Total neoadjuvant therapy in locally advanced rectal cancer

Total neoadjuvant therapy (TNT) has emerged as a transformative approach in the management of locally advanced rectal cancer. By integrating chemotherapy and radiotherapy before surgery, this treatment paradigm aims to improve tumour response, optimise patient outcomes, and enhance quality of life.

What is total neoadjuvant therapy?

TNT involves the administration of all systemic chemotherapy and radiotherapy before surgical intervention, as opposed to the traditional sequence of chemoradiotherapy followed by surgery and adjuvant chemotherapy. This upfront treatment strategy is particularly beneficial for patients with stage II or III rectal cancer.

Why is TNT used in rectal cancer?

The rationale for TNT lies in addressing both local and systemic disease early. Key benefits include:

• Improved tumour control: Early delivery of systemic chemotherapy targets micrometastases, reducing the risk of distant recurrence.
• Enhanced tumour shrinkage: Preoperative radiotherapy and chemotherapy often reduce tumour size, increasing the likelihood of a successful and less invasive surgery.
• Patient compliance: Administering chemotherapy before surgery ensures that patients complete systemic treatment, as postoperative recovery may hinder adherence to adjuvant therapy.

What does TNT involve?

TNT typically includes the following components:

• Short-course radiotherapy (SCRT) or long-course chemoradiotherapy (LCRT): Targeted radiation is delivered to shrink the tumour and address the risk of local spread.
• Systemic chemotherapy: Regimens such as FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) are used to manage micrometastatic disease.
• Interval to surgery: After completing TNT, patients often undergo restaging with imaging to assess treatment response before surgery.

What are the benefits and outcomes of TNT?

TNT has demonstrated significant advantages in clinical trials and practice:

• Higher rates of pathological complete response (pCR): Tumours often show no viable cancer cells in the resected specimen.
• Increased sphincter preservation: Downstaging of tumours reduces the need for permanent colostomies in low rectal cancers.
• Improved disease-free survival: Early systemic therapy minimises the risk of cancer recurrence.

What are the challenges and considerations of TNT?

While TNT offers many advantages, it is not without challenges:

• Toxicity: Extended chemotherapy and radiotherapy can cause side effects such as diarrhoea, fatigue and neuropathy, requiring careful management.
• Individualisation: Treatment must be tailored to the patient’s tumour characteristics, general health and preferences.
• Delayed surgery risks: In some cases, prolonged intervals between TNT and surgery may allow tumour regrowth.

Future perspectives

Ongoing research continues to refine TNT protocols, explore novel systemic agents and optimise treatment sequencing. Advances in biomarkers, such as circulating tumour DNA (ctDNA), may allow better prediction of treatment response and guide personalised therapy approaches.

By addressing both local and systemic disease early, total neoadjuvant therapy is redefining the management of locally advanced rectal cancer, offering improved outcomes and hope for patients facing this challenging diagnosis.