Current and future perspectives in the management and treatment of colorectal cancer

Abstract

In this editorial, we reviewed the article by Fadlallah et al that was recently published in the World Journal of Clinical Oncology. The article provided a comprehensive and in-depth view of the management and treatment of colorectal cancer (CRC), one of the leading causes of cancer-related morbidity and mortality worldwide. The article analyzed the therapeutic modalities and their sequencing, focusing on total neoadjuvant therapy for locally advanced rectal cancer. It highlighted the role of immunotherapy in tumors with high microsatellite instability or deficient mismatch repair, addressing recent advances that have improved prognosis and therapeutic response in localized and metastatic CRC. Innovations in surgical techniques, advanced radiotherapy, and systemic agents targeting specific mutational profiles are also discussed, reflecting on how they revolutionized clinical management. Circulating tumor DNA has emerged as a promising tool for detecting minimal residual disease, prognosis, and therapeutic monitoring, solidifying its role in precision oncology. This review emphasized the importance of technological and therapeutic advancements in improving clinical outcomes and personalizing CRC treatment.

Key Words: Colorectal cancer; Metastatic colorectal cancer; Total neoadjuvant therapy; Chemoradiotherapy; Colon surgery; Rectal surgery; Chemotherapy; Immunotherapy

Core Tip: The management of colorectal cancer remains a challenge, but recent advances in total neoadjuvant therapy for advanced rectal cancer and the growing role of immunotherapy in tumors with high microsatellite instability or deficient mismatch repair are transforming the landscape. Modern treatments include new surgical techniques, advanced radiotherapy, and therapies targeting specific mutational profiles. Additionally, circulating tumor DNA is emerging as a crucial tool in precision oncology, improving prognosis and personalizing clinical care.

INTRODUCTION

Colorectal cancer (CRC) treatment has evolved significantly in recent years, driven by a better understanding of tumor biology and technological advancements. This progress has enabled the development of more personalized medicine based on the expression of molecular markers and the implementation of targeted therapies for tumors with specific characteristics. Significant advancements in surgical and radiotherapy (RT) techniques have also been achieved, providing a more precise approach to controlling local and distant diseases. In this editorial, we reviewed the article by Fadlallah et al[1] that was published in a recent issue of the World Journal of Clinical Oncology and provided an updated perspective on the management and treatment of CRC and potential future directions.

STRATEGY IN THE MANAGEMENT AND TREATMENT OF COLON AND RECTAL CANCER

Surgical treatment of colon and rectal cancer

The local management of colon cancer with en bloc endoscopic resection is appropriate for non-invasive adenocarcinomas without the need for additional surgery. However, in cases of invasive carcinoma in pT1 polyps, a detailed evaluation with the pathologist and surgeon is crucial. If high-risk features such as lymphatic or venous invasion, high-grade differentiation, or tumor budding are identified, surgical resection with lymphadenectomy is recommended[2].

In this regard, the primary treatment for localized, resectable colon cancer is colectomy with lymphovascular drainage. Laparoscopic surgery offers significant advantages over open surgery, including lower morbidity, comparable oncological outcomes, reduced risk of infection, and lower costs. However, careful patient selection is necessary to avoid compromising survival, particularly in complex cases such as obese patients, large tumors, or advanced disease. Although resection of transverse colon tumors is challenging, laparoscopic surgery can achieve oncological outcomes comparable to open surgery[3].

Finally, robotic surgery for colon cancer, although still under study, offers advantages such as greater precision and better lymph node dissection compared to laparoscopy, which may translate into improved survival for patients with stage I-III colon cancer. However, it also presents disadvantages, such as longer surgical times, higher costs, and a steeper learning curve[4].

Regarding rectal cancer, laparoscopic surgery is safe and effective, although questions remain as to whether the oncological outcomes are equivalent to open surgery. A meta-analysis including 3709 patients found no differences in 5-year disease-free survival (DFS) between laparoscopic and open surgery [72.2% vs 70.1%; hazard ratio (HR): Not significant at 0.92; 95% confidence interval (CI): 0.80-1.06; P = 0.26], but a significantly better overall survival (OS) for laparoscopic surgery (76.2% vs 72.7%; HR: 0.85; 95%CI: 0.74-0.97; P = 0.02)[5].

