Non-operative Management of Rectal Cancer with Adjuvant Chemotherapy after Chemoradiotherapy (NORMANDY): Prospective Study

Article information

Cancer Res Treat. 2026;58(2):573-580

Publication date (electronic) : 2025 May 15

doi : https://doi.org/10.4143/crt.2025.148

Hyebin Lee¹, Hyung Ook Kim², Jason Joon Bock Lee¹, In-Gu Do³, Heon-Ju Kwon⁴, Mi Sung Kim⁴, Soo-Kyung Park⁵, Hyo-Joon Yang⁵, Yoon Suk Jung⁵, Jung Ho Park⁵, Dong-Il Park⁵, Kyung Uk Jung², Eo Jin Kim⁶, Dong-Hoe Koo^,6, Hungdai Kim^,2, Ho-Kyung Chun^2,7, KBSMC Colorectal Cancer Team, Gastrointestinal Cancer Center

¹Department of Radiation Oncology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

²Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

³Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

⁴Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

⁵Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

⁶Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

⁷Department of Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju, Korea

Correspondence: Dong-Hoe Koo, Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea Tel: 82-2-2001-8330 E-mail: dhkoo.smc@gmail.com

Co-correspondence: Hungdai Kim, Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea Tel: 82-2-2001-8330 E-mail: hungdai.kim@samsung.com

*Hyebin Lee and Hyung Ook Kim contributed equally to this work.

Received 2025 February 8; Accepted 2025 May 13.

Abstract

Introduction

Non-operative management (NOM) for rectal cancer, pioneered by Dr. Angelita Habr-Gama, has transformed the standard approach for treating patients achieving clinical complete response (cCR) following neoadjuvant chemoradiotherapy (CRT) [1]. This innovative approach highlighted the importance of rigorous patient selection, close follow-up, and personalized treatment strategies, providing an opportunity to preserve rectal function and improve quality of life [2,3].

The NOM approach offers several advantages over traditional surgical management. Most notably, it facilitates organ preservation, reducing the physical and psychological burden associated with radical surgical procedures such as abdominoperineal resection (APR) or total mesorectal excision [4]. By avoiding permanent stomas or substantial alterations to bowel function, patients experience an improved quality of life post-treatment. Furthermore, NOM reduces treatment-related morbidities, such as surgical complications and long-term effects on continence and sexual function. These advantages have contributed to the growing acceptance of NOM as a viable treatment strategy in selecting patients with rectal cancer [5,6].

However, the clinical implementation of NOM poses significant challenges. Accurate identification of patients achieving cCR is essential for the success of this strategy, necessitating a multidisciplinary approach that incorporates advanced diagnostic tools such as endoscopy, magnetic resonance imaging (MRI), and computed tomography (CT) [7]. Additionally, rigorous surveillance protocols are required to detect potential local regrowth at an early stage, ensuring timely intervention and preventing disease progression [8]. While the “watch-and-wait” strategy remains central to NOM, considerable variability exists in its clinical application, particularly concerning surveillance intervals, follow-up duration, and the management of local recurrence [9].

This study aimed to evaluate the feasibility and oncological outcomes of NOM in patients with rectal cancer who achieved a cCR following neoadjuvant CRT. In this prospective approach, NOM was combined with 4 months of capecitabine therapy, and the potential impact of adjuvant treatment was explored as a secondary consideration.

Materials and Methods

1. Study design and participants

This prospective observational trial employed a multidisciplinary approach combined with adjuvant capecitabine. Patients diagnosed with resectable rectal adenocarcinoma located ≤ 8 cm from the anal verge and classified as cT2-4 or N+ were eligible for inclusion in this prospective study. The diagnosis should be confirmed through clinical examination, endoscopy with biopsy, chest/abdominopelvic CT, and rectal MRI. Additional eligibility criteria included a performance status suitable for long-course treatment with curative intent; adequate liver, kidney, and bone marrow function for long-course CRT; age > 18 years; and the absence of distant metastases. All patients underwent neoadjuvant CRT, with a total radiation dose of 50-54 Gy delivered in 25-27 fractions, combined with concurrent administration of capecitabine (825 mg/m² twice daily every weekday during radiotherapy) as the chemotherapeutic agent. Eight weeks after CRT completion, the patients underwent comprehensive re-evaluation through clinical examination, endoscopic assessment (mandatory biopsy), chest/abdominopelvic CT, and rectal MRI (Fig. 1A). A multidisciplinary team (MDT) specializing in rectal cancer reviewed all cases to determine treatment pathways. Patients who achieved a cCR based on clinical, endoscopic, and imaging evaluations were included in the study. For those with an incomplete tumor response, complete excision was recommended. Endoscopic complete response (CR) was defined as the presence of a small white scar in the rectal wall, superficial erosion, or ulceration with a negative biopsy result. MRI was primarily used to evaluate the status of primary tumor regression (MRI tumor regression grade) and regional lymph nodes (suspected lymph nodes were considered malignant if they exceeded 5 mm in diameter and lacked heterogeneity) [8]. Patients achieving cCR received adjuvant capecitabine therapy (1,250 mg/m² twice daily) in six cycles, following a regimen of 2 weeks of treatment followed by 1 week off. If cCR evaluation remained inconclusive, reassessment was performed every 4 weeks until a definitive decision was made.

