The Evolving Landscape of Neoadjuvant Therapy for Locally Advanced Rectal Cancer In Ireland

Introduction: The management of rectal cancer in Ireland has evolved significantly in recent years, driven by advancements in imaging, therapeutic modalities including surgical techniques and a growing focus on personalised care. While surgery remains the primary treatment for rectal cancer confined to the bowel wall, for the past two decades, neoadjuvant long-course chemoradiotherapy (CRT) has become the cornerstone of treatment for locally advanced rectal cancer (LARC), aiming to downstage tumours to improve resectability and reduce recurrence rates.1-5

The potential for organ-preserving approaches in complete or near complete clinical responders (cCR and CR respectively) resulting from this adjuvant treatment has been increasingly utilised, sparing selected patients the morbidity of radical surgery, meaning that there has been increased consideration of “neoadjuvant therapy” as “primary therapy”. Most recently the concept and practice of Total Neoadjuvant Therapy (TNT), has opened new opportunities to integrate systemic chemotherapy earlier in the treatment pathway. This approach has demonstrated improved outcomes for patients with high-risk disease, including better systemic control and increased rates of pathological complete response (ypCR).6 There is increasing interest in such treatment with the specific aim of achieving cCR and avoiding surgery altogether.7, 8 Simultaneously, technological advancements in surgical approaches, particularly the incorporation of robotic-assisted and transanal surgical techniques have expanded the surgical armamentarium for rectal cancer resection meaning both extended and localised procedures are enabled as either definitive or significant component of cancer care.9, 10

Recently the NCCP addressed the growing complexity of the multimodality treatment by producing an updated guideline (2024 update to National Clinical Guidelines No 25: Diagnosis, Staging and Treatment of Rectal Cancer) providing evidence based recommendations on the neoadjuvant treatment of patients with LARC. This update supersedes the 2020 recommendations and reflects advancements in clinical practice and emerging evidence including those regarding TNT and neoadjuvant chemotherapy (nCT) but given the acceleration in the field perhaps especially in oncology a further update in a shorter interval is planned.

Summary of the NCCP 2024 update to the NCCP Clinical Guideline No. 25 for the diagnosis, staging and treatment of rectal cancer:

Objectives of the Updated Guideline

The updated guideline aims to:

1. Incorporate Recent Evidence: Synthesise findings from high-quality randomised controlled trials and international guidelines.
2. Standardise Clinical Practice: Reduce variability in neoadjuvant treatment strategies for LARC across Ireland.
3. Emphasise Patient-Centered Care: Integrate patient preferences and individual treatment goals into decision-making.
4. Improve Oncologic Outcomes: Enhance overall survival (OS), disease-free survival (DFS), and pathological complete response (ypCR) rates while minimising morbidity.

Methodology of the Guideline Update

The updated guideline for the neoadjuvant treatment of LARC was developed through a systematic process to ensure its clinical validity and applicability. A multidisciplinary team of experts, including colorectal surgeons, oncologists, radiologists, pathologists, nurses, and patient advocates, formed the Guideline Development Group (GDG). The guideline focused on addressing key clinical questions, structured using the Population, Intervention, Comparison and Outcome (PICO) framework. The primary aim was to identify patient subgroups benefiting from neoadjuvant therapies and evaluate the efficacy of TNT and nCT compared to standard approaches like nCRT.

Evidence Review and Appraisal

A systematic literature search identified relevant studies, including randomised controlled trials (RCTs) and meta-analyses published between 2015–2023. The evidence was appraised for quality using validated tools like the SIGN checklist, focusing on internal validity, statistical significance, and clinical relevance. Ten major trials including RAPIDO, OPRA, PRODIGE-23, CA0/AR)/AIO-12 and PROSPECT, along with international guidelines, were included. Recommendations were developed using the GRADE framework, assessing evidence quality, benefits versus harms, patient preferences, and resource implications. Recommendations were classified as strong or weak based on the balance of effects, with additional good practice points provided for practical considerations.

Stakeholder Consultation, Approval and Implementation

The draft guideline underwent national and international review. Feedback was collected from professional organisations, academic institutions, and external reviewers with expertise in rectal cancer management. Revisions were made based on consensus. The final draft was quality-assured by the National Cancer Control Programme (NCCP) and ratified by its executive committee. Dissemination strategies included distribution through professional networks, the HSE website, and education programs for multidisciplinary teams. A plain language summary was also created for patients.

Monitoring and Review

Implementation is planned to be supported by regular audits and monitoring of clinical outcomes. The guideline is scheduled for review in three years, with interim updates as new evidence emerges.

