Preoperative radiotherapy and total neoadjuvant therapy in locally advanced rectal cancer management: So far, so good

Jyotiman Nath; Gautam Sarma

doi:10.4103/jrcr.jrcr_20_21

REVIEW ARTICLE

Year : 2021 | Volume : 12 | Issue : 3 | Page : 100-107

Preoperative radiotherapy and total neoadjuvant therapy in locally advanced rectal cancer management: So far, so good

Jyotiman Nath, Gautam Sarma
Department of Radiation Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam, India

Date of Submission	14-Jul-2021
Date of Acceptance	26-Jul-2021
Date of Web Publication	31-Aug-2021

Correspondence Address:
Dr. Jyotiman Nath
Department of Radiation Oncology, Dr B Borooah Cancer Institute, Guwahati, Assam
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jrcr.jrcr_20_21

Abstract

The treatment outcomes of locally advanced rectal cancer (LARC) have significantly improved in the last few decades due to the continuous evolution of multimodality management. However, the distant failure remains a concern leading to more cancer-related deaths. Conventionally, preoperative chemoradiotherapy followed by total mesolectal excision and adjuvant chemotherapy is the standard of care for LARC patients. However, noncompliance to adjuvant chemotherapy due to various factors leads to more distant failure rates. As an alternative to this, multiple approaches of total neoadjuvant therapy (TNT) were investigated over time, and multiple reports have shown promising results. This review highlights the evolution of the multimodality management approach to LARC patients, emphasising preoperative radiotherapy and TNT.

Keywords: Chemotherapy, radiotherapy, rectal cancer, total neoadjuvant therapy

How to cite this article:
Nath J, Sarma G. Preoperative radiotherapy and total neoadjuvant therapy in locally advanced rectal cancer management: So far, so good. J Radiat Cancer Res 2021;12:100-7

How to cite this URL:
Nath J, Sarma G. Preoperative radiotherapy and total neoadjuvant therapy in locally advanced rectal cancer management: So far, so good. J Radiat Cancer Res [serial online] 2021 [cited 2023 Jun 7];12:100-7. Available from: https://www.journalrcr.org/text.asp?2021/12/3/100/325268

Introduction

Rectal cancer is consistently reported among the top five common cancers worldwide, although the incidence is relatively lower in India when compared with the western world. Worldwide, overall, colorectal cancer (CRC) ranks third in terms of incidence and mortality.^[1],[2] There has been a dramatic change in the management approach of rectal cancer in the last few decades. Initially, when surgery was considered the primary treatment modality, the local recurrences were between 20% and 50% despite good resections.^[3],[4] The extent of local recurrence largely depends on regional lymph nodes and the depth of tumor infiltration. The role of radiotherapy in rectal cancer has evolved mainly in a preoperative or neoadjuvant setting and concurrent chemotherapy for locally advanced patients.

Preoperative or Neoadjuvant Radiotherapy

The growing evidence of the use of neoadjuvant radiotherapy for locally advanced rectal cancer (LARC) developed in the late 1980s and during the 1990s. Neoadjuvant treatment aims to downstage the tumor in anticipation of adequate surgical resection margin leading to preservation of the anal sphincters, maintaining anal continence, and improving quality of life. The Swedish Rectal Cancer Trial was the first of its kind to show a significant benefit of neoadjuvant radiotherapy compared to surgery alone. With the use of short-course radiotherapy (SC-RT) of 5 Gy for five fractions followed by surgery, there was a substantial improvement in overall survival (OS) from 30% to 38% and reduced local recurrence rate (LRR) from 26% to 9%.^[5] However, the results of this trial were criticized as the surgery was not total mesorectal excision (TME). Professor Richard J Heald first developed the technique of TME. TME is a standard anatomical approach to pelvic dissection, which completely excises the lymphovascular fatty tissue surrounding the rectum and mesorectum. Herald also postulated that the local recurrence is significant because of leaving mesorectal tissue within the pelvis. In many pieces of the literature, the TME was associated with the lowest rate of local recurrence and subsequently became the gold standard for managing rectal cancer.

