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C Topham

Publications and source records attributed to C Topham.

15 recordsLinked to original sources
PubMed2006

A phase I and II study of 2-weekly irinotecan with capecitabine in advanced gastroesophageal adenocarcinoma.

We investigated 2-weekly intravenous irinotecan combined with oral capecitabine in patients with advanced gastroesophageal adenocarcinoma. In phase I, doses were escalated in chemotherapy naïve or pretreated patients to establish maximum tolerated doses (MTD). In phase II, patients were treated at MTD as first-line therapy with the primary end point of RECIST response. Dose levels in phase I were as follows: Level 1: irinotecan 150 mg m-2 on day 1; capecitabine 850 mg m-2 12-hourly on days 1-9. Level 2: as level 1 but capecitabine 1000 mg m-2. Level 3: as level 2 but irinotecan 180 mg m-2. Level 4: as level 3 but capecitabine 1250 mg m-2. In phase I, 21 patients were entered. Maximum tolerated dose was level 3. Dose-limiting toxicities were lethargy, diarrhoea, vomiting and mucositis. In phase II, 31 patients were entered at level 3. During the first six cycles, 13 of these patients underwent dose reduction and three patients stopped treatment for toxicity. A further six patients stopped for progressive disease. The commonest grade 3-4 toxicities were lethargy (20%), diarrhoea (17%), nausea (10%) and anorexia (10%). There were no treatment-related deaths. The response rate was 32% (95% CI 16-52%). Median overall survival was 10 months. This regimen is active in gastroesophageal adenocarcinoma. However, using the MTD defined in phase I, fewer than 50% patients tolerated six cycles without modification in phase II; therefore, modification of these doses is recommended for further study.

Adenocarcinoma↗
PubMed2004

Elderly patients with fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy.

Elderly patients are recommended to have a reduced starting dose (300 mg m(-2) once every 3 weeks) of irinotecan monotherapy. The aims of this analysis are to compare toxicity and survival according to age, performance status (PS), gender and prior radical pelvic radiotherapy (RT). The primary end points were overall survival and an irinotecan-specific toxicity composite end point (TCE) defined as the occurrence of grade 3 or 4 diarrhoea, neutropenia, febrile neutropenia, fever, infection or nausea and vomiting. Between 1997 and 2003, 339 eligible patients with advanced colorectal cancer (CRC) progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered in a multicentre randomised trial. All patients commenced irinotecan at 350 mg m(-2) once every 3 weeks. There were no differences in proportions of patients developing TCE by age (<70 vs > or =70 : 37.8 vs 45.8%; P=0.218), PS (0-1 vs 2 : 39.3 vs 41.5%; P=0.793) or prior RT (RT vs no RT : 45.1 vs 38.5%; P=0.377). Males experienced more toxicity than females (44.3 vs 32.6%; P=0.031), but this was not significant after controlling for other co-variates (P=0.06). Patients aged > or =70 had similar objective responses (11.1 vs 9%; P=0.585) and survival (median 9.4 vs 9 months; log rank P=0.74) compared to younger patients. Elderly patients derive the same benefit without experiencing more toxicity with second-line irinotecan treatment for advanced CRC. Our data do not support the recommendation to reduce the starting dose for the elderly patients.

Adult↗
PubMed2003

Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial.

BACKGROUND: Policies of UK clinicians regarding the duration of chemotherapy for patients with advanced colorectal cancer are not consistent. We aimed to compare effectiveness of continuous and intermittent chemotherapy in such patients. METHODS: Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy, were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression), or continuous chemotherapy until progression. FINDINGS: 354 patients (178 intermittent, 176 continuous) were enrolled from 42 UK centres. At randomisation, 41% of participants had part or complete response; 59% were stable. Only 66 (37%) patients allocated to intermittent treatment restarted as planned, after a median of 130 days. Median time on treatment after restarting was 84 days. Patients in the continuous group remained on treatment for a median of a further 92 days. Similar proportions of patients in both groups received second-line therapy. Patients on intermittent chemotherapy had significantly fewer toxic effects and serious adverse events than those in the continuous group. There was no clear evidence of a difference in overall survival (hazard ratio 0.87 favouring intermittent, 95% CI 0.69-1.09, p=0.23). INTERPRETATION: Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression. They showed that it is safe to stop chemotherapy after 12 weeks and re-start the same treatment on progression in patients with chemosensitive advanced colorectal cancer.

Adult↗
PubMed1999

A patient preference study comparing raltitrexed ('Tomudex') and bolus or infusional 5-fluorouracil regimens in advanced colorectal cancer: influence of side-effects and administration attributes.

