin clearance (dose/AUC) with biochemical tests (AST, bilirubin, alkaline phosphatase, albumin, creatinine) and physical characteristics (age, gender, height, weight, tumour type) was investigated. The 6 men had a significantly higher doxorubicin clearance than did the 21 women (median values, 59 and 27 lh-1 m-2, respectively; P = 0.002). Doxorubicin clearance was significantly lower in patients with breast cancer than in those with other tumours (median values, 26 and 53 lh-1 m-2, respectively; P = 0.0008). The other biochemical and physical parameters did not correlate with doxorubicin clearance. However, in multivariate analysis, gender was the only factor predicting doxorubicin clearance (r2 = 40%). The ratio of the AUCs for doxorubicinol and doxorubicin (R) was higher in the men than in the women (median values, 0.62 and 0.36, respectively; P = 0.03). We conclude that gender may be an important determinant of doxorubicin clearance in patients with normal liver biochemistry.

Adult↗
PubMed1994

Combination chemotherapy with epirubicin, cisplatin and 5-fluorouracil for the palliation of advanced gastric and oesophageal adenocarcinoma.

The palliative efficacy of laser therapy with combination chemotherapy (cisplatin, epirubicin and continuous infusion of 5-fluorouracil) was assessed in 34 patients with inoperable gastro-oesophageal cancer. Comparison was made with a group of 30 patients treated previously by laser alone. Twenty patients responded to chemotherapy. There was a significant improvement in dysphagia, as measured by a decreased laser requirement to maintain satisfactory swallowing. In this non-randomized prospective phase II trial, palliation was attained and some responses were long-lasting (median duration of response 8.7 (range 2.3 to more than 29.2) months).

Adenocarcinoma↗
PubMed1994

Received dose-intensity: a randomized trial of weekly chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.

PURPOSE: A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Forty patients with SCLC with good prognostic features (all patients with limited disease [LD], and extensive-disease [ED] patients with Eastern Cooperative Oncology Group [ECOG] 0 or 1 and plasma alkaline phosphatase levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with or without G-CSF. G-CSF (5 micrograms/kg) was self-administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin 50 mg/m2 intravenously (IV) on day 1 and etoposide 75 mg/m2 IV on days 1 and 2 alternating weekly with ifosfamide 2 g/m2 IV (with mesna) and doxorubicin 25 mg/m2 on day 1, for a total of 12 courses. Dose modifications (dose reductions and treatment delays) were made according to defined hematologic criteria. RESULTS: Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in 11 of 23 patients in the G-CSF arm (P = .20). The proportion of patients experiencing dose reductions due to leukopenia was significantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of 23, P < .04). Cycle delays due to leukopenia were similar in both arms of the study. The RDI was 82% of projected in the control arm (95% confidence interval [CI], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant). CONCLUSION: In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of G-CSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF arm.

Adult↗
PubMed1992

Phase II study of Edatrexate in stage III and IV non-small-cell lung cancer.

A total of 49 patients with advanced, previously untreated non-small-cell lung cancer (NSCLC) were treated with a new antifolate, Edatrexate (10-ethyl-10-deaza-aminopterin; 10-EdAM). Patients received 80 mg/m2 weekly for 12 weeks, and responders received a further 6 cycles at 2-week intervals. Dose reductions were carried out for haematological toxicity and mucositis. Response was assessed prior to each treatment according to WHO criteria. Among the 45 evaluable patients, 6 [13.3%; 95% confidence interval (CI), 6%-26%] achieved a partial response (PR) and 9 (20%; 95% CI, 11%-34%) showed a minor response (MR; 25%-50% reduction in the sum of 2 perpendicular tumour diameters). In those receiving four or more cycles of treatment, the PR and MR rates were 17.6% and 26.4%, respectively. The resultant toxicity mainly constituted skin rash, mucositis and myelosuppression. Edatrexate is active against NSCLC and produces toxicity profile similar to that of methotrexate.

Aged↗
PubMed1992

Uroepithelial and nephrotubular toxicity in patients receiving ifosfamide/mesna: measurement of urinary N-acetyl-beta-D-glucosaminidase and beta-2-microglobulin.