In the post-TME era, a Dutch trial showed the benefit of adding preoperative SC-RT to TME surgery, showing a reduction of local recurrence from 11% to 5% compared with surgery alone.^[6] However, the concerns with the SC-RT followed by immediate surgery potentially contribute to late radiation toxicity. The short interval between radiation and surgery does not allow sufficient time for tumor regression or downstaging for improved sphincter preservation.

As an alternative to the preoperative SC-RT schedule, a conventionally fractionated radiotherapy of 45–50.4 Gy concurrently with chemotherapy was also established. The German CAO/ARO/AIO-94 trial compared long course radiotherapy 50.4 Gy in 28 fractions with concurrent fluorouracil (5-FU) in preoperative versus postoperative setting. The preoperative group significantly benefited with a 5-year LRR of 6% versus 13%, respectively (P = 0.006).^[7],[8] The CRC collaborative group conducted a metanalysis of 14 randomized controlled trials and reported that preoperative radiotherapy is associated with a significantly lower LRR.^{[9],[10],[11]}

Subsequently, preoperative long-course radiotherapy (50/50.4 Gy in 25/28 fractions) with concurrent chemotherapy (capecitabine) followed by surgery became standard practice for locally advanced rectal adenocarcinoma across many centres worldwide.

Preoperative Short-Course Radiotherapy versus Long-Course Chemoradiotherapy

With the growing shreds of evidence of two available options of preoperative radiotherapy, controversies arose whether one is superior to another for routine practice. The Polish rectal cancer group first reported the results of their randomized control trial. The short-course approach (25 Gy in five fractions) was compared with the protracted approach of 50.4 Gy using 1.8–2 Gy per fraction with concurrent chemotherapy for T3/T4 mid to low rectal cancer. A higher pathological complete response (pCR) rate was observed in the long-course chemoradiotherapy (LC-CRT) than in the SC-RT arm (16% vs. 1%). Moreover, 4% of LC-CRT recipients and 13% of SC-RT recipients had tumor involvement of the circumferential margin (P = 0.0017). However, there was no difference in the sphincter preservation rate, local control, or OS.^[12] Trans-Tasman Radiation Oncology Group randomized 326 patients with cT3N×M0 rectal cancer to SC-RT (25 Gy in 5 fractions) followed by surgery within 1 week or LC-CRT (50.4 Gy in 28 fractions with continuous infusion 5-FU) followed by surgery at 4–6 weeks. Both regimens were followed by adjuvant 5-FU-based chemotherapy. They presented comparable prognostic results for both strategies, with a 5-year OS of 74% versus 70% (P = 0.62) and a 3-year LRR of 7.5 versus 4.4% (P = 0.24) for SC-RT versus LC-CRT, respectively.^[13] The results of these two randomized trials showed that both SC-RT and LC-CRT are reasonable therapeutic options. Later on, two Cochrane database reviews were carried out, and both found a superiority of LC-CRT compared to the SC-RT in terms of LRR.^[14],[15] However, the meta-analyses contained only five or six studies with very heterogeneous treatment regimens and in part cohorts with pre-TME surgery, limiting the informative value.

Based on the available evidence, it can be concluded that the SC-RT and the LC-CRT are not competing but complementary to each other with different scopes in the clinical scenarios. As mentioned in the major clinical guidelines, LC-CRT is preferable, particularly for patients with distal or advanced T3 and T4 tumors with positive clinical circumferential resection margin (cCRM+) and/or positive lymph nodes additionally downsize the tumor. SC-RT appears to be a safe alternative for patients with small, relatively proximal tumors and does not compromise long-term outcomes.^[16],[17]

Total Neoadjuvant Therapy: Different Approaches

Preoperative chemoradiation followed by surgery with improved technique and adjuvant chemotherapy has substantially reduced the local recurrence LARC. However, systemic failure remains a significant risk, with up to 30% of patients developing distant metastatic disease.^[18]

