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Background: Squamous cell carcinoma of the anus (SCCA) is highly sensitive to chemoradiation (CRT) which achieves good loco-regional control and preserves anal function. However, some patients require permanent stoma formation either as a result of surgery on relapse, poor anal function or treatment-related symptoms. Our aim was to determine patient, tumour and treatment-related colostomy rates following CRT and maintenance chemotherapy in the ACT II trial. Patients and methods: The ACT II trial recruited 940 patients comparing 5FU-based CRT using cisplatin (CisP) or mitomycin C (MMC) with or without additional maintenance chemotherapy. We investigated the association between colostomy-free survival (CFS) and progression-free survival (PFS) with age, gender, T-stage, N-stage, treatment and baseline haemoglobin. Results: The median follow-up was 5.1 years (n = 884 evaluable/940); tumour site canal (84%), margin (14%); stage T1/T2 (52%), T3/T4 (46%); N+ (32%), N0 (62%). Twenty out of 118 (17%) colostomies fashioned before CRT were reversed within 8 months. One hundred and twelve patients had a post-treatment colostomy due to persistent disease (98) or morbidity (14). Fifty-two per cent (61/118) of all pre-treatment colostomies were never reversed. The 5-year CFS rates were 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/No-maint. CRT with CisP did not improve CFS when compared with MMC (hazard ratio: 1.04, 95% confidence interval: 0.82-1.31, P = 0.74). The 5-year CFS rates were higher for T1/T2 (79%) than T3/T4 (54%) tumours and higher for node-negative (72%) than node-positive (60%) patients. Significant predictors of CFS were gender, T-stage and haemoglobin, while treatment factors had no impact on outcome. Similar associations were found between PFS and tumour/treatment-related factors. Conclusions: The majority (52%) of pre-treatment colostomies were never reversed. Neither CRT with 5FU/CisP nor maintenance chemotherapy impacted on CFS. The low risk of colostomy for late effects (1.7%) is likely to be associated with the modest total radiotherapy dose. The predictive factors for CFS were T-stage, gender and baseline haemoglobin.

BACKGROUND: This randomised trial compared three chemotherapy regimens in the first-line treatment of advanced colorectal cancer, in terms of their effect on overall and progression-free survival; other endpoints included toxicity, symptom palliation, and quality of life. METHODS: 905 patients were randomly assigned the de Gramont regimen (n=303; folinic acid 200 mg/m(2), fluorouracil bolus 400 mg/m(2), and infusion 600 mg/m(2) on days 1 and 2, repeated every 14 days), the Lokich regimen (n=301; protracted venous infusion of fluorouracil 300 mg/m(2) daily), or raltitrexed (n=301; 3 mg/m(2) intravenously every 21 days). Analyses were by intention to treat. FINDINGS: Median follow-up of survivors was 67 weeks. For the de Gramont, Lokich, and raltitrexed groups, respectively, median survival was 294, 302, and 266 days. The hazard ratios for overall survival were 0.88 (95% CI 0.70-1.12, p=0.17) for de Gramont versus Lokich, and 0.99 (0.79-1.25, p=0.94) for de Gramont versus raltitrexed. An increase in treatment-related deaths was seen on raltitrexed (de Gramont one, Lokich two, raltitrexed 18) due to combined gastrointestinal and haematological toxicity. Patients' assessment of quality of life showed that raltitrexed was inferior to the fluorouracil-based regimens, especially in terms of palliation and functioning. INTERPRETATION: The deGramont and Lokich regimens were similar in terms of survival, quality of life, and response rates. The Lokich regimen was associated with more central line complications and hand-foot syndrome. Raltitrexed showed similar response rates and overall survival to the de Gramont regimen and was easier to administer, but resulted in greater toxicity and inferior quality of life.

Background: The first UKCCCR Anal Cancer Trial (1996) demonstrated the benefit of chemoradiation over radiotherapy (RT) alone for treating epidermoid anal cancer, and it became the standard treatment. Patients in this trial have now been followed up for a median of 13 years. Methods: A total of 577 patients were randomised to receive RT alone or combined modality therapy using 5-fluorouracil and mitomycin C. All patients were scheduled to receive 45 Gy by external beam irradiation. Patients who responded to treatment were recommended to have boost RT, with either an iridium implant or external beam irradiation. Data on relapse and deaths were obtained until October 2007. Results: Twelve years after treatment, for every 100 patients treated with chemoradiation, there are an expected 25.3 fewer patients with locoregional relapse (95% confidence interval (CI): 17.5–32.0 fewer) and 12.5 fewer anal cancer deaths (95% CI: 4.3–19.7 fewer), compared with 100 patients given RT alone. There was a 9.1% increase in non-anal cancer deaths in the first 5 years of chemoradiation (95% CI +3.6 to +14.6), which disappeared by 10 years. Conclusions: The clear benefit of chemoradiation outweighs an early excess risk of non-anal cancer deaths, and can still be seen 12 years after treatment. Only 11 patients suffered a locoregional relapse as a first event after 5 years, which may influence the choice of end points in future studies.