The Laparoscopic-Assisted Surgery for Low Rectal Cancer trial compared this technique with conventional open resection and included rectal tumors < 6 cm, located within 5 cm of the dentate line, T3-4a, N0, or T1-4a, N1-2 treated with neoadjuvant chemoradiotherapy (CRT), and without metastasis. It found that laparoscopy and open surgery are comparable in terms of pathological outcomes related to resection margins, with a negative margin rate of 98.2% in the laparoscopy group vs 99.7% in the open surgery group (difference of -1.5%; P = 0.09). However, laparoscopy had a higher likelihood of sphincter preservation, with a statistically significant difference (71.7% vs 65.0%; P = 0.03) and shorter postoperative recovery and hospital stay[6].

Rectal tumors located less than 15 cm from the anal margin are approached with primary surgery if they are early-stage and low-risk. For locally advanced or high-risk cases, combining RT or neoadjuvant CRT (RT/CRT) with surgery is recommended[7].

Local excision is the indicated option for T1 tumors without high-risk factors. In contrast, total mesorectal excision (TME) with curative intent is recommended for those in the middle and lower thirds of the rectum. The presence of lateral pelvic lymph nodes measuring ≥ 7 mm on magnetic resonance imaging and features such as nodal heterogeneity or tumor deposits should be carefully evaluated to consider additional surgical or RT approaches[8].

TME is the recommended technique for tumors in the upper third of the rectum, while for T4 rectal cancers, en bloc resection of adjacent affected organs is required. Oophorectomy is only recommended in cases of infiltrated ovaries or when rectal cancer extends contiguously without being necessary as a routine prophylactic measure, and in this regard, laparoscopic TME has demonstrated comparable results to open TME[9].

Transanal endoscopic microsurgery is a technique used for the treatment of rectal tumors, specifically recommended for patients with cT1N0 stages, according to the European Society for Medical Oncology guidelines. However, in patients with higher surgical risk or more advanced stages, transanal minimally invasive surgery (TAMIS) may be a suitable option. This technique allows for local excision of rectal tumors through the anus without the need for abdominal incisions, significantly improving recovery time[2].

For more advanced tumors, such as cT2c/T3a/b, radical surgery with TME is recommended due to the higher likelihood of recurrence and mesorectal lymph node involvement. For cT2 tumors smaller than 4 cm, an alternative option is local excision after preoperative RT/CRT, avoiding abdominal surgery[2].

A less common but available option is TAMIS combined with TME (TAMIS-TME). This technique integrates TAMIS with TME and is indicated for tumors in the middle or distal third of the rectum (T1 to T3) that are difficult to access through other approaches. TAMIS-TME is particularly useful in patients with comorbidities that limit the possibility of more invasive surgeries or when sphincter preservation is desired, minimizing the risk of circumferential resection margin involvement[9].

Finally, navigation technology using indocyanine green injection in colorectal surgery allows for assessing anastomotic perfusion and lymphangiography for sentinel node mapping. Although its routine implementation is still debated, its use is being explored for intraoperative visualization of colorectal peritoneal and liver metastases, which could favor surgical resection planning[10].

RT treatment

In the treatment of locally advanced rectal cancer, neoadjuvant RT followed by TME has been fundamental for local control (LC) and OS. There are two options: One long-term and one short-term. The long-term treatment involves administering RT doses of 1.8-2 Gy in 25 to 28 fractions concurrently with chemotherapy. On the other hand, the short course of RT (SCRT) is characterized by administering higher doses, with 5 Gy per fraction in a total of 5 fractions, without the concurrent administration of chemotherapy. However, total neoadjuvant therapy (TNT), which integrates chemotherapy into the neoadjuvant setting, is gaining increasing relevance in this clinical context. Clinical trials such as CAO/ARO/AIO-12, OPRA, and PROSPECT, which combine long-course RT with chemotherapy, as well as studies like Polish II, RAPIDO, and ESTELLAR, which combine SCRT, reflect the growing interest in this treatment approach[11-16].

