Neoadjuvant Treatment in Rectal Cancer

Abstract

A major advance in rectal cancer was the evidence supporting short-course radiotherapy and long-course chemoradiotherapy. Both have been shown to improve local outcomes. Total neoadjuvant therapy (TNT) is the new kid on the block that provides further benefit of improving local responses as well as reducing systemic relapses, thus increasing overall survival. Details of the four key TNT trials are discussed. They pave the way for nonoperative management for patients who achieve clinical complete responses.

Keywords

TNT - NOM - LCCRT - SCRT

R. Srinath Bharadwaj

Introduction

Rectal cancer is one of the most common types of cancer in India, with an incidence rate of approximately 12.7 cases per 100,000 people per year.[1] According to a study conducted by the Indian Council of Medical Research (ICMR), the age-standardized incidence rate of colorectal cancer, which includes both colon and rectal cancer, in India is 9.81 per 100,000 population.[2] The incidence of rectal cancer in India has been increasing over the past few decades, and this trend is expected to continue in the coming years. A study conducted by Chandra et al found that the incidence of rectal cancer in India increased from 1.9 cases per 100,000 people in 1982 to 6.7 cases per 100,000 people in 2005.[3]

Total mesorectal excision (TME) is a key technical advance that has dramatically reduced the incidence of local recurrence (from up to 40% to just 3.7%).[4] The same group also published the Basingstoke experience in more than 500 patients, which reconfirmed the low rates of recurrence.[5] It also showed better overall survival (OS; 68% at 5 years).

Two approaches currently established are short-course radiotherapy (SCRT) and long-course chemoradiotherapy (LCCRT). Both of them can improve local outcomes for patients having rectal cancer. Total neoadjuvant therapy (TNT) offers advantages over both SCRT and LCCRT by increasing rates of local responses as well as reducing systemic relapses. Nonoperative management (NOM) is also gaining significance, especially for patients who achieve clinical complete responses. The principle of neoadjuvant chemotherapy is also extended to locally advanced colon cancer with proficient mismatch repair. Neoadjuvant immunotherapy is gaining traction in rectal and colon cancer patients with deficient mismatch repair.

Indications for Neoadjuvant Treatment in Rectal Cancer

Patients with advanced rectal cancer—defined as T3 or T4 tumors, circumferential resection margin (CRM) involvement, or nodal involvement—have a poor prognosis for survival and are at high risk of recurrence. Some also include cT3a/b or even cT2 when distally located. Extramural venous invasion (EMVI) is another independent poor prognostic factor that suggests such patients should be considered for neoadjuvant therapy.[6] [7]

Neoadjuvant therapy can downstage these tumors, reduce their size, and improve the probability of achieving a complete resection with negative margins. Neoadjuvant treatment may also raise the likelihood of sphincter preservation, enhance local control rates, and lower the risk of distant metastasis by eliminating micrometastases and decreasing the quantity of viable tumor cells. Whether such an approach also increases OS was an unanswered question for a long time.[8] [9] [10]

SCRT consists of 25 Gy given in five fractions. LCCRT includes 45 to 50 Gy given in 25 to 28 fractions with concurrent low-dose fluoropyrimidine-based chemotherapy, which functions as a radiosensitizer (capecitabine having been proven to be equivalent to %-fluorouracil [5FU]). Braendengen et al reported on 207 patients with who had nonresectable primary cT4 or locally recurrent rectal cancers.[11] They were randomized to preoperative radiotherapy at a dose of 50 Gy ± concomitant chemotherapy. The arm with addition of chemotherapy was found to have a higher R0 rate (84 vs. 64%, p = 0.009), better 5-year local control rates (82 vs. 67%, p = 0.030), and higher cancer-specific OS (72 vs. 55%, p = 0.020).

S-1 (fluoropyrimidine derivative) is also effective as the chemotherapy component of LCCRT. A study of 60 patients with clinical stage II or III rectal cancer gave S-1 at a dose of 80 mg/m²/d for 28 consecutive days plus radiation therapy of 50.4 Gy in 28 fractions over 5.5 weeks.[12] The tumor response rate was 83.3%, pathologic complete response (pCR) rate was 25.0%, 3-year disease-free survival (DFS) rate was 72.0%, and OS rate was 80.0%.

