Management of small (T1-T2) anal margin squamous cell carcinoma: clinical outcomes following local excision alone.

AIM: Squamous cell carcinomas of the anus are normally treated with synchronous chemoradiotherapy (CRT). Small, localized anal margin tumours may be adequately treated by local excision (LE) alone. This study aims to investigate the outcomes of patients with anal margin tumours treated with LE alone, reserving the use of CRT for salvage on local recurrence (LR). METHODS: Patients with small, localized (stage I/IIA) anal margin tumours treated by LE from October 1999 to September 2018 were identified. The effect of tumour size and resection margin on LR risk was analysed. Outcomes of overall survival and disease-free survival were measured. RESULTS: Fifty-five patients with anal margin tumours were identified. Overall 5-year LR, overall survival and disease-free survival rates were 8%, 86% and 82% respectively. Of the seven LRs, five were successfully salvaged with CRT with no further recurrence and two were not fit for CRT. Resection margins in non-fragmented tumours and tumour size did not significantly influence LR risk. CONCLUSIONS: Most small, localized anal margin tumours can be adequately treated by LE alone with low LR rates. Most patients who developed LR were salvaged using CRT, with no cancer-related deaths reported.

Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer.

BACKGROUND: The SCOPE-1 study tested the role of adding cetuximab to conventional definitive chemoradiotherapy (dCRT), and demonstrated greater toxicity and worse survival outcomes. We present the long-term outcomes and patterns of recurrence. METHODS: SCOPE-1 was a phase II/III trial in which patients were randomised to cisplatin 60 mg m-2 (day 1) and capecitabine 625 mg m-2 bd (days 1-21) for four cycles +/- cetuximab 400 mg m-2 day 1 then by 250 mg m-2 weekly. Radiotherapy consisted of 50 Gy/25# given concurrently with cycles 3 and 4. Recruitment was between February 2008 and February 2012, when the IDMC recommended closure on the basis of futility. RESULTS: About 258 patients (dCRT=129; dCRT+cetuximab (dCRT+C)=129) were recruited from 36 centres. About 72.9% (n=188) had squamous cell histology. The median follow-up (IQR) was 46.2 (35.9-48.3) months for surviving patients. The median overall survival (OS; months; 95% CI) was 34.5 (24.7-42.3) in dCRT and 24.7 (18.6-31.3) in dCRT+C (hazard ratio (HR)=1.25, 95% CIs: 0.93-1.69, P=0.137). Median progression-free survival (PFS; months; 95% CI) was 24.1 (15.3-29.9) and 15.9 (10.7-20.8) months, respectively (HR=1.28, 95% CIs: 0.94-1.75; P=0.114). On multivariable analysis only earlier stage, full-dose RT, and higher cisplatin dose intensity were associated with improved OS. CONCLUSIONS: The mature analysis demonstrates that the dCRT regimen used in the study provided useful survival outcomes despite its use in patients who were largely unfit for surgery or who had inoperable disease. Given the competing risk of systemic and local failure, future studies should continue to focus on enhancing local control as well as optimising systemic therapy.

Multicentre study of short-course radiotherapy and transanal endoscopic microsurgery for early rectal cancer.

BACKGROUND: Organ-preserving treatment for early-stage rectal cancer may avoid the substantial perioperative morbidity and functional sequelae associated with total mesorectal excision (TME). The initial results of an organ-preserving approach using preoperative short-course radiotherapy (SCRT) and transanal endoscopic microsurgery (TEMS) are presented. METHODS: Patients with cT1-2N0 rectal cancers staged using high-quality MRI and endorectal ultrasonography received SCRT, with TEMS 8-10 weeks later, at four regional referral centres between 2007 and 2013. Patients were generally considered high risk for TME surgery (a small number refused TME). RESULTS: Following SCRT and TEMS, 60 (97 per cent) of 62 patients had an R0 resection. Histopathological staging identified 20 ypT0 tumours, 23 ypT1, 18 ypT2 and one ypT3. Preoperative uT category was significantly associated with a complete pathological response, which was achieved in 13 of 27 patients with uT0/uT1 disease and in five of 29 with uT2 (P = 0·010). Acute complications affected 19 patients, the majority following TEMS. No fistulas occurred and no stomas were formed. Surveillance detected four intraluminal local recurrences at a median follow-up of 13 months, all in patients with tumours staged as ypT2. Salvage TME achieved R0 resection in three patients and a stent was placed in one patient owing to co-morbidities. CONCLUSION: SCRT with TEMS was effective in the majority of patients considered high risk for (or who refused) TME surgery.