The implementation of TNT is recommended for patients with at least one of the following factors: CT4; cN2; lateral pelvic nodes; circumferential resection margin less than 1 mm; involved mesorectal fascia; or extramural vascular invasion. It is also suggested in cases of cT3 located within 5 cm of the anal margin, cT3c/d, or nodal disease in the mesorectum. This strategy offers an excellent opportunity for the “watch and wait” approach, which has gained preponderance in patients who achieve a complete clinical response. This strategy is particularly beneficial for patients with comorbidities or those who decline surgery, as it allows them to maintain their quality of life without compromising survival[11,12,17].

The PROSPECT trial, although not exclusively focused on patients with upper rectal cancer, suggests that a strategy based solely on leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) is a viable alternative to conventional CRT, with similar DFS results. However, there was a higher rate of significant side effects with chemotherapy alone (41%) compared to CRT (23%). Long-term results, particularly regarding neuropathy, are still awaited[13].

RT modalities

External beam RT techniques used for these patients have evolved. They aim to improve dose coverage to the tumor and, in some cases, increase the dose while minimizing exposure to organs at risk, reducing treatment-related toxicities. These techniques include three-dimensional conformal RT (3D-CRT), intensity-modulated RT (IMRT) with volumetric modulated arc therapy, and image-guided RT[18,19].

The most common metastatic sites for CRC are the liver, lungs, and bones. Recent studies highlight the utility of stereotactic body RT in patients with oligometastases to improve LC and OS, although with lower response rates compared to other histologies. Being a noninvasive and highly precise technique, it is well tolerated, allowing its use even in dominant, highly symptomatic, unresected, or recurrent tumors, reducing symptoms and thus improving quality of life[20,21].

Another external RT modality is proton beam therapy (PBT), which uses protons instead of photons. This allows the bulk of the energy to be released at the end of the planned trajectory at a specific point called the “Bragg peak”. This characteristic enables precise tumor treatment while reducing the dose to at-risk organs[22].

A systematic review compared dosimetric irradiation to organs at risk and oncological outcomes between PBT and conventional photon-based RT using 3D-CRT and IMRT techniques in patients with locally advanced rectal cancer. The results showed significantly lower irradiation to the small intestine with PBT compared to 3D-CRT and IMRT, with a mean difference of -17.01 (95%CI: -24.06 to -9.96; P < 0.00001) and -6.96 (95%CI: -12.99 to -0.94; P = 0.02), respectively. Additionally, similar results were observed for the bladder and bone marrow[23].

In this context, the PRORECT clinical trial (NCT04525989) is the first multicenter, prospective, randomized phase II study evaluating the use of PBT in primary rectal cancer. This study compared preoperative SCRT using photons vs protons in treating locally advanced rectal cancer in the TNT setting. The primary objective of the trial was to assess grade ≥ 2 acute gastrointestinal toxicity, measured before the planned initiation of chemotherapy. Dose-volume histogram analysis demonstrated that SCRT with protons significantly reduced radiation doses to pelvic organs at risk compared to SCRT with photons. Despite these differences in doses delivered to organs at risk, both approaches (with photons and protons) showed equivalent conformity and homogeneity indices[24].

Another way to administer RT treatment is through intraoperative RT, which allows high doses of radiation to be precisely applied to the tumor bed during surgery. Several techniques are available for its application, including intraoperative electron beam irradiation, high-dose-rate brachytherapy in a single fraction, and orthovoltage at 250 kV or 50 kV. These techniques are particularly useful in high-risk situations, such as positive surgical margins, T4 tumors, or cases of tumor recurrence, where reirradiation is required, a challenge considering that most local recurrences following treatment with concurrent RT and chemotherapy occur within the original radiation field (65%), with a reported presacral recurrence rate of 41%[25].

The development of new technologies, such as magnetic resonance-guided RT, which combines a linear accelerator with real-time magnetic resonance imaging, has enabled daily treatment customization. This ensures the prescribed dose is precisely delivered to the tumor while protecting organs at risk. Due to continuous tumor motion tracking, this approach has reduced geometric margins without compromising the effective treatment dose[26].

