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Biomedical subjects

D Cunningham

Publications and source records attributed to D Cunningham.

At least 109 records · Page 6Linked to original sources
PubMed1996

ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group.

PURPOSE: Tomudex (ZD1694; Zeneca Ltd, Macclesfield, United Kingdom) appears to have a favorable toxicity profile (defined in phase I studies) and antitumor activity in a broad range of epithelial tumors. We report here the results of a large phase II study of Tomudex in advanced colorectal cancer (CRC). PATIENTS AND METHODS: One hundred seventy-seven patients were entered onto the study between October 1992 and September 1993. Patients were required to have advanced CRC without prior chemotherapy (adjuvant chemotherapy was permissible) and at least one measurable lesion. Tomudex (ZD1694) was administered at a dose of 3 mg/m2 intravenously once every 3 weeks in the absence of toxicity or disease progression. Patients were assessed for objective response, progression, and survival. RESULTS: Of 177 patients entered onto the study, 5% had received prior adjuvant chemotherapy and 83% had liver metastases. Objective responses were seen in 26% of patients (95% confidence interval, 19% to 33%; four complete responses [CRs] and 41 partial responses [PRs]) while median time to progression was 4.2 months and median survival 9.6 months. All sites were audited, and responses were reviewed by an independent panel. Common toxicities included mild reversible transaminitis, nausea and vomiting, and asthenia or flu-like symptoms, and World Health Organization (WHO) grade 3 and 4 leukopenia and diarrhea were seen in 6% and 9.8% of patients, respectively. Stomatitis and alopecia were common. CONCLUSION: In this large multicenter phase II study of patients with advanced CRC, interesting activity was seen (objective response rate, 26%). In addition, Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC.

Adult↗
PubMed1996

Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council.

PURPOSE: To determine the effects of interferon alpha-2a (IFN alpha) on the efficacy and toxicity of fluorouracil (FUra) and leucovorin (LV) in patients with advanced colorectal cancer. PATIENTS AND METHODS: Two hundred sixty chemotherapy-naive patients were randomized to FUra/LV alone or FUra/LV plus IFN alpha. All patients received: LV 200 mg/m2 intravenous (IV) infusion over 2 hours, then FUra 400 mg/m2 i.v. bolus plus 400 mg/m2 i.v. infusion over 22 hours, all repeated on day 2. Treatment was every 2 weeks for up to 12 cycles. Patients randomized to IFN alpha received 6 x 10(6) IU subcutaneously every 48 hours throughout. Objective response (OR) and toxicity were assessed conventionally; in addition, palliative benefit and adverse effects were assessed using quality-of-life (QoL) questionnaires. RESULTS: There were no differences in OR rate, progression-free survival, or overall survival. OR rates in assessable patients were as follows: FUra/LV alone (n = 104), complete or partial response (OR) = 27%, no change (NC) = 34%; FUra/LV/IFN alpha (n = 101), OR = 28%, NC = 30%. Median survival was 10 months in both arms. Dose-limiting FUra toxicities were not significantly increased by co-administration of IFN alpha, and the delivered FUra dose-intensity was not significantly reduced. However, QoL was adversely affected: patients on IFN alpha were less likely to report improvement in pretreatment physical and psychologic symptoms, and more likely to report new or worsening symptoms. CONCLUSION: IFN alpha, at a dose that impaired QoL, did not improve the efficacy of FUra/LV. The power of this trial is sufficient to exclude with 95% confidence a benefit of 15% in OR or 10 weeks in median survival. Accordingly, we cannot recommend the use of IFN alpha as a clinical modulator of FUra/LV in the treatment of advanced colorectal cancer.

Adult↗
PubMed1996

Comparison of interferon tolerance after autologous bone marrow or peripheral blood stem cell transplants for myeloma patients who have responded to induction therapy.

Interferon (INF) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable. In this study we have compared peripheral blood stem cell transplant (PBSCT) versus autologous bone marrow transplant (ABMT) with respect to INF tolerance. Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance. This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details, response and survival. INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients (P = NS). It was well tolerated in both groups without a significant difference in toxicity in the two arms. Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster. Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12% cheaper. We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT. Engraftment was more rapid and the procedure of PBSCT was also cheaper. Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made.

