Rectal cancer is one of the most prevalent malignancies worldwide, with early diagnosis and appropriate treatment playing crucial roles in patient outcomes. Recent advances in endoscopic technologies have led to an increase in the detection of early-stage rectal cancers.¹ Endoscopic submucosal dissection (ESD) is a popular treatment option for these early-stage lesions, offering minimally invasive management for large early colorectal cancers that cannot be resected en bloc using conventional techniques.^2,3

A post-ESD pathological examination occasionally reveals deep submucosal (SM) invasion, which is associated with a higher risk of lymph node metastasis (LNM) and local recurrence.^3,4 Studies have shown that the risk of LNM increases significantly with the depth of submucosal invasion, ranging from 1–3% for SM1 (the most superficial third) to 20–25% for SM3 (the deepest third) invasion.^5-8 In such cases, additional treatment is often necessary to ensure optimal oncological outcomes. Furthermore, the quality of life after surgery can be diminished because of potential complications and functional impairments.

Although chemoradiotherapy (CRT) has been established as an effective adjuvant therapy for locally advanced rectal cancer,⁹ its role after ESD in cases of deep SM invasion is not entirely understood. The potential benefits of CRT in this context include reducing the risk of local recurrence and addressing potential lymph node metastases. Nevertheless, the optimal timing, duration, and specific regimen of CRT after ESD remain subjects of ongoing research.^10,11

This case series examined the outcomes of patients who underwent ESD for rectal cancer and subsequently received concurrent CRT because of pathologically confirmed deep SM invasion. By analyzing these cases, the aim is to provide insight into the efficacy and safety of this treatment approach, potentially informing future management strategies for similar clinical scenarios.

1. Case 1

A 74-year-old woman presented to the outpatient clinic with complaints of blood-tinged stool and abdominal pain that had persisted for 1–2 weeks. Four months earlier, she had undergone percutaneous coronary intervention for stable angina and was on a daily regimen of edoxaban 30 mg and clopidogrel 75 mg. The examination showed that she was afebrile with normal vital signs, and her hemoglobin level was 12.3 g/dL. An abdominal CT scan showed non-specific findings. Colonoscopy revealed a 2.5 cm nodular mixed-type lateral- spreading tumor located 1–3 cm from the anal verge (Fig. 1A). The tumor was excised using an endoscopic submucosal dissection (Fig. 1B, 1C). The histological analysis identified a 1.2×1.2×0.3 cm moderately differentiated adenocarcinoma with submucosal invasion (depth: 1,500 μm) and an associated tubulovillous adenoma. No lymphatic, venous, or perineural invasions were detected, but tumor budding was intermediate.⁷ Considering the depth and tumor budding, further treatment was suggested. The patient declined surgery because of concerns about anal preservation. Consequently, definitive radiotherapy was administered at a total dose of 5,040 cGy over 28 fractions, along with four cycles of four-week interval 5-fluorouracil and leucovorin (FL) chemotherapy. Follow-up CT and colonoscopy performed 24 months later showed no evidence of recurrence (Fig. 1D, 1E).

Figure 1. (A) Colonoscopy examination revealed a nodular mixed-type lateral spreading tumor located 1–3 cm from the anal verge. (B) The tumor was removed by an endoscopic submucosal dissection. (C) The mucosal surface of the resected nodule displayed an amorphous surface pattern. (D) Follow-up colonoscopy showed no evidence of recurrence. (E) Follow-up abdominopelvic CT confirmed the absence of recurrence.

2. Case 2

A 58-year-old woman was referred to the authors’ hospital after presenting with rectal bleeding at a local medical center. She reported intermittent rectal bleeding but was otherwise asymptomatic and in good health. She had a history of a hemorrhoidectomy approximately 13 years ago and had been on continuous Levothyroxine therapy following a total thyroidectomy for thyroid cancer seven years earlier. Her vital signs were normal, and her hemoglobin level was 13.4 g/dL. Abdominal CT imaging revealed focal wall thickening at the anus. Colonoscopy revealed a 2.5 cm nodular mixed-type lateral spreading tumor located 0–2 cm from the anal verge (Fig. 2A). An endoscopic submucosal dissection was performed, and the resected specimen exhibited an amorphous mucosal surface (Fig. 2B, 2C). Histopathology revealed a 1.2×1.2×0.4 cm moderately differentiated adenocarcinoma with submucosal invasion (depth: 3,000 μm), which was associated with a tubular adenoma with high-grade dysplasia. No lymphatic, venous, or perineural invasions were identified, but intermediate tumor budding was present. Preferring to preserve the anus, she opted for additional chemoradiotherapy. Definitive radiotherapy was delivered at 5,580 cGy over 32 fractions after two cycles of FL chemotherapy, followed by a third chemotherapy cycle. Three cycles of FL chemotherapy were performed at one-month intervals. CT and colonoscopy showed no signs of recurrence at the 32-month follow-up (Fig. 2D, 2E).