Summary Background In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response. Methods We studied patients with advanced colorectal cancer, starting treatment with non-curative intent. 2135 unpretreated patients were randomly assigned to three treatment strategies in the ratio 1:1:1. Strategy A (control group) was single-agent fluorouracil (given with levofolinate over 48 h every 2 weeks) until failure, then single-agent irinotecan. Strategy B was fluorouracil until failure, then combination chemotherapy. Strategy C was combination chemotherapy from the outset. Within strategies B and C, patients were randomly assigned to receive, as the combination regimen, fluorouracil plus irinotecan (groups B-ir and C-ir) or fluorouracil plus oxaliplatin (groups B-ox and C-ox). The primary endpoint was overall survival, analysed by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 79877428. Results Median survival of patients allocated to control strategy A was 13·9 months. Median survival of each of the other groups was longer (B-ir 15·0, B-ox 15·2, C-ir 16·7, and C-ox 15·4 months). However, log-rank comparison of each group against control showed that only C-ir—the first-line combination strategy including irinotecan—satisfied the statistical test for superiority (p=0·01). Overall comparison of strategy B with strategy C was within the predetermined non-inferiority boundary of HR=1·18 or less (HR=1·06, 90% CI 0·97–1·17). Interpretation Our data challenge the assumption that, in this non-curative setting, maximum tolerable treatment must necessarily be used first-line. The staged approach of initial single-agent treatment upgraded to combination when required is not worse than first-line combination, and is an alternative option for discussion with patients.

Aims A retrospective audit was carried out to determine the rate of local recurrence (recurrent tumour within the lesser pelvis or the perineal wound) in 88 rectal cancer patients treated with 20Gy/four fractions of adjuvant preoperative radiotherapy and curative surgery. Materials and methods All patients were followed-up by clinical examination with rigid sigmoidoscopy at 6 monthly intervals if the rectum was intact, and computed tomography of the pelvis at 1, 2 and 5 years after surgery. In total, 171 patients with rectal cancer were identified under the care of one surgeon over a period of 11 years from May 1992 to April 2003. We excluded patients with rectal cancer from preoperative adjuvant radiotherapy if they had evidence at presentation of distant metastases, if they had fixed rectal tumours, were treated by local excision and had previous radiotherapy to the pelvis. On this basis, only 88 were considered for preoperative radiotherapy and curative resection with a median follow-up of 5.16 years. Results The 5-year survival by stage was Dukes A 96%, Dukes B 65% and Dukes C 36%. Overall, four patients (of 88) developed a recurrence within the lesser pelvis or the perineal wound, giving a local recurrence of 4.2% at 3 years (from a Kaplan–Meier graph). Conclusions This single-centre audit suggests that a lower dose of radiotherapy to a smaller volume provides an acceptable local recurrence rate that compares very favourably with the well-publicised Swedish and Dutch trials of 25Gy/five fractions. It was not the intention of this audit to suggest that this dose should be widely adopted. However, given the long-term gastrointestinal morbidity and risk of second malignancies, we advise caution when formulating even more intensive radiotherapy and chemoradiotherapy regimens for rectal cancer.

We investigated the activity of irinotecan given with a more convenient modified bimonthly de Gramont regimen of bolus and infusional 5-fluorouracil [IrMdG] in advanced or metastatic colorectal cancer in the first and second line setting. Irinotecan 180 mg m−2 was infused over 90 min. L-folinic acid 175 mg or d,l folinic acid 350 mg was given over 2 h followed by a bolus of 5-fluorouracil (400 mg m−2) and a 46 h continuous infusion of 5-fluorouracil (2.4–2.8 g m−2). Forty-six previously untreated patients (Group A) and 36 who had received 5-fluorouracil for metastatic disease (Group B) were recruited. Seventy-eight patients were evaluable for response. A partial response was seen in 13 out of 43 (30% [95%CI 28.1–31.9%]) in Group A and 8/35 (23% [95% CI 17.9–28.1%]) in Group B. 40% (95%CI 38.1–41.9%) of Group A and 26% (95% CI 20.9–31.1%) of Group B patients achieved disease stabilisation. The median progression free survival from the start of this treatment was 7 months (95% CI 4.4–9.6 months) in Group A and 5 months (95% CI 2.8–7.2 months) in Group B. Median overall survival was 14 months (95% CI 9.0–18.9) in Group A and 11 months (95% CI 5.9–16.1) in Group B. Grade 3–4 toxicity in both treatment groups were similar; leucopenia 17% and diarrhoea 7–8%. Grade 3–4 mucositis was not seen and severe alopecia affected only three patients. IrMdG is an active and well-tolerated regimen for both the first and second line treatment of advanced colorectal cancer. British Journal of Cancer (2002) 87, 1216–1220. doi:10.1038/sj.bjc.6600641 www.bjcancer.com © 2002 Cancer Research UK

The use of elastomeric infusional devices to administer chemotherapy is becoming established in a number of malignancies. Historically, hospitals have admitted patients for treatments such as the deGramont regimen, used in advanced colorectal cancer. This consists of intermittent infusional 5-fluorouracil (5-FU) and folinic acid and usually requires two to three inpatient days, every two weeks. We performed a prospective, single-center, study to assess the feasibility of administering the deGramont regimen on an outpatient basis using elastomeric infusional devices. In addition, we assessed patient acceptability of this mode of administration and the effects on quality of life (using the self-completed EORTC QLQ-C30 questionnaire). Crude cost-benefit analysis was performed and we attempted to define the group of patients for whom this is a viable option. Twenty-six patients, all receiving the same regimen, were recruited into the study. Two cohorts were (nonrandomly) allocated to receive either standard inpatient (n=13) or novel out-patient (n=13) chemotherapy. Administration of the deGramont regimen using elastomeric infusional devices through an indwelling central venous catheter was found to be both feasible and highly acceptable to patients. Those patients receiving this modality of administration reported marked benefits, improved morale and did not suffer from impaired quality of life. Taking into account the costs of inpatient hospital stay, the outpatient regimen conferred considerable cost savings. Given the continued use of this popular regimen, either alone or in combination with newer, more active agents such as irinotecan and oxaliplatin, these findings have potential implications for a large number of patients and institutions. It also raises possibility of exploring this approach for other types of ambulatory infusion device chemo-therapy and may hasten the advent of home-based chemotherapy.

