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Outcomes using induction chemotherapy followed by long-course chemoradiotherapy as total neoadjuvant therapy for locally advanced rectal cancer
Background
Total neoadjuvant therapy (TNT) for rectal cancer is being adopted worldwide as a promising means to improve outcomes for patients with locally advanced rectal cancer. However, the optimal TNT regime is not well established, with differing regimes and sequencing of radiotherapy and chemotherapy suggested in clinical trials and published series. In 2008 we adopted a TNT approach based on the EXPERT trial (Chua 2006) as a region of six oncology centres. The regime consisted of induction chemotherapy (capecitabine-oxaliplatin) followed by long-course chemoradiotherapy, total mesorectal excision, with adjuvant chemotherapy considered post-operatively. We report here our experience over 12 years with comparison to contemporary published literature.
Methods
Retrospective data was collected for all patients with locally advanced rectal adenocarcinoma (some of whom also had operable oligometastatic disease) treated with the EXPERT regime between 2008 and 2020. Local control and survival rates were calculated using the Kaplan-Meier method.
Results
215 patients treated with the EXPERT regime are included. Median age was 60.6 years (range 27.4-79.0), and 66% were male. 69% had stage 3 disease and 20% stage 4 disease at diagnosis. 91% of patients received neoadjuvant capecitabine-oxaliplatin chemotherapy, receiving a median of 3.87 out of 4 planned cycles. 27.4% required dose reductions. Long-course radiotherapy was given with capecitabine (92.1%), 5-FU (4.2%) or raltitrexed (1.9%) and no chemotherapy (1.9%). The majority of patients received a total dose of 50Gy (range 9-54Gy). Radiological response was seen in 87.4% of patients (9.8% complete, 77.6% partial). 43.1% of patients were radiologically down-staged. 173 patients had radical surgery, with 90.2% achieving an R0 resection and 15.6% had a pathological complete response (pCR). At baseline, 76.6% had circumferential resection margin (CRM) involvement which decreased to 17.2% at surgery. 3-year progression free survival (PFS) was 62% (CI 54-69) and 5-year PFS was 56% (CI 48-65). 43.0% of patients recurred, of whom 15.7% had metastatectomies and remained disease-free at the time of analysis. 3-year recurrence free survival (RFS) out of the patients who had a complete resection at surgery was 69% (CI 62-77) and 5-year RFS was 67% (CI 59-75). Median overall survival (OS) was 118 months (CI 97-not reached), 3-year OS was 80% (CI 74-86) and 5-year OS was 69% (CI 62-77). Excluding patients with metastatic disease at presentation, median OS was 133 months (CI 118-not reached), 3-year OS was 85% (CI 79-91) and 5-year OS was 79% (CI 71-86).
Conclusions
Our results present the real-world outcomes of patients with rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy, demonstrating high rates of R0 resection even in CRM involved patients. The 3-year OS rates (excluding stage 4 patients) are comparable to results from both the EXPERT (83%) and RAPIDO (89%) trials. Compared to two recent meta-analyses of TNT (Kasi 2020 and Petrelli 2020), our cohort had a lower pCR rate, 15.6% compared with 29.9% and 22.4% respectively. This large series of EXPERT data, with a long median follow-up compared to other reported studies will be a useful comparator in the pursuit for improving definition of the optimal TNT regime.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
