Systematic review of treatment intensification using novel agents for chemoradiotherapy in rectal cancer.

BACKGROUND: With the well established shift to neoadjuvant treatment for locally advanced rectal cancer, there is increasing focus on the use of radiosensitizers to improve the efficacy and tolerability of radiotherapy. There currently exist few randomized data exploring novel radiosensitizers to improve response and it is unclear what the clinical endpoints of such trials should be. METHODS: A qualitative systematic review was performed according to the PRISMA guidelines using preset search criteria across the PubMed, Cochrane and Scopus databases from 1990 to 2017. Additional results were generated from the reference lists of included papers. RESULTS: A total of 123 papers were identified, of which 37 were included; a further 60 articles were obtained from additional referencing to give a total of 97 articles. Neoadjuvant radiosensitization for locally advanced rectal cancer using fluoropyrimidine-based chemotherapy remains the standard of treatment. The oral derivative capecitabine has practical advantages over 5-fluorouracil, with equal efficacy, but the addition of a second chemotherapeutic agent has yet to show a consistent significant efficacy benefit in randomized clinical assessment. Preclinical and early-phase trials are progressing with promising novel agents, such as small molecular inhibitors and nanoparticles. CONCLUSION: Despite extensive research and promising preclinical studies, a definite further agent in addition to fluoropyrimidines that consistently improves response rate has yet to be found.

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.

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.

Intensity-modulated Radiotherapy for Rectal Cancer in the UK in 2020.

AIMS: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance. MATERIALS AND METHODS: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out. RESULTS: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres. CONCLUSION: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance.

Radiation, chemotherapy and biological therapy in the curative treatment of locally advanced rectal cancer.

OBJECTIVE: To review the published evidence relating to the use of radiotherapy (RT), chemotherapy and biological therapy as adjuncts to surgery in the curative treatment of rectal cancer. METHODS: Searches were carried out of the MEDLINE and CANCERLIT databases together with conference abstracts from key meetings including the American Society of Clinical Oncology Annual Meeting and Gastrointestinal Cancers Symposium and the ECCO/ESMO Multidisciplinary Congress. RESULTS: RT reduces local pelvic recurrence when used as an adjunct to surgery, even when this is performed optimally by total mesorectal excision (TME). RT is usually given as short-course preoperative radiotherapy (SCPRT) followed by immediate surgery which produces no or very little downstaging or long-course concurrent chemoradiation (CRT) followed by a 6-8 week gap prior to surgery which produces significant downstaging. The prognostic importance of achieving a clear histological circumferential resection margin is now well recognised and pathological assessment of the quality of surgery can predict long-term outcomes. Internationally there is considerable heterogeneity in the staging modalities and criteria used in deciding which approach might be used, in the reporting of histological results and in RT parameters (time/dose/fractionation/volume). Attempts to increase the potency of CRT have included the addition of concurrent chemotherapeutic and biological agents to the standard fluoropyrimidine although there is little randomised data and none with regard to long-term survival outcomes. Neither SCPRT nor downstaging CRT have been shown to reduce the rate of subsequent distant metastatic relapse which remains a significant clinical problem. The potential additional benefit of neoadjuvant or adjuvant chemotherapy in addition to SCPRT or long-course CRT remains ill-defined. Late morbidity can include bowel and sexual dysfunction, pelvic fractures and second malignancies with considerably more being known in relation to SCPRT than long-course CRT. CONCLUSIONS: Improvements in imaging, pathology and surgical technique combined with multimodality treatment using RT and chemotherapy are leading to continuing improvements in the long term outcome for patients with rectal cancer although much remains to be learnt regarding the optimum strategy for use of these in different clinical contexts and their relationship to long-term morbidity.

Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication.

The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Activities responsible for this removal have, so far, not been identified. We show that Mre11 3' to 5' exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cells.

Preoperative downstaging chemoradiation with concurrent irinotecan and capecitabine in MRI-defined locally advanced rectal cancer: a phase I trial (NWCOG-2).