Raltitrexed (Tomudex), a thymidylate synthase inhibitor, is an alternative to 5-fluorouracil (5-FU)/leucovorin (LV) for the first-line treatment of advanced colorectal cancer. Following the completion of four phase III studies with raltitrexed at the recommended dose of 3.0 mg/m(2), it is opportune to review the efficacy and tolerability data of raltitrexed and suggest guidelines for appropriate patient management. Data are analysed from four phase III and five phase II studies including over 1300 patients with advanced colorectal cancer, some of whom were elderly or received higher doses of raltitrexed. Median survival with raltitrexed was comparable to that of bolus or infusional 5-FU/LV in three of the four randomised studies and objective response rates in the four trials were similar for the two agents. Response rates were at least comparable in elderly patients in phase II studies. For the majority of patients, treatment with raltitrexed was well tolerated even at doses higher than that recommended or in the elderly. As with other cytotoxic agents, serious and potentially life-threatening side-effects can occur; nevertheless, adherence to simple patient guidelines should minimise the incidence of serious side-effects with raltitrexed; these include the assessment of renal function before each and every treatment, dosage adjustment in the presence of renal impairment and close monitoring with prompt treatment of toxicities, particularly diarrhoea and neutropenia.

Irinotecan is active against colorectal cancer in patients whose disease is refractory to fluorouracil. We investigated the efficacy of these two agents combined for first-line treatment of metastatic colorectal cancer.387 patients previously untreated with chemotherapy (other than adjuvant) for advanced colorectal cancer were randomly assigned open-label irinotecan plus fluorouracil and calcium folinate (irinotecan group, n=199) or fluorouracil and calcium folinate alone (no-irinotecan group, n=188). Infusion schedules were once weekly or every 2 weeks, and were chosen by each centre. We assessed response rates and time to progression, and also response duration, survival, and quality of life. Analyses were done on the intention-to-treat population and on evaluable patients.The response rate was significantly higher in patients in the irinotecan group than in those in the no-irinotecan group (49 vs 31%, p0.001 for evaluable patients, 35 vs 22%, p0.005 by intention to treat). Time to progression was significantly longer in the irinotecan group than in the no-irinotecan group (median 6.7 vs 4.4 months, p0.001), and overall survival was higher (median 17.4 vs 14.1 months, p=0.031). Some grade 3 and 4 toxic effects were significantly more frequent in the irinotecan group than in the no-irinotecan group, but effects were predictible, reversible, non-cumulative, and manageable.Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival, with a later deterioration in quality of life. This combination should be considered as a reference first-line treatment for metastatic colorectal cancer.

Summary Background In phase II studies, irinotecan is active in metastatic colorectal cancer, but the overall benefit has not been assessed in a randomised clinical trial. Methods Patients with proven metastatic colorectal cancer, which had progressed within 6 months of treatment with fluorouracil, were randomly assigned either 300–350 mg/m 2 irinotecan every 3 weeks with supportive care or supportive care alone, in a 2:1 ratio. Findings 189 patients were allocated irinotecan and supportive care and 90 supportive care alone. The mean age of the participants was 58·8 years; 181 (65%) were men and 98 (35%) were women. WHO performance status was 0 in 79 (42%) patients, 1 in 77 (41%) patients, and 2 in 32 (17%) patients. Tumour-related symptoms were present in 134 (71%) patients and weight loss of more than 5% was seen in 15 (8%) patients. With a median follow-up of 13 months, the overall survival was significantly better in the irinotecan group (p=0·0001), with 36·2% 1-year survival in the irinotecan group versus 13·8% in the supportive-care group. The survival benefit, adjusted for prognostic factors in a multivariate analysis, remained significant (p=0·001). Survival without performance-status deterioration (p=0·0001), without weight loss of more than 5% (p=0·018), and pain-free survival (p=0·003) were significantly better in the patients given irinotecan. In a quality-of-life analysis, all significant differences, except on diarrhoea score, were in favour of the irinotecan group. Interpretation Our study shows that despite the sideeffects of treatment, patients who have metastatic colorectal cancer, and for whom fluorouracil has failed, have a longer survival, fewer tumour-related symptoms, and a better quality of life when treated with irinotecan than with supportive care alone.