The effect of three ifosfamide/mesna regimens on urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and beta-2-microglobulin (beta 2 M) was studied. All regimens produced significant increases in these urinary proteins, indicating nephrotubular damage. In regimen A (n = 15), plasma nitrobenzylpyridine (NBP) alkylating activity area under the curve (AUC) on day 1 correlated with the percentage increase above baseline of maximum urinary NAG activity (r2 = 0.538, P = 0.0022) and maximum beta 2 M concentration (r2 = 0.413, P = 0.0097). In regimen B (n = 5), plasma NBP alkylating activity AUC correlated with the percentage increase above baseline of maximum NAG activity (r2 = 0.843, P = 0.03) and beta 2 M (r2 = 0.78, P = 0.046). In these two regimens the renal exposure to ifosfamide metabolites correlated with the increases in urinary NAG and beta 2 M. The relation of these urinary protein abnormalities to longer term effects on renal function with different ifosfamide/mesna schedules requires further study.

Acetylglucosaminidase↗
PubMed1992

Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests.

The influence of liver biochemistry tests on epirubicin pharmacokinetics has been investigated in 52 women with advanced breast cancer, 27 of whom had radiologically proven liver metastases. Patients received epirubicin 12.5-120 mg m-2 given as an i.v. bolus. Epirubicin levels were measured by HPLC following the first cycle of treatment. Epirubicin elimination, expressed as clearance (dose/AUC), in the 22 patients with normal AST and bilirubin was compared with that of 30 patients with a raised AST +/- raised bilirubin. Epirubicin clearance was significantly reduced in the patients with a raised AST, whether their serum bilirubin was normal (22 patients) or elevated (eight patients). In the 30 patients with a raised AST +/- raised bilirubin, epirubicin clearance correlated strongly with the level of AST (r = -0.72) but not with serum bilirubin, alkaline phosphatase, albumin or creatinine. Using a multiple regression analysis, AST was the only one of these biochemical variables predictive of epirubicin clearance (r2 = 0.47, P = 0.0006). We conclude that a raised serum AST is a more sensitive and reliable measure of abnormal epirubicin pharmacokinetics than increased bilirubin. These findings have implications for anthracycline treatment in patients with abnormal liver biochemistry.

Adult↗
PubMed1991

Comparative pharmacokinetics of doxorubicin given by three different schedules with equal dose intensity in patients with breast cancer.

The pharmacokinetics of doxorubicin given according to three different schedules with a similar dose-time intensity have been studied and compared in 16 women with metastatic breast cancer. Six patients were treated with doxorubicin 75 mg/m2 by i.v. bolus repeated every 3 weeks; 5 patients received doxorubicin by 4-day continuous infusion every 3 weeks (4 at 75 mg/m2 and 1 at 60 mg/m2); 5 patients received 25 mg/m2 by i.v. bolus given weekly. Timed blood samples were collected and plasma levels of doxorubicin and its metabolite doxorubicinol were measured by high-performance liquid chromatography with fluorescence detection. Peak plasma concentrations were measured, and areas under the concentration-time curves calculated. Peak plasma levels of doxorubicin were significantly lower with the 4-day infusion than with either of the bolus injections. The 4-day infusion, however, gave significantly greater total exposure to doxorubicin and doxorubicinol, as indicated by area under the concentration-time curve, than weekly or 3-weekly bolus treatment. A single bolus injection of doxorubicin 25 mg/m2 yielded a total exposure to doxorubicin approximately half that achieved with a 75 mg/m2 bolus injection. Over a 3-week period, therefore, total exposure to doxorubicin would be greater with the weekly low-dose schedule than with the 3-weekly administration. We conclude that drug scheduling has significant effects on doxorubicin pharmacokinetics.

Breast Neoplasms↗
PubMed1991

Sequential chemotherapy in good-prognosis patients with small-cell lung cancer.