Fig. 1.

(A) Study scheme. (B) Surveillance schedule. cCR, clinical complete response; CEA, carcinoembryonic antigen; CFS, colonoscopy; CH/AP-CT, chest/abdomino-pelvic computed tomography; CRT, chemoradiotherapy; DRE, digital rectal examination; F/U, follow-up; Fx, fraction; MDT, multidisciplinary team; MR, magnetic resonance imaging; PreOP, preoperative; R-CRC, rectal cancer; RT, radiotherapy; SFS, sigmoidoscopy; TAE, transanal excision; TME, total mesorectal excision; Tx, treatment.

Results

1. Patient characteristics

A total of 89 patients diagnosed with resectable rectal adenocarcinoma underwent neoadjuvant CRT between January 2018 and December 2023. Detailed characteristics of the CRT population are described in Table 1. Males comprised 62.9% of the patients, and the median age was 62 years (range, 27 to 84 years). Tumor response was assessed after CRT, resulting in CR in 17 patients (19.1%), partial response (PR) in 51 patients (57.3%), stable disease (SD) in 18 patients (20.2%), and progressive disease in three patients (3.4%). Among patients classified as CR or PR, five patients (5.6%) had inconclusive assessments at the initial evaluation and underwent reassessment every 4 weeks. After reassessment, four patients were confirmed as CR and one patient was confirmed as PR through MDT evaluation (Fig. 2). Surgical treatment was performed in patients with PR or SD. Specifically, 60 patients (67.4%) underwent low anterior resection (LAR), six patients (6.7%) underwent APR, and three patients (3.4%) underwent transanal excision. Moreover, three patients were deemed unresectable and received palliative chemotherapy. Seventeen patients (19.1%) who achieved cCR were enrolled in this study under the NOM strategy. Males accounted for 64.7% of this group, with a median age of 65 years (range, 53 to 84 years).

Table 1.

Patients’ characteristics

Fig. 2.

CONSORT diagram after neoadjuvant chemoradiotherapy. APR, abdominoperineal resection; CR, clinical complete response; CRT, chemoradiotherapy; LAR, low anterior resection; NED, no evidence of disease; PD, disease progression; PR, partial response; SD, stable disease; TAE, transanal excision.

2. Tumor and treatment characteristics

The median distance of the primary tumor from the anal verge was 3.2 cm (range, 0.0 to 8.0 cm). Clinical T3 category was the most common (64.7%), and N1/2 was observed in 88.2% of the patients (Table 2). The adjuvant capecitabine therapy was initiated at a median of 8.9 weeks (range, 8.3 to 19.0 weeks) after completing CRT. Eleven patients (64.7%) completed all six cycles of treatment. Among them, four patients aged 70 years or older received a 25% dose reduction due to concerns related to age and tolerability, while the remaining seven received the full-dose regimen. However, six patients (35.3%) did not complete the planned capecitabine therapy due to early recurrence (three patients) and patient refusal (three patients). Recurrence was detected at 4 months in two patients and at 6 months (immediately prior to the final planned dose) in the remaining patient. These cases highlight the potential value of more frequent follow-up—perhaps every 2 months—in the early post-treatment period, even among patients initially assessed as having achieved cCR, to enable timely detection of recurrence.

Table 2.

Tumor and treatment characteristics

3. Oncological outcomes of cCR patients under the NOM strategy

The median follow-up duration for the 17 patients was 31.4 months (interquartile range, 19.1 to 61.3). During the follow-up period, six patients (35.3%) experienced local regrowth, with a local regrowth rate of 34.5% at 2 years, increasing to 47.6% at 4 years (Table 3, Fig. 3, S1 Fig.). Despite these regrowth rates, non-regrowth DFS rate (defined as the absence of any cause of death, local pelvic recurrence, and distant metastasis, but not including local regrowth) [6] remained 100.0% at 2 years and 77.8% at 4 years. The treatment modalities for the six patients who experienced local regrowth were as follows: one patient underwent LAR followed by adjuvant capecitabine, and two received LAR followed by adjuvant FOLFOX (folinic acid/5-fluorouracil/oxaliplatin). One patient was treated with APR followed by capecitabine, and another underwent transanal minimally invasive surgery (TAMIS) followed by capecitabine. The remaining patient received re-CRT followed by salvage APR. Consequently, among the six patients with local regrowth, two underwent APR and subsequently received permanent colostomies. At the time of the final assessment, four of the six patients had no evidence of disease, resulting in an overall disease-free status in 15 patients (88.2%). However, pelvic recurrence was observed in one patient, and lung metastasis was identified in another; therefore, distant metastasis was observed in two patients (11.8%). Notably, the OS rate at 4 years was 100%, demonstrating excellent long-term survival outcomes in this cohort.