Summary Background Chemoradiation became the standard of care for anal cancer after the ACT I trial. However, only two-thirds of patients achieved local control, with 5-year survival of 50%; therefore, better treatments are needed. We investigated whether replacing mitomycin with cisplatin in chemoradiation improves response, and whether maintenance chemotherapy after chemoradiation improves survival. Methods In this 2×2 factorial trial, we enrolled patients with histologically confirmed squamous-cell carcinoma of the anus without metastatic disease from 59 centres in the UK. Patients were randomly assigned to one of four groups, to receive either mitomycin (12 mg/m 2 on day 1) or cisplatin (60 mg/m 2 on days 1 and 29), with fluorouracil (1000 mg/m 2 per day on days 1–4 and 29–32) and radiotherapy (50·4 Gy in 28 daily fractions); with or without two courses of maintenance chemotherapy (fluorouracil and cisplatin at weeks 11 and 14). The random allocation was generated by computer and patients assigned by telephone. Randomisation was done by minimisation and stratified by tumour site, T and N stage, sex, age, and renal function. Neither patients nor investigators were masked to assignment. Primary endpoints were complete response at 26 weeks and acute toxic effects (for chemoradiation), and progression-free survival (for maintenance). The primary analyses were done by intention to treat. This study is registered at controlled-trials.com, number 26715889. Findings We enrolled 940 patients: 472 were assigned to mitomycin, of whom 246 were assigned to no maintenance, 226 to maintenance; 468 were assigned to cisplatin, of whom 246 were assigned to no maintenance, 222 to maintenance. Median follow-up was 5·1 years (IQR 3·9–6·9). 391 of 432 (90·5%) patients in the mitomycin group versus 386 of 431 (89·6%) in the cisplatin group had a complete response at 26 weeks (difference −0·9%, 95% CI −4·9 to 3·1; p=0·64). Overall, toxic effects were similar in each group (334/472 [71%] for mitomycin vs 337/468 [72%] for cisplatin). The most common grade 3–4 toxic effects were skin (228/472 [48%] vs 222/468 [47%]), pain (122/472 [26%] vs 135/468 [29%]), haematological (124/472 [26%] vs 73/468 [16%]), and gastrointestinal (75/472 [16%] vs 85/468 [18%]). 3-year progression-free survival was 74% (95% CI 69–77; maintenance) versus 73% (95% CI 68–77; no maintenance; hazard ratio 0·95, 95% CI 0·75–1·21; p=0·70). Interpretation The results of our trial—the largest in anal cancer to date—show that fluorouracil and mitomycin with 50·4 Gy radiotherapy in 28 daily fractions should remain standard practice in the UK. Funding Cancer Research UK.

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.

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 × 10 × 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 andP =0.09, respectively). There was a highly significant reduction in local recurrences in the irradiated group (12.8 percent x-ray therapyvs. 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.

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; P0.001 by Spearman's test) and Ki67 LIs (r = 0.32; n = 87; P0.001). The IUdRimm LI was also significantly related to the Ki67 LI (r = 0.44; n = 60; P0.001). 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; P0.001 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.

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.

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.

Income (activity) and expenditure (costs) form the basis of a modern hospital's ‘business intelligence’. However, clinical engagement in business intelligence is patchy. This article describes the principles of business intelligence and outlines some recent developments using web-based applications.

Purpose: The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment (CMT) using radiotherapy (RT), infusional 5-fluorouracil, and mitomycin C over RT alone. The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome. Methods and Materials: A total of 577 patients were randomly assigned RT alone or CMT. After a 6-week gap responders received a boost using either additional external beam radiotherapy (EBRT) (15 Gy) or iridium-192 implant (25 Gy). The effect of boost, the gap between initial treatment (RT alone or CMT) and boost (Tgap), and overall treatment time (OTT) were examined for their impact on outcome. Results: Among the 490 good responders, 436 (89%) patients received a boost after initial treatment. For boosted patients, the risk of anal cancer death decreased by 38% (hazard ratio [HR]: 0.62, 99% CI 0.35–1.12; p = 0.04), but there was no evidence this was mediated via a reduction in locoregional failure (LRF) (HR: 0.90, 99% CI 0.48–1.68; p = 0.66). The difference in Tgap was only 1.4 days longer for EBRT boost, compared with implant (p = 0.51). OTT was longer by 6.1 days for EBRT (p = 0.006). Tgap and OTT were not associated with LRF. Radionecrosis was reported in 8% of boosted, compared with 0% in unboosted patients (p = 0.03). Conclusions: These results question the benefit of a radiotherapy boost after a 6-week gap. The higher doses of a boost may contribute more to an increased risk of late morbidity, rather than local control.

The effect of granulocyte colony-stimulating factor (G-CSF) on neutropenia, infection, and cytotoxic chemotherapy administration was studied in a randomized trial in patients receiving intensive weekly chemotherapy for non-Hodgkinxybs lymphoma (NHL). Eighty patients (aged 16 to 71 years) with high-grade NHL (Kiel) of any stage were randomized to receive VAPEC-B chemotherapy alone (39 patients) or with G-CSF administered as a daily subcutaneous dose of 230 micrograms/m2 (41 patients). Prophylactic ketoconazole and cotrimoxazole were administered to all patients throughout treatment. The protocol specified identical dose modification and antibiotic treatment criteria bor both groups. Neutropenia (absolute neutrophil count [ANC] less than 1.0 x 10(9)/L) occurred in 15 of 41 (37%) of the G-CSF-treated patients and in 33 of 39 (85%) of the controls, giving a relative risk for control patients of 2.31 (95% confidence interval [CI], [1.51, 3.54]; P = .00001). Fever (greater than or equal to 37.5 degrees C) with neutropenia (ANC less than 1.0 x 10(9)/L) occurred in 9 of 41 (22%) of the G-CSF group and in 17 of 39 (44%) of the controls (relative risk for control, 2.26; 95% CI [1.01, 5.06]; P = .04). There were fewer treatment delays, with shorter duration (P = .01) in patients receiving G-CSF. Chemotherapy doses were reduced in 4 of 41 (10%) of the G-CSF patients and 13 of 39 (33%) of the controls (P = .01). The dose intensity of cytotoxic chemotherapy was significantly increased in patients receiving G-CSF (median of 95% in G-CSF group compared with 83% in control patients). Three vascular deaths occurred in the G-CSF group. Delays in the control group most commonly resulted from neutropenia (19 patients, compared with 2 patients in the G-CSF-treated group, P = .000007). Severe mucositis was the major dose-limiting toxicity in G-CSF-treated patients, but did not occur more frequently than in controls (15 patients in each group). Overall, patients randomized to receive G-CSF achieved a greater dose intensity than control patients, but this did not result in significant differences in drug toxicity (other than neutropenia), intravenous antibiotic usage, or hospitalization between the two groups.

