Radiother Oncol 2024;199: doi.org/10.1016/j.radonc.2024.110465

Highlight brachytherapy papers: interview with Nguwah Than, first author

What was your motivation for initiating this study?

We initiated this study to investigate whether there was any benefit associated with starting non-surgical treatment with contact X-ray brachytherapy (CXB) rather than with external beam radiotherapy (EBRT) for selected rectal cancer patients who had small tumours (≤3cm). Various sequences of treatment that have involved EBRT followed by CXB and vice-versa have previously been used in non-randomised settings. The recent organ preservation in early cT2-cT3 rectal adenocarcinoma (OPERA) phase-3 randomised controlled trial demonstrated an impressive three-year organ preservation rate in patients who started with CXB (97%) compared with those who began with EBRT (68%) [1]. However, in this trial, CXB was used as the initial treatment modality only for small tumours (≤3cm), while upfront EBRT was used for larger tumours (>3cm). This left a gap in the evidence regarding the optimal treatment sequence of CXB and EBRT for small tumours (<3cm). Therefore, we aimed to compare the oncological outcomes of these two treatment approaches specifically in patients who had operable, early-stage, small rectal cancers (≤3cm in diameter).

What were the main challenges during the work? 

Our main challenge was the analysis of outcomes in a non-randomised retrospective cohort that had been treated over the past 16 years. Unsurprisingly, our records contained some missing data, making it difficult to account for unobserved differences and potential confounders, even after propensity-matching analyses. Additionally, the CXB-first group was heterogeneous: one-third of patients completed a full CXB course followed by EBRT, while two-thirds received a split course of treatment (one to three CXB fractions, then EBRT, with additional CXB for residual disease). We combined these two cohorts into the CXB-first group, due to the relatively small number of participants in each subgroup, which may have biased the evaluation of treatment outcomes.

Another challenge was ensuring we included all suitable patients in our study. Patients were referred to one of four CXB centres by local multidisciplinary teams across the UK. These teams had the choice of starting with EBRT or referring for upfront CXB. Moreover, patients who achieved complete clinical response after neoadjuvant (chemo)-radiation alone were followed up locally through a ‘watch and wait’ approach. We could not capture all these potential patients in our study because they were never referred to the Clatterbridge Cancer Centre and were not registered in our database. This may have caused the outcomes of our research not to reflect the full picture.

What are the most important findings of your study?

Our study found that starting with CXB rather than upfront EBRT in patients who had small rectal tumours (≤3cm) achieved a significant improvement in three-year overall survival rate (85% vs. 77%, p = 0.02, [HR: 0.58 (95% CI: 0.37-0.91)]). However, no significant differences were observed in local tumour control (12% vs. 18%, p = 0.47), distant relapse (6% vs. 10%, p = 0.53), three-year organ preservation (75% vs. 70%, p = 0.20, [HR: 0.66 (95% CI: 0.35-1.26)]), or disease-free survival rates (82% vs. 78%, p = 0.17, [HR: 0.47 (95% CI: 0.16-1.38)]). A higher rate of post-treatment self-limiting rectal bleeding was also reported in patients who started with CXB (grade 1 (26% vs. 15%) and grade 2 (6% vs. 3%)) (p = 0.08 ).

What are the implications of this research?

Our study suggests that starting treatment of small rectal cancers (≤3cm) with CXB rather than EBRT is linked to an improved overall survival rate, although it carries a higher risk of G1/2 late rectal bleeding. These findings partially align with emerging evidence from other recent studies. Notably, a new guideline from the French National Society of Gastroenterology now recommends CXB as the first-line treatment for cT2N0M0 rectal cancers that measure ≤3cm [2]. Therefore, findings from our study support the development of a definitive protocol, in which treatment is started with CXB followed by EBRT, for patients who have early-stage small rectal cancers (≤3cm) and who wish not to undergo surgery or are not fit enough to face a surgical approach.

Nguwah Than

References

1. Gerard, J.P., Barbet, N., Schiappa, R. et al., Neoadjuvant chemoradiotherapy with radiation dose escalation with contact x-ray brachytherapy boost or external beam radiotherapy boost for organ preservation in early cT2–cT3 rectal adenocarcinoma (OPERA): a phase 3, randomised controlled trial. The Lancet Gastroenterology & Hepatology, 2023. 8(4): p. 356-367. https://doi.org/10.1016/S2468-1253(22)00392-2

2. French National Society of Gastroenterology, Diseases and cancers of the digestive system. Rectal Cancer, 2023. Available from: https://www.snfge.org/tncd/cancer-du-rectum [accessed 5 September 2023].