Effect of Valvular Surgery in Carcinoid Heart Disease: An Observational Cohort Study.

CONTEXT: Carcinoid heart disease (NET-CHD) is associated with the development of symptom-limited exercise capacity and high rates of morbidity and mortality. OBJECTIVE: This study sought to determine the survival, cardiac function, and functional class following surgery. DESIGN AND SETTING, AND PATIENTS: This was a retrospective observational cohort study between 2005 and 2015 at a European Centre of Excellence for Neuroendocrine Tumours, Queen Elizabeth Hospital Birmingham. England consisting of 62 consecutive patients referred to the NET-Cardiology Service. INTERVENTIONS: Subjects were assessed at referral using transthoracic echocardiography (with saline contrast) and transesophageal echocardiography, and 77% with confirmed NET-CHD underwent cardiovascular magnetic resonance imaging. Symptomatic patients with concomitant severe valvular dysfunction were referred for surgery with stable NET disease. MAIN OUTCOME MEASURE: Survival of patients with proven NET-CHD following medical and surgical treatments was measure. RESULTS: In total, 47/62 patients were diagnosed with NET-CHD. Thirty-two patients (68%) underwent surgery with bioprosthetic valve replacements in all subjects; tricuspid, n = 31; pulmonary, n = 30; mitral, n = 3; and aortic, n = 3. Four patients underwent concomitant coronary artery bypass grafting. There were 4 (13%) early post-operative deaths. One- and 2-y survival rates after surgery were 75 and 69% compared with 45 and 15% in un-operated patients. Post-operatively, functional class was improved (pre-New York Heart Association Classification [NYHA], 2.6 [0.5] vs post-NYHA, 1.7 [1.1]), P < .05, right-ventricular (RV) size was reduced (136 ml/m(2) [25] vs 71 ml/m(2) [7]; P < .01) with preserved RV ejection fraction (61% ± 9 vs 55% ± 10; P = .26). CONCLUSION: Valve surgery improved functional class and resulted in RV reverse remodelling with improved survival rates at 2 y compared with those not proceeding to operation. These data highlight the importance of close collaboration between NET clinicians, cardiology, and cardiothoracic surgery teams. Early referral can improve functional capacity but more research is needed to define the selection of appropriate candidates and randomized data are needed to define the effect of surgery on prognosis.

Patient-reported outcomes during and after definitive chemoradiotherapy for oesophageal cancer.

BACKGROUND: Limited data describe patient-reported outcomes (PROs) of localised oesophageal cancer treated with definitive chemoradiotherapy(CRT). The phase 2/3 SCOPE-1 trial assessed the effectiveness of CRT±cetuximab. The trial for the first time provided an opportunity to describe PROs from a multi-centre group of patients treated with CRT that are presented here. METHODS: Patients undergoing CRT±cetuximab within the SCOPE-1 trial (258 patients from 36 UK centres) completed generic-, disease- and treatment-specific health-related quality of life (HRQL) questionnaires (EORTC QLQ-C30, QLQ-OES18, Dermatology Life-Quality Index (DLQI)) at baseline and at 7, 13, 24, 52 and 104 weeks. Mean EORTC functional scale scores (>15 point change significant), DLQI scores (>4 point change significant) and proportions of patients (>15% significant) with 'minimal' or 'severe' symptoms are presented. RESULTS: Questionnaire response rates were good. At baseline, EORTC functional scores were high (>75%) and few symptoms were reported except for severe problems with fatigue, insomnia and eating-related symptoms (e.g., appetite loss, dysphagia, dry mouth) in both groups(>15%). Functional aspects of health deteriorated and symptoms increased with treatment and by week 13 global quality of life, physical, role and social function significantly deteriorated and more problems with fatigue, dyspnoea, appetite loss and trouble with taste were reported. Recovery occurred by 6 months (except severe fatigue and insomnia in >15% of patients) and maintained at follow-up with no differences between groups. CONCLUSIONS: CRT for localised oesophageal cancer has a significant detrimental impact on many aspects of HRQL; however, recovery is achieved by 6 months and maintained with the exception of persisting problems with severe fatigue and insomnia. The data suggest that the HRQL recovery after definitive CRT is quicker, and there is little lasting deficit compared with treatment including surgery. These data need to be compared with HRQL data from studies evaluating treatments including surgery for oesophageal cancer.

Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial.

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. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN 26715889.

Linear accelerator stereotactic radiosurgery for vestibular schwannomas: a UK series.

AIMS: To evaluate non-auditory toxicity and local control after linear accelerator stereotactic radiosurgery (SRS) for the treatment of vestibular schwannomas. MATERIALS AND METHODS: The institutional policy was to use SRS for radiologically progressing vestibular schwannomas. Case notes and plans were retrospectively reviewed for all patients undergoing SRS for vestibular schwannomas between September 2002 and June 2012. All patients were surgically immobilised using a BrainLab stereotactic head frame. The treatment plan was generated using BrainLab software (BrainScan 5.03). The aim was to deliver 12 Gy to the surface of the target with no margin. Patients with a minimum of 12 months of follow-up were included for toxicity and local control assessment. Radiological progression was defined as growth on imaging beyond 2 years of follow-up. Overall local control was defined in line with other series as absence of surgical salvage. RESULTS: Ninety-nine patients were identified. Two patients were lost to follow-up. After a median follow-up interval of 2.4 years, the actuarial radiological progression-free survival at 3 years was 100% and overall local control was also 100%. However, two patients progressed radiologically at 3.3 and 4.5 years, respectively. Twenty-one of 97 (22%) evaluable patients suffered trigeminal toxicity and this was persistent in 8/97 (8%). Two of 97 (2%) suffered long-term facial nerve toxicity (one with associated radiological progression causing hemi-facial spasm alone). One of 97 (1%) required intervention for obstructive hydrocephalus. No statistically significant dosimetric relationship could be shown to cause trigeminal or facial nerve toxicity. However, 7/8 patients with persistent trigeminal nerve toxicity had tumours in contact with the trigeminal nerve. CONCLUSIONS: SRS delivering 12 Gy using a linear accelerator leads to high local control rates, but only prospective evaluation will fully establish short-term toxicity. In this study, persistent trigeminal toxicity occurred almost exclusively in patients whose tumour was in contact with the trigeminal nerve.

Can radiobiological parameters derived from squamous cell carcinoma of the head and neck be used to predict local control in anal cancer treated with chemoradiation?

OBJECTIVES: Parameters have been derived in head and neck cancer to account for the additional biological effective dose provided by synchronous chemotherapy. The purpose of this study was to establish whether such parameters could be used to predict local control differences in anal cancer. METHODS: In anal cancer two randomised trials of radiotherapy vs chemoradiotherapy and two trials randomising between different synchronous chemotherapy regimens were identified. To predict differences in local control between the arms of the first two studies, a global value of 9.3 Gy for the chemotherapy biologically effective dose was employed. For the last two trials, values specific to differing chemotherapy schedules were derived. These values were added to the calculated biological effective dose for the radiotherapy component in order to predict local control outcomes in anal cancer trials. RESULTS: The predicted difference in local control using the global value of 9.3 Gy for the addition of synchronous chemotherapy in the trials of radiotherapy vs radiotherapy and synchronous chemotherapy was 24.6% compared with the observed difference of 21.4%. Using schedule-specific values for the contribution of chemotherapy, the predicted differences in local control in the two trials of differing synchronous chemotherapy schedules were 7.2% and 12% compared with the observed 18% and 0%. CONCLUSION: The methods initially proposed require modification to result in adequate prediction. If the decreased cisplatin dose intensity employed in anal cancer is modelled, more satisfactory predictions for such trials can be achieved. ADVANCES IN KNOWLEDGE: This revised modelling may be hypothesis generating.

