INTRODUCTION
Rectal cancer is among the most prevalent malignancies of the digestive tract and, with the steady rise in incidence rates worldwide, poses a serious threat to human health[1]. Despite significant improvements in cure rates due to advances in surgical techniques and more comprehensive treatment strategies, postoperative recurrence remains an issue[2,3]. Specifically, postoperative early recurrence (ER) and metastasis are major risk factors for patient mortality and significantly affect the survival rates of patients with colorectal cancer (CRC). Therefore, it is essential to identify the risk factors for postoperative recurrence and metastasis. Cho et al[4] reported recurrence rates of 65.6% after 2 years from radical resection of CRC, 29.3% after 2-5 years, and 5.1% after 5 years, indicating that most recurrences and metastases occur within 2 years of surgical resection. The 2017 National Comprehensive Cancer Network Guidelines explicitly recommend patient follow-up after radical resection of CRC every 3-6 months for the first 2 years and then every 6 months. On the basis of the higher incidence of ER, a postoperative cut-off of 2 years has been utilized in some studies of early and late recurrence and metastasis[5]. However, other researchers have defined ER as recurrence within 1-3 years postresection, so there is currently no standardized timeframe for ER after rectal cancer surgery[6-8]. Postoperative ER poses significant challenges to the treatment of patients because of its complexity and rapid onset. Tsai et al[9] recently conducted a retrospective study on the timing and risk factors for ER in patients with resectable rectal cancer. On the basis of an analysis of recurrence-free survival, they defined ER as recurrence within 8 months of rectal cancer surgery.
RISK FACTORS FOR EARLY POSTOPERATIVE RECURRENCE
Tsai et al[9] reported that age, preoperative neoadjuvant therapy, length of hospital stay, tumour location, and pathological stage all affect the risk of ER after rectal cancer surgery. Rectal cancer patients aged over 70 years presented a significantly increased risk of postoperative ER. This is likely due to age-related factors such as a decline in physical function, weakened immunity, and reduced treatment tolerance. While preoperative concurrent chemoradiotherapy can reduce tumour size, lower patient tumour stage, and improve surgical success rates, it has also been found to increase the risk of postoperative ER. This may be attributable to factors such as damage to normal tissue from radiotherapy and the reproliferation of tumour cells in the interval between radiotherapy and surgery. Patients with a postoperative hospital stay exceeding 9 days also had a greater risk of ER, possibly due to poor recovery, more complications, and nosocomial infections. Despite the controversy regarding the effect of tumour distance from the anal verge on prognosis, it has been shown that patients with lower rectal cancer have a greater risk of postoperative ER due to surgical challenges and low rates of anal preservation[10]. Pathological stage is another critical factor for the likelihood of postoperative recurrence of rectal cancer. Patients with later-stage rectal cancer (e.g., stage III or IV) are more prone to postoperative recurrence, which also tends to occur significantly earlier in these patients.
In addition to the variables identified in the study by Tsai et al[9], numerous additional factors have been shown to affect recurrence and metastasis in patients with CRC. The clinical risk factors for a poorer prognosis in advanced rectal cancer patients include vascular invasion, positive circumferential resection margins, and lymph node metastasis[11]. Reports have also suggested that the depth of tumour invasion and the number of lymph node metastases are independent prognostic determinants[12]. Tumour invasion that reaches the T1 and T2 Levels does not significantly reduce survival rates. However, survival rates decrease markedly when tumour invasion reaches the T3 level and decline further at T4. Survival rates also decrease as the number of metastatic lymph nodes increases, with significantly reduced survival rates in patients with more than four metastatic lymph nodes. Radical resection status is another factor that affects prognosis and recurrence risk in rectal cancer patients, with patients who undergo radical surgery showing significantly higher survival rates than those who undergo palliative surgery[13]. Research has also revealed a negative correlation between tumour size and prognosis, with larger tumours typically indicating a greater likelihood of ER and metastasis[14]. Furthermore, the serum levels of CEA and CA19-9 are reliable diagnostic and prognostic indicators of gastrointestinal malignancies, particularly CRC, as their abnormal expression is a good predictor of recurrence and metastasis in patients with CRC[15]. Molecular markers and tumour gene mutation testing have the potential to predict recurrence in early-stage CRC[16]; however, their roles remain incompletely understood. Investigating specific biomarkers or gene mutations, such as KRAS, BRAF, and TP53 mutations, may provide valuable insights for predicting the recurrence of CRC[17,18]. Furthermore, high-risk histological subtypes, such as mucinous carcinoma and signet ring cell carcinoma, are associated with an increased risk of recurrence in patients with CRC.
