Unveiling the profound advantages of total neoadjuvant therapy in rectal cancer: a trailblazing exploration

Kyung Uk Jung; Hyung Ook Kim; Hungdai Kim; Donghyoun Lee; Chinock Cheong

doi:10.4174/astr.2023.105.6.341

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Jung, Kim, Kim, Lee, Cheong, and on the behalf of Korean Society of Korean Society of Coloproctology: Unveiling the profound advantages of total neoadjuvant therapy in rectal cancer: a trailblazing exploration

Review Article

Colorectal

Annals of Surgical Treatment and Research 2023; 105(6): 341-352.

Published online: 29 November 2023

DOI: https://doi.org/10.4174/astr.2023.105.6.341

Unveiling the profound advantages of total neoadjuvant therapy in rectal cancer: a trailblazing exploration

Kyung Uk Jung¹

, Hyung Ook Kim¹

, Hungdai Kim¹

, Donghyoun Lee²

, Chinock Cheong³

; on the behalf of Korean Society of Korean Society of Coloproctology

¹Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.

²Department of Surgery, Jeju National University Hospital, Jeju National University College of Medicine, Jeju, Korea.

³Department of Surgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea.

Corresponding Author: Kyung Uk Jung. Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea. Tel: +82-2-2001-8408, Fax: +82-2-2001-8360, sahelgrean@gmail.com

Received 17 October 2023 Revised 29 October 2023 Accepted 29 October 2023

The Korean Surgical Society

https://creativecommons.org/licenses/by-nc/4.0/

Annals of Surgical Treatment and Research is an Open Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The standard treatments for locally advanced rectal cancer typically involved neoadjuvant therapy with either short-course radiation or long-course chemoradiation, followed by radical surgery and adjuvant chemotherapy. While the advancement of surgical techniques and the adoption of multimodal therapy have greatly contributed to reducing local failure, there has been limited improvement in overall survival, primarily due to the stagnation in systemic failure. In response to this challenge, a new strategy known as total neoadjuvant therapy (TNT) has emerged, involving the administration of both full-dose chemotherapy and radiation before surgery. It has shown promise in reducing systemic failure, enhancing tumor regression, and improving treatment adherence, ushering in a new era in the standard treatment of locally advanced rectal cancer. This review aims to summarize the evolution of multimodal treatments for locally advanced rectal cancer, ultimately converging into the current TNT strategy, and provides an assessment of the benefits and limitations of TNT based on available evidence, serving as a foundation for selecting the best treatment option.

Keywords: Adenocarcinoma, Chemotherapy, Neoadjuvant therapy, Radiotherapy, Rectal neoplasms

INTRODUCTION

Colorectal cancer is the third most common cancer worldwide, following breast and lung cancers, and it is the second most common cause of cancer-related death after lung cancer [1]. Globally, an estimated 1.6 million colorectal cancer patients are diagnosed each year, with rectal cancer patients accounting for over one-third of all cases in South Korea [2]. While the incidence and mortality rates of colorectal cancer have decreased in recent years in some developed countries, including Korea [3], there is a paradoxical increase in the number of young colorectal cancer patients under the age of 50 years, with an annual growth rate of approximately 1%–4% [4]. These patients more often present with tumors located in the rectum and at advanced stages of the disease, which complicates treatment [5].