Current chemotherapy regimens used in advanced colorectal cancer (ACRC) are similar in terms of efficacy, but differ importantly in terms of side-effects and administration profiles. These differences may impact significantly on patients' lives. We have evaluated patient preferences between raltitrexed ('Tomudex') and 5-fluorouracil-based chemotherapy regimens, with regard to side-effect attributes (raltitrexed and Mayo regimens) and administration attributes (raltitrexed, Mayo, De Gramont and Lokich regimens) in a study based on 82 patients with ACRC. Patients completed a series of rating tasks on how 'upsetting' these attributes were to them using a visual analogue scale (VAS) in a structured interview conducted by a research nurse. Mucositis and asthenia were the most and least upsetting side-effects, respectively. The side-effect profile of raltitrexed was clearly preferred by 78% of patients versus 14% for Mayo (P < 0.001). When side-effects and administration attributes were combined into an overall profile, 91% of patients selected raltitrexed as their clearly preferred regimen, versus 6% for Mayo (P < 0.001). The administration regimen of raltitrexed was ranked most acceptable (mean rank score 1.5 compared with Mayo 2.6, De Gramont 2.7, and Lokich 3.3). Given similar palliative effects, patients with ACRC exhibit preferences for raltitrexed over other regimens, based on administration and/or side-effect attributes. Such preferences should constitute an important part of decisions relating to the choice of chemotherapy regimen in ACRC.

Adult↗
PubMed1997

Patient preferences for chemotherapy schedules used in the treatment of advanced colorectal cancer--a pilot study.

Patient preferences in cancer chemotherapy are an increasingly important issue and need to be better understood. In this pilot study, 45 patients with advanced colorectal cancer were shown 'blinded' descriptions of four different chemotherapy regimens [three 5-fluorouracil (5-FU)-based regimens and Raltitrexed (Tomudex)] and asked to select which they most and least preferred assuming equal efficacy and safety. Patients also rated how troublesome were factors associated with attending hospital and/or receiving chemotherapy. The Raltitrexed regimen was most preferred by 87% of patients, generally because the visit schedule for administration was more convenient. In most cases, patients expressed a strong preference. Continuous 5-FU administered via a Hickman line and portable infusion pump was the least preferred treatment (80%), and the factors associated with wearing a Hickman line permanently were rated as 'very troublesome' or 'fairly troublesome' by 98% of patients. In conclusion, patients prefer convenient chemotherapy regimens which cause minimal disruption of their normal daily routine.

Adult↗
PubMed1995

A 10-year prospective audit of outcome of surgical treatment for colorectal carcinoma.

The outcome of 555 patients who underwent surgery under the care of a surgeon with an interest in colorectal disease was examined prospectively over a 10-year period with no exclusions. There was a 4.7 percent incidence of clinical leaks (10 percent for anterior resection) and an overall corrected 10-year survival rate after curative surgery of 58, 59 and 48 percent for right colonic, left colonic and rectal tumours respectively. The incidence of isolated local recurrence was 8 percent after curative surgery for carcinoma of the rectum. Twenty-five percent of patients with rectal tumours required abdominoperineal excision. Patients who underwent curative abdominoperineal excision of the rectum had corrected 5- and 10-year survival rates of 48 and 36 percent, compared with 60 and 58 percent respectively for curative anterior resection. The perioperative mortality rate of those undergoing palliative surgery was 8 percent, and 75 percent died within 2 years from distant and not local disease. A policy of always attempting resection was validated by the fact that 99 percent of primary tumours were removed with a low perioperative mortality rate (4 percent overall), a high curative resection rate and a low morbidity rate.

Adult↗
PubMed1995

Informal out-patient discussions with patients following surgery for large bowel cancer: are they beneficial?

The value of informal out-patient discussions as a useful, additional method of assessment for both patient and doctor during a busy out-patient clinic is considered. One hundred patients were interviewed by a research or stoma care sister at their first follow-up visit after surgery for large bowel cancer in the combined Oncology/Surgical out-patient clinic of a district general hospital. Particular interest was taken of patients' awareness of diagnosis (85% understood) and operation (93% understood), general well-being (74% had resumed limited activity), dependency on the primary health care team (13%), family history of bowel or associated cancers (as many as 31% had one or more first degree relatives affected) and the suitability for research trials, including adjuvant radiotherapy/chemotherapy (29% were entered). Patients appreciated the opportunity to discuss problems at a particularly stressful period of their lives. It would seem that when problems are identified and an overall assessment of patients' needs made, relevant information is provided for doctors which is influential in improving patient care.

Aftercare↗
PubMed1993

Exploration of subsite binding specificity of human cathepsin D through kinetics and rule-based molecular modeling.