Finally, due to significant advances in RT techniques, dose intensification has become an active area of research, aiming to improve LC and tumor regression grade. It is being evaluated as a strategy to optimize the effect of neoadjuvant CRT before surgical resection. In this context, some studies have shown that RT doses of up to 60 Gy, administered concomitantly with chemotherapy, can achieve a pathological complete response in up to 78% of cases[27]. Table 1 summarizes the different treatment options for resectable CRC.

Table 1 Treatment options for resectable colorectal cancer.

Treatment modality	Description	Additional comments
Surgery	Laparoscopic surgery, robotic surgery and navigation surgery	Laparoscopic surgery: Reduced infection risk compared to open surgery; Robotic surgery: Improved precision, dexterity, lymph node dissection; Navigation surgery: Real-time blood flow visualization, useful for lymph node mapping
Radiotherapy in resectable patients	Adaptive radiotherapy adjusts treatment in real time; Image-guided radiotherapy; Volumetric arc modulation; Intraoperative radiotherapy; Magnetic resonance-guided radiotherapy	Modalities used for tumor reduction and preoperative microscopic disease in resectable rectal cancer; Advanced techniques improve precision and minimize toxicities
Total neoadjuvant therapy	Combines radiotherapy and preoperative chemotherapy to improve local control and reduce the risk of metastasis	Indicated for locally advanced rectal cancer (cT3, cT4 or N +); It improves the rate of complete pathological response and can avoid surgery in selected cases with complete response, favoring wait and see
Adjuvant chemotherapy	Indicated in high-risk stages II and in stages III after surgery; Fluoropyrimidines + oxaliplatin	Improves disease-free survival by eliminating residual tumor cells; Sequentially in postoperative treatment is key to reducing the risk of recurrence
Immunotherapy	Currently under investigation for locally advanced MSI-H/dMMR cancer in the neoadjuvant setting	Pembrolizumab and nivolumab are being studied in clinical trials but are not used as standard in resectable non-MSI-H/dMMR disease
Circulating tumor DNA	Biomarker used to detect minimal residual disease after curative treatment	It helps to identify patients at high risk of relapse and decide on the use of adjuvant chemotherapy after surgery

MSI-H/dMMR: High microsatellite instability/deficient mismatch repair.

Systemic treatment

Treatment of advanced and metastatic CRC: Adjuvant chemotherapy is indicated in advanced stages (IIB and IIC) of CRC, although it is not recommended for stage II patients with a low risk of recurrence. Treatment regimens include combinations of fluoropyrimidines, oxaliplatin, and irinotecan, often enhanced with leucovorin[2]. Additionally, bevacizumab, a humanized monoclonal antibody that blocks vascular endothelial growth factor (VEGF), helps limit blood supply to the tumor by inhibiting angiogenesis. This treatment, combined with chemotherapy, is a standard strategy in the management of metastatic CRC (mCRC)[2].

Targeted therapies in mCRC: In managing mCRC, personalized treatment based on the molecular characteristics of the tumor is crucial. Fadlallah et al[1] provided a detailed description of this approach, highlighting the use of monoclonal antibodies, such as cetuximab, targeting the epidermal growth factor receptor (EGFR), which is a transmembrane tyrosine kinase receptor of the ErbB family. When bound to its ligand, it can activate pathways such as rat sarcoma-rapidly accelerated fibrosarcoma-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-protein kinase B, which control cell proliferation and survival, playing a key role, especially in patients whose tumors present specific mutations such as BRAF V600E or KRAS G12C, mutations in the BRAF and KRAS genes, respectively, which are associated with cancer progression. The combination of cetuximab with encorafenib, a BRAF inhibitor, has shown significant improvement in survival for patients with mCRC harboring the BRAF-V600E mutation[28].

On the other hand, panitumumab, another monoclonal antibody targeting EGFR, has shown similar efficacy to cetuximab in patients with KRAS wild-type mCRC (non-mutated KRAS gene) but with a lower incidence of adverse events such as paronychia[29].

Finally, human epidermal growth factor receptor 2 (HER2), a receptor from the ErbB family, is overexpressed in approximately 5% of patients with mCRC, activating pathways that promote tumor proliferation through autophosphorylation of its cytoplasmic domain[30]. In patients with HER2 + mCRC who have shown resistance to irinotecan, oxaliplatin, and fluoropyrimidines, the combined use of trastuzumab, a humanized monoclonal antibody, and tucatinib, a selective HER2 inhibitor, has shown promising results[31]. These therapies have expanded treatment options for specific subgroups of patients.

