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Biomedical subjects

R D James

Publications and source records attributed to R D James.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1995

Definition of local recurrence after surgery for rectal carcinoma.

Local recurrence rates of rectal carcinoma have been analysed among 284 patients in a prospective randomized multicentre trial of adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Wide variations in local recurrence rates are demonstrated depending on the definition of local recurrence employed and the subgroup studied. Thus after surgical operation alone, rates as high as 43.3 per cent or as low as 12.7 per cent can be calculated. After both adjuvant preoperative radiotherapy and operation the overall local recurrence rate is 12.8 per cent, although the local recurrence rate inside the radiotherapy field (true recurrence) may be as low as 2.3 per cent. It is recommended that local recurrence after operation for rectal carcinoma be defined as any detectable local disease at follow-up, occurring either alone or in conjunction with generalized recurrence, in patients who have undergone resection. A rate should be given both for all patients and for those operated on for cure, but not for the latter group alone as this could introduce bias.

Humans↗
PubMed1995

Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, ChlVPP/EVA, in the initial treatment of Hodgkin's disease.

PURPOSE AND METHODS: Between December 1984 and August 1992, 423 patients with newly diagnosed Hodgkin's disease (HD) were entered onto a randomized clinical trial that compared the regimen of mechlorethamine, vinblastine, procarbazine, and prednisone (MVPP) with a doxorubicin-containing hybrid regimen (chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin [ChlVPP/EVA]). Median age for the group was 29.5 years (range, 15.2 to 68.8), and 52% had bulk disease. RESULTS: After chemotherapy, patients in the hybrid arm of the trial had a higher complete remission (CR) rate (68.1% v 55.3%) and a lower failure rate (2.4% v 12.5%) than those in the MVPP arm. There were also fewer deaths during treatment in the hybrid arm of the trial (five v 13). With a median follow-up period for survivors of 4.5 years (range, 0 to 9), actuarial 5-year progression-free survival (PFS) for all cases is 80% in the hybrid arm and 66% in the MVPP arm (P = .005). A nonsignificant trend toward a better overall survival in the hybrid arm of the trial has also been identified. CONCLUSION: These results suggest that ChlVPP/EVA hybrid is superior to MVPP in the treatment of HD. It has therefore been adopted as standard first-line therapy at the two centers.

Adolescent↗
PubMed1994

Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial.

PURPOSE: A prospective, randomized clinical trial was conducted by the Northwest Rectal Cancer Group to study the effects of preoperative radiotherapy given one week before surgery in locally advanced (tethered or fixed) rectal carcinoma. METHODS: A total of 284 patients were entered into the trial between 1982 and 1986; 141 were allocated to receive surgical treatment alone, and 143 were allocated to receive preoperative radiotherapy. A 10 x 10 x 10 cm volume in the posterior pelvis, centered on the tumor, was irradiated at a dose of 20 Gy, divided into four daily fractions of 5 Gy each. RESULTS: No differences were observed in any of the clinicopathologic variables in the two arms of the trial; there were no striking down-staging effects in the irradiated tumors. After a minimum follow-up period of 96 months, the overall and cancer-related mortality rates were similar in both arms of the study (P = 0.21 and P = 0.09, respectively). There was a highly significant reduction in local recurrences in the irradiated group (12.8 percent x-ray therapy vs. 36.5 percent surgery; P = 0.0001). The majority of local recurrences after preoperative radiotherapy occurred inside the radiotherapy field (10 cases; 7 percent), with only six cases (5 percent) outside the field. No significant difference was observed in the rates of distant metastasis between the two treatment groups (P = 0.73). CONCLUSIONS: Although there is no statistically significant survival benefit in the whole series, there is a survival benefit for the subset of patients considered by the surgeon to have undergone a curative operation. We recommend that this form of adjuvant therapy should be offered to all patients with locally advanced rectal cancer who are to undergo radical surgery.

Aged↗
PubMed1994

An evaluation of five different methods for estimating proliferation in human colorectal adenocarcinomas.