Neoadjuvant therapy involving short-course radiation or long-course chemoradiation followed by total mesorectal excision (TME) and adjuvant chemotherapy are the current standard multimodal treatments for locally advanced rectal cancer. The establishment of the TME principle and the development of meticulous surgical techniques have contributed to a decrease in local recurrence rates to under 10% [6 7]. In addition, during the past decades, numerous randomized controlled trials (RCTs) have been conducted to determine standardized regimens for neoadjuvant or adjuvant therapy [8 9 10]. However, the survival outcome of locally advanced rectal cancer, even with the use of chemoradiation and TME, has remained relatively stable, without significant improvement. The decrease in mortality rates for rectal cancer has decelerated, which was mainly attributed to a high incidence of distant metastasis, ranging between 29% and 39% [11]. To overcome this period of stagnation, a new therapeutic strategy, total neoadjuvant therapy (TNT), aims to administer both a full dose of systemic chemotherapy and radiation before surgery. Theoretically, TNT facilitates tumor regression and inhibits tumor progression during the interval from radiation therapy to surgery [12 13]. Several RCTs are currently being conducted on TNT strategies globally. In this era of a paradigm shift toward TNT, we summarize and review the evolution of multimodal treatments for locally advanced rectal cancer, ultimately converging into the current TNT strategy.

EVOLUTION OF MULTIMODAL TREATMENT FOR LOCALLY ADVANCED RECTAL CANCER

For the past few decades, there have been several dramatic changes in the treatment of locally advanced rectal cancer, leading to better oncologic outcomes. One of the driving forces behind these changes has been the understanding of the importance of the circumferential resection margin (CRM) and subsequent advancements in surgical techniques, exemplified by Heald’s TME. The other key factor was the shift from single-modality treatment using surgery alone to a multimodal approach integrating radiation and chemotherapy.

Initially, radiation and chemotherapy were incorporated into the treatment regimen for rectal cancer independently. Radiation was primarily used for palliation before the 1960s, but in the 1970s, it began to be employed in the context of curative surgery with the purpose of downsizing preoperatively [14] or reducing local failure postoperatively [15 16]. Chemotherapy was also adopted as an adjuvant therapy around the 1970s, with a belief in its systemic effect. It was expected to both reduce local recurrence and enhance overall survival (OS) by controlling remnant cancer cells on the surgical site and disseminated micrometastases. During the 1980s and 1990s, a series of studies established concurrent chemoradiation as a superior approach compared with either treatment in isolation, and 5-fluorouracil (5-FU) based chemotherapy concurrent with pelvic radiation became the most common approach for resectable locally advanced rectal cancer. This combined modality treatment reduced local failure to about half compared with single-modality therapy and improved the survival rate by approximately 10% [17 18 19 20].

In 1997, the Swedish Rectal Cancer Trial demonstrated a clear benefit of neoadjuvant radiation compared with surgery alone, with a reduction of over half in the local recurrence rate and a significantly improved 5-year OS rate in the neoadjuvant radiation group. However, because the study was conducted during a period when TME was not yet widely adopted, the superior oncologic outcomes in the neoadjuvant radiation group were criticized as a result of radiation compensating for suboptimal surgery. In 2001, the Dutch Colorectal Cancer Trial demonstrated the effectiveness of neoadjuvant radiation in reducing local recurrence even in the context of standardized TME. While a survival benefit similar to that seen in the Swedish trial was not observed in the Dutch trial, the results of these 2 studies led to the acceptance of neoadjuvant radiation as an effective method for reducing local recurrence. Subsequent studies evaluating different types of radiation regimens have shown that combining preoperative radiation with 5-FU–based chemotherapy enhances local control effects, leading to the increased popularity of neoadjuvant chemoradiation using 5-FU–based regimens as radiosensitizers [21]. The addition of other agents such as oxaliplatin, irinotecan, or various monoclonal antibodies to a 5-FU–based radiosensitizer regimen was also explored. However, the outcomes were generally disappointing, resulting in increased toxicities without any improvement in sphincter preservation or pathological complete response (pCR) rate [22 23 24 25 26 27]. Only the German CAO/ARO/AIO-04 trial showed improvement in pCR rates and 3-year disease-free survival (DFS) associated with the addition of oxaliplatin, without increased toxicity [28]. However, this study had significant structural variations beyond the incorporation of oxaliplatin, suggesting that its results require careful interpretation.

