Organ and Function Preservation in Gastrointestinal Malignancies.

Radiation plays an important role in organ preservation for gastrointestinal malignancies, with a watch and wait strategy enabling surgery to be avoided in patients who are not suitable or who are refusing surgery. Brachytherapy boost allows the radiation dose to be escalated, which plays a pivotal role in the successful outcome of achieving organ preservation. Here we describe the role of brachytherapy in two common gastrointestinal malignancies (oesophagus and rectum). Their indications and how the brachytherapy procedures are carried out, together with the dose and fractionation commonly used are discussed. The use of brachytherapy needs to be included in the training curriculum at all academic centres so that its use is developed by the newer generation of radiation oncologists. Its current non-use due to bias, lack of training and availability is no longer justified, given the overwhelming published evidence for the role of brachytherapy to improve organ preservation for both radical treatment and palliation in gastrointestinal malignancies.

A cohort study of local excision followed by adjuvant therapy incorporating a contact X-ray brachytherapy boost instead of radical resection in 180 patients with rectal cancer.

AIM: Recent data have suggested near-equivalent oncological results when treating early rectal cancer by local excision followed by radio- ± chemotherapy rather than salvage radical surgery. The aim of this retrospective study was to assess the use of contact X-ray brachytherapy within this paradigm. METHOD: All patients had undergone local excision and were referred to our radiotherapy centre for treatment with contact X-ray brachytherapy. Postoperative (chemo)radiotherapy was also given in their local hospital in most cases. Variables assessed were local excision method, postoperative therapy received, follow-up duration, disease-free survival, salvage surgery and stoma-free survival. RESULTS: In total, 180 patients with a median age of 70 (range 36-99) years were assessed. Following local excision, pT stages were pT1 = 131 (72%), pT2 = 44 (26%), pT3 = 5 (2%). All patients received contact X-ray brachytherapy boosting at our centre and, in addition, 110 received chemoradiotherapy and 60 received radiotherapy alone. After a median follow-up of 36 months (range 6-48), 169 patients (94%) remained free of local recurrence. Of the 11 patients with local recurrence (three isolated nodal), five underwent salvage abdominoperineal excision. Eight patients developed distant disease, of whom five underwent metastasis surgery. At last included follow-up 173 (96%) patients were free of all disease and 170 (94%) were stoma free. CONCLUSIONS: Contact therapy can be offered in addition to external beam radio (±chemo) therapy instead of radical surgery as follow-on treatment after local excision of early rectal cancer. This combination can provide equivalent outcomes to radical surgery. The added value of contact therapy should be formally assessed in a clinical trial.

Contact X-ray Brachytherapy as an Adjunct to a Watch and Wait Approach is an Affordable Alternative to Standard Surgical Management of Rectal Cancer for Patients with a Partial Clinical Response to Chemoradiotherapy.

AIMS: Emerging evidence suggests that contact X-ray brachytherapy (CXB) may increase the clinical complete response rate and durability when administered after standard chemoradiotherapy in patients with rectal cancer. The addition of CXB in partial responders is therefore probably cost-effective. The affordability of widening access to CXB in the UK, however, has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling with Monte Carlo simulation was used to evaluate long-term costs for the management of patients with rectal cancers who were given a CXB boost when a clinical complete response was not initially achieved following chemoradiotherapy in order to facilitate a watch and wait approach. A third-party payer (National Health Service) perspective was adopted, probabilistic sensitivity analysis was carried out and a scenario analysis was performed to investigate the effect of the number of referral centres and number of patients treated with CXB. RESULTS: We estimate that 818 (95% confidence interval 628-1021) patients per year are eligible for CXB as an adjunct to a watch and wait approach in England and Wales. As this management is less costly than surgical management for each individual patient, the more patients treated, the more affordable the technology. Even if as few as 125 patients are treated nationally in 15 centres, the cost of implementing this technology would be less than £4 million. If the average number of patients treated in each centre is 30, this technology would be cost saving within 5 years. CONCLUSIONS: The cost of CXB is not prohibitive according to the National Institute for Health and Care Excellence threshold for implementation of new technology and may even be cost saving within 5 years compared with standard surgical management, depending on the uptake of the technology and the number of referral centres.

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.