Five different methods of determining cell proliferation have been compared in samples taken from a group of 125 human colorectal tumours labelled in vivo with iododeoxy-uridine (IUdR). The labelling index (LI) was obtained immunocytochemically using monoclonal antibodies against proliferating cell nuclear antigen (PCNA), the Ki67 antigen and IUdR (IUdRimm). Incorporation of IUdR was also determined flow cytometrically (IUdRfcm) and PCNA expression was measured in both formalin- and methanol-fixed tissue (PCNAf and PCNAm respectively). There was significant variation in the results obtained both within and between the different assays. Paired analysis of the data showed that the correlation between the different methods of determining the LI was poor. However, the IUdRfcm LI was significantly correlated with both IUdRimm (r = 0.39; n = 78; P < 0.001 by Spearman's test) and Ki67 LIs (r = 0.32; n = 87; P < 0.001). The IUdRimm LI was also significantly related to the Ki67 LI (r = 0.44; n = 60; P < 0.001). The median IUdRfcm and IUdRimm LIs were significantly higher in the aneuploid vs. the diploid tumours (17.4% vs. 6.2% for IUdRfcm; 23.2% vs. 18.9 for the IUdRimm; P < 0.001 and P = 0.014 respectively by Mann-Whitney U-test) but none of the other proliferative indices showed this relationship. Finally, none of the LIs showed a significant association with the clinical characteristics of the tumours such as stage, grade, age, sex or fixity. The findings of this investigation highlight the need for carefully controlled studies when assessing the value of proliferation markers in solid human tumours.

Adenocarcinoma↗
PubMed1994

Weekly VAPEC-B chemotherapy for high grade non-Hodgkin's lymphoma: results of treatment in 184 patients.

UNLABELLED: BACKGROUND AND PATIENTS: A weekly schedule of chemotherapy (VAPEC-B) has been used to treat 184 consecutive patients with high grade non-Hodgkin's lymphoma (NHL). Median age for the group was 57 years (range 17-84) and 56% had stage IV disease. RESULTS: Following chemotherapy, 114 (62%) patients achieved CR or CR(u), 32 (17%) PR and 15 (8%) had not responded or progressed. Response to VAPEC-B was highly stage dependent with 70% or more of patients with stages I-III achieving CR or CR(u) but only 50% of those with stage IV. Twenty-four (15%) patients died during treatment with VAPEC-B and in 13 cases death was due to sepsis. This complication occurred mainly in patients with stage IV disease aged 60 years or older. After a median follow up period of 4.1 years, the actuarial 4 year survival for 184 patients is 45%, an overall result heavily influenced by the poor outcome for 103 patients with stage IV disease (4 year survival of 28%). Patients with earlier stage disease fared correspondingly better (44% for stage III, 68% for stage II and 80% for stage I). CONCLUSIONS: VAPEC-B gives similar results to other chemotherapy regimens currently used in the treatment of high grade NHL and has the advantage of brevity. Caution is advised in patients over the age of 60 especially in the presence of stage IV disease and dose reduction or haemopoietic growth factor support should be considered in these circumstances.

Adolescent↗
PubMed1993

An assessment of the reliability and reproducibility of measurement of potential doubling times (Tpot) in human colorectal cancers.

An assessment has been made of the reproducibility of measuring tumour proliferation using in vivo iododeoxyuridine (IUdR) labelling and flow cytometry. The variation that occurs between different institutions (Paterson Institute for Cancer Research, Manchester and the Gray Laboratory, Northwood), different observers and different runs on the same flow cytometer have been measured on 139 samples from 53 patients with colorectal cancer. The results demonstrate that the IUdR technique for measuring tumour proliferation is reproducible. Correlations were seen between measurements of Tpot obtained by different individuals and on separate machines. However, direct comparisons of the measured parameters showed that there were highly significant differences in the values obtained between institutes and observers (P < 0.001). Despite these variations, there were still significant detectable differences in Tpot measurements between individual tumours (P < 0.001). Analysis of the results obtained by running the same samples on two separate occasions on the same machine showed that the technique was highly reproducible and that the staining procedure was stable. Eighty per cent of the samples were similarly assigned to either above or below the median Tpot value, regardless which observer/laboratory combination was utilised. These data suggest that large clinical trials using Tpot should employ a single centre and a single individual to prepare, run and analyse samples.