MONITORING OF EARLY POSTOPERATIVE RECURRENCE
Gathering a detailed medical history, performing physical examinations, and conducting tumour marker tests (e.g., for CEA) are basic requirements of postoperative follow-up. These assessments can promptly identify abnormalities and indicate the need for imaging studies. Computed tomography and magnetic resonance imaging of the abdomen, pelvis, and chest are essential for accurate evaluation of postoperative recurrence of rectal cancer. These imaging technologies can clearly display morphological changes in a tumour and the surrounding tissues, which facilitates the detection of occult foci of recurrence. Colonoscopy is also invaluable, as it allows direct observation of lesions in the colorectal mucosa, aiding in the detection of local recurrences[19]. Although the optimal frequency of imaging may vary on the basis of individual patient risk factors, standard clinical practice typically recommends conducting imaging studies (e.g., computed tomography or magnetic resonance imaging) every 6-12 months during the first two years after surgery, as this period is associated with the highest risk of recurrence. For CEA levels, monitoring is generally advised every 3 to 6 months; however, specific intervals may be influenced by baseline levels and the patient's medical history. Regarding intervention, an elevated CEA level that exceeds the normal range (typically > 5 ng/mL in nonsmokers) should prompt further investigation. However, the specific threshold for intervention may vary on the basis of trends and patient-specific factors. In lower- and middle-income countries, the specific intervention thresholds may be higher than those observed in developed nations owing to variations in economic conditions. A consistent increase in CEA levels or significant findings from imaging studies would likely necessitate a more thorough examination, additional imaging modalities, or even early intervention with adjuvant therapies.
Advances in molecular biology techniques have enabled researchers to identify several molecular markers associated with rectal cancer recurrence. Circulating tumour DNA (ctDNA) testing is a noninvasive method that can dynamically conduct multiple assessments of molecular changes in a patient’s tumour. This allows clinicians to select the optimum interventions on the basis of the results[20]. Numerous studies have shown a significant correlation between ctDNA positivity during postoperative monitoring and tumour recurrence. This is a particularly useful tool, as ctDNA positivity occurs considerably earlier than radiographically detectable indications of recurrence. A study of 230 patients with stage II colon cancer that utilized a prior tumour strategy and the Safe-SeqS technique revealed that, among the 178 patients who received no adjuvant chemotherapy, ctDNA positivity 4-10 weeks postoperatively indicated an extremely high risk of recurrence [hazard ratio (HR) = 18, P < 0.001]. Notably, 85% of the patients exhibited ctDNA positivity before or at the time of radiographic recurrence, whereas only 41% had corresponding CEA positivity during the same period (P = 0.002). This amounted to a median time from ctDNA positivity to radiographic recurrence more than 5 months earlier than that achievable with CEA testing, which is sufficient time to achieve positive results through changes in the treatment strategy[21]. Similar results were reported in the Galaxy study in Japan, in which 18.0% (n = 187) of the 1039 patients with stage II-IV CRC were ctDNA positive 4 weeks postoperatively, and recurrence occurred in 61.4% (115/187) of these patients. Among the ctDNA-negative patients, only 9.5% experienced recurrence 4 weeks after surgery [HR = 10, 95% confidence interval (95%CI): 7.7–14.0, P < 0.0001]. The 18-month disease-free survival rates of ctDNA-positive and -negative patients were 38.4% (95%CI: 31.4%-45.5%) and 90.5% (95%CI: 88.3%-92.3%), respectively[22]. Therefore, ctDNA testing could be a useful predictive tool and guide the monitoring of postoperative recurrence of rectal cancer.
TREATMENT OF EARLY POSTOPERATIVE RECURRENCE
For patients with local recurrence of rectal cancer, radical surgical resection or radiotherapy may be considered if the patient’s physical condition allows and if the new lesion is localized. In patients who cannot undergo surgery, palliative treatment with radiotherapy or chemotherapy can be utilized. When rectal cancer recurs as oligometastatic, active efforts should be made to implement surgical resection, with adjuvant systemic chemotherapy or targeted therapy, to improve therapeutic effects and maximize patient survival. According to reports, the 5-year survival rate for locally recurrent rectal cancer ranges from 30.0% to 54.2%. In cases where R0 resection is achieved, the 5-year survival rate can increase significantly, reaching between 48.4% and 72.4%. Preoperative neoadjuvant therapy has been shown to increase the R0 resection rate and significantly improve patient prognosis[23-25]. Rödel et al[26] reported that among 35 patients with locally recurrent rectal cancer, R0 resection was achieved in 28 patients (80%) following preoperative chemoradiotherapy, with curative resections achieved in 17 of these patients. The three-year survival rate for this cohort was found to be 82%. The extent of curative surgery is a critical factor influencing both patient survival and local control outcomes. For patients with extensive metastasis and those who cannot undergo surgery, a comprehensive chemotherapy-based treatment strategy should be adopted. With recent developments and advances, immunotherapy has begun to demonstrate satisfactory efficacy in the treatment of rectal cancer, providing an additional treatment option.
CONCLUSION
Early postoperative recurrence of rectal cancer is a critical prognostic factor that affects the long-term survival of patients. An in-depth analysis of risk factors, the optimization of monitoring approaches, and the development of personalized treatment strategies could effectively mitigate the risk of recurrence, improve treatment outcomes, and enhance patients’ quality of life. The promise of ongoing developments in molecular biology, imaging techniques, and therapeutic approaches suggests that improved monitoring and treatment of postoperative recurrence of rectal cancer will usher in brighter prognostic prospects for patients in the near future.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade C
Novelty: Grade B, Grade B, Grade B
Creativity or Innovation: Grade B, Grade B, Grade C
Scientific Significance: Grade B, Grade B, Grade C
P-Reviewer: Dey T; Qiu XW S-Editor: Lin C L-Editor: A P-Editor: Wang WB