Serious concerns regarding patient compliance with adjuvant therapy were raised. Various reports have shown that 25%–50% of eligible patients with LARC never initiated adjuvant chemotherapy after preoperative radiotherapy and surgery. This was attributed to postoperative complications, frailty, and debilitation, or patient refusal.^[19],[20] To address the issues of unidentified micrometastatic disease at the time of presentation and poor patient compliance to adjuvant chemotherapy, it was proposed to move systemic chemotherapy to the neoadjuvant setting. Various studies have investigated whether the addition of systemic chemotherapy in the neoadjuvant setting known as total neoadjuvant therapy (TNT) impacts local recurrence and survival.

Different strategies for TNT are currently proposed without consensus on the best approach. One-way of delivering chemotherapy is to divide adjuvant chemotherapy giving a limited number of cycles before preoperative RT, and then the remaining cycles postoperatively named induction chemotherapy. In contrast, another way is to deliver complete systemic chemotherapy after preoperative RT, called consolidation chemotherapy.

Total neoadjuvant therapy with induction chemotherapy approach

Various studies assessing the effect of induction chemotherapy as a part of the TNT approach are shown in [Table 1]. Fernandez-Martos et al. conducted a prospective trial in Spain where 108 LARC patients with distal or middle third, T3-T4 and/or N + rectal adenocarcinoma were randomly assigned to preoperative CRT followed by surgery and four cycles of adjuvant capecitabine and oxaliplatin (CAPOX) or four cycles of CAPOX followed by CRT and surgery. There was no difference in the rates of pathologic complete response. The TNT arm showed significantly reduced toxicities (19% vs. 54%, P < 0.001). Moreover, the patients in the TNT arm were more compliant toward receiving complete intended chemotherapy (91% vs. 51%, P < 0.001).^[21],[22]

Table 1: Various trials investigating total neoadjuvant therapy approach (induction and consolidation chemotherapy)

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The results of a retrospective cohort analysis from Memorial Sloan Kettering Cancer Center were published in 2018. They compared 811 patients treated with either the traditional approach (preoperative chemoradiation and planned postoperative chemotherapy, n = 320) or the TNT (induction FU and oxaliplatin-based chemotherapy followed by chemoradiation, n = 308). The patients undergoing TNT were more likely to complete the planned treatment without a miss of chemotherapy doses. Moreover, the complete response rate was higher in the TNT arm than in the traditional arm (36% vs. 21%).^[23]

The PRODIGE 23 is a Phase III multicenter, randomized, open-label trial comparing induction chemotherapy and TNT approach with standard preoperative chemoradiotherapy followed by surgery and adjuvant chemotherapy. A total of 461 patients were randomized. The investigational TNT arm received six cycles of neoadjuvant mFOLFIRINOX followed by chemoradiotherapy (50 Gy in 25 fractions concurrently with oral capecitabine). It was followed by TME and finally adjuvant 3 months of modified FOLFOX (mFOLFOX) and capecitabine. The standard-of-care group received chemoradiotherapy, TME, and adjuvant chemotherapy for 6 months. The preliminary results of the study published in May 2021. The primary endpoint was disease-free survival (DFS) at 3 years. After overall median follow-up of 46·5 months, 3-year DFS rates were 76% (95% confidence interval [CI] 69–81) in the neoadjuvant chemotherapy group and 69% (95% CI 62–74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49–0·97; P = 0·034). The 3-year OS rates were 91% in the neoadjuvant group and 88% in the standard-of-care group. No differences were seen in overall locoregional relapse rates between the groups (P = 0.56). The compliance with FOLFIRINOX in the study was very high, with more than 90% of patients completing six treatment cycles. Moreover, the use of FOLFIRINOX did not compromise the uptake of surgery, increase surgical morbidity, or adversely affect compliance with adjuvant chemotherapy. The preliminary results of this PRODIGE 23 TNT trial showed that using FOLFIRINOX before preoperative chemoradiotherapy significantly improved the outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer with improved DFS and reduced neurotoxicity. Hence, this approach can be a practice changer in the coming days.^[24]