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.

There is clearly a need for a more precise definition of the effect of adjuvant therapy on long term survival and so, in November 1989, the UKCCCR launched AXIS, an international randomised trial designed to be large enough to get definite evidence about any survival benefit of intraportal 5-FU and of perioperative radiotherapy

There is strong evidence that colorectal cancer survival differs between socioeconomic groups. We analysed data on 2481 patients diagnosed during 1989-1997 and recruited to a randomised controlled clinical trial (AXIS, ISRCTN32414363) of chemotherapy and radiotherapy for colorectal cancer. Crude and relative survival at 1 and 5 years was estimated in five categories of socioeconomic deprivation. Multiple imputation was used to account for missing data on tumour stage. A multivariable fractional polynomial model was fitted to estimate the excess hazard of death in each deprivation category, adjusting for the confounding effects of age, stage, cancer site (colon, rectum) and sex, using generalised linear models. Relative survival in the trial patients was higher than in the general population of England and Wales. The socioeconomic gradient in survival was much smaller than that seen for colorectal cancer patients in the general population, both at 1 year -3.2% (95% CI -7.3 to 1.0%, P=0.14) and at 5 years -1.7% (95% CI -8.3 to 4.9%, P=0.61). Given equal treatment, colorectal cancer survival in England and Wales does not appear to depend on socioeconomic status, suggesting that the socioeconomic gradient in survival in the general population could well be due to health-care system factors.

Aims : To analyse the treatment outcome for patients with stage I and II infra-diaphragmatic Hodgkin's lymphoma. Materials and methods : A retrospective review of case notes for 33 consecutive patients treated between 1988 and 2000. Twenty-five out of 33 patients received radiotherapy alone, three out of 33 patients received minimal initial chemotherapy (MIT) (4 weeks VAPEC B) and five patients received six cycles of ChlVPP EVA hybrid chemotherapy before radiotherapy. Radiotherapy was given as a limited field in 32 out of 33 patients. Results : Twenty-seven out of 33 patients were men (82%), and the median age was 47 years. Fifteen of the 33 patients were stage IA, 15 were IIA, 1 was IB and 2 were IIB. The median follow-up was 71 months. Histological subtype was lymphocyte predominant (15/33), nodular sclerosis (11/33), mixed cellularity (4/33), lymphocyte-rich classical (1/33) and unclassifiable (2/33). The 5-year overall survival was 89% and 5-year relapse-free survival was 85%. The median time to relapse was 37 months (range 7–65 months). One out of five relapses was within the previous radiotherapy field. All five relapses had received radiotherapy alone and four were salvaged with chemotherapy. There have been four second malignancies and one patient transformed to high-grade non-Hodgkin's lymphoma. No patient has died of Hodgkin's lymphoma. Conclusions : In our cohort of patients with infra-diaphragmatic stage I and II Hodgkin's lymphoma treated with limited-field radiotherapy, no patients died from uncontrolled disease. The use of MIT may reduce the risk of relapse and obviate the need for conventional salvage chemotherapy. Late relapses may occur, and second malignancies are a cause for concern underlining the need for long-term follow-up.

Background Current consensus is that a combination of radiotherapy and chemotherapy may provide the optimal treatment for patients with unresectable rectal cancer. Raltitrexed has proven efficacy in the treatment of advanced colorectal cancer and has an acceptable toxicity profile. The aim of this phase I study was to determine the recommended dose of raltitrexed in combination with radiotherapy in patients with unresectable/recurrent rectal cancer. Patients and methods Patients were treated with radiotherapy (25 fractions at 2.0 Gy per fraction) five times per week for 5 weeks. Raltitrexed was administered on days 1 and 22 at 2.0, 2.6 and 3.0 mg/m2. Results A total of 20 patients were entered into the study. Dose-limiting toxicities were recorded in three of 20 patients following the first dose of raltitrexed; one patient at 2.6 mg/m2 (grade 3 diarrhoea, grade 3 neutropenia and grade 2 pyrexia) and two patients at 3.0 mg/m2 (one grade 3 neutropenia and one grade 4 diarrhoea). The most common non-haematological and haematological treatment-related adverse events were diarrhoea (11 of 20, two grade 3, one grade 4) and leukopenia (eight of 20, one grade 3, one grade 4), respectively. Conclusions The recommended dose of raltitrexed in combination with radiotherapy for future studies is 2.6 mg/m2.

Summary 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.