A sequential combination chemotherapy regimen was evaluated in 23 patients with small-cell lung cancer (16, limited disease; 7, extensive disease). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal serum sodium and albumin levels and alkaline phosphatase values of less than 1.5 times the upper limit of normal. Treatment comprised ifosfamide and either vindesine or vincristine given on weeks 0, 2 and 4; cisplatin and etoposide given on weeks 6, 9 and 12; and doxorubicin and methotrexate given on weeks 15 and 17. The overall response rate at the end of chemotherapy was 91% and the complete response rate was 43%. Treatment was generally well tolerated and the delivered dose intensity was 83% of that projected. Median survival was 54 weeks, with 4 patients (17%) being alive 2 years after the completion of therapy.

Adult↗
PubMed1991

A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial.

In a study of chemotherapy as palliative treatment, 300 patients with untreated limited and extensive stage small cell lung cancer (SCLC), who did not have progressive disease after the first cycle of chemotherapy, were randomised to receive either regular 'planned' chemotherapy or chemotherapy given 'as required' (AR). All patients received the same chemotherapy: cyclophosphamide 1 gm m-2 i.v., vincristine 2 mg i.v., and etoposide 120 mg m-2 i.v. on day 1, and etoposide 100 mg b.d. orally on days 2 and 3. Planned chemotherapy was given regularly every 3 weeks. AR chemotherapy was given for tumour-related symptoms, or for radiological progression of disease. Both groups of patients were assessed every 3 weeks and a maximum of eight cycles of chemotherapy was given. A detailed quality of life assessment was made using daily diary cards. The median survival (MS) of patients given AR chemotherapy was not significantly worse than those receiving planned treatment [MS: Planned = 36 weeks (95% C.I. 32-40 weeks), AR = 32 weeks (95% C.I. 28-37 weeks) P = 0.960]. In the AR patients the median interval between treatments was 42 days. On average AR patients received half as much chemotherapy as planned patients. AR patients with a treatment-free interval (TFI) of more than 8 weeks between the first and second cycles of chemotherapy survived longer than those in whom this interval was less than 4 weeks; [MS: TFI greater than 8 = 47 weeks (95% C.I. 32-53 weeks); TFI less than 4 = 24 weeks (95% C.I. 17-34 weeks) P = 0.013]. Contrary to expectation, in the quality of life assessment the AR patients scored themselves as having more severe symptoms than patients receiving planned treatment. AR chemotherapy is a novel method of attempting to use cytotoxic drugs palliatively, which resulted in less drug treatment for approximately equivalent survival. However the palliative effect seen with as required treatment was less satisfactory than with planned chemotherapy.

Aged↗
PubMed1991

The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients.

1. We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens. Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) years were studied on seven treatment occasions with 5 g m-2 ifosfamide (median ifosfamide dose 8.88 g) as a 24 h intravenous infusion with mesna. Plasma was assayed for ifosfamide by gas liquid chromatography and for alkylating activity by the nitrobenzylpyridine method. 2. After ifosfamide 5 g m-2 infused over 0.5 h, the decay of the plasma ifosfamide concentration was monoexponential with a median (range) t1/2,z of 5.4 h (3.6-10.4 h). The median clearance was 60 ml min-1 (47-104) and the median volume of distribution was 388 (329-783) ml kg-1. Plasma nitrobenzylpyridine alkylating activity showed a biexponential decay in four patients and a monoexponential decay in two, with a median AUC of 102 (24-177) nmol nor nitrogen mustard eq h ml-1. 3. When ifosfamide 5 g m-2 was given as a 24 h infusion, the decay of the plasma ifosfamide concentration was monoexponential, the median (range) t1/2,z was 4.5 (3.4-6.1), the median volume of distribution was 563 (292-818) ml kg-1 and the median clearance was 79 (59-116) ml min-1. Plasma nitrobenzylpyridine alkylating activity decayed monoexponentially and the median AUC was 49 (45-131) nmol nor nitrogen mustard eq ml-1 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.

Adult↗
PubMed1990

Mitomycin, ifosfamide and cisplatin in non-small-cell lung cancer.

