SUMMARY: The American Cancer Society estimates that 45,230 new cases of rectal cancer will be diagnosed in the US in 2021. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined is 67%.
Management of invasive locally advanced rectal cancer (LARC), defined as Stage II (T3-4, N0) or Stage III (T1-4, N+) disease, mandates a multidisciplinary approach, and neoadjuvant chemoradiation therapy (CRT) followed by Total Mesorectal Excision (TME) and adjuvant chemotherapy is often recommended , whereas standard therapy for early-stage lesions involves surgery with or without adjuvant chemoradiation. The trimodality treatment approach was established as the standard of care for LARC based on the findings from the landmark German trial. Preoperative neoadjuvant CRT decreased the local recurrence rate (7.1% vs 10.1%; P=.048) and was associated with lower rates of treatment-related toxicity. Long course Radiation Therapy (RT) remains the preferred approach in the United States, with short course RT as an alternative in selected patients. With regards to chemotherapy, 4 months of adjuvant systemic chemotherapy following 2 months of Fluoropyrimidine-based chemotherapy with concurrent RT and surgery, is the recommended guideline by the National Comprehensive Cancer Network.
Even though the current standard of care for LARC have demonstrated a significant decrease in local recurrence rates from 25% to less than 10%, the high rates of distant relapse of approximately 30% indicate that there is a need for the further optimization of treatment sequencing. Patients with rectal cancer should undergo accurate staging with MRI, as this can better determine the proximity of the primary tumor to the mesorectal fascia, the presence of extramural vascular invasion, and involvement of the extramesorectal pelvic lymph nodes and anterior peritoneal reflection, compared to endoscopic rectal ultrasound (ERUS).
More recently, optimizing the delivery of trimodality treatment by intensifying neoadjuvant treatment has gained popularity. This strategy called Total Neoadjuvant Therapy (TNT) involves moving chemotherapy from the postoperative (adjuvant) to the preoperative setting. The potential benefits of TNT include earlier administration of full doses of systemic treatment with fewer adverse events and better compliance, assessment of the tumor response after neoadjuvant therapy, down staging tumors to increase the likelihood of pathological Complete Response (pCR) and complete resection, opportunities for the selective omission of Radiation Therapy (RT) and potential nonoperative management through a Watch and Wait strategy. Further, earlier administration of uninterrupted systemic chemotherapy can potentially eradicate occult micrometastases and help assess chemosensitivity.
For patients receiving TNT, the optimal sequence of induction chemotherapy followed by ChemoRadiotherapy (CRT) versus CRT followed by consolidation chemotherapy, before Total Mesorectal Excision surgery, has remained unclear. Only two randomized trials, the Organ Preservation in Rectal Adenocarcinoma (OPRA) in the US, and the German Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer (CAO/ARO/AIO-12), have investigated this approach.
The CAO/ARO/AIO-12 is a multicenter, randomized, Phase II trial, which included 306 eligible patients with rectal adenocarcinoma, up to 12 cm above the anal verge based on rigid rectoscopy. Enrolled patients had either clinical T3 tumor less than 6 cm from the anal verge, clinical T3 tumor in the middle third of the rectum (6 cm or more, up to 12 cm) with extramural tumor spread into the mesorectal fat of more than 5 mm (more than clinical T3b), clinical T4 tumors, or lymph node involvement, based on MRI. All enrolled patients had a CT of the chest and abdomen to exclude distant metastases.
Patients were randomly assigned to either Group A (N=156) for induction chemotherapy before CRT, or to Group B (N=150) for consolidation chemotherapy after CRT. Radiation therapy consisted of IMRT to the primary tumor and to mesorectal, presacral, and internal iliac lymph nodes, to a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy with radiotherapy consisted of Fluorouracil 250 mg/m2 IV as a Continuous Infusion on days 1 thru 14 and days 22 thru 35, along with Oxaliplatin 50 mg/m2 IV, given as a 2-hour infusion on days 1, 8, 22, and 29 of radiotherapy. Induction and consolidation chemotherapy consisted of Oxaliplatin 100 mg/m2 IV, as a 2-hour infusion, followed by a Leucovorin 400 mg/m2 IV, given as a 2-hour infusion, followed by Fluorouracil 2400 mg/m2 IV, given as a continuous 46-hour infusion and repeated on day 15, for a total of 3 cycles. All patients underwent Total Mesorectal Excision (TME) independent of tumor response on approximately day 123 after initiation of TNT. Adjuvant chemotherapy after TME was not recommended. The Primary end point was pathological Complete Response (pCR) and Secondary end points included Disease Free Survival (DFS), cumulative incidence of locoregional recurrence and distant metastases, Overall Survival (OS), chronic toxicities, Quality of Life and stool incontinence.
The authors first reported the results of this study in 2019, and it was shown that up-front CRT followed by consolidation chemotherapy resulted in a higher pCR (25% versus 17%; combined pCR and clinical Complete Response 28% versus 21%).The rates of CRT-related Grade 3 or 4 toxicity were lower in the consolidation chemotherapy group (27% versus 37%) and compliance with CRT was better. However, compliance with chemotherapy was worse in the consolidation chemotherapy group than in the induction chemotherapy group.
The researchers in this publication presented long-term outcomes of this trial, including the secondary outcomes of DFS, chronic toxicity, Quality of Life (QoL), and stool incontinence. After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR=0.95; P=0.82). The 3-year cumulative incidence of locoregional recurrence (6% versus 5%) and distant metastases (18% versus 16%) were not significantly different between the two treatment groups. At 3 years, chronic Grade 3-4 toxicities occurred in 11.8% of patients in group A and 9.9% of patients in group B. The Quality of Life score decreased after Total Mesorectal Excision but returned to pretreatment levels 1 year after randomization with no difference between the treatment groups. Stool incontinence deteriorated one year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels.
It was concluded from the secondary analysis of this randomized trial that CRT followed by chemotherapy before TME resulted in higher pathological Complete Response, without compromising DFS, toxicity, QoL, or stool incontinence. Based on these findings, the authors proposed that CRT followed by consolidation chemotherapy is the preferred Total Neoadjuvant Therapy sequence, if organ preservation is a priority.
Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer: Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial. Fokas E, Schlenska-Lange A, Polat B, et al. for the German Rectal Cancer Study Group. JAMA Oncol. Published online November 18, 2021. doi:10.1001/jamaoncol.2021.5445.