Contact radiotherapy boost in association with 'watch and wait' for rectal cancer: initial experience and outcomes from a shared programme between a district general hospital network and a regional oncology centre.

AIM: Recent data have highlighted the potential of more intensive neoadjuvant protocols to increase and sustain the rate of complete response in rectal cancer managed nonoperatively. This study aimed to review the outcome of all patients from our district general hospitals network who had received standard neoadjuvant therapy and were additionally referred to a centre of excellence for contact X-ray brachytherapy or high-dose-rate brachytherapy boost. METHOD: A retrospective, chart-based review of all patients co-managed in this manner was performed. Patient details were retrieved from a prospectively maintained departmental database. Indications for treatment, patient outcome and serial data from follow-up clinical and radiological assessment were analysed. RESULTS: Seventeen patients treated over a 6-year period were identified. Median follow-up was 20 (5-54) months. Fourteen patients were clinically staged as T2 or T3 and eight were clinically node positive. Three patients died, of whom only one was initially a surgical candidate but refused an exenteration. Of the 14 patients who remain alive, 11 (79%) have a sustained complete (n = 8) or partial (n = 3) response. Two patients had an incomplete response, one is being palliated and the other awaits salvage surgery. One patient underwent abdominoperineal excision for suspected local recurrence. Currently 13 (93%) surviving patients are stoma free. CONCLUSIONS: This series shows that the addition of a radiotherapy boost offered sustained responses and stoma-free survival even in advanced disease and adverse patient populations whilst providing the majority of care closer to home.

Can increasing the dose of radiation by HDR brachytherapy boost following pre operative chemoradiotherapy for advanced rectal cancer improve surgical outcomes?

AIM: Preoperative radiotherapy has been shown to improve local control in advanced rectal carcinoma compared with surgery alone. Several large randomized trials have confirmed that chemoradiotherapy (CRT) is better than radiotherapy alone. This pilot study was designed to increase the radiation dose using high-dose rate (HDR) brachytherapy boost following preoperative CRT to evaluate whether this strategy improves the outcome of surgery without increase in toxicity. METHOD: Since October 2004, we have used the new rectal HDR applicator for brachytherapy boost in 68 patients following CRT. The patients had CT and MRI Scans as part of staging. All had locally advanced disease either bulky low T2 or T3 with threatened circumferential resection margin and multiple suspicious lymph nodes. They were offered preoperative CRT either by 5-FU infusion 1 g/m(2) day 1-4 (week 1 + 5) or by oral capecitabine 825 mg/m(2) Monday-Friday for 5 weeks together with CT planned external beam RT 45Gy in 25 fractions over 5 weeks (CRT). Those downstage on repeat MRI scan were offered additional HDR Boost 10Gy directly to the tumour followed by surgery 6-8 weeks later [group A]. Four patients proceeded directly to surgery but because of involved resection margin had a HDR brachytherapy boost as postoperative treatment [group B]. Thirty patients were not planned for immediate surgery after CRT and brachytherapy boost, as they were either elderly or considered high risk for anaesthesia [group C]. RESULTS: There were 34 patients (median age 67 (range 39-81) years in group A, including 24 men). The PS was 0-1. The clinical stage at presentation was cT2 in five, cT3 in 23 and T4 in six patients and cN0 in 2, cN1 in 21 and N2 in 11. Thirty-three patients had CRT, and one had radiotherapy alone. All patients completed treatment without interruption. Twenty-nine patients had surgery following CRT and brachytherapy boost including anterior resection in 10 patients, Abdominoperineal excision (APR) in 18 and Hartmann's resection in one. Five patients did not have the intended surgery. Twenty-four (83%) patients had an RO resection compared with 63% having conventional preoperative CRT using bolus 5FU regimes. Pathological complete remission (pCR) was achieved in 9 (31%) compared with 12% patients having conventional CRT. There was no increase in G 3-4 toxicity from RT and no delay in wound healing or increase in anastomotic leakage. One of the four patients in group B developed local recurrence. The thirty patients in group C who had modified radical CRT followed by brachytherapy boost as a definitive treatment will be reported in a further communication. CONCLUSION: Increasing the dose of radiation by HDR brachytherapy boost appears to improve the RO resection and pCR rates compared with conventional CRT. The follow up is too short to judge its effect on disease-free survival. This study will be extended to compare this strategy in a randomized phase III trial with conventional CRT in patients who are not fit for more intensive CRT (HERCULES).