Chemotherapy with mitomycin C, ifosfamide and cisplatin (MIC) is reported to produce responses of 56% and 69% in inoperable non-small-cell lung cancer (NSCLC). We evaluated the regimen in 45 similar patients who received up to six courses of 6 mg/m2 mitomycin C, 3 g/m2 ifosfamide, and 50 mg/m2 cisplatin every 3 weeks. In all, 18 patients had limited disease (LD) and 27 had extensive disease (ED). A total of 18 patients responded (40%), 9/18 with LD and 9/27 with ED; there were 4 complete responders. The median duration of response was 25 weeks, and median survival was 32 weeks (range, 2-96 weeks). Toxicity was moderate. Nausea and vomiting were controlled with i.v. dexamethasone and high-dose metoclopramide. Other toxicities included myelosuppression and alopecia. This study confirms that MIC is one of the most active regimens for treatment of NSCLC, with acceptable toxicity.

Adult↗
PubMed1990

A phase II study of ifosfamide and cisplatin chemotherapy for metastatic or relapsed carcinoma of the cervix.

A total of 44 women received a combination of ifosfamide (1.5 g/m2 daily x5) and cisplatin (50 mg/m2 on day 1 only) as first-line chemotherapy for recurrent or metastatic carcinoma of the cervix. In all, 12/42 (38%) evaluable patients responded, with the median duration of response being 7 months. Bone marrow and gastrointestinal toxicity were frequently severe. There were 3 septic deaths. Although cisplatin plus ifosfamide is an active combination against this disease, these results suggest that it is no more so than either drug used alone.

Adult↗
PubMed1990

Quality of life during chemotherapy for small cell lung cancer: assessment and use of a daily diary card in a randomized trial.

Fifty-three patients who were taking part in a randomized trial of chemotherapy in small cell lung cancer (SCLC) were entered into a study of quality of life measurement using a daily diary card. Patients received either four or eight cycles of initial chemotherapy and daily records were scored, using a four point scale of nausea, sickness, appetite, sleep, mood, pain, activity and general well being. Two hundred and fifty-six of a possible 379 cards were returned (68% compliance). The first 31 patients took part in an assessment of the diary card where comparison was made with nurse ratings using the card, the EORTC questionnaire and the Spitzer quality of life index. These comparisons showed appropriate convergent and divergent validity and demonstrated the sensitivity of the diary card to short term changes compared with the other measures. In the randomized trial the diary card demonstrated a worsening of sickness and related variables as treatment continued. This spilled over into mood and general well being although physical variables of pain, sleep and activity were largely unaffected. Prophylactic cranial irradiation was associated with a transient increase in sickness and vomiting. The study shows that the diary card is an instrument sensitive to short term changes in quality of life and thus especially useful for comparing effects during the period of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

The response of cerebral metastases in small cell lung cancer to systemic chemotherapy.

Although small cell lung cancer (SCLC) is very chemosensitive, cerebral metastases are treated with radiotherapy in the belief that they are protected from chemotherapy by the blood-brain barrier (BBB). The validity of this assumption has not been tested in clinical practice. In a randomised trial of treatment in 610 patients with SCLC, 19 patients who had symptomatic cerebral metastases at presentation were treated initially with chemotherapy, and cranial irradiation withheld. Chemotherapy was cyclophosphamide 1 g m-2 i.v. day 1, vincristine 2 mg i.v. day 1 and etoposide 100 mg tds p.o. days 1-3, repeated every 21 days, with response assessed objectively by computerised tomography (CT) or radionuclide brain scan, and by clinical examination. A post-chemotherapy scan was obtained in 14 patients, eight of whom achieved a partial remission and one a complete remission of the cerebral metastases. The radiologically proven responses were sustained and accompanied by rapid neurological improvement. Of the remaining five patients who were assessed by clinical examination alone, one had improved neurological function after chemotherapy. The response rate for SCLC cerebral metastases treated with chemotherapy was therefore 10/19 (53%). Chemotherapy has the advantage over cranial irradiation of simultaneously treating both cerebral metastases and extracranial disease. The place of chemotherapy in the management of cerebral metastases in this and other chemosensitive tumours should be reconsidered since these findings indicate that the BBB does not prevent response to chemotherapy.

Adult↗