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A Dynamite Solution for Management of Locally Advanced Rectal Cancer

February 27, 2023

By John F. Gleason, Jr., MD

Rectal cancer is a commonly encountered disease in our clinics. Colorectal cancers include primary gland producing cancer cells, which is the type of cell that becomes cancerous, starting in the large bowel. The reason we stress the need for a colonoscopy or other screening for polyps starting at age 45 is to try to catch precancerous changes that eventually lead to colorectal cancer. Before I tell you about TNT (Total Neoadjuvant Therapy), let us first discuss rectal cancer more generally.


Colorectal Cancer Treatment Options

While cancers that occur in the rectum and other parts of the colon (ascending, transverse, descending, and sigmoid) appear the same under a microscope and are treated with the same chemotherapy drugs and surgical approaches, there is a distinction concerning the role of radiation treatment. The vast majority of people with colon cancers do NOT receive radiation as part of their primary therapy for a localized cancer. However, radiation is commonly employed as part of treatment for rectal cancers. Why? It is a matter of real estate, or rather anatomy. The pelvis narrows like a funnel as you move towards the feet. The rectum lives in the pelvis and this more narrowed location with surrounding bone, muscle, and genital & urinary organs makes getting a wide clear surgical margin more difficult. These cancers also commonly spread to lymph nodes in the fat surrounding the rectum or along the sides of the pelvis. Historically, the local failure rate (regrowth) was much higher for rectal cancers than those located higher in the colon. Clinical trials decades ago showed the important role of radiation to reduce cancer recurrence for patients with involved lymph nodes or deeper tumors (T3 or T4). 


Colorectal Cancer Trials

The initial clinical trials gave radiation after surgery combined with low dose chemotherapy (chemoRT). Full dose chemo (i.e. FOLFOX) was also given after surgery to reduce the chances of the cancer spreading to other parts of the body. Chemotherapy plays a critical role in treatment of colorectal cancers and improves the chance of cure. Later studies showed that neoadjuvant (before surgery) chemoRT had a number of advantages over the adjuvant (after surgery) chemoRT regimens including: lower risk of pelvic recurrence, higher chance of surgery achieving a negative margin (clearing all the disease), less likelihood of long-term side effects (diarrhea), and improved chance of sphincter-sparing surgery (avoiding permanent ostomy bag). This neoadjuvant chemoRT approach became the standard. However, the full dose chemo was still given adjuvantly (after surgery). This type of regimen is still an appropriate option for patients based on national guidelines. 


doctor showing patient chart


Total Neoadjuvant Therapy

Now we get to TNT, which is the newest paradigm for advanced stage colorectal cancer patients. TNT means Total Neoadjuvant Therapy. Total in the sense that we complete ALL the non-surgical treatments (radiation and chemo) before surgery. The best way to offer TNT is still being determined. There is variation in how it is organized. One option is to first complete the radiation (+/- chemo) prior to the full dose chemo (FOLFOX). Another approach is to do the full dose chemo (FOLFOX) followed by the radiation (+/- chemo). There is also variation in the radiation. Most commonly, patients  are treated with standard course chemoRT over 5.5 weeks because it allows us to safely deliver a higher effective dose of radiation, with some series showing a lower risk of pelvic recurrence. Nevertheless, a shorter course RT can make sense in certain clinical situations.

Adoption of TNT continues to grow rapidly. Full dose chemo (FOLFOX) is a critical component of treatment for locally advanced rectal cancer patients and delivering it after surgery can be associated with delays related to patient compliance, tolerance, and post-op complications. Therefore, there is an advantage to getting the chemo completed before surgery. In many cancers, we think administering chemo prior to surgery will destroy any microscopic distant disease so people are less likely to develop metastases, which pose the most important threat to the patient’s cure rate. Clinical trials and meta-analyses suggest improved pathologic complete response rates, disease-free survival, and distant metastasis-free survival with TNT. TNT approaches will allow us to further study the watch and wait approach used on current trials where patients may be able to defer surgery if they have a clinical complete response to initial TNT and would otherwise require a permanent ostomy because of a very low-lying rectal tumor. 

The role of chemotherapy and radiation for rectal cancer has evolved significantly over numerous generations of clinical trials, as summarized above. It will continue to evolve. Current studies aim to better determine the ideal type of TNT approach for individual patients and further explore organ-preserving options where some patients may not need surgery. Your doctors should use an individualized plan for you, based on your tumor location and the extent of disease identified.


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