Table 3.

Treatment outcomes of complete response patients under the nonoperative management strategy

Fig. 3.

Oncological outcomes. (A) Local regrowth rate. (B) Non-regrowth disease-free survival. CRT, chemoradiotherapy.

Discussion

This study was conducted prospectively using an MDT approach, incorporating advanced imaging modalities such as MRI and CT, along with endoscopic and pathological evaluations. Patients who achieved cCR after neoadjuvant CRT were offered NOM therapy. Beyond the watch-and-wait strategy, the treatment protocol included systemic chemotherapy with adjuvant capecitabine over 4 months. Patients were evaluated every 2 months during the first year of follow-up to monitor local regrowth. This rigorous follow-up schedule ensured early detection and timely intervention. For patients experiencing local regrowth, TAMIS was employed as a salvage treatment, emphasizing the study’s organ-preserving approach. At the 8-week post-CRT evaluation, MDT assessments identified cCR in 19% of the patients, highlighting the efficacy of the preoperative CRT protocol and the role of MDT in treatment decision-making. Previous findings, such as those from the STELLAR trial, support the importance of MDT in improving survival outcomes [11].

The findings of this study emphasize the need for individualized treatment approaches that balance the benefits of organ preservation with the risks of recurrence and overtreatment. However, certain aspects warrant further exploration to optimize treatment outcomes. Although adjuvant capecitabine was employed to reduce recurrence, further exploration may be necessary to enhance local control. Approaches such as intensified surveillance protocols, integration of additional local therapies such as TAMIS in select cases, or modification of systemic chemotherapy regimens should be considered [12,13].

The concept of non-regrowth DFS focuses on outcomes specific to disease control without local regrowth [6]. Notably, non-regrowth DFS may be more closely associated with OS than local regrowth rate. This metric emphasizes the importance of effective local control as a distinct outcome measure and highlights the need for strategies to balance locoregional and distant disease management [14]. Despite favorable local outcomes, reducing distant metastases remains a critical challenge. Strategies to address distant recurrence could include the incorporation of more potent systemic chemotherapy regimens, such as total neoadjuvant therapy (TNT), or use of novel adjuvant therapies, such as immunotherapy or targeted agents [15].

Recently, oxaliplatin-based TNT approaches have been introduced into rectal cancer treatment for organ preservation and, in some cases, the omission of radiotherapy [16]. Compared to TNT-based strategies, such as those used in the AIO-12 and OPRA trials [15,17], our protocol represents a more conservative approach with certain distinguishing features. First, incorporating interim evaluation allows for identifying patients with cCR, which may facilitate selective surgical decision-making and help avoid overtreatment in some cases. This strategy aims to support organ preservation in appropriately selected patients. Second, our study’s use of adjuvant capecitabine provides a less intensive systemic option than doublet or triplet TNT regimens, such as FOLFOX or FOLFIRINOX (folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin) chemotherapy [18,19]. We acknowledge that the lower intensity of systemic therapy in our approach may limit its potential to reduce distant metastasis, and further comparative studies are warranted to clarify its long-term efficacy in oncologic outcomes.

Although this study demonstrated favorable oncological outcomes when combined with adjuvant capecitabine therapy, certain limitations must be considered. Compared with previous watch-and-wait landmark studies, such as the OnCoRe Project (local recurrence rate of 35%; distant metastasis rate of 5%) [6] and the Danish Colorectal Cancer Center (local recurrence rate of 26%; distant metastasis rate of 10%) [8], our study showed similar local recurrence and distant metastasis rates after adding 4 months of adjuvant capecitabine. This lack of significant improvement can be attributed to several potential factors. First, the relatively small sample size may have limited the statistical power to detect modest differences in the local recurrence or distant metastasis rates. Second, differences in patient demographics, tumor characteristics, and treatment intensities compared with prior studies could have influenced the outcomes. For instance, the higher proportion of patients with advanced tumor stages (T3/4 or N2) in this study may have contributed to the observed rates. Finally, a relatively modest CR rate achieved using this strategy should be noted. Recent advancements in TNT have shown superior response rates (21%-28%), including higher rates of pathological and cCR, making TNT an emerging standard in rectal cancer management [19,20]. Nevertheless, this study is valuable as a representative example of a multidisciplinary approach. Further studies should focus on comparing this strategy with TNT-based approaches to determine the optimal protocol for achieving higher rates of organ preservation without compromising long-term oncological outcomes.

In conclusion, approximately 20% of patients with lower rectal cancer could achieve a cCR following neoadjuvant CRT, making them eligible candidates for NOM. The present study demonstrated favorable oncological outcomes using NOM combined with adjuvant capecitabine administered for 4 months. This strategy represents a proactive alternative to the conventional “watch-and-wait” approach, focusing on integrating systemic therapy to enhance disease control. To further improve the efficacy and safety of NOM, a multidisciplinary approach tailored to individual patient conditions, incorporating advanced imaging, biomarker-based patient selection, and innovative therapies, is warranted.

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