Adenocarcinoma↗
PubMed1993

Intra-tumoral heterogeneity of tumour potential doubling times (Tpot) in colorectal cancer.

Intra-tumoural heterogeneity of proliferation has been assessed by taking multiple biopsies from 30 colorectal cancers. Following in vivo IUDR labelling, dual parameter flow cytometry was used to measure tumour DNA index (DI) and labelling index (LI) and to derive DNA synthesis time (Ts) and potential doubling time (Tpot). Heterogeneity was seen for all parameters under investigation. Overall coefficients of variation (CV) and logarithmic transformation of Ts and Tpot (due to their non-gaussian distributions) indicate that LI (CV 25%) was the most variable parameter. Intra-tumoral heterogeneity in Tpot (lnTpot CV = 22%) was less than inter-individual variation (CV = 63%), suggesting that this variation should not be a limitation to the possible usefulness of this technique as an independent prognostic indicator. Correlations of Tpot values were examined between the shortest, the median and the value for a pooled homogenate sample from a single tumour. Using an homogenate, it was possible to accurately predict classification of tumour Tpot values as being below the median ('fast tumours') in 15 of 19 cases (79%). The data suggest that assaying an homogenate may allow a more rapid analysis of a multiply sampled tumour.

Adenocarcinoma↗
PubMed1992

Recombinant human erythropoietin in patients with ovarian carcinoma and anaemia secondary to cisplatin and carboplatin chemotherapy: preliminary results.

Preliminary results from the first 21 patients of a group of 30 with International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV epithelial ovarian carcinoma and anaemia are reported. Patients entered this open-label, comparative-group, out-patient study and were randomized to receive conventional support alone (control patients) or recombinant human erythropoietin (r-HuEPO) in addition to conventional support for 6 months. The aim of the study was to determine the effects of r-HuEPO on the anaemia induced by platinum-based chemotherapy. Patients randomized to r-HuEPO therapy received 300 U/kg subcutaneously 3 times weekly in addition to conventional chemotherapy. All patients underwent regular haematological monitoring. One patient developed a deep venous thrombosis after 17 doses of r-HuEPO; it was thought that this event may have been related to therapy and the patient was withdrawn from the study. Three other withdrawals occurred after 11, 15 and 40 doses of r-HuEPO because of progressive anaemia, metoclopramide-induced skin rash and change of chemotherapy, respectively. In the 21 patients analysed to date, there was a notable reduction in blood transfusion requirements during the 6 months of chemotherapy and an improvement in mean serial haemoglobin concentrations in patients on r-HuEPO compared with the control group. In conclusion, r-HuEPO has the potential for reducing haematological toxicity in patients with ovarian carcinoma receiving platinum-based chemotherapy. Also, r-HuEPO may allow modest dosage increments in chemotherapy or the addition of abdominopelvic radiotherapy.

Adult↗
PubMed1991

Prognostic factors in colorectal carcinoma treated by preoperative radiotherapy and immediate surgery.

The clinicopathologic staging of colorectal cancer is the subject of recent debate. We studied morphologic variables in a series of tumors resected from 284 patients. Half had been prospectively, randomly allocated to receive a 4-day schedule of preoperative pelvic radiotherapy followed by immediate surgery. There was a significant (P less than 0.01) difference in the distribution of tumors of various histopathologic grades between irradiated (XS) and unirradiated (S) patients and borderline differences in the predictive values of venous spread, tumor grading, and local spread. However, these differences were less marked in 180 tumors examined by one review pathologist. They were thought to be due to misinterpretation of changes induced by radiotherapy. No differences were detected in the distribution of tumors of various sizes and Dukes' stage in the XS and S groups. The review pathologist recorded a borderline (P = 0.049) difference in the distribution of tumors of various CEA staining patterns between the XS and S groups. In a Cox regression model. Dukes' staging remained the most important predictive variable for survival and pelvic recurrence in the XS and S groups. Dukes' staging was apparently unchanged by this schedule of preoperative radiotherapy, but Broders' grading may be unreliable. Any new clinicopathologic staging system for colorectal cancer should record when preoperative radiotherapy is delivered. More studies of radiotherapy effects are required.