Preoperative chemoradiotherapy for rectal cancer: a comparison between intravenous 5-fluorouracil and oral capecitabine.

INTRODUCTION: Capecitabine provides an attractive alternative to intravenous (IV) 5-flourouracil (5-FU) in chemoradiation regimes for rectal cancer by avoiding the need for intravenous access and inpatient stay. We aimed to compare retrospectively the efficacy of concurrent capecitabine with IV 5-FU in preoperative pelvic chemoradiation schedules for rectal cancer in our centre. METHOD: Patients treated from January 2005 to June 2007 were included. Information was collected on patient characteristics; treatment details; pathological response to treatment; recurrence and survival. All statistical analyses were performed using SPSS V17. RESULTS: All patients had pelvic radiation. Ninety-nine patients were treated with capecitabine and 97 with 5-FU. The two groups were well matched for age, sex and TNM stage. There were significantly more PS (performance status) 0 patients in the capecitabine group (51%vs 30%) (P = 0.001). Of the 99 patients in the capecitabine group, 91 (92%) were able to undergo surgery with 84 (93%) achieving R0 resection. In the 5-FU group, these proportions were 87 (90%) and 70 (80%). The difference in the rate of R0 resection was statistically significant (P = 0.024). The APR rate was 35% in the capecitabine group compared with 47% in the 5-FU group (P = 0.06). There was no significant difference in pathological complete response (pCR) rates between capecitabine (14%) and 5-FU(12%). A higher pCR rate (30%) was observed in patients who underwent a brachytherapy boost (P = 0.051). There were three local recurrences in the whole patient group, (capecitabine 1; 5-FU 2). Thirty-five patients had distant metastases, 14 in the capecitabine and 21 in the 5-FU group. There was no significant difference in the risk of recurrence between the two groups. Six patients in each group had grade 3 toxicity with diarrhoea being more common with capecitabine. CONCLUSIONS: Preoperative chemoradiotherapy with capecitabine for rectal cancer is efficacious and comparable to 5-FU (IV). It is more convenient, is well tolerated and avoids the need for inpatient admission.

Whither papillon? Future directions for contact radiotherapy in rectal cancer.

Although contact radiotherapy was developed 70 years ago, and is highly effective with cure rates of over 90% for early rectal cancer, there are few centres that offer this treatment today. One reason is the lack of replacement of ageing contact X-ray machines, many of which are now over 30 years old. To address this problem, the International Contact Radiotherapy Evaluation (ICONE) group was formed at a meeting in Liverpool in 2005 with the aim of developing a new contact X-ray unit and to establish clinical protocols that would enable the new machine to safely engage in the treatment of rectal cancer. As a result of these efforts, a European company is starting production of the new Papillon RT-50 machine, which will be available shortly. In addition, the ICONE group is planning an observational study on contact X-ray and transanal endoscopic microsurgery (CONTEM) for curative treatment of rectal cancer. This protocol will ensure standardised diagnostic procedures, patient selection and treatment in centres across the world and the data will be collected prospectively for analysis and audit. It is hoped that the CONTEM trial will provide the scientific evidence that is needed to obtain a broader acceptance of local contact radiotherapy as a treatment option for selected cases with early stage rectal cancer.

High dose rate brachytherapy as a boost after preoperative chemoradiotherapy for more advanced rectal tumours: the Clatterbridge experience.

