Total Neoadjuvant Therapy, A Standard of Care for High-Risk Locally Advanced Rectal Cancer

For patients with locally advanced rectal cancer, the current treatment involves chemoradiation (chemoRT) followed by surgery and adjuvant chemotherapy with fluorouracil and oxaliplatin. While this treatment strategy results in excellent local control, many patients eventually develop distant recurrence. Total neoadjuvant therapy (TNT), in which induction chemotherapy prior to chemoRT is given in place of postoperative adjuvant therapy, is a potential alternative treatment that may allow for more complete delivery of chemotherapy, increased downstaging, earlier introduction of systemic chemotherapy, and the potential for nonoperative treatment. TNT has demonstrated efficacy for locally advanced rectal cancer in several small institutional studies and has been included in clinical guidelines, despite lack of randomized clinical trials.

In a retrospective analysis, results from 628 patients with locally advanced rectal cancer treated at Memorial Sloan Kettering Cancer Center from 2009 to 2015 were evaluated to compare the efficacy of two treatment cohorts, TNT versus standard chemoRT plus planned adjuvant chemotherapy. Among TNT regimens, most patients received induction with FOLFOX (8 cycles) followed by chemoRT. Patients in the TNT group received greater percentages of the planned oxaliplatin and fluorouracil doses than patients in the adjuvant chemotherapy group and required fewer dose reductions. TNT was also associated with higher rates of complete response (CR) at 12 months (35.7% vs 21.3%).

More patients in the TNT treatment group did not undergo surgery (24% vs 8%), and, in patients who received surgery, minimally invasive surgery was more common in the TNT group (72% vs 47%). Among patients who underwent surgery within 12 months, the pathologic CR rate was 18.3% with TNT and 16.6% for patients who did not receive neoadjuvant chemotherapy. For patients who did not have surgery, sustained clinical CR was achieved in 21.8% of patients in the TNT group, compared to 5.9% of patients in the chemoRT plus adjuvant chemotherapy group. No patients with sustained clinical CR developed distant recurrence within 12 months.

The investigators concluded that this analysis supports the efficacy of TNT for patients with locally advanced rectal cancer, with better control of local disease and reduced rates of distant recurrences compared to chemoRT plus adjuvant therapy. Additionally, TNT reduces the need for invasive surgery and may allow for nonoperative treatment in place of surgery. In an accompanying commentary, the authors agreed, suggesting TNT may be considered a standard of care for select patients with high-risk locally advanced rectal cancer, particularly in node-positive patients with low-lying rectal tumors or those with T4 disease. In patients with lower risk disease, the potential to use TNT to enhance organ preservation should be carefully balanced with the risks associated with chemotherapy, including long-term neuropathy and potential mortality.

JAMA Oncol. 2018 March 22 [Epub ahead of print].

Clinical Opinion Poll

What frontline therapy would you recommend for a 49 y/o woman diagnosed with low tumor burden metastatic ALK+ NSCLC (lung and liver metastases, normal brain MRI, PS0)?