BACKGROUND: The aim of this study was to investigate the safety of neoadjuvant chemoradiation using radiotherapy (RT) combined with concurrent capecitabine and irinotecan for locally advanced rectal cancer before surgery. METHODS: Forty-six patients were recruited and treated on the basis that MRI scanning had shown poor-risk tumours with threatening (< or =1 mm) or involvement of the mesorectal fascia. Conformal RT was given using 3 or 4 fields at daily fractions of 1.8 Gy on 5 days per week to a total dose of 45 Gy. Concurrently oral capecitabine was given twice daily throughout radiotherapy continuously from days 1 to 35 and intravenous irinotecan was given once per week during weeks 1 to 4 of RT. Dose levels were gradually escalated as follows. Dose level 1: capecitabine 650 mg m(-2) b.i.d. and irinotecan 50 mg m(-2); Dose level 2: capecitabine 650 mg m(-2) b.i.d. and irinotecan 60 mg m(-2); Dose level 3: capecitabine 825 mg m(-2) b.i.d. and irinotecan 60 mg m(2); Dose level 4: capecitabine 825 mg m(-2) b.i.d. and irinotecan 70 mg m(-2). RESULTS: Diarrhoea (grade 3, no grade 4) was the main serious acute toxicity with lesser degrees of fatigue, neutropenia, anorexia and palmar-plantar erythrodysesthesia. The recommended dose for future study was dose level 2 at which 3 of 14 patients (21%) developed grade 3 diarrhoea. Postoperative complications included seven pelvic or wound infections and two anastomotic and two perineal wound dehiscences. There were no deaths in the first 30 days postoperatively. Of 41 resected specimens, 11 (27%) showed a pathological complete response (pCR) and five (12%) showed an involved circumferential resection margin (defined as < or =1 mm). The 3-year disease-free survival (intent-to-treat) was 53.2%. CONCLUSION: In patients with poor-risk MRI-defined locally advanced rectal cancer threatening or involving the mesorectal fascia, preoperative chemoradiation based on RT at 45 Gy in 25 daily fractions over 5 weeks with continuous daily oral capecitabine at 650 mg m(-2) b.i.d. days 1-35 and weekly IV irinotecan at 60 mg m(-2) weeks 1-4, provides acceptable acute toxicity and postoperative morbidity with encouraging response and curative resection rates.

Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study.

BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

Preoperative neo-adjuvant therapy for curable rectal cancer--reaching a consensus 2008.

OBJECTIVE: Our aim was to determine the range of neo-adjuvant therapy the multidisciplinary team (MDT) currently offers patients with curable (M(0)) rectal cancer. METHOD: A senior oncologist from each of the four oncology centres in north Wales and the north-west of England (approximate target population 8 million - Glan Clwyd, Clatterbridge, Christie and Preston) reviewed his/her understanding of the current evidence of neo-adjuvant therapy in rectal cancer. Then a representative from each centre was asked to identify which of three neo-adjuvant options (no neo-adjuvant therapy, short-course radiotherapy 25 Gy over five fractions and long-course chemoradiotherapy) he/she would use for a rectal cancer in the upper, middle or lower third of the rectum staged by magnetic resonance imaging as being T(2)-T(4) and/or N(0)-N(2). RESULTS: In all cases of locally advanced rectal cancer (T(3a) N(1)-T(4)), oncologists from the four oncology centres recommended long-course chemoradiotherapy before rectal resection. This consensus was maintained for cases of lower third T(3a) N(0) cancers. Thereafter, the majority of patients with rectal cancer are offered adjuvant short-course radiotherapy. CONCLUSION: Neo-adjuvant therapy is less likely to be offered if the tumour is early (T(2), N(0)) and/or situated in the upper third of the rectum.

Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study.

BACKGROUND: To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy. PATIENTS AND METHODS: A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS). RESULTS: PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83-1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86-1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand-foot syndrome (4% versus < 1%) were more common with XELOX. CONCLUSION: XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

Magnetic resonance imaging in rectal cancer downstaged using neoadjuvant chemoradiation: accuracy of prediction of tumour stage and circumferential resection margin status.