Socioeconomic deprivation adversely affects survival of patients with rectal cancer.

BACKGROUND: The aim was to examine the influence of socioeconomic deprivation on stage at presentation, perioperative mortality, permanent stoma rates and overall survival in patients with rectal cancer. METHODS: Data on patient demographics, mode and stage of presentation, and short- and longer-term outcomes were extracted from a database of patients with rectal cancer. Comparisons were made after stratification into quintiles of socioeconomic deprivation. RESULTS: In total 486 patients were identified. Fewer patients from the most deprived group than from the least deprived group underwent resectional surgery (79.2 versus 93 per cent; P = 0.005). Permanent stoma rates among patients who had surgery were 40.8 and 30 per cent respectively (P = 0.110). The overall 5-year survival rate was 32.8 per cent for the most deprived compared with 64.0 per cent for the least deprived patients (P < 0.001). Respective rates for those who underwent resectional surgery were 49.9 and 72 per cent (P = 0.030). CONCLUSION: In rectal cancer, socioeconomic deprivation appears to be associated with poorer outcomes and survival. This has important implications for healthcare planning.

Use of imatinib mesylate in gastrointestinal stromal tumours: Pan-Birmingham Cancer Network experience.

AIMS: Imatinib mesylate, a selective tyrosine kinase receptor inhibitor of KIT and PDGFRalpha, is currently licensed for the treatment of unresectable or metastatic gastrointestinal stromal tumours (GISTs), which are KIT positive. Partial response rates in 65% of patients and stable disease in 20% of patients are typically seen. The aim of this study was to assess the effectiveness and toxicity of an unselected cohort of patients treated with imatinib mesylate and to compare these results with published data. MATERIALS AND METHODS: A retrospective audit of the use of imatinib mesylate in GISTs within the Pan-Birmingham Cancer Network was carried out. In total, 39 patients were identified, the first commenced imatinib mesylate in September 2001. RESULTS: The most common primary tumour sites were small intestine (19 [49%]) and stomach (12 [31%]). Initial curative resection was carried out in 21 (54%), palliative resection in three (8%) and 15 (38%) were unresectable. Of those who had curative resection, the median time to recurrence was 13 months (range 2-276). Common sites of metastases were liver (19 [49%]) and peritoneum (12 [31%]). At 24 months 70% remained on imatinib. A partial response was reported in 23 (59%), stable disease in seven (18%) and disease progression in four (10%). Five patients (13%) have yet to be reassessed at 3 months. Imatinib was well tolerated with minor side-effects; peri-orbital oedema (nine [23%]), skin rash (four [10%]), minor gastrointestinal bleed (one [3%]). No significant toxicity was documented in 18 (46%). CONCLUSIONS: The response rates achieved in this unselected cohort of patients are consistent with published data. The duration of tumour control is good, with most patients responding to imatinib mesylate for more than 2 years. Side-effects are mild and acceptable.

Chemoradiotherapy for locally advanced pancreatic cancer: a radiotherapy dose escalation and organ motion study.

AIMS: To determine the efficacy of radiation dose escalation and to examine organ motion during conformal radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Thirty-nine patients who were consecutively treated with chemoradiotherapy were studied. Fifteen patients, treated from 1993 to 1997, received 50 Gy in 20 fractions (group I). Twenty-four patients, treated from 1997 to 2003, received an escalated dose of 55 Gy in 25 fractions (group II). Intra-fraction pancreatic tumour motion was assessed in three patients using megavoltage movies during radiation delivery to track implanted radio-opaque markers. RESULTS: Improved survival rates were seen in latterly treated group II patients (P=0.083), who received escalated radiotherapy to smaller treatment volumes due to advances in verification. Worse toxicity effects (World Health Organization grade 3-4) were reported by some patients (<10%), but treatment compliance was similar in both groups, indicating equivalent tolerance. Substantial intra-fraction tumour displacement due to respiratory motion was observed: this was greatest in the superior/inferior (mean=6.6 mm) and anterior/posterior (mean=4.75 mm) directions. Lateral displacements were small (<2 mm). CONCLUSIONS: Dose escalation is feasible in pancreatic cancer, particularly when combined with a reduction in irradiated volume, and enhanced efficacy is indicated. Large, globally applied margins to compensate for pancreatic tumour motion during radiotherapy may be inappropriate. Strategies to reduce respiratory motion, and/or the application of image-guided techniques that incorporate individual patients' respiratory motion into radiotherapy planning and delivery, will probably improve pancreatic radiotherapy.

Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response.

AIMS: With the aim of improving locoregional control, the use of preoperative chemoradiotherapy (CRT) for rectal cancer has increased. A pathological complete response (pCR) is often used as a surrogate marker for the efficacy of different CRT schedules. By analysing factors affecting pCR, this analysis aims to guide the development of future trials. MATERIALS AND METHODS: Searches of Medline, EMBASE and the electronic American Society of Clinical Oncology abstract databases were carried out to identify prospective phase II and phase III trials using preoperative CRT to treat rectal cancer. Trials were eligible for inclusion if they defined: the CRT drugs, the radiation dose and the pCR rate. Phase I patients were excluded from the analysis. A multivariate analysis examined the effect of the above variables on the pCR rate and in addition the use of neoadjuvant chemotherapy, the type of publication (peer reviewed vs abstract), the year of publication and whether the cancers were stated to be inoperable, fixed or threatening the circumferential resection margin were included. The method of analysis used was weighted linear modelling of the pCR rate. RESULTS: Sixty-four phase II and seven phase III trials were identified including a total of 4732 patients. Statistically significant factors associated with pCR were the use of two drugs, the method of fluoropyrimidine administration (with continuous intravenous 5-fluorouracil being the most effective) and a higher radiotherapy dose. Although the use of two drugs was associated with a higher rate of pCR, no single schedule seemed to be more effective. None of the other factors analysed significantly influenced pCR. CONCLUSIONS: A higher rate of pCR is seen in studies using two drugs, infusional 5-fluorouracil and a radiotherapy dose of 45 Gy and above.

Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials.

Pathological complete response (pCR) has been used as a marker for the efficacy of pre-operative chemoradiotherapy (CRT) schedules in rectal cancer. To date there have been no randomized trials comparing CRT regimens in rectal cancer. Prospective phase II and CRT arms of randomized trials reported up to January 2004 were included, providing they defined the following minimum variables: drugs employed during CRT, radiotherapy dose and pCR rate. Multivariate analysis was used to examine the relationship of these variables on the pCR rate. In addition, the use of neoadjuvant chemotherapy, the type of publication (peer reviewed vs meeting abstract) and whether the tumours were stated to be unresectable/clinically fixed or to have threatened circumferential margins were investigated. The method of analysis was weighted linear modelling of the pCR rate which was normalized by the arcsine transformation. Phase II and phase III trials were identified including a total of 3157 patients. On multivariate analysis only the use of continuous infusion 5FU (p = 0.01), the use of a second drug (p = 0.001) and radiation dose (p = 0.02) were associated with higher rates of pCR. The use of a two drug regimen, the mode of delivery of 5FU and the radiation dose appear to be related to the incidence of pCR following CRT for rectal cancer. These results may generate hypotheses for future randomized trials. Important factors not considered in this analysis include the variability in pathological examination and in the time interval between CRT and surgery. In addition, the toxicity of the CRT regimens requires further investigation.

Review of second-line chemotherapy for advanced gastric adenocarcinoma.

Palliative chemotherapy has been shown to improve survival compared with best supportive care alone in patients with unresectable or recurrent gastric cancer. However, patients receiving chemotherapy eventually develop progressive disease. At this stage, no standard second-line chemotherapy can be offered. No randomised-controlled trial data suggest a benefit of second-line chemotherapy compared with supportive care alone. We review the published data concerning the use of second-line chemotherapy in gastric adenocarcinoma. Response rates to second-line therapy in phase II trials are similar to those seen for other cancers that are more commonly retreated. In addition, data suggest that patients who respond to second-line therapy consistently survive longer compared with non-responders, and, perhaps more importantly, symptomatic benefit may be obtained from second-line therapy.