Adult↗
PubMed1996

Inflammation of solar keratoses following systemic 5-fluorouracil.

Several cutaneous reactions have been reported following systemic 5-fluorouracil (5-FU) for the treatment of malignancies. We report three patients with marked inflammation of the solar keratoses following continuous infusion of 5-FU for solid tumours. This side-effect with 5-FU, only previously reported in three other cases, was beneficial as most solar keratoses cleared following the inflammatory reaction. The reasons why 5-FU should be selectively taken up by solar keratoses are discussed.

Aged↗
PubMed1995

Sepsis reduces isoflurane MAC in a normotensive animal model of sepsis.

Patients with sepsis often require anaesthesia for surgical procedures. Anaesthesia can be unpredictable and the most haemodynamically stable agents are used. No data are available for the minimum alveolar concentration (MAC) requirements in such patients or in animal models of sepsis. We have characterized the effect of sepsis on the MAC of isoflurane in a normotensive rodent model of sepsis. The minimum inhibitory concentration (MIC) of isoflurane to an identical stimulus was determined for rodents subjected to caecal ligation and perforation (CLP n = 8), or sham laparotomy (n = 7). The calculated MAC of isoflurane was reduced in the septic animals compared with the sham animals (MAC of isoflurane, CLP = 0.8%, sham = 1.4% P < 0.003). No statistical differences were found in the haemodynamic variables measured in either group. Isoflurane leads to haemodynamic stability during anaesthesia in this animal model of sepsis. However, the MAC requirement for isoflurane is reduced by sepsis.

Anesthetics, Inhalation↗
PubMed1995

Regenerated hair cells in the European starling: are they more resistant to kanamycin ototoxicity than original hair cells?

Previous work from our laboratory [Marean et al. (1993) Hear. Res. 71, 125-136] has shown that a 10 day dose of 200 mg/kg/day kanamycin produced damage to the basal 34% of the starling basilar papilla. We also observed that repeating the dosing schedule following a 4 month survival period resulted in significantly less damage to the regenerated auditory epithelium. The present study investigated whether or not this apparent resistance was the result of a tendency for regenerated hair cells to be less susceptible to kanamycin ototoxicity, or if other, systemic factors may be involved. Eight European starlings were given subcutaneous injections of 200 mg/kg/day kanamycin for 10 days. Serum levels of kanamycin were measured at the time of sacrifice for all birds, and the basilar papillae of all birds were examined by scanning electron microscopy (SEM). Two of these birds (Group 1) were sacrificed immediately following the dosing period. Two of the birds were allowed to survive for 60 days (Group 2). Two of the birds were redosed with 200 mg/kg/day for 10 days after 60 days survival (Group 3). Finally, two birds were redosed with 250 mg/kg/day until serum levels of kanamycin were the same as Group 1 when sacrificed (> 9 micrograms/ml). The SEM results showed that the regenerated auditory epithelium of the birds dosed a second time sustained less damage compared to previously untreated ears, even though the dosing regimen was the same (Group 3 versus Group 1). The regenerated auditory epithelium of birds dosed a second time sustained the same damage as previously untreated animals when the dosage was increased to attain similar serum levels (Group 4 versus Group 1). These results suggest metabolic changes occur in the starling in response to the initial dose of kanamycin which do not necessarily involve changes in hair cell resistance to ototoxicity.

Animals↗
PubMed1995

A single-blind, randomised, vehicle-controlled dose-finding study of recombinant human granulocyte colony-stimulating factor (lenograstim) in patients undergoing chemotherapy for solid cancers and lymphoma.