In 2004, the German Colorectal Study Group reported the results of a landmark study that compared preoperative and postoperative chemoradiation [29]. The study demonstrated a significantly lower local recurrence rate, reduced toxicity, improved overall compliance, and a higher rate of sphincter preservation in the preoperative chemoradiation group. Despite its failure to demonstrate an OS benefit, the treatment protocol used in the German study formed the foundation of modern standard care for locally advanced rectal cancer. For the past 20 years, the standard of care for locally advanced rectal cancer has consisted of neoadjuvant chemoradiation followed by TME and adjuvant chemotherapy.

Nevertheless, experiments have continued to find more optimal regimens, encompassing factors such as radiation dosages, chemotherapy options, sequencing, and optimal timing of surgery. One of the prominent debates revolves around the effectiveness of preoperative short-course radiation versus long-course chemoradiation and the optimal timing of surgery. Conventional neoadjuvant chemoradiation with long-course radiation typically involves delivering 45–50.4 Gy in 1.8–2 Gy daily fractions over 5–6 weeks, followed by surgery within 4–8 weeks. By contrast, short-course radiation generally consists of delivering 25 Gy with 5 Gy daily fractions over 5 days, with surgery within a week after completing radiation. Traditionally, long-course chemoradiation was expected to be associated with enhanced tumor regression, which might translate into a higher rate of sphincter-preserving surgeries and a lower local recurrence rate. On the other hand, short-course radiation was expected to offer advantages in terms of patient compliance and cost-effectiveness due to its shorter schedule. In addition, the shorter interval between radiation and surgery was anticipated to prevent the development of micrometastases during the waiting period. In reality, long-course chemoradiation demonstrated a higher pCR rate and pathologic downstaging in several studies compared with short-course radiation, as expected. However, this approach did not result in a higher rate of sphincter-preserving surgeries or superior long-term oncologic outcomes [30 31]. Rather, it raised the question of the best timing for surgery after short-course radiation. The question was partially answered in the Stockholm III trial, which compared long-course radiation with a delay for surgery, short-course radiation without delay, and short-course radiation with a delay [32]. Short-course radiation followed by TME 4–8 weeks later showed a similar pCR rate compared with long-course radiation, without adding more surgical morbidity.

The other argument focused on the effectiveness of adjuvant chemotherapy following the completion of neoadjuvant chemoradiation and TME. Despite significant improvements in local control, none of the various strategies have definitively shown an association with enhanced OS. Systemic recurrence remains the main problem in patients with locally advanced rectal cancer, with a cumulative incidence of 30% over 10 years [33 34]. Adjuvant chemotherapy following neoadjuvant treatment and TME in the “standard” protocol has been administered with the purpose of suppressing systemic recurrence, but its effectiveness has fallen short of theoretical expectations. Several randomized trials such as EORTC 22921, Italian, and CHRONICLE comparing adjuvant chemotherapy after neoadjuvant radiation or chemoradiation with TME with surveillance alone failed to show a statistically significant benefit in terms of OS and the risk of distant recurrence with the addition of adjuvant chemotherapy [35 36 37]. One of the primary reasons for the ineffectiveness of adjuvant chemotherapy is poor compliance. Patients could not receive the recommended dose of chemotherapy in the appropriate time interval because of multiple factors, including toxicity, delays in starting treatment secondary to postoperative complications, disease progression, and patient refusal. The completion rates for adjuvant chemotherapy in the aforementioned 3 studies were barely around 50%. The potential progression of micrometastatic disease during the waiting period after neoadjuvant chemoradiation was also considered one reason for the persistent systemic failure of the standard protocol [38]. The need for a window period to achieve adequate tumor regression, along with the necessity for early chemotherapy to control micrometastatic disease in high-risk patients, has led to a new treatment strategy for locally advanced rectal cancer: TNT.