PURPOSE: To test the hypothesis that a chemotherapy regimen of relatively low toxicity and 11 weeks’ duration (doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone [VAPEC-B]) is at least as effective in terms of disease control as 6 months’ treatment with chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin (ChlVPP/EVA hybrid), which is associated with a high risk of permanent sterility. PATIENTS AND METHODS: Two hundred eighty-two patients with previously untreated Hodgkin’s disease, clinical stages I/II (plus mediastinal bulk and/or B symptoms) and clinical stages III/IV were randomized at three United Kingdom and one Italian center to receive either six monthly cycles of ChlVPP/EVA hybrid or 11 weekly cycles of VAPEC-B. After chemotherapy and a restaging evaluation, radiotherapy was administered to sites of previous bulk or residual radiographic abnormality before patients were observed off treatment. RESULTS: Further accrual to the trial was halted at the planned third interim analysis in September 1996. After a median follow-up of 4.9 years, freedom from progression (FFP), event-free survival (EFS), and overall survival (OS) are all significantly better in the population treated with ChlVPP/EVA than VAPEC-B, where the comparative 5-year results are 82% and 62% (FFP), 78% and 58% (EFS), and 89% and 79% (OS), respectively. The superiority of ChlVPP/EVA was seen in both low-risk and intermediate/high-risk patients, although subset analysis suggested that ChlVPP/EVA and VAPEC-B produce equivalent results in the best-prognosis patients (Hasenclever score ≤ 2, nonbulky disease). CONCLUSION: Apart from possibly in the best-prognosis group, where results are equivalent, ChlVPP/EVA hybrid produces significantly better FFP, EFS, and OS than VAPEC-B in patients with previously untreated Hodgkin’s disease.

In colorectal cancer, leucovorin-modulated 5-fluorouracil (5-FU) has been the mainstay of both adjuvant treatment and treatment of metastatic disease for many years. In advanced disease, response rates of 10–43% are reported; efforts to improve efficacy through schedule modification, including prolonged infusions, have led to limited success. New agents with improved efficacy, tolerability and ease of administration are required. Among the newer drugs, irinotecan and oxaliplatin are becoming established as first- and second-line treatment for advanced disease. Their novel mechanisms of action have proven to be of value in 5-FU-resistant patients. In tandem with these developments, thymidylate synthase inhibition has remained an important objective and oral fluoropyrimidines such as capecitabine and UFT (uracil plus tegafur)/leucovorin have been developed with this goal in mind. Two large, phase III studies of capecitabine in metastatic disease demonstrated objective response rates of 26.6 and 24.8%. UFT/leucovorin has also been evaluated in phase III trials, with an 11.7% response rate reported. Both agents are being evaluated in combination with oxaliplatin and irinotecan, and ultimately oral fluoropyrimidines as monotherapy or combination therapy may replace intravenous (i.v.) 5-FU as first-line treatment for metastatic colorectal cancer.

Summary Background The optimal adjuvant therapy for operable rectal cancer is likely to be a combination of radiotherapy and chemotherapy. Raltitrexed (‘Tomudex’) is a specific thymidylate synthase inhibitor with a convenient administration schedule, acceptable and manageable toxicity, radiosensitising properties, and proven efficacy in the treatment of advanced colorectal cancer. It may, therefore, offer advantages compared with standard 5-FU chemotherapy regimens used in colorectal cancer. The aim of this phase I, dose-escalation study was to determine the recommended dose of raltitrexed for use with postoperative pelvic radiotherapy in patients with rectal cancer. Patients and methods Patients with resected Dukes' stage B or C rectal cancer were treated with a combination of raltitrexed and radiotherapy (50.4 Gy at 1.8 Gy per fraction over five to six weeks). At least three patients were treated at each of three escalating raltitrexed dose levels (2.0, 2.6 and 3.0 mg/m2) once every three weeks. Toxicity was assessed by the recording of WHO adverse events and biochemistry and haematology determinations. Results A total of 22 patients entered the study, 17 of whom had Dukes' stage C disease. All three patients entered at a dose level of 3.0 mg/m2 experienced dose-limiting toxicity (DLT) (2 patients had grade 3 leucopenia and 1 patient had grade 2 leucopenia and grade 3 diarrhoea); however, only 2 of 11 patients entered at a dose level of 2.6 mg/m2 experienced DLT (1 patient had grade 4 neutropenia and 1 patient died probably due to aspiration pneumonia unrelated to treatment). The most common haematological toxic events were leucopenia (8 patients) and anaemia (6 patients). Only four haematological or biochemical toxic events were of grade 3 or 4. Other common toxicities were diarrhoea and nausea, which occurred in 15 and 9 patients, respectively. Conclusions This study demonstrates that raltitrexed can be combined with postoperative radiotherapy for treatment of patients with Dukes' stage B or C rectal cancer. The recommended dose of raltitrexed in this setting is 2.6 mg/m2 which is close to the full monotherapy dose.

3532 Background: Concurrent CRT is standard treatment for patients (pts) with SCCA. We explore tumor- and treatment-related CFS in a phase III trial (ACT II), which mandated standardised radiation fields and a uniform dose (50.4Gy in 28 daily fractions of 1.8Gy). Methods: The ACT II trial (940 pts) compared both CisP (n=468) versus MMC (n=472) combined with 5-FU/CRT, and 2 cycles of maintenance CT (Maint, n=448) versus none (No-maint, n=446). We investigated the association between CFS and baseline factors (age, sex, T stage, size of tumour, nodal status) and treatment using Cox regression. CFS events included baseline colostomies not reversed at first follow up after treatment and post-treatment colostomies. Results: Median follow-up (all pts) was 5.1 years. Median age: 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%). Of 884 evaluable patients only 20/118 (17%) baseline colostomies were reversed within 8 months, and 37 later. 112 pts had a post-treatment colostomy due to persistent disease (98) or morbidity (14). The 5-year CFS rates by stage were 86% T1, 77% T2, 57% T3 and 47% T4; 72% N0, 60% N+; by treatment arm 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/No-maint respectively. The 5-year CFS rates were 72% and 60% for N0 and N+ respectively. The most significant predictors of colostomy in multivariable Cox regression analyses were T stage, sex and baseline haemoglobin (p