Selection of anti-EGFR or anti-VEGF therapies: The choice between anti-EGFR therapies, such as cetuximab or panitumumab, and anti-VEGF therapies, such as bevacizumab, may depend on factors like tumor sidedness and molecular characteristics. In rat sarcoma wild-type tumors (gene without mutations), anti-EGFR antibodies offer a higher response rate when combined with chemotherapy, especially in left-sided tumors. In previously treated patients, the combination of ramucirumab (targeting VEGFR-2) with leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI) has shown improved OS compared to FOLFIRI alone, according to the RAISE trial[32].

Advances in targeted therapies and genomic mutations: The BRAF-V600E mutation, present in up to 15% of mCRC patients, is a key therapeutic target. Combining BRAF inhibitors (encorafenib) and mitogen-activated protein kinase inhibitors (binimetinib) has proven more effective than monotherapy, achieving a more comprehensive blockade of tumor signaling. Moreover, studies have emphasized that genomic profiling of tumors is essential for predicting treatment response beyond tumor-sidedness[33].

Immunotherapy in mCRC: High microsatellite instability (MSI-H) reflects a high mutation rate in repetitive DNA sequences. At the same time, deficient mismatch repair (dMMR) indicates a malfunction in the system that normally corrects DNA replication errors. MSI-H/dMMR tumors rapidly accumulate mutations, promoting oncogenesis and making them more susceptible to immunotherapy due to their high mutational burden. Programmed death-1 (PD-1) inhibitors block a protein in T cells that suppresses the immune response when activated by the tumor. By inhibiting PD-1, these drugs allow T cells to recognize and attack tumor cells more effectively, a particularly effective approach in MSI-H/dMMR tumors[34,35]. The Keynote-177 study demonstrated that pembrolizumab, a PD-1 inhibitor, significantly improved outcomes in patients with MSI-H mCRC[36]. Clinical trials such as Checkmate 8HW are also evaluating combinations of immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, which have revolutionized the therapeutic management of these patients[37].

New combinations and clinical trials, such as the NEST-1 study, evaluated the neoadjuvant combination of botensilimab (anti-cytotoxic T-lymphocyte associated protein 4) and balstilimab (anti-PD-1) in patients with mCRC, showing efficacy in both proficient mismatch repair (pMMR)/microsatellite stable (MSS) and dMMR/MSI-H patients. These advances demonstrate the potential of immunological therapies in treating CRC[38]. Table 2 summarizes the different options in mCRC.

Table 2 Treatment options for metastatic colorectal cancer.

Treatment modality	Description	Additional comments
Surgery	Indicated for resection of resectable liver, lung or peritoneal metastases	Combined with neoadjuvant or adjuvant chemotherapy in patients with good performance status
Systemic chemotherapy	Indicated in metastatic disease as part of a sequential approach, combined with or without biological agents	It is essential to control metastatic disease, regardless of the site of the metastases
Adaptive radiation therapy	It offers the ability to adjust treatment in real time using magnetic resonance imaging to improve precision	Indicated for oligometastases or metastases in the liver and lung
Image-guided radiotherapy and volumetric modulation techniques	It allows for greater precision in dosing	Used in patients with metastases in specific sites (liver, lung) who are not candidates for surgery
Stereotactic radiotherapy	Indicated for the treatment of oligometastatic metastases in the liver, lung, and bones	Non-invasive and precise technique for symptom control or to prolong survival
Targeted therapies EGFR (cetuximab)	Indicated in RAS wild-type metastatic tumors in combination with chemotherapy	Requires confirmation of RAS mutational status and molecular evaluation of the tumor
Targeted therapies VEGF (bevacizumab)	Indicated in metastatic colorectal cancer, regardless of mutational status, in combination with chemotherapy	Blocks tumor angiogenesis to improve the outcomes of systemic treatment
Targeted therapy BRAF (encorafenib)	Indicated for patients with BRAF-V600E mutation in combination with cetuximab for metastatic colorectal cancer	Used after progression on prior chemotherapy
Targeted therapy HER2 (trastuzumab)	Indicated for patients with HER2-positive, RAS wild-type metastatic colorectal cancer that does not respond to standard chemotherapy	Used in combination with tucatinib
Checkpoint inhibitors	Pembrolizumab, nivolumab, ipilimumab are indicated in metastatic cancer with MSI-H or dMMR	Effective in patients with high microsatellite instability, but not in pMMR/MSS tumors