EVIDENCE FOR TOTAL NEOADJUVANT THERAPY

The concept of “TNT” for the treatment of locally advanced rectal cancer involves the administration of both radiation and chemotherapy before surgery. These strategies vary substantially in terms of radiation protocols and chemotherapy options. However, they all share the common feature of administering the full adjuvant dose of chemotherapy as part of neoadjuvant therapy, rather than lower radiosensitizing doses as used previously. Researchers of TNT hypothesized that early systemic chemotherapy might reduce the risk of systemic failure by controlling potential micrometastases, while simultaneously facilitating better protocol adherence, reducing toxicity, enhancing locoregional tumor regression, and consequently, leading to a survival benefit.

Total neoadjuvant therapy adopting short-course radiation vs. neoadjuvant chemoradiation

Table 1 shows indications, protocols, and findings of representative RCTs that used TNT adopting short-course radiation for rectal cancer. The Polish II trial, which initiated recruitment in 2008, was a pioneering study of TNT [39 40]. This trial compared preoperative short-course radiation followed by FOLFOX (5-FU, leucovorin, and oxaliplatin) chemotherapy with the standard long-course chemoradiation for the treatment of primary or locally recurrent fixed cT3 or cT4 rectal cancers. It reported lower acute toxicity (75% vs. 83%) and better OS at 3 years (73% vs. 65%) in the TNT group [39]. It also reported a higher pCR rate in the TNT group, although the difference did not reach statistical significance. This survival benefit disappeared at 8 years (DFS, 43% vs. 41%; OS, 49% in both groups) [40]; nevertheless, the lower toxicity, tendency toward enhanced tumor regression, a protocol adherence rate of up to 99%, and non-inferior oncologic outcomes observed in the TNT group have served as significant driving forces for numerous prospective studies on TNT.

The RAPIDO (Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation) trial played a pivotal role in the implementation of TNT [41]. In this trial, 920 patients with high-risk locally advanced rectal cancer (cT4, cN2, compromised CRM, and/or enlarged lateral pelvic lymph nodes) were randomized into either the TNT or standard treatment group. The TNT group received preoperative short-course radiation, sequential full-dose chemotherapy, and following TME, while the standard group underwent standard long-course neoadjuvant chemoradiation followed by TME and optional adjuvant chemotherapy. Chemotherapy for both groups consisted of CAPOX (capecitabine and oxaliplatin) or FOLFOX4. Three-year disease-related treatment failure, the primary endpoint of the study, was significantly lower in the TNT group (23.7% vs. 30.4%), mainly due to the reduced rate of distant metastasis, particularly liver metastases [42]. The TNT also showed a significant benefit in terms of pCR rate (28.4% vs. 14.3%). This finding aligns with previous evidence indicating that the addition of consolidation chemotherapy, composed of a 5-FU and oxaliplatin-based regimen, enhances the pCR rate [43].

Recently, the STELLAR (Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer) trial reported results from a randomized comparison of preoperative short-course radiation followed by 4 cycles of CAPOX and standard long-course chemoradiation for distal or middle-third primary cT3–4 and/or lymph node-positive rectal cancer. Both groups underwent TME 6–8 weeks after preoperative treatment, followed by adjuvant CAPOX. The trial demonstrated significant benefits in the pCR rate (22.5% vs. 12.6%) and 3-year OS (86.5% vs. 75.1%) in the TNT group [44]. Although TNT was associated with an approximately twofold higher rate of grade 3-plus toxicity compared with standard treatment, the compliance rate for neoadjuvant chemotherapy was up to 98%.