Members of the transforming growth factor beta (TGF-beta family, in particular TGF-beta 1, are some of the most potent inhibitory growth factors in a variety of cell types. Resistance to TGF-beta 1-induced growth inhibition is frequently observed in colorectal carcinomas and is associated with tumour progression. Perturbations of TGF-beta 1 expression and function, therefore, may contribute to the loss of some constraints on tumour cell growth. In this study we have examined the expression of TGF-beta 1 and its precursor latency-associated peptide (LAP)-TGF-beta in human colorectal tumours using immunohistochemical techniques. In 86% of the tumours the LAP-TGF-beta complex was present in both the stromal and epithelial cells, whereas the mature TGF-beta 1 peptide was expressed in the glandular epithelium of 58.3% of these tumours. Intense staining for TGF-beta 1 was positively associated with advanced Dukes' stage. Furthermore, there was a significant correlation between the presence of TGF-beta 1 in the tumours and a shorter post-operative survival. This was most significant in a subgroup of patients who had received only a palliative operation. These results suggest that TGF-beta 1 expression may be useful as an independent prognostic indicator for a subgroup of patients who have a particularly poor prognosis. Images Figure 1 Figure 2

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.

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.

4004 Background: In the ACT I trial, relapse-free survival was improved with CRT compared to RT alone, but the CR rate at 6 weeks was similar (39% CRT, 30% RT alone; p=0.08). Most studies assessed CR between 6 and 12 weeks following completion of CRT. We investigated the association between observation of CR at 3 different time-points and progression-free and overall survival (PFS, OS), to determine the optimal time to assess this early endpoint. Methods: ACT II recruited 940 pts between 2001 and 2008. It compared, in a factorial design, CisP versus MMC when combined with 5-FU CRT, and two cycles of maintenance chemotherapy versus no maintenance. CR (complete absence of tumour and node negative) was assessed by rectal exam or imaging at 11, 18 and mandated CT at 26 weeks after the start of CRT. Median follow-up was 5 years. Pts were excluded from analysis if assessment was not done/ missing at one or more time points (n=245). Data from 695 pts were analysed. Results: Pt characteristics (all 940) median age 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N+ (32%), N0 (62%). CisP did not improve OS (HR: 0.96, p=0.89) or PFS (HR: 0.85, p=0.43) compared to MMC. This is consistent with the lack of an absolute difference at 18 and 26 weeks, but not at 11 weeks (where a difference was found). CR patients (compared to not-CR) had a significantly lower risk of progression/death. The association between these outcomes and response was strongest at 26 weeks. 202/695 (29%) pts not in CR at 11 weeks were CR at 26 weeks. Conclusions: 29% of pts not in CR at 11 weeks achieved CR at 26 weeks. Early surgical salvage would not have been appropriate for these pts. We recommend assessment at 26 weeks in future trials. [Table: see text]

4029 Background: Concurrent chemoradiation (CRT) is standard treatment for patients with squamous cell carcinoma of the anus. Although the majority of patients achieve long term disease control, locoregional failure is either detected early (failure to enter complete remission) or at a later date as locoregional recurrence. We explore the pattern and timing of disease recurrence within a phase III trial (ACT II), which mandated standardised radiation fields and doses (50.4Gy in 28 daily fractions). Methods: The UK ACT II trial recruited a total of 940 patients (2000 -2008) and compared cisplatin with mitomycin when combined with 5flurouracil CRT and two cycles of maintenance chemotherapy versus no maintenance using a factorial 2x2 design. Patient characterstics: T1/2 52%, T3/4 46%; N+ 32% N0 62%. The loco-regional response to treatment was assessed by clinical examination at 11, 18 and 26 weeks after CRT. Clinical examination was performed every two months for year 1; 3-monthly for year 2; then 6-monthly for years 3-5. CT scans of chest/abdomen/pelvis were performed at 6,12 24 months. Sites of failure were recorded on a case record form (primary site [PS], inguinal [ING], pelvic nodes [PEL], metastatic [METS]. Results: After a median follow up of 5 years, the crude pelvic failure (PF) rate is 18% (163/924). Of the 163 PF, 133 pts (82%) were pelvic only and 30 (18%) had PF + metastasis. 93% of all pelvic recurrences were detected during the first three years (54% yr 1, 26% yr 2 and 13% yr 3). The pattern was similar for PF only and PF + mets (data not shown). Only 46 (4%) of patients had [METS] as the first disease related event. 117/133 (88%) patients with PF only are evaluable for analysis of the pattern of failure., 53% occurred at the primary site (PS) only, 23% were PS + nodal (5% [ING] 13% [PEL] and 5% [ING+PEL], and 25% nodal only (6% [ING],14% [PEL] and 5% [ING+PEL]). Conclusions: The ACT II trial results with mature follow-up demonstrate a low rate of pelvic failure. Intensive follow up to detect potentially salvageable pelvic failure should be restricted to a maximum of three years in future trials as only 7% of relapses occur beyond this time point.

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.

The case history is reported of a 51-year-old man with metastatic colonic carcinoma who was receiving a continuous 5-fluorouracil infusion via a central venous catheter and who developed cardiac perforation and pericardial effusion. This complication has not previously been reported in association with continuous chemotherapy infusion.

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.