The family of aspartic proteinases includes several human enzymes that may play roles in both physiological and pathophysiological processes. The human lysosomal aspartic proteinase cathepsin D is thought to function in the normal degradation of intracellular and endocytosed proteins but has also emerged as a prognostic indicator of breast tumor invasiveness. Presented here are results from a continuing effort to elucidate the factors that contribute to specificity of ligand binding at individual subsites within the cathepsin D active site. The synthetic peptide Lys-Pro-Ile-Glu-Phe*Nph-Arg-Leu has proven to be an excellent chromogenic substrate for cathepsin D yielding a value of kcat/Km = 0.92 x 10(-6) s-1 M-1 for enzyme isolated from human placenta. In contrast, the peptide Lys-Pro-Ala-Lys-Phe*Nph-Arg-Leu and all derivatives with Ala-Lys in the P3-P2 positions are either not cleaved at all or cleaved with extremely poor efficiency. To explore the binding requirements of the S3 and S2 subsites of cathepsin D, a series of synthetic peptides was prepared with systematic replacements at the P2 position fixing either Ile or Ala in P3. Kinetic parameters were determined using both human placenta cathepsin D and recombinant human fibroblast cathepsin D expressed in Escherichia coli. A rule-based structural model of human cathepsin D, constructed on the basis of known three-dimensional structures of other aspartic proteinases, was utilized in an effort to rationalize the observed substrate selectivity.

Amino Acid Sequence↗
PubMed1993

Comparison of single-agent epirubicin and 5-fluorouracil/epirubicin/mitomycin in patients with advanced adenocarcinoma of the pancreas.

In a randomized trial we compared single-agent epirubicin with the FEM (5-fluorouracil/epirubicin/mitomycin) combination in patients with locally advanced and/or metastatic adenocarcinoma of the pancreas. Sixty patients previously untreated with radiotherapy or chemotherapy were randomly assigned to receive either 100 mg/m2 epirubicin or FEM in the following doses: 5-fluorouracil, 600 mg/m2 to a maximum of 1 g; epirubicin, 50 mg/m2; mitomycin, 6 mg/m2 to a maximum of 10 mg. Treatment was given every 28 days via intravenous bolus; because of its association with delayed myelotoxicity, mitomycin was given every other cycle. A total of 47 patients are evaluable for toxicity and survival, 22 who received FEM and 25 epirubicin. Preliminary results of this ongoing study show no difference in survival between the two arms. Toxicity has been easily managed. A similar number of patients in each arm had elevated serum bilirubin levels, but dose reductions of 50% allowed all these patients to continue treatment.

Adenocarcinoma↗
PubMed1992

Sister chromatid exchange (SCE) frequency in lymphocytes of patients with colorectal carcinoma treated with razoxane.

The increased risk of neoplasia following cytotoxic therapy for both malignant and nonmalignant disease is well known. Sister chromatid exchange (SCE) frequencies in patients receiving such chemotherapy are often elevated, and the persistence of high levels after treatment may provide an indicator for susceptibility to secondary neoplasia. The cytostatic drug razoxane has been used for the treatment of psoriasis, acute myeloid leukemia (AML), and colorectal carcinoma. Prolonged use of this drug, however, has been associated with the subsequent development of AML and, up to November 1987, 16 cases of acute leukemia following razoxane treatment have been reported. We report the SCE frequencies for 34 patients with colorectal carcinoma who were receiving or had previously been treated with razoxane. Our results show no significant increase in SCE levels in the razoxane group compared with either normal controls or untreated patients.

Acute Disease↗
PubMed1991

Randomised trial of epirubicin alone versus 5-fluorouracil, epirubicin and mitomycin C in locally advanced and metastatic carcinoma of the pancreas.

Sixty-nine unselected patients with locally advanced and metastatic carcinoma of the pancreas, who had not received previous chemotherapy or radiotherapy were randomised to receive either 5-fluorouracil, epirubicin and mitomycin C (FEM) or epirubicin. Survival was not significantly different in the two arms. Toxic reactions (WHO grade greater than 3) in the FEM and epirubicin arm respectively included nausea (2), (4), severe alopecia (1) (3) and leucopenia (1), (5), none of these were statistically significant. We therefore suggest that combination chemotherapy should not be used in preference to single agent chemotherapy as standard treatment for locally advanced or metastatic cancer of the pancreas.

Antineoplastic Agents↗
PubMed1976

Clinical trial of combination chemotherapy and specific active immunotherapy in disseminated melanoma.

Fifty-six patients with disseminated malignant melanoma were randomly allocated to two treatment groups. The first group C received combination chemotherapy consisting of DTIC and ICRF 159. The second group (C+I) received the same chemotherapy but were also immunized with 2 X 10(7) irradiated allogeneic melanoma cells mixed with 50 mug of percutaneous BCG. The survival rates in both treatment groups C and (C+I) were not significantly different, and only minor enhancement of the chemotherapy was found in the (C+I) group. A similar pattern of tissue response was observed in both groups: lymph node, skin and, to some extent liver metastases, respond better than other sites.

Antigens, Neoplasm↗