Total neoadjuvant therapy adopting long-course radiation vs. neoadjuvant chemoradiation

The TNT protocol, which adopted long-course chemoradiation with similar fractions and doses as the standard neoadjuvant treatment, was also developed and examined around the same time as the short-course radiation TNT. In 2006, the Spanish Grupo Cancer de Recto initiated patient recruitment for a phase II RCT that compared long-course chemoradiation TNT to the standard treatment [45 46]. Patients with distal or middle third T3–4 and/or lymph node-positive rectal cancer were randomly assigned to 4 cycles of CAPOX followed by chemoradiation and surgery, or chemoradiation, surgery, and postoperative adjuvant CAPOX (Table 2). The primary endpoint was the pCR rate, which did not differ statistically between the 2 groups (14.3% vs. 13.5%). Although no differences in DFS or OS were demonstrated at the 5-year follow-up published in 2015, the higher compliance and more favorable acute toxicity associated with the TNT strategy shed light on the use of the long-course chemoradiation TNT protocol [45 46].

Similar to how the RAPIDO trial became the hallmark of TNT with a short-course radiation protocol, the UNICANCER-PRODIGE 23 (Neoadjuvant Chemotherapy with FOLFIRINOX and Preoperative Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer; PRODIGE 23) trial showed promising results for TNT with a long-course chemoradiation protocol [47]. In this trial, TNT consisted of 6 cycles of FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) followed by long-course chemoradiation and TME, whereas the standard of care included long-course chemoradiation and TME. Both groups received adjuvant chemotherapy, which consisted of CAPOX or FOLFOX. However, the duration of adjuvant chemotherapy differed between the groups, with 3 months for the TNT group and 6 months for the standard care group. After a median follow-up of about 4 years, 3-year DFS was significantly improved in the TNT group (76% vs. 69%). As in the RAPIDO trial, the difference was mainly attributable to the reduction in systemic recurrence. The pCR rate was also significantly higher in the TNT group (27.8% vs. 12.1%).

Sequence of total neoadjuvant therapy: induction vs. consolidation

The sequence of TNT regimens is classified as either induction (chemotherapy first) or consolidation (radiation first). It has not yet been determined which sequence is superior, and 2 RCTs examined induction and consolidation chemotherapy as part of TNT. Both of these studies adopted the long-course chemoradiation TNT protocol.

The phase II CAO/ARO/AIO-12 (Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy) trial compared 4 cycles of FOLFOX before (induction) or after (consolidation) long-course chemoradiation (Table 3) [48 49]. The consolidation TNT protocol was associated with better adherence to radiation (97% vs. 91%) but worse adherence to chemotherapy compared with the induction TNT protocol (85% vs. 92%). The pCR rate was significantly higher in the consolidation group (25% vs. 17%), with slightly lower rates of acute toxicity (27% vs. 37%) and comparable rates of chronic toxicity (9.9% vs. 11.8%). There was no significant difference in 3-year DFS and OS between the 2 groups, with a median follow-up of 43 months.

The OPRA (Organ Preservation of Rectal Adenocarcinoma) phase II trial also compared induction and consolidation TNT protocols using FOLFOX or CAPOX [50]. Both groups received 8 cycles of FOLFOX or 5 cycles of CAPOX chemotherapy before or after long-course chemoradiation, and they were restaged about 8 weeks after completing TNT. The primary goal of the OPRA trial was to determine whether patients with a good response could be managed without surgery, so once the response was graded as complete or near-complete, patients followed a watch-and-wait strategy with close follow-up. If tumor regrowth was detected during follow-up, patients underwent salvage procedures, including surgical resection. The 3-year DFS rate was identical in both groups (76%). After 3 years of follow-up, the TME-free survival rate was significantly higher in the consolidation group (60% vs. 47%), with no difference in the 3-year DFS rate (76% in both groups).

