Review
Current State of Neoadjuvant Radiotherapy for Rectal Cancer

https://doi.org/10.1016/j.clcc.2021.10.008Get rights and content

Abstract

Colorectal cancer is the third most commonly diagnosed cancer, with rectal cancer accounting for 30% of cases. The current standard of care curative treatment for locally advanced rectal cancer is (chemo)radiotherapy followed by surgery and adjuvant chemotherapy. Although neoadjuvant radiotherapy has reduced the risk of local recurrence to less than 10%, the risk of distant metastasis remained high at 30% affecting patient survival. In addition, there is a recognition that there is heterogeneity in tumor biology and treatment response with good responders potentially suitable for treatment de-escalation. Therefore, new treatment sequencing and regimens were investigated. Here, we reviewed the evidence for current neoadjuvant treatment options in patients with locally advanced rectal adenocarcinoma, and highlight the new challenges in this new treatment landscape.

Introduction

In 2020, colorectal cancer is the third most commonly diagnosed cancer but is the second leading cause of cancer-related deaths.1 Colorectal cancer is considered a disease of the developed world, with up to 9x incidence rates in developed countries such as Australia and Northern America, compared to developing countries. Rectal cancer accounts for approximately 30% of colorectal cancer diagnoses. In the early 2000s, the standard of care for management of locally advanced rectal cancer is neoadjuvant radiotherapy (with/ without chemotherapy) followed by surgery and adjuvant chemotherapy. The introduction of neoadjuvant radiotherapy and total mesorectal excision (TME) surgery has reduced the 5-year local recurrence rates to 10% or less.2, 3, 4, 5 The risk of developing distant metastatic disease, however, remained high at 30% in those with locally advance disease.2,3,5,6 In the past decade, to improve patients’ survival, patients’ quality of life, treatment compliance and cost-effectiveness, novel treatment regimens were designed and trialed. In parallel of the developments of these new treatment options, there is a recognized need and advancements in the field of biomarkers to aid treatment personalization to patient's tumor biology.

Section snippets

Preoperative Versus Postoperative (Chemo)radiotherapy

Postoperative chemoradiotherapy was established as the standard of care for locally advanced rectal cancer in the 1990s following the GITSG 7175,7 NCCTG 7947518 and the NSABP R-019 trials demonstrating improved survival and locoregional control with adjuvant chemoradiotherapy.

With treatment-related side-effects of up to 61% in adjuvant trials, the sequencing of radiotherapy in relation to surgery was investigated in the 1990s. The proposed potential benefits of preoperative chemoradiotherapy

Short Versus Long Course Radiotherapy

The Swedish Rectal Cancer Trial utilized short course preoperative radiotherapy in their trial design randomizing patients to 25Gy in 5 fractions radiotherapy followed by early surgery or surgery alone. The preoperative arm had significantly lower local recurrence rates (12% vs. 27%, P< .001) and better 5-year overall survival (38% vs. 30%, P= .008). As the study was conducted in the pre-TME surgery era, one of the main criticisms was that patients did not undergo adequate surgery, thereby

Total Neoadjuvant Therapy (TNT)

Despite the use of adjuvant chemotherapy, distant disease now accounts for approximately 30% of recurrences in patients with locally advanced rectal (T3/T4) cancer.3,5,24 Decline in patient performance status following rectal surgery compromises the intended intensity of adjuvant chemotherapy. Treatment compliance is higher in the preoperative setting when patients are fitter and more likely to complete the intended treatment. In addition, with a shift in the treatment paradigm towards delayed

Nonoperative Approach After Chemoradiotherapy

As up to 30% of patients who receive preoperative chemoradiotherapy reportedly achieve pathological complete response,33, 34, 35, 36 it was proposed that this subgroup of patients may be spared surgery. Habr-Gama et al37 first described the long-term results of an observational study where patients who had complete clinical response after chemoradiotherapy were spared surgery. The nonoperative management surveillance approach described was stringent and rigorous with monthly follow-up visits

Omission of Neoadjuvant Radiotherapy

More recently, there has been interest to explore strategies that allow for omission of neoadjuvant radiotherapy given the potential impact of late effects on patient long-term quality of life.

An early single institution phase II study examined the potential use of neoadjuvant FOLFOX (6 cycles) and bevacizumab in 32 patients with stage II-III rectal cancer, with responders to proceed to surgery without radiotherapy and nonresponders to have radiotherapy before surgery.44 Of the 30 patients who

Imaging and Blood Biomarkers for Omission of RT or Surgery

With some recent studies indicating the potential for omission of radiotherapy or surgery in some patients, there is a need for the development of methods for identification of treatment responders to allow for optimal patient selection for these treatment strategies. Imaging, blood and tissue biomarkers have been investigated and require further validation or development of consensus guidelines for use in the clinical setting.

MRI is an established imaging modality for staging in rectal cancer

Conclusions

The management of locally advanced rectal cancer remained an evolving landscape. Clinicians and patients now have multiple treatment options to consider: short versus long course radiotherapy, total neoadjuvant therapy, nonoperative approach, and omission of radiotherapy. With the multitude of acceptable and reasonable treatment options, we are now in need of a strategy to “match patient to the right treatment,” optimizing the therapeutic effect of each treatment modality whilst limiting

Declaration of Competing Interest

None.

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