No direct comparison between LCCRT and SCRT has been reported. Hence, we do not know which is better in terms of late toxicities and quality of life (QoL).[13] [14] [15]

The Swedish Rectal Cancer Trial found that SCRT gave better survival rates and lower incidence of local recurrence compared with surgery alone.[16]

A 12-year follow-up of the Dutch TME trial showed that patients with stage III disease and a negative CRM who received radiation therapy before surgery had better 10-year survival rates compared with those who received surgery alone.[8] Similar findings have been reported by studies from Poland, Australia, and New Zealand[17] [18]

A systematic review conducted in 2014 identified 16 studies (randomized controlled trials [RCTs], phase II trials, and retrospective studies) that evaluated the interval between SCRT and resection of rectal cancer. The immediate-surgery group (1- to 2-week interval) had lower rates of severe acute postradiation toxicity, but higher rates of minor postoperative complications than the delayed surgery group (5- to 13-week interval). The pCR rates were significantly higher in the delayed-surgery group, with no differences in sphincter preservation and R0 resection rates.[19]

The Stockholm III trial also investigated the optimal interval between SCRT and surgery in 455 patients within the two-arm randomization, and showed similar oncologic outcomes and long-term health-related QoL between the immediate-surgery group and 4- to 8-week delay group following SCRT. However, a lower rate of postoperative complications was observed in the group that delayed surgery following SCRT (53 vs. 41%; odds ratio [OR], 0.61; 95% confidence interval [CI], 0.45–0.83; p = 0.001).[20]

Benefits of Neoadjuvant Treatment in Rectal Cancer

Several studies have reported that neoadjuvant therapy can reduce tumor size and nodal involvement, leading to higher rates of complete response and sphincter preservation.[21] [22] This is particularly important for patients with tumors located in the lower rectum, as it can reduce the need for abdominoperineal resection (APR), a surgery that involves removing the anus and the rectum, leading to permanent colostomy. Neoadjuvant therapy has also been shown to improve local control rates and reduce the risk of distant metastasis. The use of neoadjuvant CRT (nCRT) in rectal cancer has been associated with a significant reduction in local recurrence rates, ranging from 8 to 11%, compared with surgery alone, which has been reported to have a local recurrence rate of up to 30%.[23] [24] The use of neoadjuvant therapy has also been shown to improve OS and DFS in rectal cancer patients. A meta-analysis of 14 RCTs investigating the use of neoadjuvant therapy in rectal cancer patients found a significant improvement in 5-year OS and DFS in patients receiving neoadjuvant therapy compared with surgery alone.[25]

Drawbacks of Neoadjuvant Treatment in Rectal Cancer

Despite its benefits, neoadjuvant therapy is not without potential drawbacks. One of the most significant concerns is the potential for increased toxicity and adverse effects from the treatment, including gastrointestinal and genitourinary toxicity, hematologic toxicity, and radiation-induced complications such as proctitis and sexual dysfunction. However, many of these adverse effects can be managed or minimized with appropriate supportive care and close monitoring. Another potential drawback of neoadjuvant therapy is the potential for disease progression during the treatment period, leading to delays in surgery or the need for additional therapy. However, recent studies have suggested that SCRT followed by immediate surgery may be a feasible and effective alternative to longer neoadjuvant treatment regimens, reducing the risk of disease progression and avoiding prolonged treatment periods.[26] [27]

Total Neoadjuvant Therapy as an Alternative to SCRT or CRT

TNT delivers full-dose adjuvant therapy preoperatively.[28] The objective was to improve compliance, reduce systemic recurrence, and provide superior OS. The results from the four most important trails are shown in [Table 1] (PRODIGE23, STELLAR, RAPIDO, and OPRA).[29] [30] [31] [32] [33] [34] [35]

Table 1 Comparison of four trails using TNT in the study arm

Study name (N)	Primary endpoint	TNT arm	Control arm	pCR study	pCR control	DFS study	DFS control	R0 resection study	R0 resection control
PRODIGE 23 (N = 461)	3-y DFS	CT, CRT, TME	CRT, TME	28	12	76	69	95	94
RAPIDO (N = 920)	3-y DRTF	SCRT, CT, TME	CT, CRT, TME	28	14	23.7	30.4	90	90
OPRA (N = 324)	DFS	CT, CRT, TME	CRT, CT, TME	NA	NA	76	76	91	88
STELLAR (N = 599)	DFS	SCRT, CT, TME	CRT, TME	17.2	13.9	64.5	62.3	91.5	87.8

Abbreviations: CRT, long-course chemoradiotherapy; CT, chemotherapy; DFS, disease-free survival; NA, not available; pCR, pathological complete response; R0, zero residual disease at surgery; SCRT, short-course radiotherapy; TME, total mesorectal excision; TNT, total neoadjuvant therapy.

TNT is better than SCRT or LCCRT for pCR and for systemic relapses.

The 2017 European Society of Medical Oncology (ESMO) guideline recommend TNT for patients with cT3 cancers with Meso Rectal Fascia positive (MRF+), cT4 cancers, and patients with involvement of lateral lymph nodes. The National Comprehensive Cancer Network (NCCN) guidelines published subsequently include TNT as an option for less advanced tumors as well.[6] [7]

Several recent studies have investigated a de-escalation of the neoadjuvant chemotherapy component of TNT—using a single agent or the elimination of the radiotherapy component.

