Total Neoadjuvant Therapy for Rectal Cancer Aims to Improve Outcomes
In the U.S., it is common for patients with rectal cancer to undergo neoadjuvant long-course chemoradiotherapy over six weeks using a single chemotherapeutic drug as a radiosensitizer, which is not particularly effective against micrometastatic disease. Then patients undergo surgery six to 10 weeks after the completion of chemoradiotherapy. Only after they have recovered from their operation, typically four to six weeks in the absence of complications, do they receive triple-drug cytotoxic chemotherapy.
“When you add up all those delays, it could be many months before a patient with rectal cancer ever receives effective chemotherapy,” says Thomas E. Read, M.D., a professor and chief of the division of gastrointestinal surgery at UF Health. “It has never made sense to many of us that full-dose chemotherapy was being administered so remote from diagnosis. As surgeons, we have gotten better at controlling local disease. We need to get patients effective chemotherapy to control micrometastatic distant disease sooner.”
To target micrometastasis earlier in the course of treatment, the team at UF Health has instituted a relatively novel protocol for patients with clinical stage II or III rectal cancer:
- Newly diagnosed patients are staged with a CT, MRI, serum measurement of carcinoembryonic antigen, endoscopy with biopsy, clearing colonoscopy to the cecum and tumor molecular profiling to check for deficient DNA mismatch repair, or MMR, and next-generation sequencing, or NGS, status. Each patient’s case is reviewed by a multidisciplinary gastrointestinal tumor board.
- Once a patient is confirmed to have clinical Stage II or III rectal cancer, they begin total neoadjuvant therapy, or TNT, which is a short-course radiotherapy (5 Gy x 5 fractions over one week), followed by eight cycles of FOLFOX chemotherapy for four months. They are then restaged before undergoing surgery, generally two to four weeks after the last chemotherapy dose.
Although the UF Health protocol is relatively novel, several other institutions are also using TNT for rectal cancer and some employ short-course radiotherapy in their protocols, Read notes. In prospective randomized trials, short-course radiation with neoadjuvant multiagent chemotherapy has been just as effective as long-course concurrent radiation. “Since micrometastatic disease is treated early on, and with upfront radiotherapy, we are better able to assess its ultimate downstaging effect on the tumor,” Read says. “Surgery comes last, so if the patient has the misfortune of surgical complications, there is no delay in their chemotherapy as they have already received chemotherapy preoperatively.”
Read says the new protocol is part of the continuing effort to optimize care for patients with rectal cancer. “When I came to the University of Florida a year or so ago, I was impressed with the commitment of the entire team to explore novel treatment algorithms for patients suffering from rectal cancer. The medical and radiation oncologists helped shaped this protocol. Hopefully it will lead to improved outcomes. This is now our standard algorithm for patients with clinical Stage II or III disease who are not enrolled in a clinical trial.”
Read and his colleagues expect that eventually they will be able to identify patients who can be treated with definitive chemoradiotherapy and a “watch and wait” approach, avoiding surgery altogether.