Neoadjuvant chemotherapy in the context of total neoadjuvant therapy

In 2023, the results of the PROSPECT (Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery) trial were reported. Patients with cT2N+ and cT3 rectal cancer were randomized into either the FOLFOX group or the conventional neoadjuvant chemoradiation group. In the FOLFOX group, patients received 6 cycles of mFOLFOX6 and were evaluated for tumor regression before undergoing surgery. If a patient could not complete at least 5 cycles of FOLFOX or if the primary tumor did not decrease by at least 20%, they received chemoradiation before surgery. Postoperative chemoradiation was recommended when R0 resection was not possible. Postoperative adjuvant chemotherapy was recommended for both groups but was not mandatory. The results showed that most of the patients in the FOLFOX group achieved a minimum of 20% tumor regression, with only 9.1% receiving additional chemoradiation before surgery. The 5-year OS (89.5% vs. 90.2%) and local recurrence rate (1.8% vs. 1.6%) were not significantly different between the 2 groups [51]. Acute toxicity during neoadjuvant therapy was significantly higher in the FOLFOX group (41.0% vs. 22.8%). However, the authors argued that the acute toxic effects reflected the longer treatment period in the FOLFOX group. Moreover, the FOLFOX group showed a significantly lower rate of fatigue and neuropathy and better sexual function at 12 months after surgery [52].

Immunologic agent in the context of total neoadjuvant therapy

Recently, the potential benefits of immunologic agents were examined in the context of TNT. In the NRG-GI002 trial, the addition of the neoadjuvant and adjuvant programmed cell death (PD)-ligand 1 blocker pembrolizumab to the induction FOLFOX TNT for distal, bulky, and high risk of metastatic rectal cancer was not associated with increased toxicity, but it could not demonstrate additional advantages in terms of tumor regression [53]. However, more recently, Cercek et al. [54] reported promising results of a neoadjuvant anti-PD-1 monoclonal antibody, dostarlimab, for mismatch repair deficit locally advanced rectal cancer. The trial initially planned to examine the effect of the addition of dostarlimab to the neoadjuvant chemoradiation in the context of TNT. However, the treatment did not progress to the chemoradiation stage because all 12 patients (100%) achieved a complete clinical response after anti-PD-1 treatment [54].

INTERPRETING TOTAL NEOADJUVANT THERAPY STUDY RESULTS AND FUTURE PERSPECTIVES

The late 2010s and early 2020s witnessed the emergence of the TNT strategy, ushering in a new era in the standard treatment of locally advanced rectal cancer. Multiple randomized trials on TNT have reported their long-term results [40 41 42 44 47 48 49 50 52], and a multitude of meta-analyses and reviews that interpret the results have also been published [55 56 57]. The NCCN (National Comprehensive Cancer Network) guidelines first endorsed the TNT strategy for both CRM-threatening and CRM-negative tumors in their 2022 guidelines [58]. TNT has emerged as a new alternative to the long-standing standard neoadjuvant therapy, challenging its status as the sole standard treatment. However, without excessive enthusiasm, we have to carefully interpret the results of the studies.

The theoretical benefits of TNT are as follows: early administration of a systemic dose of chemotherapy would prevent the progression of micrometastases into overt metastatic disease during the waiting period. The efficacy of chemotherapy might improve because the vasculature remains intact before surgery. The combination of neoadjuvant chemotherapy or chemoradiation with full-dose chemotherapy might enhance tumor regression, potentially facilitating both radical resection and sphincter-sparing surgery. Furthermore, patients may tolerate TNT better due to their preserved overall condition compared with the postoperative period, potentially leading to increased adherence to the entire treatment protocol. Some benefits have been proven, while others have remained theoretical expectations.

RAPIDO and PRODIGE 23, 2 hallmark phase 3 RCTs, played a pivotal role in the adoption of TNT. Representing short-course radiation and long-course chemoradiation TNT protocols, respectively, they demonstrated the feasibility and efficacy of TNT with an approximately twofold higher pCR rate and significantly increased DFS in the TNT group compared with conventional neoadjuvant chemoradiation. These findings were mainly attributed to a significant reduction in distant metastasis. However, decreased systemic relapse did not lead to a significant OS benefit at around 50 months of follow-up. Interestingly, the enhanced pCR rate also did not lead to a significant reduction in the local recurrence rate or an increase in the number of R0 resections and sphincter-preserving surgeries. Enhanced pCR was mirrored in the more recent study STELLAR, with significantly increased OS in the TNT group without any difference in DFS at 35 months of follow-up.