OBJECTIVE: The aim was to examine the accuracy of magnetic resonance imaging (MRI) in predicting circumferential resection margin (CRM) involvement, T- and N-stage in patients with locally advanced carcinoma of the rectum, who had undergone long-course downstaging chemoradiation (CRT). METHOD: Patients with rectal cancer were selected for long-course downstaging CRT if their tumour was considered to threaten (< or = 1 mm) or involve the CRM on MRI. Eighty such patients had a repeat MRI at a median of 6 weeks post-CRT followed by surgical excision soon thereafter. The findings on the post-CRT MRI were compared with histological examination of the surgical specimen. RESULTS: For CRM involvement, post-CRT restaging MRI had an accuracy of 81% (65/80) a sensitivity of 54% (7/13), a specificity of 87% (58/67), a positive predictive value of 44% (7/16) and a negative predictive value of 91% (58/64). Accuracy for T- and N-staging was 43% (34/80) and 78% (62/80), respectively. 38% of T-stages were overstaged and 20% understaged. 4% of N-stages were overstaged and 19% understaged. The 13 patients with histological positive CRM had worse clinical outcomes than the 67 patients with negative CRM in terms of disease-free survival (relative risk of reduced DFS 4.6, P = 0.001) and overall survival (relative risk of death 3.6, P = 0.016). CONCLUSION: Magnetic resonance imaging has good specificity and negative predictive value for predicting an uninvolved CRM post downstaging CRT in locally advanced rectal cancer although sensitivity and positive predictive value for an involved CRM were unsatisfactory. The shortcomings of MRI stem from poor differentiation of viable tumour from posttreatment changes and inability to identify small nodal and tumour deposits. Clinical correlates in this group of patients have confirmed the importance of achieving a clear CRM at surgery.

RCT on gentian violet versus a hydrogel dressing for radiotherapy-induced moist skin desquamation.

OBJECTIVE: Radiotherapy-induced moist desquamation is a significant problem but there is a paucity of randomised data on which to base treatment decisions. The current prospective randomised trial compared gentian violet (GV) to a hydrogel dressing in this context. METHOD: Thirty patients undergoing radiotherapy to the head and neck region or breast who had developed moist desquamation in the radiotherapy field were randomised to treatment with 0.5% aqueous gentian violet (GV) (n=16) or a hydrogel dressing (n=14). The area of desquamation was regularly measured until healing or withdrawal from the study. RESULTS: The likelihood of healing with the hydrogel was greater than GV with a hazard ratio for healing of 7.95 (95% CI 2.20-28.68; p=0.002). The median time to healing for hydrogel was 12 days but had not been reached for GV by 30 days. Over the first 14 days the median'area under curve' of moist desquamation for GV was 82.6 cm2 (range 31.8-320.7 cm2) and that for hydrogel 20.0 cm2 (range 3.8-301.0 cm2) (difference significant at p=0.003). Ten of 16 patients treated with GV withdrew from the study (due to stinging in five and failure to heal in five) compared with two of the 14 treated with hydrogel (difference significant at p=0.021). CONCLUSION: Hydrogel dressings are more likely to heal radiotherapy-induced moist desquamation and are better tolerated than GV.

A Prospective Phase I/II Study of Docetaxel, Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3).

AIMS: This open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma. MATERIALS AND METHODS: Patients with adenocarcinoma or squamous cell carcinoma of the oesophagus or stomach, of good performance status, deemed too advanced for curative treatment, were given systematically increasing doses of 3 weekly DCC to ascertain the MTD. Phase II administered up to six cycles of DCC at the MTD, assessing response and toxicity. RESULTS: Between November 2007 and November 2012, 15 patients were recruited into phase I and 41 into phase II. The MDT was a 21 day cycle of docetaxel 60 mg/m2 IV day 1, cisplatinum 60 mg/m2 IV day 1 and oral capecitabine 1000 mg/m2 daily in two divided doses for days 1-21. The most common phase II grade 3-4 toxicities were neutropenia 88% (10% febrile neutropenia), fatigue 15%, sensory neuropathy 10% and non-neutropenic infection 10%. The overall response rate was 51%, median progression-free survival was 7.4 months (confidence interval 6.7-9.4) and median overall survival was 10.9 months (confidence interval 7.7-13.7). CONCLUSION: DCC was tolerable and feasible with promising efficacy, and may be suitable for future investigation in both first-line metastatic and neoadjuvant settings.