In the PROSPECT trial, a total of 1,194 patients were randomized to receive either neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or CRT.[36] [37] The 5-year DFS was 80.8% in the FOLFOX arm and 78.6% in the CRT arm. We also have the preliminary results of the CONVERT trial where neoadjuvant CAPOX was compared with CRT.[38] The FOWARC trial studies whether neoadjuvant FOLFOX alone or in combination with radiotherapy was superior to CRT in terms of 3-year DFS.[39] There was no differences in R0 resection rates, 3-year local recurrence rates, DFS, or OS.[40]

Surgical de-escalation has also been explored, in selected cases—even leading to the concept of NOM.

The GRECCAR publication is a prospective observational study in patients with complete clinical response (cCR) or near-complete response. They underwent local excision (LE) after CRT.[41] Of the 257 patients who underwent LE, need for TME was found in 104 (42%) patients. Interestingly, patients undergoing completion TME had higher rates of systemic relapse. Another study of 55 patients showed that organ preservation was possible in 70% patients.[42] The Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC) trial is a further extension for patients who opt for organ preservation. They were randomized to SCRT or LCCRT. Those who achieved cCR were offered NOM and those with partial response were given LE.[43]

The major potential advantages of NOM are avoiding the long-term sequelae of surgical morbidity (following major rectal resection) and their impact on functionality and QoL.[44]

The term cCR applies to patients with no residual neoplastic tissue upon clinical examination and imaging modalities as well as absence of lymph node involvement on magnetic resonance imaging (MRI).

In a systematic review and meta-analysis of 22 studies involving 1,048 patients with rectal cancer who underwent NOM after achieving a cCR with nCRT, DFS and OS rates at 2 years were 88.4 and 97.7%, respectively.[45] In a separate investigation encompassing 117 patients who underwent NOM subsequent to attaining a cCR via nCRT, the rate of local recurrence-free survival (LRFS) at the 5-year mark was 92%, while the rate of OS at the 5-year mark was 87%.[46]

Numerous factors have been correlated with favorable outcomes subsequent to NOM, encompassing tumor location, size, and depth of invasion, alongside the existence of dubious lymph nodes prior to nCRT.[47] Superior outcomes were observed in patients who presented with tumors situated in the upper rectum, smaller tumors measuring less than 3 cm, and tumors that did not exhibit invasiveness beyond the muscularis propria subsequent to NOM. Furthermore, it was observed that patients devoid of any dubious lymph nodes on MRI prior to nCRT exhibited a greater likelihood of attaining a cCR and a diminished hazard of relapse.[47]

Functional outcomes important in rectal cancer management are those related to bowel, urinary, and sexual functions. nCRT followed by TME surgery has been documented to result in bowel dysfunction of 42 to 82.6%, urinary dysfunction of 20 to 77%, and sexual dysfunction of 29 to 72%.[48] [49] [50] [51] The documentation of better health-related QoL and functional outcomes following neoadjuvant chemoradiation and NOM is steadily growing.[52]

While NOM presents a promising avenue for rectal cancer patients who attain a cCR following nCRT, it necessitates meticulous patient selection and vigilant monitoring through frequent imaging modalities to promptly identify any indications of disease recurrence.

An attempt to improve on NOM is the use of hyperthermic intraperitoneal chemotherapy (HIPEC). The Dutch COPOPEC and Spanish multicenter clinical trial HIPECT4 showed that it resulted in better locoregional control. However, DFS and OS remain unchanged.[53] [54]

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors are a type of cancer immunotherapy that works by blocking the interaction between immune checkpoint proteins and their receptors, thus enhancing the ability of the immune system to recognize and attack cancer cells. In recent years, there has been growing interest in the use of immune checkpoint inhibitors in the treatment of locally advanced rectal cancer. Several clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors in this setting. For example, the CheckMate 142 trial was a phase II trial that evaluated the use of the immune checkpoint inhibitors nivolumab and ipilimumab in patients with metastatic colorectal cancer, including a subset with locally advanced rectal cancer. The study found that the combination of nivolumab and ipilimumab resulted in a response rate of 55% in patients with deficient mismatch repair (dMMR) metastatic colorectal cancer, including a complete response rate of 13%.[55]

Another study, the KEYNOTE-177 trial, evaluated the use of the immune checkpoint inhibitor pembrolizumab as a first-line treatment for patients with advanced or metastatic colorectal cancer with high microsatellite instability (MSI-H) or dMMR status. The study found that patients who received pembrolizumab had a significantly longer progression-free survival compared with those who received chemotherapy (16.5 vs. 8.2 months).[56]

In a small phase II study of patients with stage II or III rectal cancer with dMMR/MSI-H, the neoadjuvant therapy potential of dostarlimab-gxly, a checkpoint inhibitor, was also explored.[57] During the study, patients were initially treated with dostarlimab-gxly for 6 months, and CRT and surgery were scheduled for those with residual disease. Astonishingly, all 12 patients in the trial demonstrated a cCR to dostarlimab-gxly, and no patients required CRT or surgery at the time of publication. During the follow-up period, which ranged from 6 to 25 months, there were no reports of progression or recurrence.