In a systemic review of 8507 patients from 22 randomised trials, radiotherapy has been shown to reduce the risk of local recurrence and death from rectal cancer compared with surgery alone. Recent large randomised trials confirmed that chemoradiotherapy was better than radiotherapy alone. Contact radiotherapy as a boost after external beam radiotherapy (without chemotherapy) has also been shown to improve local control and sphincter preservation in the Lyon 092 trial. Brachytherapy has now been used as preoperative treatment for rectal cancer and showed similar results. The Swedish and Dutch trial results of short-course preoperative radiotherapy have shown improved local control in favour of the radiotherapy group. Similar to the Scandinavian group, investigators from McGill University in Montreal adopted a short course using brachytherapy instead of external beam radiotherapy. However, surgery was delayed for 4-8 weeks to achieve downstaging. The radiation dose was delivered directly on to the tumour and the surrounding normal tissues were spared the effects of radiation. This approach has been shown to reduce the side-effects seen with external beam short-course radiotherapy, but maintains the benefit of improved local control. The Danish group used brachytherapy as a boost after external beam chemoradiotherapy for more advanced rectal tumours and have shown improved pathological complete remission and R0 resection rates. The Mount Vernon group used a similar rectal applicator for inoperable rectal cancer patients and achieved good local and symptom control. The brachytherapy group at Clatterbridge used the same approach as the Danish group, but reduced the external beam radiotherapy dose and increased the brachytherapy dose to lower the side-effects. All 16 patients (100%) had R0 resection compared with 63% with conventional preoperative chemoradiotherapy using a bolus 5-fluorouracil regimen. Pathological complete remission was achieved in seven (44%) patients compared with 2-12% with conventional chemoradiotherapy. There was no increase in grade 3-4 toxicity from radiotherapy and no delay in wound healing or anastamotic leakage. The inclusion of high dose rate brachytherapy seems to increase the pathological complete remission rates and improves the R0 resection rates with no detriment to the side-effects as the increased dose of radiation from the high dose rate boost is confined mainly to the tumour. This treatment may be particularly suitable for elderly patients where intensive chemoradiotherapy regimens are not suitable. Several trials are planned to define the role of preoperative high dose rate brachytherapy in rectal cancer and the results are awaited with interest.

Combined modality treatment of early rectal cancer: the UK experience.

With the introduction of colorectal screening in the UK, more patients will probably be diagnosed with early rectal cancer. The UK has an increasingly elderly population and not all patients diagnosed with early rectal cancer will be suitable for radical surgery. Therefore, a national plan is needed to develop the provision of alternative local treatment with equity of access across the country. Here we review the Clatterbridge Centre for Oncology multimodality treatment policy, which has been in clinical practice since 1993 and we discuss its rationale. Clatterbridge is the only centre in the UK offering Papillon-style contact radiotherapy. In total, 220 patients have been treated over 14 years, most of whom were referred from other centres. One hundred and twenty-four patients received Papillon (contact radiotherapy) as part of their multimodality management. The guidelines of the Association of Coloproctology of Great Britain and Ireland recommend local treatment for T1 tumours<3 cm in diameter, but this refers to treatment by surgery alone. There are no published national guidelines for radiotherapy. We plan each treatment in stages and achieve excellent local control (93% at 3 years) with low morbidity. We conclude that radical local treatment for cure can be offered safely to carefully selected elderly patients. Close follow-up is necessary so that effective salvage treatment can be offered. Because of a lack of randomised trial evidence, at present local radiotherapy is not yet accepted as an alternative option to the gold standard surgical treatment. Even with international collaboration, a randomised trial will be difficult to complete as the number of cases requiring local radiotherapy is small due to the highly selective nature of the treatment involved. However, an observational phase II trial is planned. In addition, the Transanal Endoscopic Microsurgery Users Group is also planning a phase II trial using preoperative radiotherapy. These studies will provide evidence to help establish the true role of radiotherapy in early rectal cancer.

Salvage surgery after inadequate combined local treatment for early rectal cancer.

The outcome of salvage surgery after failed local treatment of early rectal cancer is crucial because it determines the overall survival and therefore influences the initial choice of local therapy. The published results of salvage surgery are controversial and unclear. We treated 220 patients with early rectal cancer between 1992 and 2007 and report our experience of salvage surgery. There was an overall salvage rate of 68% (30/44) and a salvage cure rate of 87% (26/30). Immediate surgical salvage was carried out for incompletely eradicated local disease no longer than 6 months after the completion of treatment and had an 87.5% (21/24) salvage rate with a 90% (19/21) cure rate. Delayed salvage was carried out when local recurrence occurred after an apparent cure was sustained for at least 3 months and was undertaken in nine of 11 (82%) patients with local recurrence alone with an 86% (6/7) cure rate for salvage surgery. These data suggest that salvage surgery is effective management after failed local treatment. These high cure rates may reflect the fact that local recurrence is usually intraluminal after multimodality treatment, as initially involved lymph nodes are often sterilised. Follow-up after initial local treatment must be thorough and intensive, particularly during the first 3 years, in order to identify patients who are suitable for salvage and to enable prompt surgery.