Multicentre prospective audit of surgical outcomes and acute complications following short course pre-operative radiotherapy for resectable rectal cancer.

BACKGROUND: The addition of short course pre-operative radiotherapy to total mesorectal excision reduces local recurrence in resectable adenocarcinoma of the rectum. In a previous retrospective study potential factors associated with early complications following this combination were identified. The aim of this study was to examine these relationships in a prospective multicentre audit. METHODS: One hundred and seven patients who received short course pre-operative radiotherapy in four cancer centres between 1 October 2001 and 30 September 2002 were included. Data including patient age, radiotherapy field length, overall treatment time, operation type, surgical outcomes and complications occurring within 3 months of the 1st day of radiotherapy were collected. These were compared and combined with the previously studied cohort of 176 patients treated at one centre between 1st January 1998 and 31st December 1999. RESULTS: In the prospective cohort only patient age (P=0.001) was significantly associated with acute complications. However, both the overall treatment time (median 9.0 vs 11.0 days P <0.0001) and field length (median 16.6 vs 17.0 cm P=0.03) were significantly shorter in this cohort when compared to the previous retrospective study. In patients from both studies (n=283), increasing age (P=0.002) and field length (independent of operation type) (P=0.02) were independently associated with an increased risk of acute complications. CONCLUSIONS: This study suggests that meticulous selection of patients for short course pre-operative radiotherapy and smaller planning target volumes may be associated with a lower risk of acute complications. The use of MRI scanning to stage pelvic disease may reduce the number of patients with R1 resections receiving short course pre-operative radiotherapy.

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer.

A randomised phase III trial of MVAC (methotrexate, vincristine, doxorubicin, cisplatin) vs gemcitabine and cisplatin (GC) (G 1000 mg m(-2) days 1, 8, and 15 plus C 70 mg m(-2) day 2, q 4 wks) indicated GC had similar efficacy and lower toxicity (JCO 2000). Significant haematologic toxicities in the GC arm occurred on day 15, necessitating dose adjustments in 37% of cycles. We conducted a phase I/II dose escalation trial using GC on a 21-day cycle, with G and C split between days 1 and 8. The objective of the study to define maximum-tolerated dose and dose-limiting toxicity (DLT), objective response rate, and overall survival. In all, 32 patients with locally advanced, relapsed, or metastatic disease received: dose level 1, G/C 1000/35; level 2, 1100/35; level 3, 1200/35; level 4, 1200/45 mg m(-2) (G and C given on days 1 and 8 every 3 wks). A total of 19 patients had glomerular filtration rate <60 ml min(-1) and 19 patients had metastatic disease. Dose-limiting toxicity was haematologic (grade 4 thrombocytopenia) at dose level 2. Of 151 cycles, at day 15, platelets were <100 in 61 cycles; neutrophils <0.5, platelets <50 in 26 cycles. Only seven cycles were deferred due to haematological toxicity; four for renal toxicity (chemotherapy instituted posthydration). Overall response rate was 65.5% on an intention-to-treat analysis (75% [21/28] for assessable patients), with four complete responses (12.5%) and 17 partial responses (53%). After the median follow-up of 17.2 months (range 13.1-32.4 months), 12 patients remain alive. The overall median survival was 16 months (range 10.1-26.6 months). G plus C every 3 weeks is active and well tolerated in an outpatient setting, even in patients receiving prior platinum-based regimens and with poor renal reserve.

Late toxicity after short course preoperative radiotherapy and total mesorectal excision for resectable rectal cancer.

AIMS: The late toxicity of short-course preoperative radiotherapy (SCPRT) after total mesorectal excision (TME) in resectable rectal cancer has not been adequately documented. The acute toxicity in a series of 176 consecutive patients has been previously reported. In this study, the late toxicity in the same cohort is presented. MATERIALS AND METHODS: Side-effects occurring more than 3 months after the start of SCPRT were graded using the EORTC/RTOG late radiation toxicity system. We performed multivariate analysis to identify associated factors. RESULTS: Of 176 patients, 15 died within 3 months of SCPRT and five patients were lost to follow-up. One hundred and fifty-six patients were assessable at a median follow-up interval of 41 months: severe (grade 3-4) toxicity was seen in 20 patients (13%), of which 13 were gastrointestinal (8%); three urological (2%); three thromboembolic (2%), and one musculoskeletal (1%). On multivariate analysis, abdomino-perineal (AP) resection (P < 0.02) was associated with a lower risk of grade 3-4 toxicity. CONCLUSIONS: In this retrospective study, the rate of late grade 3-4 toxicity after SCPRT and TME was 13%. Although AP resection seems to be associated with a lower incidence of late toxicity, this could be counterbalanced by the impact of a stoma on quality of life. These factors should be considered when determining the optimal management of resectable rectal cancers.