This particular approach of TNT gained popularity for patients with advanced disease with a higher risk of distant metastasis and difficulty for surgical resection. It has been postulated that the upfront chemotherapy agents reach tumor cells directly as the vasculature is not disrupted by radiotherapy or surgery.^{[25],[26],[27]}

Total neoadjuvant therapy with consolidated chemotherapy approach

Various studies using the concept of consolidation chemotherapy as a part of TNT are depicted in [Table 1]. A Phase II study enrolled LARC patients to either surgery or 2, 4, or 6 cycles of mFOLFOX followed by surgery. Eighty percent of patients completed planned chemotherapy without a missed dose or dose reduction. It was reported that patients treated with six cycles of mFOLFOX had significantly improved pathologic complete response compared to patients who went straight to surgery 6–8 weeks after completing chemoradiation (P = 0.011). The long-term results demonstrated that the addition of mFOLFOX after chemoradiotherapy and before surgical excision increased compliance with systemic therapy and improved DFS.^[28],[29]

A large Phase III Polish study provided valuable data regarding the long-term outcome of the consolidated chemotherapy approach. The group randomized over 500 patients to short-course radiation followed by consolidation chemotherapy and surgery versus long-course chemoradiation with consolidation chemotherapy followed by surgery. The study arms showed similar pathological complete response, DFS, local failure rate, and treatment-related toxicities. However, the SC-RT group showed improved 3-year OS and better compliance to treatment. So far, these studies have suggested that consolidation chemotherapy can be a safe and feasible option in the TNT approach.

The RAPIDO trial, a large Phase III, international, multicenter, randomized study design, also used a similar approach of TNT, the results of which were published recently. A total of 920 LARC patients were randomly assigned. The investigational arm received SCRT (5 Gy ×5 fractions) followed by six cycles of CAPOX or nine cycles of FOLFOX4 and then TME. The standard arm received capecitabine-based chemoradiotherapy (50–50.4 Gy in 25–28 fractions) followed by TME and postoperative eight cycles of CAPOX or twelve cycles of FOLFOX4. The primary endpoint was a 3-year disease-related treatment failure. There were significantly fewer disease-related treatment failure events in the experimental group at 3 years than in the standard of care group (P = 0·019). At 3 years, the cumulative probability of distant metastases was 20·0% in the experimental group compared with 26·8% in the standard of care group (P = 0·0048). There is a significant improvement the TNT group (27.7% vs. 13.8%, P < 0.001). The study concluded that SC-RT followed by 18 weeks of chemotherapy before TME surgery significantly reduces disease-related treatment failure in patients with LARC compared with the standard chemoradiotherapy arm. In addition, a higher rate of pathological complete response rate can potentially contribute to organ preservation. With improved tolerability, this approach can be a new standard of care for patients with high-risk LARC.^[30]

Many clinical trials are ongoing, investigating the effectiveness and efficacy of the TNT approach. The outcomes of the trials will help understand tumor characteristics and provide essential information on optimising the TNT approach.

Risk stratified organ preservation approach

Based on current evidence, it is evident that the TNT approach gives many benefits in managing LARC patients. The benefit is not only in terms of oncological outcome but also patient compliance. One more advantage of the TNT approach is that the chemosensitivity of the tumor can be assessed before surgery, and based on that, the risk stratification can be done. Based on these, it was postulated that a particular group of patients having complete response following neoadjuvant chemotherapy could be kept on a “wait and watch” policy to omit surgery or radiotherapy or both. Past few studies have suggested that these specific subgroups of patients can be kept under the wait and watch approach with very close follow-up. However, the most crucial aspect is how to assess these patients for no residual disease.