Patient Eligibility Criteria

Patients eligible for neoadjuvant therapy were defined as those with locally advanced, operable rectal cancer, with eligibility determined by a multidisciplinary team (MDT) based on the following criteria:

1. Tumour Characteristics

• Staging: Tumours classified as cT2 N+ M0, cT3-4 N any M0, or other high-risk categories based on TNM classification.
• Location: Tumours involving the distal, middle, or upper third of the rectum, particularly those at risk of circumferential resection margin (CRM) involvement.

2. Radiologic Findings

• Baseline Imaging:
• MRI: Assessment of mesorectal fascia (MRF) involvement, extramural vascular invasion (EMVI), and tumour proximity to the anal verge.
• Endorectal Ultrasound (ERUS): Detailed evaluation of tumour depth and nodal involvement.
• CT: Identification of distant metastases.

3. Clinico-Pathological Risk Factors

• CRM positivity or proximity.
• EMVI or enlarged lateral lymph nodes.
• Tumour fixation or involvement of adjacent structures.

4. Patient Factors

• Performance Status: ECOG/WHO scores of 0–2 in most clinical trials.
• Comorbidities and Age: Consideration of overall functional status and tolerability of therapy.

5. Patient Preferences

• Desire for organ preservation and tolerance for treatment-related toxicities.

6. Treatment Goals

• Oncologic control with curative intent, optimising tumour resectability and minimising recurrence risks.

The guideline identified TNT and nCT as primary modalities for managing LARC, emphasising their potential to improve oncologic outcomes and treatment adherence.

1. TNT

TNT integrates both systemic chemotherapy and radiotherapy in the preoperative setting, differing from traditional approaches where systemic therapy is administered postoperatively. TNT can be delivered as:

• Induction: Chemotherapy followed by long-course chemoradiotherapy (LCRT).
• Consolidation: LCRT followed by systemic chemotherapy.

Consolidation Total Neoadjuvant Therapy (TNT)

• STELLAR, RAPIDO, POLISH II: Comparable or better DFS with TNT compared to chemoradiotherapy. RAPIDO demonstrated reduced disease-related treatment failures.
• OS Improvement: Observed in STELLAR and POLISH II but not in RAPIDO.
• ypCR Rates: Significantly improved in STELLAR and RAPIDO; trends favoring TNT in POLISH II and KCSG CO 14-03.

Induction Total Neoadjuvant Therapy (TNT)

• PRODIGE-23 (Conroy et al., 2021): Significant improvement in DFS and higher ypCR rates with TNT; trend towards improved OS (not statistically significant).
• GCR-3 (Fernandez-Martos et al., 2015): No significant difference in DFS or OS between TNT and chemoradiotherapy.

2. Sequencing Strategies:

• OPRA: Consolidation chemotherapy following radiotherapy achieved better TME-free survival compared to induction chemotherapy.
• CAO/ARO/AIO-12: Supported consolidation chemotherapy, reporting higher ypCR rates and DFS improvements.

3. Neoadjuvant Chemotherapy (nCT)

nCT involves the administration of systemic chemotherapy without radiotherapy prior to surgery. It offers a potential alternative for patients who may not require radiation therapy, thereby reducing associated toxicities.

Evidence Supporting nCT

• Key Trials:

o CONVERT (Mei et al., 2023): Similar ypCR rates between neoadjuvant CAPOX chemotherapy and chemoradiotherapy.

o PROSPECT (Schrag et al., 2023): Chemotherapy is non-inferior to chemoradiotherapy for DFS and OS.

Patient Selection for nCT

• Appropriate for patients with lower-risk disease and minimal risk of CRM involvement.
• Radiotherapy can be introduced later if an adequate response to chemotherapy is not achieved.

Recommendations for Clinical Practice

1. Multidisciplinary Team (MDT) Approach

o Treatment decisions should be made during MDT conferences, integrating radiologic, pathologic, and clinical data.

o MDT recommendations should address:

• Tumour location and staging.
• Imaging findings, including CRM involvement and EMVI.
• Patient-specific factors, such as comorbidities, age, and treatment preferences.

2. Individualised Treatment

o Shared decision-making is essential, ensuring detailed discussions on the risks, benefits, and treatment objectives for each patient.

o Non-operative management (e.g., watch-and-wait (W&W) strategy) should be considered for patients demonstrating a cCR following TNT.

Practical Considerations for Implementation

1. Patient Education

o Clear and continuous communication about treatment options, expected outcomes, and potential side effects is vital.

o Provision of a plain language summary can enhance patient understanding and engagement.

2. Multidisciplinary Communication

o Active participation of multiple MDT members during consultations allows patients to address their questions at different stages of care.