This study evaluated the effect of glycosylated recombinant human granulocyte colony-stimulating factor (rHuG-CSF; lenograstim) on neutrophil granulocyte counts and on cells of other haematopoietic lineages in 66 patients with solid cancer or lymphoma who received myelosuppressive chemotherapy. Beginning 1 day after completion of chemotherapy, patients received lenograstim (at dosages of 0.5, 2, 5 or 10 micrograms/kg) or vehicle subcutaneously once daily for 14 consecutive days. Compared with vehicle, lenograstim significantly accelerated neutrophil recovery after chemotherapy in a dose-dependent manner. Mean neutrophil counts recovered to > 1.0 x 10(9) cells/l by day 13 in the vehicle group compared with days 11, 10, 8 and 7 in the 0.5, 2, 5 and 10 micrograms/kg lenograstim groups, respectively. Doses of 0.5 and 2 micrograms/kg of lenograstim had a significant effect on the duration of neutropenia (< 1.0 x 10(9) cells/l), the area under the absolute neutrophil count (ANC) curve and the time to ANC nadir. The dose of 5 micrograms/kg additionally decreased the total area of neutropenia and gave the narrowest range of values for all neutrophil parameters, while the 10 micrograms/kg dose brought no added benefit. A dose-response effect of lenograstim on time to neutrophil recovery was observed both for patients who received chemotherapy on a single day (n = 35) and for those who received chemotherapy over several days (n = 29). Based on these findings, a dose of 5 micrograms/kg/day was chosen for further trials.

Adjuvants, Immunologic↗
PubMed1995

Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours.

Hepatobiliary tumours are rare, often present late and have a poor prognosis, with no current effective systemic therapy available. This study aimed to evaluate the activity and toxicity of epirubicin, cisplatin and continuous infusional 5-fluorouracil (5-FU) (ECF) in patients with these tumours. From March 1991 to November 1993, 25 patients with advanced biliary tumours and 7 with hepatoma were treated with epirubicin 50 mg/m2 and cisplatin 60 mg/m2 intravenously (i.v.) day 1, each given every 21 days and 5-FU 200 mg/m2/day given as a continuous 24 h i.v. infusion throughout the treatment course. 8 of the 20 (40%) evaluable patients with biliary tumours responded. Median duration of response was 10 months. 2 of the 7 (29%) patients with hepatoma responded. The regimen was well tolerated with minimal haematological and non-haematological toxicity. This novel regimen is active in advanced hepatobiliary tumours.

Adult↗
PubMed1995

Squamous oesophageal cancer can be downstaged using protracted venous infusion of 5-fluorouracil with epirubicin and cisplatin (ECF).

21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our unit and effective in treating gastric adenocarcinoma, consisting of continuous venous infusion of 5-fluorouracil for up to 24 weeks (200 mg/m2/day) with epirubicin (50 mg/m2) and cisplatin (60 mg/m2) every 3 weeks. 12 patients (57%) had an objective response. The median relapse free period was 7 months, median survival from start of chemotherapy 8.4 months, and median survival from diagnosis, 14 months. Symptomatic improvements were reported by 10/11 patients with pain (91%), 8/9 with anorexia (89%), 8/10 with reflux (80%) and 10/14 with dysphagia (71%). Grade 3 or 4 toxicity was reported by 11 patients: 5 had haematological toxicity, 3 vomiting, 2 infection and 1 diarrhoea. One patient developed peripheral neuropathy, 1 renal impairment and another peripheral vascular disease. Following chemotherapy, surgery was attempted in 5 patients. One remains well 3 years on, 2 had macroscopic clearance of tumour but died of postoperative complications. In 2, disease was irresectable. This regimen of moderate toxicity is effective at improving symptoms in the majority of patients. In some patients, tumours are briefly downstaged so that inoperable tumours may become operable.

Adult↗
PubMed1995

'Tomudex' (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The 'Tomudex' Colorectal Cancer Study Group.