Despite these promising results, the use of immune checkpoint inhibitors in locally advanced rectal cancer is still considered investigational and is currently being evaluated in ongoing clinical trials. For example, the NRG GI002 trial is a phase II trial that is currently investigating the use of the immune checkpoint inhibitor durvalumab in combination with chemoradiation therapy in patients with locally advanced rectal cancer.[58] In conclusion, there is growing interest in the use of immune checkpoint inhibitors in the treatment of locally advanced rectal cancer, and early data from clinical trials suggest that these agents may be effective in this setting. However, more research is needed to determine the optimal patient selection, dosing, and sequencing of these agents in combination with other treatments such as chemoradiation therapy. Finally, neoadjuvant immunotherapy is gaining importance too, especially in those with dMMR colorectal cancer.[59] Only time will tell whether it will ever replace surgical intervention and become part of NOM.

Pembrolizumab has an established role in the management of solid tumors having MSI-H and/or dMMR cancers. A recent study with the majority of colorectal cancer patients (27/35) documented the best response rate of 82% and pCR rate of 65% (in those who underwent surgery).[60] Ten of 35 cases continued on pembrolizumab and opted for NOM (no surgical resection). Disease progression was found in six patients, all of whom were able to undergo salvage resection. These data cemented the value of pembrolizumab in neoadjuvant therapy of rectal cancer.

PD-1 antibodies have also demonstrated benefit in neoadjuvant setting of patients with proficient mismatch repair (pMMR) genes. Addition of sintilimab in the study arm of a randomized phase 2 study involved a total of 134 cases.[61] The complete response rate (primary end point) was 26.9% in the control arm and 44.8% with the addition of sintilimab.

This differs from the first report of dostarlimab for dMMR rectal cancer in which all 12 patients had a radiographic complete response. And more recently, the same is reconfirmed in 42 patients. Sustained cCR for 12 months was observed in 24 patients with a median follow-up of 26.3 months.[62]

Conclusion

Neoadjuvant therapy has emerged as a valuable approach in the management of rectal cancer, offering the potential for improved outcomes and increased rates of complete response and sphincter preservation. The use of neoadjuvant therapy is supported by a large body of evidence from clinical trials, which have demonstrated its efficacy in downstaging tumors, improving local control rates, and reducing the risk of recurrence and distant metastasis. Despite potential drawbacks, such as increased toxicity and the potential for disease progression, the benefits of neoadjuvant therapy in rectal cancer are clear, and its use is likely to become more widespread as newer, more effective treatment strategies continue to emerge, especially the NOM strategy and the role of neoadjuvant immunotherapy [Table 2].[57] [60] [61] [62] [63] [64]

Table 2 Take-home messages (neoadjuvant treatment in rectal cancer)[57] [60] [61] [62] [63] [64] [65]

1	The RAPIDO protocol is more suited for non-T4 tumors
2	The PRODIGE protocol is more suited for patients with N2/EMVI disease
3	NOM is unlikely to be applicable to patients with T4b because they have least chance of achieving CCR
4	The OPERA trial shows how NOM can be used with a 3-y organ preservation benefit for patients with early (CT2–cT3) stage disease whose tumors are <3 cm in size
5	Meta-analysis of various PD-1 inhibitors (including sintilimab, toripalimab, camrelizumab, avelumab, pembrolizumab, and tislelizumab) have reported benefit either as single agents or in combination and results in a better pCR rates with low incidences of immune-related adverse events (irAEs), especially for colorectal patients harboring MSI-H/dMMR tumors
6	More data are now available with dostarlimab (N = 48). Current data suggest, it will become the most effect immunotherapy for deficient mismatch repair (dMMR), locally advanced cancer, especially rectal (and endometrial) cancers
7	Sintilimab has been shown to give superior results even in proficient MMR (pMMR) tumors
8	Neoadjuvant pembrolizumab leads to better pathologic, radiographic, and endoscopic response rates, suggesting a prominent role in NOM strategies and organ preservation

Abbreviations: c, clinical; CCR, clinical complete remission; EMVI, extramural venous invasion; MSI-H, high microsatellite instability; N, lymph node; NOM, nonoperative management; pCR, pathologic complete response; T, tumor stage.

Note: RAPIDO, PRODIGE and OPERA are acronyms of clinical trials whose details are mentioned in the corresponding references.

Conflict of Interest

None declared.

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Publication History

Article published online:
28 January 2025