This paper describes the results of treating 74 patients with squamous cell carcinoma of the anal canal and perianal skin using interstitial radio-therapy as primary treatment. This technique does not involve irradiation of regional lymph nodes. The local control rate for patients with tumours smaller than 5 cm and with negative inguinal nodes was significantly better than for the remaining patients (64 versus 23 per cent). Only 3 of 41 patients with tumours less than 5 cm diameter had clinically significant nodes at presentation, while in 33 patients with tumours larger than 5 cm there were 6 with involved nodes at presentation. Local treatment using interstitial radiotherapy is suggested as useful primary treatment for small, node-negative carcinomas, with surgery held in reserve for failures.

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 (P0·01). There was a significant reduction in local recurrence in irradiated patients (P

Ten patients treated for ‘limited’ stage small cell lung cancer presented during follow-up with epigastric or back pain together with nausea and/or vomiting. Upper abdominal lymphadenopathy was shown to be the first symptomatic site of relapse. A single fraction of radiotherapy provided a convenient, effective form of palliation. Ultrasound scanning proved an accurate, readily available technique for the diagnosis of this form of intra-abdominal disease.

T1 and T2 relaxation times have been calculated in 30 patients with rectal carcinoma and seven patients with a fibrotic pelvic mass. The relaxation times were calculated using a multipoint iterative method with data from seven total saturation recovery and six spin-echo sequences. The results show that the calculated T1 relaxation value is a useful discriminant between carcinoma and pelvic fibrosis and should improve the detection of early tumour recurrence.

One hundred eleven patients with inoperable but limited-stage small cell lung cancer were treated with three courses of cyclophosphamide (1.5, 2.5, and 3.5 g/m2, respectively) and VP-16-213 followed by methotrexate and thoracic radiotherapy. The total duration of treatment was 3 months. Patients were included who had pleural effusions, contralateral neck nodes, and bone marrow infiltration. The complete response (CR) rate was 56%, the majority confirmed by repeat bronchoscopy, with an 81% overall response rate. The minimum follow-up was 14 months. Median survival for all 111 patients was 11 months and 14 months (1-34+) for complete responders; the median survival was also 11 months for the 91 patients with conventional limited-stage disease, although 15 of the 19 patients alive at 14 months or more were from this subpopulation. There was no significant difference in the survival of those CR patients whose response was confirmed bronchoscopically and patients whose CR was assessed only radiologically and clinically. Forty-four patients with leukopenia (less than 1000 cells/microliter) received intravenous antibiotics for malaise and suspected infection. Close monitoring between treatments and direct access of patients to the hospital was encouraged. The majority of patients improved symptomatically as assessed by Karnofsky and Respiratory scores. These results support the view that short but intensive treatment without long-term or maintenance chemotherapy is beneficial.

Serum CA 125, quantified by an immunoradiometric assay employing the monoclonal antibody 0C125 was found to be elevated in 48/58 (83%) of patients with established ovarian cancer. All histological types of carcinoma were antigen positive and there was a positive correlation between the frequency and level of serum CA125 and body burden of tumour. Twenty patients undergoing chemotherapy had serial CA125 estimations following a prospective protocol. Variation in CA125 level reflected disease progression or regression in 21/23 instances. Three of 9 patients tested showed an acute elevation of CA125 in the first week following chemotherapy and this effect predicted a good response to treatment. The natural half-life of CA125 in serum was estimated at approximately 4.8 days, sufficiently short to allow changes in tumour volume to be rapidly reflected by a change in circulating antigen level. Although none of 15 patients with non-Hodgkin lymphoma demonstrated antigen levels outside the normal range, 11/27 patients with non-ovarian adenocarcinoma showed elevated CA125 levels, a specificity of 58% for this latter group. The value of CA125 in the management of ovarian malignancy is discussed.

In 1979 and 1980 more than 4000 cases of large-bowel cancer were treated annually in the Northwest region of England. Of these, 35.5% were within 13 cm of the anal verge. The prognosis following surgery in operable rectal cancer is 30% surviving at 5 years. A large proportion of patients die with evidence of recurrent rectal cancer in the pelvis. Local recurrence appears to be associated with invasion of tumor into surrounding structures which are not removed by conventional surgery [2, 3]. Of 48 patients with locally recurrent tumour investigated by computerised axial tomography (CAT) scanning at the Christie Hospital, 38 had disease limited to structure which were in contact with the original tumour before surgery [10]. In a recent MRC study [5] 765 cases of rectal cancer were assessed before surgery. When tumour appeared to have penetrated into surrounding structures, causing some loss of mobility, it was found that local recurrence following surgery was twice as common (70% versus 37% at 5 years). Furthermore, in over 60% of the cases with tumour penetration it was felt that a complete surgical resection could not be performed. Residual tumour in surrounding structures can regrow to give recurrence.

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.

An analysis has been made of the symptomatic response and survival of 143 patients following radiotherapy for locally recurrent rectal cancer. Computerized tomography (CAT) was performed on 45 patients. Of 119 evaluable patients, 54 had a good response to radiotherapy, 29 a moderate response and 36 no apparent response. Median response was 9 and 3 months respectively in the good and moderate groups. Median survival was 15, 9 and 5 months for the three groups. Latent interval between surgery and radiotherapy appeared to be of prognostic importance. When this exceeded 2 yr median survival was 12 months compared with 7 months for patients with a latent interval of less than 2 yr. Tumour volume measured by computed tomography may have prognostic importance. Radiotherapy should be considered for most patients with symptomatic recurrence. Surgery might be combined with radiotherapy for selected groups of patients with good prognosis.