Short Course Radiotherapy in Treatment of Rectal Cancer: Evolving Paradigm

Radiation therapy is a part of multimodality treatment for many cancers. It is used for definitive, adjuvant, palliative and neoadjuvant approaches in cancer treatment. Rectal cancer is one such malignancy where radiation therapy is used in neoadjuvant treatment along with chemotherapy.

Historically, in Southern Europe and U.S.A., conventionally fractionated radiotherapy (45–50 Gy, 1.8 or 2 Gy per fraction) was given concurrently with chemotherapy and surgery was carried out 4–8 weeks later. The short-course radiation  (hypofractionation) which consists of five fractions of 5 Gy delivered over 1 week with surgery carried out during the next week was the most extensively used treatment for resectable rectal cancer in Northern Europe.

Radiobiologically, the radiation dose in both regimens was comparable for tumour control whereas the short course arm for was better for normal organs sparing.

Initial trials of hypofractionated radiation, Stockholm I, Uppsala et al & St.Marks Hospital trial, showed that short course RT was associated with higher late small bowel obstruction and higher post-operative mortality but these were attributed to the large radiation fields and limitations of the radiation techniques prevalent at that time. Subsequent MRC 07 study showed a better local control with hypofractionated radiation and adjuvant chemotherapy (high risk cases) but there was no overall survival benefit.

The advantages of hypofractionated regimens over long course regimens are convenience (savings in time for patients and departments), better compliance and lower costs. The disadvantage of hypofractionated radiotherapy followed by immediate surgery was that the tumor did not show any pathological regression.

As clinical research gathered pace in Europe over the last few decades, it was observed that the short course RT along with chemotherapy and delayed surgery resulted in better local control and no increase in late side effects. This was possible as radiation helped in better control and early initiation of full dose chemotherapy resulted in better metastatic control.

Recently RAPIDO trial further firmly established the neoadjuvant short course radiotherapy and chemotherapy as a preferred option for patients with locoregionally advanced resectable carcinoma rectum as a new standard of care.

In this multicentre randomized, controlled, phase 3 trial, participants who were classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes) were randomly assigned (1:1) to either the experimental (short course) or standard of care group (long course).

Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy or nine cycles of FOLFOX4 followed by total mesorectal excision (TME).

Patients allocated to the standard of care group received 25 to 28 daily fractions with concomitant twice-daily oral capecitabine followed by TME and, in high risk patients, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4.

The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population.

Out of 920 patients, 912 eligible patients were followed up for a median of 4·6 years. At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% in the experimental group versus 30·4% in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019).

The most common grade 3 toxicity in both the preoperative groups was diarrhoea, which was more common in the experimental group. Neurological toxicity during adjuvant chemotherapy was more common in the standard of care group. Serious adverse events occurred in 38% participants in the experimental group and, in the standard of care group, in 34% patients without adjuvant chemotherapy and in 34% of patients receiving adjuvant chemotherapy.

The world is presently undergoing the corona pandemic, which makes the short course radiotherapy an even more attractive option of treatment as it reduces the hospital visits of the patient significantly.

Apart from definitive treatment, short course radiotherapy 25 Gy/5 # over 8 days is very effective for palliation of bleeding and pain as it gives good long term relief of symptoms and is very well tolerated by the patients.

At RGCIRC, this approach has been adopted for the benefit of patients and our observation is that with the help of proper radiation equipment and a focused multi modality team, it is feasible to deliver this treatment for the benefit of rectal cancer patients.

Dr. Jaskaran Singh Sethi

Sr. Consultant & Unit Head GI Radiation Oncology. RGCIRC