New Standard Emerges for Locally Advanced Rectal Cancer

Pam Harrison

December 18, 2020

A new approach to the treatment of patients with high-risk, locally advanced rectal cancer reduces the rate of treatment failure, and may also increase rate of organ preservation, compared with the traditional approach.

Patients treated with a short-course radiotherapy followed by chemotherapy before surgery showed a reduced disease-related treatment failure at 3 years compared with the traditional approach of neoadjuvant chemoradiation followed by surgery plus or minus adjuvant chemotherapy.

This finding comes from the phase 3 RAPIDO trial.

This experimental treatment also doubles the rate of pathological complete response compared with standard of care, which is an added bonus, the researchers comment, as it may increase the opportunity for patients to seek an organ preservation nonsurgical option.

"Preoperative short-course radiotherapy followed by chemotherapy and total mesorectal excision could be considered as a new standard of care," the researchers conclude. The team was led by Renu Bahadoer, MD, University Medical Center, Leiden, the Netherlands.

A "prominent benefit" of the experimental treatment — especially in this era of COVID-19 — is the reduction in the number of treatment days spent in healthcare facilities (12 days compared with 25-28 days with the traditional approach for the preoperative period alone), the researchers note. "If adjuvant chemotherapy is given…the reduction is even more pronounced," they add, "and this reduction in time spent in hospital minimizes the risk for these susceptible patients and improves hospitals' ability to implement physical distancing during the COVID-19 pandemic situation." 

The study was published online December 7 in Lancet Oncology.

The new approach looks "promising" and is likely to become the new standard of care — especially in the current climate of COVID-19 when fewer visits to healthcare facilities are highly desirable, agree editorialists Avanish Saklani, MBBS, and colleagues from the Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India, writing in an accompanying commentary.

They also agreed that the protocol is likely to increase the number of patients being offered a "watch-and-wait" strategy, because of its ability to induce a significantly higher pathological complete response.

However, the editorialists add a note of caution, "Whether or not this new treatment paradigm will have similar outcomes in a younger population with aggressive disease biology…is unknown." 

Details of the RAPIDO Trial

The RAPIDO trial enrolled 912 eligible patients, and was conducted across 54 hospitals and radiotherapy centers in 7 different countries. The median age of the cohort was 62 years, but 40% of the cohort were 65 years or older.

Eligible patients had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumor [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes considered metastatic).

They were randomly assigned 1:1 to receive either the experimental or standard treatment.

Patients in the experimental group received a short-course of radiotherapy, delivered in five fractions of 5 Gy each, given over a maximum of 8 days.

This was followed by chemotherapy, preferably started within 11 to 18 days after the last radiotherapy session. It consisted of six cycles of CAPOX (capecitabine, oxaliplatin) or nine cycles of FOLFOX4 (oxaliplatin, leucovorin, fluorouracil), and the choice was per physician discretion or hospital policy.

Surgery (total mesorectal excision) was then carried out 2 to 4 weeks later.

In the standard-of-care group, patients received radiotherapy and concomitant chemotherapy (with oral capecitabine). Radiotherapy was administered in 28 daily fractions of 1.8 Gy up to 50.4 Gy, or 25 fractions of 2.0 Gy up to 50.0 Gy, the choice between the two made by the physician or hospital policy.

This was followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4.

"The primary endpoint was disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, a new primary colorectal tumor, or treatment-related death," Bahadoer and colleagues observe.

At 3 years, rates of disease-related treatment failure were significantly lower in the experimental group, at 23.7% vs 30.4% in the standard of care group (P = .019). So, too, was the probability of distant metastases, at 20% vs 26.8% for the standard-of-care group (P = .0048).

In addition, the rates of pathological complete response were twice as high at 28% in the experimental group compared to 14% in the standard-of-care group (P < .0001).

The editorialists also suggest that this increase in pathological complete response seen in the experimental arm is probably the result of additional chemotherapy after the delivery of initial radiotherapy.

In contrast, the cumulative probability of locoregional failure at 3 years was higher in the experimental group at 8.3% compared with 6% for the standard-of-care group, although this difference was not statistically significant  (P = .12).

In the editorial, Saklani and colleagues comment that the higher rates of locoregional failure seen in the experimental group might possibly indicate that a proportion of patients in that arm were either nonresponders or poor responders to radiotherapy, or could be related to the considerable delay in surgery necessitated by the presurgical course of chemotherapy lasting some 18 weeks.

The authors suggest that "an interim restage MRI scan after three cycles of chemotherapy can potentially identify this group of patients who are non-responders to preoperative treatment, thus potentially prompting an earlier surgery than planned, and thus possibly improving overall survival outcomes."

The most common grade 3 or higher adverse events (AEs) reported during preoperative treatment occurred in 48% of patients in the experimental arm compared with 25% of patients in the standard-of-care group. In the subgroup of patients in the standard-of-care arm who received adjuvant chemotherapy,  slightly over one third of patients developed grade 3 or higher AEs.

Serious AEs occurred in roughly equal numbers of patients in both groups (38% vs 34% in the standard-of-care arm). There were four treatment-related deaths in each of the two arms.

Bahadoer has disclosed no relevant financial relationships, but many coauthors have relationships with various pharmaceutical companies, as listed in the original article. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online December 7, 2020. Abstract, Editorial

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