'Tomudex' (ZD1694), a direct and specific thymidylate synthase (TS) inhibitor entered phase III studies in November 1993. We present here the first analysis of a randomised multicentre, international phase III study. 439 patients with previously untreated advanced colorectal cancer were randomised to Tomudex 3.0 mg/m2 given once every 3 weeks or 5-fluorouracil (5-FU) 425 mg/m2 and leucovorin (LV) 20 mg/m2 for 5 days (the Mayo regimen), given every 4-5 weeks. Patients were evaluated weekly for toxicity and every 12 weeks for objective response. The two groups were well matched in terms of demographic characteristics. The mean age of the patients was 61 years and most had either liver (78%) or lung (25-29%) metastases. Ninety seven per cent of patients allocated to Tomudex and 94% of those allocated to 5-FU plus LV had measurable disease. Response was assessed using WHO/UICC criteria; all response data were source validated; 19.8% of patients who received Tomudex and 12.7% of patients who received 5-FU plus LV had complete or partial responses (P = 0.059, odds ratio 1.7, 95% confidence limits 0.98-2.81). There were no statistically significant differences in time to progression or survival between the two groups. Patients who received Tomudex spent a substantially shorter time in hospital for dosing and had significantly lower rates of grade 3 and 4 toxicities such as leucopenia and mucositis. Patients who received Tomudex had a significantly higher incidence of reversible grade 3 or 4 increase in transaminases, which appear to be of limited clinical significance. Improvement in quality of life, weight gain and performance status was seen in both groups. Tomudex has benefits in terms of higher response rates, reduced toxicity and more frequent palliative benefits when compared with 5-FU plus LV in the management of advanced colorectal cancer, and has a more convenient administration schedule.

Adult↗
PubMed1995

Adjuvant chemotherapy for oesophagogastric cancer with epirubicin, cisplatin and infusional 5-fluorouracil (ECF): a Royal Marsden pilot study.

Previous trials of adjuvant chemotherapy for oesophagogastric cancer have shown only modest or no improvement in survival. However, the regimens used in these studies produce low response rates in patients with advanced disease. ECF is a new regimen which results in higher response rates and may therefore be more effective in the adjuvant setting. Twenty-nine patients who had undergone a potentially curative resection for oesphagogastric carcinoma were treated with ECF [epirubicin 50 mg m-2 and cisplatin 60 mg m-2 for 18 weeks]. The median age was 52.5 years. Three patients had oesophageal tumours, 14 had tumours of the oesophagogastric junction (OGJ) and 12 had gastric tumours. All were adenocarcinomas apart from one undifferentiated carcinoma. One patient had stage I disease, nine stage II, 17 stage II and two stage IV. The mean number of chemotherapy cycles per patient was 5.2 (range 2-8). The median follow-up was 8.4 months (1.5-36.3 months). Eleven patients relapsed during follow-up (38%). One patient had an anastomotic recurrence and ten patients distant metastases. Overall 3 year survival was 61.5% (95% confidence interval 42-79); 3 year survival in stage II was 50% (21.2-86.3) and in stage III 65.6% (40-86). Chemotherapy was well tolerated, with grade 3/4 toxicity as follows: leucopenia 13.5%, nausea and vomiting 10%, diarrhoea 3.5%, infection 3.5% and thrombocytopenia 3.5%. There were no treatment-related deaths. We conclude that ECF can be administered safely as adjuvant treatment to patients with surgically resected gastro-oesophageal carcinoma. The results, especially in patients with stage III disease, are encouraging and support the investigation of this regimen within a prospective randomised trial.

Adenocarcinoma↗
PubMed1995

Ovarian metastases from primary gastrointestinal malignancies: the Royal Marsden Hospital experience and implications for adjuvant treatment.

We investigated the pattern and frequency of ovarian metastases in patients with primary gastrointestinal malignancies and evaluated the response to surgery, chemotherapy and in three cases radiotherapy. The literature reports that this group of patients have a poor prognosis, but no report has specifically addressed the response to chemotherapy. Using a database which is generated prospectively, we analysed 51 patients with primary gastrointestinal malignancies and ovarian metastases. All patients received chemotherapy but only 36 were evaluable for response; five had adjuvant treatment and ten had non-measurable disease. Seventeen patients had surgical oophorectomy and three patients received radiotherapy. The overall response rate to chemotherapy was 22%; eight partial responses and no complete responses. When stratified according to site of response, 11 (31%) patients had a partial response at sites of extraovarian metastases and only five (14%) had a partial response in the ovaries. Seven patients with primary colorectal cancer had a differential response in favour of extraovarian sites. The median survival was 9 months for the 51 patients. Three premenopausal women with resected gastric carcinoma received adjuvant chemotherapy and relapsed only in the ovaries. In primary colorectal tumours the response of ovarian metastases to chemotherapy is less than that for other sites. Therefore, the ovary may be a sanctuary site for metastases which has important implications for adjuvant chemotherapy in women. These women could be followed up regularly by transvaginal ultrasonography to detect such metastases at an early stage when they would be amenable to surgical resection. Surgery should be considered for selected patients who develop metachronous metastases, as patients may be rendered disease free for several months.