3. Resource Allocation

o The need for increased radiological and endoscopic follow-up for patients opting for a W&W approach is anticipated.

o Sufficient consultation time and access to specialised oncology services to support patient-cantered care needs to be ensured.

4. Audit and Monitoring

o Cancer centres should conduct regular audits to assess adherence to the guidelines and evaluate patient outcomes.

Benefits and Harms

Benefits

1. Improved Complete Response Rates: Total neoadjuvant therapy (TNT) or neoadjuvant chemotherapy (nCT) may enhance the likelihood of tumour shrinkage or disappearance, facilitating more effective and less invasive surgery.
2. Tumour Downstaging: Preoperative therapy reduces tumour size and stage, simplifying surgical removal and potentially avoiding extensive procedures like permanent colostomy.
3. Enhanced Local Control: Neoadjuvant therapy reduces the risk of local recurrence by addressing the tumour before surgery.
4. Organ Preservation: In cases of complete clinical response, non-operative management (e.g., “W&W”) may be viable, preserving organ function.
5. Better Treatment Adherence: Administering therapy preoperatively may improve adherence to the planned treatment regimen.

Harms

1. Increased Toxicity: Combined chemotherapy and radiation can lead to side effects such as fatigue, gastrointestinal symptoms, skin reactions, and hematologic toxicity.
2. Over-treatment Risk: Some patients may receive unnecessary neoadjuvant therapy, exposing them to treatment risks without

added benefit.

3. Risk of Incomplete Response: Delayed surgery due to neoadjuvant therapy may

lead to disease progression

or metastasis in non-responding patients.

Authors Commentary considering other International Guidelines

Potential Advantages of TNT: One of the most notable advantages of TNT is the increased rate of ypCR, where no residual tumour is detected in surgical specimens following treatment with figures reported as being in the region of 30-40%.13,14 Achieving ypCR has been previously associated with improved long-term oncologic outcomes, including better survival rates and reduced recurrence risk.21 Additionally, these therapies contribute to effective tumour downstaging, making previously unresectable or borderline resectable tumours operable and reducing the extent of surgical intervention required. This improved resectability not only facilitates curative surgery but also minimises the need for more invasive procedures.

Enhanced local control is another purported benefit, as preoperative neoadjuvant therapy reduces the likelihood of local recurrence, especially in high-risk tumours with features like positive circumferential resection margins or extramural vascular invasion, although increased rates of local failure was a surprising outcome of the long-term data from the RAPIDO trial.15 Furthermore, in the increased number of patients achieving a cCR, TNT may enable organ-preserving approaches, such as a W&W strategy, potentially avoiding surgical morbidity altogether. Preoperative systemic therapy also improves adherence to planned treatment regimens, as patients are more likely to complete therapy prior to surgery than in a postoperative setting, where recovery and complications may hinder compliance.

Potential Drawbacks of TNT: While TNT has become a cornerstone of treatment for high-risk rectal cancer due to its ability to improve systemic control and ypCR rates, emerging evidence highlights some potential drawbacks that suggest a more nuanced, risk-adaptive approach may be warranted. While TNT has facilitated non-operative management, W&W and organ-sparing surgery with local excision for patients achieving a cCR or near cCR,7, 8, 22, 23 such strategies carry inherent risks, including local tumour regrowth. The OPRA trial demonstrated higher organ preservation rates with TNT but also noted increased tumour regrowth compared to opportunistic W&W strategies.7, 8 Approximately 25–30% of patients managed with W&W after TNT experience local regrowth, and salvage surgery is only feasible in 85–90% of cases, and this is may be associated with higher rates of APR and permanent stoma. Moreover, studies indicate that patients experiencing regrowth have significantly higher rates of distant metastases compared to those who undergo upfront surgery.24, 25 Patients with nCR may require prolonged observation to determine if they achieve cCR, delaying definitive surgery.26, 27 This approach can increase surgical complexity due to fibrosis and be associated with increased morbidity and worse specimen quality.28 Such delays may also heighten the risk of local recurrence, particularly in tumours with chemoradiation resistance.

One of the most concerning findings is the increased rate of local recurrence in the long-term follow up of the RAPIDO trial, where the TNT arm (short course radiotherapy and chemotherapy) exhibited a locoregional recurrence rate of 10%, compared to 6% in the CRT group despite improved distant disease free survival.15 There are also reports of a survival paradox where patients achieving ypCR after TNT do not experience improved overall survival compared to those treated with nCRT alone.25 This paradox may reflect the inclusion of tumours with more aggressive biology in TNT protocols, which achieve ypCR or cCR but retain poor long-term prognoses. The notion that the route to ypCR or cCR impacts survival underscores the need for a personalised treatment approach even in such cases.

