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).

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.