A Cost-Effectiveness Analysis of Contact X-ray Brachytherapy for the Treatment of Patients with Rectal Cancer Following a Partial Response to Chemoradiotherapy.

AIMS: Following chemoradiotherapy in patients with rectal cancer, the addition of contact X-ray brachytherapy (CXB) in partial responders might increase the proportion of patients with a clinical complete response (cCR) and who are thus suitable for watch and wait management. However, the long-term cost-effectiveness of this approach has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling and a Markov simulation were used to compare long-term costs, quality-adjusted life years (QALYs) and cost-effectiveness from a third-party payer (National Health Service) perspective for treatment strategies after chemoradiotherapy; watch and wait with CXB when a cCR was not initially achieved after external beam radiotherapy (EBRT) (WWCXB), watch and wait with EBRT alone (WWEBRT) and radical surgery for all patients. The effect of uncertainty in model parameters and patient demographics was investigated. RESULTS: WWCXB had a higher QALY payoff than both radical surgery and WWEBRT and was less costly in most scenarios and demographic cohorts. In all plausible scenarios, WWCXB was the most cost-effective, at a threshold of £20 000/QALY. This finding was insensitive to uncertainty associated with model parameters. CONCLUSIONS: WWCXB is likely to be cost-effective compared with both WWEBRT alone and radical surgery. These findings support the use of CXB boost as an adjunct to a watch and wait strategy.

Weekly fluorouracil at 425 mg/m(2) plus low-dose folinic acid for 24 weeks as adjuvant treatment for colorectal cancer: assessment of toxicity and delivery.

AIMS: To assess the toxicity and dose delivery of weekly bolus 5-fluorouracil (5-FU) at 425 mg/m(2) plus low-dose folinic acid (FA) for 24 weeks as adjuvant treatment for colorectal cancer. MATERIALS AND METHODS: Data were collected on toxicity and dose reductions, stoppages, delays and intensity from 100 consecutive patients receiving this adjuvant regimen after curative surgery. RESULTS: There were 53 men and 47 women (median age: 64 and 65 years, respectively); 77 patients with colon cancer and 23 with cancer of the rectum; 34 patients with Dukes' stage B and 66 with Dukes' stage C. Thirty-seven patients experienced at least one grade 3 or 4 toxicity, mainly diarrhoea (20 patients) or fatigue (14 patients). Only one grade 4 toxicity was noted (diarrhoea). In multivariate analysis, increased grade 3 and 4 toxicity was significantly associated with female gender (P = 0.001) and age >65 years (P = 0.046). Forty patients completed the 24 cycles without dose reduction or delay. Forty-one patients required at least one dose reduction. The median 'conventional' dose intensity (DI), calculated from the first cycle to the last, was 408 mg/m(2)/week (96%). The median DI over 24 weeks was 387 mg/m(2)/week (91%). A higher median 24-week DI was delivered to men (407 mg/m(2)/week, 96%) than women (361 mg/m(2)/ week, 85%; P = 0.009). Women older than 65 years showed a significantly reduced median DI over 24 weeks (347 mg/ m(2)/week, 82%) compared with men aged 65 years or younger (407 mg/m(2)/week, 96%; P = 0.049) and men older than 65 years (425 mg/m(2)/week, 100%; P = 0.001), although the difference against women aged 65 years or younger (377 mg/ m(2)/week, 89%) was not statistically significant (P = 0.09). CONCLUSION: This regimen has shown what might be considered high rates of grade 3 and 4 toxicity for an adjuvant treatment, although the delivered DI was acceptable. Caution is urged in the treatment of elderly female patients who have statistically higher rates of grade 3 and 4 toxicity and lower DI.

Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer.