Any universal application of TNT also risks over-treating patients with low-risk tumours who might achieve optimal outcomes with less aggressive modalities, such as CRT or surgery alone. The PROSPECT trial highlighted the potential for chemotherapy-only approaches in carefully selected low-risk patients, avoiding unnecessary radiation and its associated morbidity. Moreover, there is an increasing realisation that low risk tumours such as those high in the rectum, without a threatened CRM or adverse radiological variables (e.g. mrEMVI or mrTDs). may proceed directly to surgery even with the presence of mesorectal lymphadenopathy. TNT may also intensify treatment-related toxicity, particularly hematologic and gastrointestinal side effects. Studies such as RAPIDO and PRODIGE-23 demonstrated higher rates of treatment-associated adverse events compared to standard LCRT alone.14, 16 These toxicities not only compromise quality of life during treatment but may also affect long-term patient recovery.

Comparison with other guidelines: Recent National Comprehensive Cancer Network (NCCN) guidelines explicitly recommend immune checkpoint inhibitors for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors,29 reflecting emerging evidence in this area.30,31 This represents a key divergence from the NCCP guidelines, which, while recommending testing for MSI-H status, do not include specific guidance for immunotherapy. Furthermore, the NCCN strongly advocates for consolidation chemotherapy in TNT strategies, citing superior outcomes from the OPRA trial. In contrast, the NCCP guidelines allow for more flexibility in treatment sequencing.

The European Society of Medical Oncology (ESMO) guidelines place a particular emphasis on individualised risk stratification using high-resolution MRI to assess key prognostic factors, including CRM involvement, EMVI and lateral lymph node involvement.32 This detailed stratification enables tailored treatment decisions, such as short-course preoperative radiotherapy (SCPRT) or conventional LCRT based on MRI findings. While both NCCP and ESMO advocate for TNT in high-risk cases, ESMO places greater emphasis on CRM involvement and nodal clearance as critical determinants for preoperative strategy. Similarly, both guidelines support NOM in patients achieving a cCR. However, ESMO offers more detailed guidance on intensive surveillance strategies, including MRI and endoscopy intervals, to monitor for tumour regrowth. Notably, while ESMO also highlights the importance of identifying MSI-H status, it does not explicitly recommend immunotherapy for these tumours similar to the recent NCCP document.

Despite their differences, all three guidelines emphasise the centrality of multidisciplinary decision-making, evidence-based stratification, and the need for individualised treatment planning.

Concluding Remarks:

In summary the 2024 Update to the NCCP guidelines for the diagnosis, staging and management of rectal cancer represents the significant evolution in the management of LARC in Ireland. The adoption of TNT and nCT reflects a paradigm shift toward more personalised, multidisciplinary care. These approaches offer the potential for enhanced tumour downstaging, reduced distant recurrence rates, and organ preservation, ensuring that treatment aligns with both clinical objectives and patient preferences, particularly for high risk rectal tumours.

However, to mitigate the challenges outlined above, a risk-adaptive approach to TNT is suggested. Correct patient selection using established clinical and radiological criteria, particularly MRI-defined criteria, such as CRM involvement and adverse MRI features, should guide TNT application. Baseline evaluation should be performed to exclude high-risk patients unlikely to benefit from W&W, and who should undergo TME regardless of tumour regression grade. Timely response assessment should occur with scheduled surgery for those with poor or partial responses, while patients should be made aware of both the risks as well as the advantages of organ preserving approaches. Limiting the duration of consolidation chemotherapy to 12 weeks and the interval to surgery to 16-20 weeks would mitigate the risk of progression in chemoradioresistant tumours.33 In contrast low-risk patients may benefit from de-escalated regimens, such as CRT, chemotherapy-only protocols or direct to surgery.34, 35

In future the use of biomarkers ctDNA and mid-treatment or sequential imaging could better stratify patients based on tumour biology and response.36, 37 Future guidelines should also address the management of those with an nCR including extended surveillance to monitor conversion to cCR, balanced against the risk of delaying surgery.38, 39 In the interim, MDTs will need to consider several complexities outside the scope of the guidelines. These include nuanced decisions about organ preservation and salvage surgery, strategies to avoid overtreatment, and the role of immunotherapy in MSI-H tumours. Additionally, MDTs must evaluate the use of TNT as a primary treatment for early-stage rectal cancer where achieving a cCR and organ preservation is a pre-specified patient treatment goal, even in cases where neoadjuvant therapy would not typically be considered due to the disease’s early stage.

References available on request

Written by Éanna J. Ryan, Ronan A. Cahill

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