One possible explanation for the persistent local recurrence rate in TNT is the existence of a subset of nonresponders who may actually progress during the extended neoadjuvant therapy period, thus offsetting the benefit derived from the pCR achievement group. Of note, the proportion of patients with pT4 disease (a more advanced stage, which can be related to the higher proportion of nonresponders) was somewhat higher in the TNT arm compared with the standard-of-care arm consistently in the RAPIDO, PRODIGE 23, and STELLAR trials, although the difference did not reach a statistically significant level.

For the lack of OS benefits in the 2 former studies, RAPIDO and PRODIGE 23, their immature follow-up may serve as an excuse. The influence of distant metastases on OS is not immediately evident and requires a certain amount of time. Furthermore, the availability of salvage treatment, the overall health status of patients, accessibility to medical resources, and the quality of general supportive care have improved significantly, which may even further extend the time interval from systemic relapse to fatal event for patients. By contrast, there could be opposing doubts regarding the significantly improved OS in the TNT group in the STELLAR trial. The median follow-up of the STELLAR trial was only 35 months, which is relatively short. As seen in the Polish II trial, significant 3-year OS benefits disappeared in subsequent reports at 8 years, and the significant OS benefit reported in 2020 might also disappear in long-term follow-up. Regardless of which theoretical explanation may seem more plausible, in the end, only time will provide the right answer to the question.

A significant subset of patients with rectal cancer, especially those with bulky low-lying tumors, cannot avoid an abdominoperineal resection (APR). The evolution of multimodal approaches and various types of surgical techniques has allowed for sphincter-saving surgery in some cases treated with APR in previous decades [59 60 61 62]. However, even in patients who successfully preserve their sphincter, persistent bowel, bladder, and sexual dysfunction following TME commonly impairs their quality of life [63 64 65 66]. With these findings, there have been continuous efforts to preserve the organ itself beyond the sphincter only, including local excision or nonoperative management and surveillance [67 68 69]. To support such an approach, achieving optimal tumor regression through highly multimodal treatments is essential. The OPRA trial, conducted in this context, compared the effects of induction and consolidation TNT, and it demonstrated a higher rate of organ preservation in the consolidation TNT group. While the OPRA trial focused on locally advanced tumors of AJCC (American Joint Committee on Cancer) stage II or III, the enhanced tumor regression effect of the TNT approach is expected to be beneficial for the advancement of organ-sparing efforts in early lower-lying rectal cancer as well [70 71 72 73]. However, a watch-and-wait policy is not currently considered a standard of care or routinely recommended in practice. It should be approached with caution and usually within the context of a clinical trial.

By contrast, there have been concerns about the short-term and long-term toxicity of radiation itself, even without the impact of surgery. Pelvic radiation can lead to late complications, including more severe adverse effects such as pelvic fracture, second cancers, and myelosuppression, in addition to persistent functional deterioration [74]. The PROSPECT trial investigated whether the tumor regression effect of neoadjuvant treatment could be preserved without radiation. The results demonstrated that approximately 90% of the study population could sidestep radiation, leading to improved functional outcomes after TME compared with the conventional neoadjuvant chemoradiation group.

While OPRA focused on organ preservation and PROSPECT focused on the omission of radiation, a common and crucial aspect in both studies was the selective application of multimodal treatment based on restaging. These efforts laid the foundation for the future of personalized medicine in the context of rectal cancer treatment. Although the total number of cases was small, the surprisingly favorable effect of neoadjuvant immunologic agents on mismatch repair deficit rectal cancer also emphasizes the need for personalized medicine [75].