Improved surgical technique plus selective preoperative radiotherapy have decreased rectal cancer pelvic local recurrence from, historically, 25% down to about 5-10%. However, this improvement has not reduced distant metastatic relapse, which is the main cause of death and a key issue in rectal cancer management. The current standard is local pelvic treatment (surgery ± preoperative radiotherapy) followed by adjuvant chemotherapy, depending on resection histology. For circumferential resection margin (CRM)-threatened cancer on baseline magnetic resonance imaging, downstaging long-course preoperative chemoradiation (LCPCRT) is generally used. However, for non-CRM-threatened disease, varying approaches are currently adopted in the UK, including straight to surgery, short-course preoperative radiotherapy and LCPCRT. Clinical trials are investigating intensification of concurrent chemoradiation. There is also increasing interest in investigating preoperative neoadjuvant chemotherapy (NAC) as a way of exposing micro-metastatic disease to full-dose systemic chemotherapy as early as possible and potentially reducing metastatic relapse. Phase II trials suggest that this strategy is feasible, with promising histological response and low rates of tumour progression during NAC. Phase III trials are needed to determine the benefit of NAC when added to standard therapy and also to determine if it can be used instead of neoadjuvant radiotherapy-based schedules. Although several measures of neoadjuvant treatment response assessment based on imaging or pathology are promising predictive biomarkers for long-term survival, none has been validated in prospective phase III studies. The phase III setting will enable this, also providing translational opportunities to examine molecular predictors of response and survival.

High dose rate intraluminal radiotherapy for carcinoma of the bronchus: outcome of treatment of 406 patients.

In April 1988 the Christie Hospital started using the microSelectron-HDR machine to deliver intraluminal radiotherapy (ILT) to inoperable bronchial carcinomas causing symptoms due to endobronchial disease. Results of treatment in the first 406 patients with primary non-small-cell carcinoma are presented. Three main categories of patient were defined. Category 1 consisted of 324 patients (79.8%) who were previously unirradiated and received a single fraction of ILT as their primary treatment, mostly to a dose of 1500 cGy (76%) or 2000 cGy (23%) at 1 cm from the centre of the iridium-192 treatment source. The percentage of these patients whose symptoms or signs were improved at 6 weeks following ILT were as follows: stridor 92%, haemoptysis 88%, cough 62%, dyspnoea, 60%, pain, 50% and pulmonary collapse, 46%. Approximately two-thirds of these patients (67.3%) derived long lasting palliation and required no further treatment during their lifetime. The other third of patients needed subsequent treatment at some stage because of recurrence of their symptoms and in this situation external beam radiotherapy (EB) or a repeat ILT treatment was effectively utilised. Category 2 consisted of 65 patients (16%) who had previously received EB but required ILT when their tumour recurred. At 6 weeks post-ILT levels of symptom palliation were broadly similar to those obtained if ILT was used in previously unirradiated individuals, although the improvement was not so well sustained with time and only 7% showed improvement in pulmonary collapse at 6 weeks. Category 3 consisted of 17 patients (4.2%) in whom ILT was used concurrently with EB as a combined initial treatment. Similar levels of palliation were seen when compared with patients who received a single ILT treatment only. Overall, ILT was well tolerated in terms of early and late morbidity. In conclusion, the efficiency of a single ILT treatment in palliating symptoms due to endobronchial tumour in previously unirradiated individuals is comparable with that reported in series where treatment for advanced lung cancer combines a prolonged course of EB concurrently with several ILT treatments.

Massive haemoptysis death and other morbidity associated with high dose rate intraluminal radiotherapy for carcinoma of the bronchus.

