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Total Neoadjuvant Therapy (TNT) in Rectal Cancer in the Community Setting

Presentation by Leah Biller, MD, Dana Farber Cancer Institute

At the Total Health 2023 Evolution conference held in Boston, Massachusetts, Dr Leah Biller from Dana Farber Cancer Institute presented an overview of the use of the total neoadjuvant therapy, or TNT approach, for patients with rectal cancer.


Rectal Cancer: Diagnosis and Staging


Dr Biller began with a brief overview of rectal cancer diagnosis and staging.  She noted that diagnosis of rectal cancer begins with a pathologic examination of the tumor specimen, and most rectal cancers are adenocarcinomas.  A computed tomography (CT) scan of the chest, abdomen and pelvis (CAP) is done to determine if the cancer has spread beyond the rectum. Other diagnostics include magnetic resonance imaging (MRI) of the rectum to help determine stage and degree of spread into the rectal wall and lymph nodes, and a determination of the mismatch repair, or ‘MMR’ status, which helps to define treatment options and also screens for a condition known as Lynch Syndrome, which is associated with increased colon cancer risk.


About TNT Therapy


Dr Biller noted that the primary goal of rectal cancer treatment is to reduce risk of recurrence and/or metastasis (spread beyond the rectum) and to improve patient’s overall survival (OS).  Additional goals are focused on preserving the patients’ quality of life (QoL), by minimizing overtreatment and maximizing effective treatments, as well as personalizing the treatment plan based on the patient’s goals.  She reviewed that until recently, the standard treatment for locally advanced rectal cancer (defined as stage T3/4, with positive lymph nodes, N+), typically consisted of chemotherapy + radiotherapy (chemoradiotherapy), followed by surgical excision of the tumor (total mesorectal excision, or TME), followed by chemotherapy in the adjuvant (post-surgical) period.


Dr Biller noted that the purpose of the TNT approach to rectal cancer treatment is to move the chemotherapy into the neoadjuvant, or pre-surgical, portion of treatment.  Use of the TNT approach, Dr Biller noted, may be beneficial to increase compliance with chemotherapy (as patients may have complications after surgery), to reduce the amount of time a patient may need an ostomy (a pouch system for fecal waste removal), to potentially improve local control of their cancer, and lastly, there may be a possibility for non-operative treatment after TNT.


Dr Biller noted results from the OPRA Trial, which examined the use of chemotherapy first followed by chemoradiotherapy, or the reverse approach, with chemoradiotherapy first, followed by chemotherapy, for patients with Stage II – III rectal cancer.  The study showed that a “watch and wait” approach for patients having a complete clinical response (cCR) to their TNT resulted in a similar disease free survival (DFS) interval as compared with previous observations from historical data.   In addition, while the sequence of treatment did not significantly impact the DFS, there was a benefit for using chemoradiotherapy first in terms of organ preservation, and Dr Biller noted that, for patients who desire not to have a permanent ostomy, the chemoradiotherapy first approach might be a preferred option.  She further noted that, for patients with regrowth of their tumor during the watch and wait period who required surgery (i.e., a TME), their outcomes were similar to those who received the surgery upfront (meaning there was no adverse impact of the watch and wait approach on outcomes).


Dr Biller briefly reviewed results from the RAPIDO Trial, a phase III study that examined a variation of the TNT approach, using a short-course chemoradiotherapy (scCRT) treatment versus the conventional standard of care (with long-course CRT first) for patients with high risk rectal cancers.  She noted that 5 year OS was similar, but there was a higher risk for locoregional recurrence with the scCRT treatment versus conventional treatment (10% vs. 6%; P=0.027).  She further noted that, while this was not a direct comparison of scCRT versus long-course CRT in the TNT setting, there is a study currently underway, ACO/ARO/AIO-18.1, to investigate this comparison.