Adult↗
PubMed1995

Current options in the management of gastrointestinal cancer.

Surgery is the standard approach for localized gastrointestinal malignancy both in the upper GI tract and for cancer of the large bowel. Adjuvant chemotherapy following curatively resected colorectal cancer, results in a definite survival advantage. The use of chemotherapy in an attempt to downstage inoperable gastric cancer to allow for subsequent radical resection has yielded promising results. Likewise improved survival rate in patients treated with adjuvant chemotherapy after resection, justify further exploration of perioperative chemotherapy in operable gastric cancer. In squamous oesophageal cancer, modem chemo-radiation regimens are superior to radiotherapy alone in localized disease. Some series demonstrate impressive survival rates in the absence of surgical intervention raising the question as to the precise role of surgery in a combined modality approach. Ongoing randomized trials will clarify the relative contributions of these treatment modalities in the management of this disease. In metastatic disease of both upper GI and colonic tumours maintenance of good quality of life should be the primary endpoint. Randomised trials of chemotherapy against best supportive care have provided strong justification for the use of chemotherapy in the management of advanced gastric, pancreatic and colorectal cancer.

Colorectal Neoplasms↗
PubMed1995

The prognostic value of CEA, beta HCG, AFP, CA125, CA19-9 and C-erb B-2, beta HCG immunohistochemistry in advanced colorectal cancer.

BACKGROUND: Evaluation of the prognostic significance of a group of tumour markers and their ability to predict response to chemotherapy may allow better targeting of palliative treatment in advanced colorectal cancer. PATIENTS AND METHODS: Using a prospectively acquired database of 377 patients (pts) with advanced colorectal adenocarcinoma, the prognostic significance of serum CEA (342 pts), beta HCG (203 pts), AFP (208 pts), CA125 (150 pts), CA-19-9 (76 pts) as well as C-erb B-2 (197 pts). Serum markers were taken prior to 5-FU based chemotherapy and immunohistochemistry was performed on diagnostic samples RESULTS: Tumour markers of poor prognostic significance in the univariate analysis were CEA > or = 5 micrograms/l (p = 0.006; median survival (MS 59 weeks vs 38 weeks) and CA125 > or = 35 U/ml (p = 0.01 MS 51 weeks vs. 30 weeks). Tumour markers elevated at greater than 10 times the normal value which correlated with a poor prognosis were CEA (p = 0.001; MS 47 weeks vs. 35 weeks), Serum beta HCG (p < 0.0001; MS 44 weeks vs. 7 weeks) and CA125 (p < 0.0001; MS 38 weeks vs. 15 weeks). Poor performance status ( > 2) and poorly differentiated tumour histology were also correlated to poor survival. In the multivariate analysis, tumour markers of independent poor prognosis were CEA > or = 5 micrograms/l (Hazard Ratio (HR) 1.8; 95% Confidence Internal (CI) 2.8-1.2), CEA > or = 50 micrograms/l (HR 1.6; CI 2.1-1.2), CA125 > or = 35 U/ml (HR 1.5; CI 2.3-1.0), CA 125 > or = 350 U/ml (HR 5.0; CI 9.6-2.6) and serum BHCG > or = 0 IU/l (HR 11.7; CI 30-4.5). Poor performance status (HR 6.7-5.0) and poorly differentiated histology (HR 2.8-1.0) were the other important factors in the model. No pretreatment tumour marker correlated with response to chemotherapy. CONCLUSIONS: This is the largest prognostic study of each tumour marker in advanced disease and it clarifies previous conflicting reports. Serum AFP, CA19-9 and immunohistochemical stains beta HCG and C-erb B-2 have no prognostic significance. Serum CEA, beta HCG, CA125 in advanced colorectal cancer prior to chemotherapy do convey an independent poor prognosis which may reflect not just tumour burden but aggressive biology.

Adenocarcinoma↗