Several unanswered questions remain that require further investigation to optimize TNT strategies. While the indications for the studies all included “locally advanced rectal cancer,” the composition of these subsets varies depending on the study. For example, the RAPIDO trial includes approximately twice as many cT4 cancers compared with the STELLAR trial, which will undoubtedly impact the study results. The optimal regimen and duration of systemic chemotherapy within the TNT approach have yet to be determined. While most TNT studies utilized 5-FU and oxaliplatin-based regimens, PRODIGE 23 opted for FOLFIRINOX. The duration of neoadjuvant chemotherapy also varies among studies and remains a subject of debate. Currently, there has not been a head-to-head comparison of different preoperative chemotherapy regimens within the context of TNT. Consequently, the choice of the chemotherapeutic regimen is at the discretion of the treating physician. It’s also worth noting that there hasn’t been a direct 1:1 comparison between short-course radiation and long-course chemoradiation within the context of TNT. In addition, short-course radiation was not used in the studies comparing induction and consolidation protocols, so evidence is lacking for this treatment sequence. Concerns about overtreatment have been present since the inception of neoadjuvant treatments even before the rise of TNT, and surveillance protocols are not standardized. Further investigation into the predictors of nonresponders to TNT and the subsequent recurrence is warranted, similar to the era of neoadjuvant therapy in the past [76 77].

CONCLUSION

The evolution of a treatment paradigm for locally advanced rectal cancer is a very good example of how multimodal and multidisciplinary management can improve the outcomes of patients with cancer. The introduction of TNT has revolutionized the landscape of rectal cancer treatment, bringing substantial benefits in terms of tumor regression and DFS. Recent trials in the context of TNT, such as OPRA and PROSPECT, have highlighted the potential for more customized treatment approaches that can significantly improve a patient’s functional outcomes without compromising oncologic results. The promising effect of immunologic agents for a specific subset of patients also emphasizes the need for treatment stratification. Further long-term follow-up data and research to identify specific subsets that truly benefit are still needed to confirm the full advantages of TNT. However, the increasing number of treatment options, in conjunction with meticulous restaging processes and comprehensive surveillance, would bring us closer to the ultimate goal of personalized medicine.

Notes

Fund/Grant Support: None.

Conflict of Interest: No potential conflict of interest relevant to this article was reported.

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Table 1

Landmark trials for TNT adopting short-course radiation

TNT, total neoadjuvant therapy; RAPIDO, Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation trial; STELLAR, Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer; EMVI, extramural vascular invasion; MRF, mesorectal fascia involvement; LPLN, lateral pelvic lymph node involvement; DRTF, disease-related treatment failure; DFS, disease-free survival; SCRT, short-course radiation; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; CRT, chemoradiation; CAPOX, capecitabine and oxaliplatin; CAPE, capecitabine; NR, not reported; pCR, pathological complete response.

^a)Statistically significant outcome (P < 0.05). ^b)Disease-related treatment failure. ^c)Neoadjuvant chemotherapy only.

Table 2

Randomized controlled trials for TNT adopting long-course chemoradiation

TNT, total neoadjuvant therapy; GCR, Grupo Cancer de Recto; PRODIGE 23, Neoadjuvant Chemotherapy with FOLFIRINOX and Preoperative Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer; DFS, disease-free survival; CAPOX, capecitabine and oxaliplatin; CRT, chemoradiation; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; CAPE, capecitabine; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; pCR, pathologic complete response.

^a)Statistically significant outcome (P < 0.05).

Table 3

Randomized controlled trials comparing induction or consolidation TNT regimens

TNT, total neoadjuvant therapy; CAO/ARO/AIO-12, Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy; OPRA, Organ Preservation of Rectal Adenocarcinoma; AV, anal verge; AJCC, American Joint Committee on Cancer; DFS, disease-free survival; FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; CRT, chemoradiation; CAPE, capecitabine; WW, wait and watch; NR, not reported; pCR, pathologic complete response.

^a)Statistically significant outcome (P < 0.05). ^b)Inverse of TME-free survival.

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