Impaired postoperative neutrophil leucocytosis and acute complications following short course preoperative radiotherapy for operable rectal cancer.

AIM: Postoperative mortality following total mesorectal excision is increased if this is performed more than 3 days after the completion of short course preoperative radiotherapy. Suppression of neutrophil leucocytosis which is normally seen following surgery has been a suggested reason. This study was to determine the relationship between postoperative complications and perioperative neutrophil counts. METHOD: A database of 176 patients treated at a single radiotherapy centre in 1998 and 1999 was used. A two-sample Wilcoxon test was used to compare preoperative neutrophil counts, postoperative neutrophil counts and their ratio in patients with and without complications. RESULTS: There was no association between acute complications and preoperative (P = 0.25) or postoperative (P = 0.45) neutrophil count. The post/preoperative ratio was significantly higher in patients without complications (median 1.61 vs 1.16, P = 0.02). CONCLUSIONS: There appears to be an inverse relationship between the magnitude of postoperative neutrophil leucocytosis and the risk of acute complications following short course preoperative radiotherapy.

Retrospective study of acute toxicity following short-course preoperative radiotherapy.

BACKGROUND: The use of short-course preoperative radiotherapy (25 Gy in five fractions over 1 week) in resectable rectal cancer reduces local recurrence but is associated with an increased risk of postoperative complications and late toxicity. This study aimed to identify those patients who are unlikely to benefit from short-course preoperative radiotherapy and the factors associated with acute toxicity. METHODS: All patients who received short-course preoperative radiotherapy at a university hospital in 1998 and 1999 were included in this retrospective study. The association between complications occurring within 3 months and patient demographics, radiotherapy technique, surgical details and overall treatment time (OTT) was assessed by univariate and multivariate analysis. RESULTS: The mortality rate at 30 days was 6 per cent in the 177 patients identified. Thirty-seven per cent of patients had either Dukes' A tumours, surgically incurable disease or positive circumferential margins. One or more complications occurred in 38 per cent of patients. On multivariate analysis an OTT of more than 13 days (P = 0.03), age (P = 0.02) and length of the radiotherapy field (P = 0.05) were associated with an increased risk of complications. CONCLUSION: Surgery within 1 week of completing short-course preoperative radiotherapy improved preoperative staging and use of an optimal radiotherapy technique will result in fewer patients at risk of acute toxicity.

The use of chemoradiotherapy in oesophageal cancer.

The results of treatment for oesophageal carcinoma remain poor and few patients are curable by surgery alone. The use of chemoradiotherapy (CRT) given as a definitive treatment or in combination with surgery may improve locoregional control and survival, when compared with radiotherapy or surgery alone. Using the keywords "chemoradiotherapy" and "radiochemotherapy", a Medline-based literature review (1980-2001) was performed. Additional literature was obtained from original papers and published meeting abstracts. Two-year survival rates of 28-72% in squamous cell carcinoma and 14-29% in adenocarcinoma from definitive CRT were reported. This is comparable to results achievable by surgery alone. The use of preoperative CRT followed by surgery may further improve survival, but current data are insufficient to justify this approach within routine clinical practice. Acute treatment-related toxicity is increased with CRT. In selected patients with localised unresectable oesophageal cancer, definitive CRT is recommended. There are uncertainties about the role of routine surgery following CRT in patients with resectable disease. For the future, the pretreatment staging of patients needs to be improved and standardised, the optimal CRT regimen needs to be defined and the role of predictive markers for CRT response needs to be developed.