Adenocarcinoma↗
PubMed1991

Lack of a relationship between colony-forming efficiency and surviving fraction at 2 Gy.

The relationship between in vitro radiation sensitivity and colony-forming efficiency has been examined for primary human tumors of the cervix, colorectum, and lymph gland. Tumors were cultured using the Courtenay-Mills soft agar clonogenic assay and radiosensitivity was assessed as surviving fraction at 2 Gy. There was no correlation between colony-forming efficiency and surviving fraction at 2 Gy, giving confidence to the use of surviving fraction at 2 Gy as a predictor of clinical outcome.

Cell Survival↗
PubMed1989

Timing of prophylactic antibiotics in abdominal surgery: trial of a pre-operative versus an intra-operative first dose.

When prophylactic antibiotics are used in abdominal surgery it is customary to give the first dose before the operation. Whilst intra-operative antibiotics may be effective in elective surgery, there may be an advantage to starting pre-operatively when there is already an infective focus such as appendicitis. Antibiotics started pre-operatively (group P) have been compared with antibiotics started after initial abdominal exploration (group T). Three intravenous doses of 500 mg metronidazole plus 1 g cephazolin were given in a randomized, double-blind study of 700 emergency and elective high-risk abdominal operations. Antibiotic plasma concentrations at the end of the operation were significantly lower in group P but lay well within the therapeutic range. Wound infection rates, which included minor and delayed infections, were similar in both groups (group P, 57 of 342, 16.7 per cent; group T, 55 of 358, 15.4 per cent; 95 per cent confidence intervals for the difference being -4.1 to +6.7 per cent. In appendicitis, wound infection rates were 12.1 and 13.9 per cent for groups P and T respectively. However, non-fatal deep sepsis was more common in group P (nine cases) than in group T (two cases) (chi 2 = 4.9, P less than 0.05). Postoperative infection was twice as common in obese patients whose body mass index (BMI) was greater than or equal to 26 (39 of 132, 30 per cent) than in thin patients whose BMI was less than 24 (41 of 288, 14 per cent; chi 2 = 13.8, P less than 0.001). This study failed to show any advantage to starting antibiotics pre-operatively, even in appendicitis.

Abdomen↗
PubMed1989

Predicting local recurrence of carcinoma of the rectum after preoperative radiotherapy and surgery.

A prospective study of prognostic factors has been carried out in a group of 186 patients with tethered rectal carcinomas. Of these, 97 were randomized to surgery alone and 89 to receive preoperative radiotherapy (20 Gy in four fractions). DNA ploidy was determined by flow cytometry. DNA aneuploidy was detected in 60 patients (62 per cent) in the surgery only group, but in only 33 patients (37 per cent) after radiotherapy (P less than 0.01). There was a significant reduction in local recurrence in irradiated patients (P less than 0.0001). DNA diploid tumours were less likely to recur locally. This was more marked in the radiotherapy group (P = 0.01) than in the surgery only group (P = 0.06). After radiotherapy, only the surgeons' assessments of a 'curative' resection and DNA ploidy were independent predictors of local recurrence in multivariate regression analysis, whilst Dukes' classification was not. In conclusion, DNA ploidy may indicate response to radiotherapy and is an important predictor of subsequent local tumour progression.

Combined Modality Therapy↗
PubMed1989

The value of radiotherapy for rectal cancer.

Discrepancies in morbidity and local recurrence rates in published clinical trials of pelvic XRT for colorectal cancer are caused by a variety of complex factors. It is, however, clear that XRT is able to cure early rectal carcinomas and is particularly useful in alleviating the symptoms of advanced or recurrent disease. The selection of appropriate cases for combinations of XRT and surgery can be made on the basis of digital examination under anaesthetic. One aim of these combinations is to reduce the number of patients with mobile tumours of the lower two-thirds of the rectum who require a permanent colostomy. In the absence of effective chemotherapy for metastatic disease, liver XRT may have a place in controlling the growth rate of occult liver metastases in selected patients.

Colorectal Neoplasms↗