A multicenter retrospective study from China has recently reported the results of the watch and wait approach versus surgery for rectal cancer patients with the complete clinical response after neoadjuvant chemoradiotherapy. A total of 117 patients with Stage II/III rectal adenocarcinoma who had a complete clinical response after neoadjuvant chemoradiotherapy were matched against 354 patients who underwent surgery. After a median follow-up of 38.2 months, the watch-and-wait strategy group exhibited a higher LRR (14.9% vs. 1.1%), but most (85.7%) were salvageable. Three-year nonregrowth local recurrence-free survival was comparable between the two groups (98% vs. 98%, P = 0.506). However, the watch-and-wait group presented an obvious advantage in sphincter preservation, especially in patients with a tumor located within 3 cm of the anal verge (89.7% vs. 41.2%, P < 0.001). Although the study had many limitations, the authors concluded that the wait and watch strategy for Stage II/III rectal adenocarcinoma patients achieving complete clinical response after preoperative CRT may be feasible with higher sphincter preservation.

The assessment of clinical response and a robust follow-up strategy is paramount for the wait and watch policy. Magnetic resonance imaging (MRI) has been well established to diagnose and assess treatment response in rectal cancer patients. High-resolution MRI can predict the outcome based upon the assessment of tumor regression and circumferential resection margin status before surgery, enabling the identification of poor and good responders. Thus, MRI can help to stratify risk appropriately and identify potential candidates for organ preservation.^{[31],[32],[33],[34]}

Keeping MRI as a robust tool for assessment, the TRIGGER trial was designed. The TRIGGER trial is a multicenter, randomized control feasibility study to validate the evaluation of tumor response based on an MRI-derived tumor regression grading system named magnetic resonance tumor regression grade. It is a three-arm prospective study with two investigational arms. After the preoperative CRT, the good responder group will be subjected to a nonoperative approach with further systemic chemotherapy. The poor responder group will be subjected to chemotherapy followed by surgery. This Phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life, and health economics analysis.^[35] Besides this, other trials are going on that will try to evaluate the TNT nonoperative approach in the management of LARC [Table 2].

Table 2: Ongoing trials on total neoadjuvant therapy and organ preservation approach

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Omission of radiotherapy in total neoadjuvant therapy approach

Few attempts have been made to see the effectiveness of omitting radiotherapy as a part of TNT. Few single-arm studies have demonstrated that chemotherapy alone in a neoadjuvant setting can lead to good oncological outcomes.^{[36],[37],[38]} A Phase II study showed that complete pathological response was achieved in all study patients without adding radiotherapy.^[39] Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT) is an ongoing multi-site two-group seamless Phase II/III randomized trial. The standard neoadjuvant chemoradiation is compared with neoadjuvant chemotherapy with the selective use of chemoradiation for patients with LARC.^[40] Besides these, more trials are undergoing to investigate the effectiveness and efficacy of the TNT approach [Table 2]. The results of these trials might change the clinical decision-making in the multimodality management of LARC.

Conclusion

Various approaches to multimodality management of LARC have been studied in the last few decades. While preoperative radiotherapy with either SCRT or LC-CRT followed by TME and adjuvant chemotherapy was the standard of care until TNT's concept evolved. With the development of much evidence, the practice of TNT is gaining more popularity. With the good oncological outcome, the TNT approach has provided more patient adherence to the prescribed course of treatment. The results of the two recently published Phase III studies viz. RAPIDO and PRODIGE 23 have established that TNT with TME is a more innovative option for LARC patients to overcome the potential difficulties with traditional adjuvant chemotherapy. Beyond this, TNT allows assessing chemosensitivity and tumor response before surgery. However, both trials evaluated two different approaches of management, but the results of both are promising. Few efforts have been made to see the effectiveness of the wait and watch policy for organ preservation and omission of radiotherapy from the TNT approach. However, the data are not matured enough to conclude. The results of these trials and the ongoing trials on the TNT approach will probably change the management paradigm of LARC patients in the coming days.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

[53]

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