Escalation and De-Escalation of Treatment


Dr Biller then reviewed data comparing strategies for using more intensive therapy (escalation) or reducing treatment (de-escalation) using TNT approaches.  She reviewed results from the PRODIGE-23 Trial comparing TNT treatment with a more intensive chemotherapy regimen (FOLFIRINOX) as compared to conventional treatment (CRT).  Initial findings from the trial at three years showed significant improvement in DFS (76% vs. 69%; P=0.034) and a higher pathologic complete response (pCR) rate (28% vs. 12%; P<0.001) for patients in the FOLFIRINOX group, and notably, there were less serious events of grade 3 or higher (45% vs. 76%), including grade 3/4 neuropathy (12% vs. 21%), with the FOLFIRINOX regimen as compared with conventional treatment.  More recently reported findings from the trial, at 7 years (BOX 1), also showed significant improvement in DFS, metastasis free survival (MFS) and OS in patients receiving upfront chemotherapy with FOLFIRINOX versus conventional treatment. Dr Biller noted that a question remaining from the trial is whether it is the TNT approach, or the FOLFIRINOX regimen itself, that was most important for the outcome.  In this regard, she noted the ongoing JANUS Trial (NCT05610163), which is assessing the efficacy of the triplet therapy (FOLFIRINOX) as compared to the doublet regimen (FOLFOX) as a component of the TNT approach for locally advanced rectal cancer.

Box 1.  7-Year Efficacy and Safety Results from the PRODIGE-23 Trial


TNT (FOLFIRINOX) versus CRT (Conventional)


7-Year DFS Improvement

+ 5.7 months


7-Year MFS Improvement

+ 7.1 months


7-Year OS Improvement)

+ 4.3 months


Dr Biller then reviewed results from the PROSPECT Trial, a de-escalation study which was designed to answer the question of whether patients can safely avoid radiation therapy which is associated with significant side effects such as impaired fertility and sexual dysfunction.  Patients in the trial (Stages T2/N1, cT3/NO, or cT3/N1) had to be candidates for a low anterior resection (LAR) or what is known as ‘sphincter-sparing’ surgery.  The results of the trial showed that neoadjuvant chemotherapy with FOLFOX was non-inferior to neoadjuvant chemoradiotherapy in this population, and local recurrence rates were similar (1.8% vs. 1.6%, respectively).  Notably, QoL outcomes were also improved in the chemotherapy alone arm, including male and female sexual dysfunction outcomes, suggesting a QoL benefit of avoiding chemoradiotherapy.                       

A Chemoradiotherapy-Free Approach for Some Rectal Cancers


In the final portion of her presentation, Dr Biller reviewed what she described as “very exciting data” for the small subset of rectal cancers (<3%) whose tumors are designated as mismatch repair deficient (MMR-D) with microsatellite instability high (MSI-H) status; such patients generally have a poor prognosis with limited response to standard neoadjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin-based chemotherapy regimens.  Checkpoint inhibitors are a type of immunotherapy that help the body’s immune system to more efficiently recognize and target cancer cells for killing.  In this study, patients were treated with neoadjuvant dorstarlimab, a checkpoint inhibitor, and per study design those who had a cCR would be treated with non-operative management, while those who had residual disease (i.e., no cCR after neoadjuvant therapy) would undergo standard of care chemoradiotherapy, and if still no cCR, undergo surgery.  Although the study, published in the New England Journal of Medicine, only had data for 12 patients so far, all achieved a cCR and were able to successfully avoid chemoradiotherapy, with no evidence of progression or recurrence, and a completely non-operative management for their rectal cancer. There were also no grade 3 or higher adverse events observed with the treatment.  Dr Biller noted that this approach which represents a significant advance in rectal cancer treatment continues to be investigated in other patients whose tumors have MMR-D/MSI-H status.

Quick Summary

  • New trial data support the use of multiple strategies for rectal cancer management, with alternative sequencing of neoadjuvant therapies, as compared with the conventional approach of chemoradiation, followed by surgery, followed by adjuvant chemotherapy. 

  • Multidisciplinary team review is needed to consider the best approach, which should be personalized based on individual patient factors (e.g., tumor location, degree of lymph node involvement, and patient preferences) which can impact the choice of treatment.

  • Chemoradiation may not be needed for low-risk tumors that are eligible for LAR (sphincter-sparing surgery)

  • Use of neoadjuvant immunotherapy alone may be sufficient for MMR-D/MSI-H rectal cancers. 

Speaker Disclosure Information: Dr Biller reported no disclosures for this presentation.


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