Figure 2. (A) Colonoscopic examination identified a nodular mixed-type lateral spreading tumor situated 0–2 cm from the anal verge. (B) The tumor was excised using an endoscopic submucosal dissection. (C) Examination of the resected specimen’s nodule revealed an irregular mucosal surface. (D) Follow-up colonoscopy showed no evidence of recurrence. (E) Follow-up Abdominopelvic CT confirmed the absence of recurrence.

3. Case 3

A 60-year-old man underwent a screening colonoscopy at a local medical center and was referred for further evaluation of a rectal tumor. He was asymptomatic and in good health. His vital signs were normal, and his hemoglobin level was 14.4 g/dL. Abdominal CT imaging indicated focal low-density wall thickening in the rectum. A colonoscopy revealed a 2.0 cm elevated lesion with a central depressed area located 1–3 cm from the anal verge (Fig. 3A). The tumor was removed via endoscopic submucosal dissection, exhibiting an amorphous surface pattern on the resected specimen (Fig. 3B, 3C). The histology examination confirmed a 1.0×1.2×0.5 cm moderately differentiated adenocarcinoma with submucosal invasion (depth: 3,900 μm) and a pre-existing tubular adenoma with low-grade dysplasia. No evidence of lymphatic, venous, or perineural invasion nor tumor budding was observed. After a multidisciplinary team meeting, it was decided to proceed with additional radiotherapy to preserve the anus according to the patient’s wishes. Definitive radiotherapy was administered at 5,040 cGy over 28 fractions. Seven months post-procedure, the follow-up CT and colonoscopy revealed no recurrence (Fig. 3D, 3E).

Figure 3. (A) Colonoscopic examination detected an elevated lesion with a central depressed area located 1–3 cm from the anal verge. (B) The lesion was removed by an endoscopic submucosal dissection. (C) The central surface of the resected specimen exhibited an amorphous surface. (D) Follow-up colonoscopy revealed no evidence of recurrence. (E) Follow-up Abdominopelvic CT indicated no signs of recurrence.

According to the 2019 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines, deep SM invasion of ≥1,000 μm, positive lymphovascular invasion, grade 2/3 tumor budding, and certain histological types are identified as the risk factors for LNM in colorectal cancer. An intestinal resection with a lymph node dissection is recommended when these factors are present.¹⁰ On the other hand, the rate of LNM can vary significantly when these risk factors are combined, ranging from 7.4% to 46.9%.¹¹ A previous study found that deep SM invasion alone was not an independent risk factor for LNM. Moreover, the absolute risk was low (2.6%) if poorly differentiated histology, tumor budding, and lymphovascular invasion were absent.¹²

Complications from colorectal surgery vary widely, with postoperative mortality being significantly high due to anastomotic leakage.¹³ Many patients also suffer from postoperative bowel symptoms, including increased stool frequency, fecal incontinence, fragmentation, urgency, difficulties in emptying, and increased intestinal gas.¹⁴ These outcomes raise questions regarding the advantages of radical surgery, highlighting the need to consider alternative treatment options.

This case series illustrates the outcomes of three patients with rectal cancer who underwent ESD followed by CRT or radiotherapy alone due to deep submucosal invasion. The findings suggest that ESD combined with CRT or radiotherapy can be a viable option for patients with early-stage rectal cancer and significant risk factors for recurrence, such as deep submucosal invasion and tumor budding. Reports of radiotherapy or chemoradiotherapy after a surgical local examination in early rectal cancer with deep SM invasion have been published, but this is the first case report of radiotherapy or chemoradiotherapy after ESD to the authors’ knowledge.

None of the three cases showed evidence of recurrence on the follow-up CT and colonoscopy, indicating the effectiveness of this combined treatment approach. This supports the potential role of CRT or radiotherapy as an adjunct to ESD in managing rectal cancer with high-risk features. The decision to proceed with CRT or radiotherapy rather than surgery was influenced by the patient's desire to preserve their anal function because the treatments available offer similar oncological outcomes but variable quality of life.

Future research should focus on optimizing the timing, duration, and specific regimens of CRT following ESD, as these remain areas of ongoing investigation. In addition, larger studies are needed to confirm the efficacy and safety of this combined treatment approach and to identify which patient populations would benefit the most.

In conclusion, these cases show that ESD followed by CRT or radiotherapy is a feasible and effective treatment strategy for rectal cancer with deep submucosal invasion, providing favorable oncological outcomes while preserving the anal function.

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