Four hundred and six patients with primary non-small cell carcinoma of the bronchus causing symptoms due to endobronchial disease, were treated with intraluminal radiotherapy (ILT) using the microSelectron-HDR machine at the Christie Hospital, Manchester, between April 1988 and the end of 1992. An assessment of morbidity for this treatment is presented, particularly with regard to the risk factors and causes of massive haemoptysis death. The most common early side-effect was a mild transient exacerbation of cough which usually resolved within 2-3 weeks. At various times following ILT treatment 83 bronchoscopies were carried out randomly in 55 patients. In bronchoscopies carried out within the first 3 months following ILT, no tumour was visible in 80% of cases. A mucosal radiation reaction score (RRS) was used to grade bronchoscopic appearance after ILT treatment. Overall, 55% of bronchoscopic examinations showed some degree of mucosal radiation reaction. The majority of radiation reactions from 6 months onwards after ILT demonstrated a degree of fibrosis. A radiation reaction was seen more frequently after treatment with 2000 cGy as opposed to 1500 cGy at 1 cm from the central axis of the radiation source. Thirty-two patients were identified who had died from massive haemoptysis (MH) as a terminal event. A Cox multivariate regression analysis showed that the treatment-related factors of increased dose at first ILT (P = 0.004), prior laser treatment at the site of ILT (P = 0.020) and second ILT treatment in the same location as the first ILT treatment (P = 0.047), all significantly increased the relative risk of MH death compared with their effect on the relative risk of death from other causes (OC). (In addition a fourth treatment-related factor, namely the concurrent use of ILT and external beam radiotherapy (EB) had a P value of 0.08). Twenty out of 25 assessable MH-death patients (80%) had evidence of recurrent or residual tumour before death but 5 patients (20%) did not. For surviving patients the instantancious risk of death at any one time (the cause-specific death rate expressed as deaths per 100 cases per month), showed a sharp peak for MH deaths between 9 and 12 months post ILT in contradistinction to OC death where the peak was between 3 and 6 months post ILT. These findings may imply a role for late radiation reaction in the treatment-related risk factors identified as increasing the relative risk of MH death and possible mechanisms are discussed. The results have implications for treatment regimes that use a dose of 2000 cGy at 1 cm in a single fraction technique, that have a high frequency of previous laser treatment, that use multiple, repeated ILT treatments in the same location and that use ILT concurrently with EB.

Long-term survival and symptom palliation in small primary bronchial carcinomas following treatment with intraluminal radiotherapy alone.

Between April 1988 and December 1992, 37 patients with small, previously unirradiated, primary non-small cell carcinomas of the bronchus causing symptoms due to endobronchial disease were treated at the Christie Hospital, Manchester, with a single fraction of high dose rate intraluminal radiotherapy (ILT) using the microSelectron-HDR machine. Small primary (SP) lesions were defined as being less than 2 cm in diameter in a direction perpendicular to the central axis of the iridium-192 treatment source. Fifteen patients (41%) were treated to a dose of 15 Gy and 22 patients (59%) to 20 Gy at a distance of 1 cm from the central axis of the source. At 6 weeks following ILT, improvement in symptoms was seen in the following percentages of patients: haemoptysis 96%, pulmonary collapse 69%, cough 55% and dyspnoea 52%. The magnitude of improvement in these symptoms was largely maintained in patients surviving to 4 months and then 12 months post-ILT. Median actuarial survival was 709 days, 2-year survival 49.4% and 5-year survival 14.1%. Overall, there was no significant difference in survival after treatment with 20 Gy compared with 15 Gy at 1 cm. At the close of study, there were four patients still alive without disease recurrence with survivals of 38, 48, 49 and 63 months. All had had biopsy-proven squamous cell carcinomas and all had been treated with 20 Gy at 1 cm. Five patients died from massive haemoptysis as a terminal event at 4, 9, 9, 10 and 11 months post-ILT, well below the median survival for this group of patients. Again, all had been treated with 20 Gy as opposed to 15 Gy at 1 cm. Over the same time period, 287 patients with non-small cell carcinomas of more than 2 cm in diameter (large primary lesions, LP), were treated with a single fraction of ILT only, as their initial treatment. A consistently greater percentage of patients with SP lesions showed an improvement in the symptoms of haemoptysis and pulmonary collapse when compared with patients with LP lesions. Patients with LP lesions demonstrated a decreased actuarial survival when compared with SP lesions, with median survival being 156 days, 2-year survival 3.1% and no survivors beyond 39 months. This study demonstrates that, in patients with small endobronchial carcinomas a single fraction of ILT can give efficient palliation of symptoms and lead to long term disease-free survival, but that a dose of 20 Gy may be at the limit of bronchial radiation tolerance for a single dose technique employing a high dose rate source.

Microvascular free tissue transfer in the management of squamous cell carcinoma of the tongue during pregnancy.

We describe a 36-year-old patient with a stage III carcinoma (pT2N1M0) of the tongue that presented in the second trimester of pregnancy. It was treated by primary excision and reconstruction with a free flap. To our knowledge this is the first reported case of successful microvascular free tissue transfer for oral cancer during pregnancy.