dMMR: Mismatch repair deficiency; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; MSI-H: High microsatellite instability; MSS: Microsatellite stable; pMMR: Proficient mismatch repair; RAS: Rat sarcoma protein family; VEGF: Vascular endothelial growth factor.

CURRENT CHALLENGES AND FUTURE PERSPECTIVES

Adopting advanced technologies and personalized surgical approaches has become essential to improving clinical outcomes and reducing complications in cancer treatment. In this context, minimally invasive and robotic surgery has demonstrated the ability to offer more precise and less invasive procedures, promoting faster patient recovery. However, future innovations, such as fluorescence-guided surgery and augmented reality, are expected to improve intraoperative visualization further and increase precision in tumor resection[39].

Artificial intelligence and big data analysis are also beginning to be used in RT treatment planning. These technologies allow predicting responses, personalizing dosage, and optimizing treatment plans. Integrating adaptive RT and real-time imaging to adjust doses and reduce toxicity is anticipated to improve therapeutic outcomes, enabling a more precise and personalized approach to rectal cancer treatment[40].

Currently, organ-preserving surgery and multimodal approaches have gained prominence, allowing the implementation of strategies such as “watch and wait” in rectal tumors. These approaches prioritize sphincter preservation and combine neoadjuvant and adjuvant therapies with various systemic treatment options to maximize efficacy. Clinical trials like JANUS and ENSEMBLE are investigating whether triple chemotherapy offers advantages over double chemotherapy in terms of complete clinical response and DFS in patients with rectal cancer. These studies are expected to increase the number of patients eligible for non-surgical approaches and modify future recommendations for TNT[41,42].

On the other hand, immunotherapy, which was proven effective in mCRC, especially in patients with dMMR or MSI-H, is being evaluated as a neoadjuvant treatment. Early studies indicate that it could improve pathological complete response rates in non-mCRC, with more significant benefits in dMMR/MSI-H patients than those with proficient mismatch repair/microsatellite stable, opening new therapeutic options for these groups[43].

A high mutational burden is observed in CRC with dMMR or MSI, along with notable immune cell infiltration in the tumor microenvironment. Although ICIs have shown efficacy in treating mCRC with dMMR/MSI, up to 30% of patients experience progression despite treatment. This phenomenon suggests that dMMR/MSI CRC is a heterogeneous group of tumors with different sensitivities to ICIs, highlighting the need for more advanced diagnostic and therapeutic strategies to improve outcomes in this subgroup of patients[44].

Circulating tumor DNA (ctDNA), a fraction of cell-free DNA released into the bloodstream by tumor cells, has become a fundamental tool in precision oncology. Its ability to detect minimal residual disease and guide therapeutic decisions has established it as an essential marker in CRC management. ctDNA allows for non-invasive, real-time evaluation of the genomic profile of the tumor, which is especially useful for early detection of recurrences and monitoring treatment response. Several studies have shown that ctDNA levels decrease after surgical resection and systemic treatment, while an increase in these levels can predict recurrence months before it becomes detectable through imaging[45].

In prognostic terms, ctDNA postoperatively is associated with a higher risk of recurrence. A recent meta-analysis demonstrated that patients with positive ctDNA after surgery have a significantly higher risk of recurrence compared to those with negative ctDNA. This finding underscores the utility of ctDNA for early intervention with therapeutic measures before recurrences become visible on imaging tests[46].

The GALAXY study reinforces the prognostic value of ctDNA. This long-term trial showed that patients with positive ctDNA at any time had significantly lower DFS than those with negative ctDNA. At 24 months, DFS was 28.9% in the ctDNA-positive group vs 85.9% in the negative group (HR: 10.53; 95%CI: 8.74 to 12.69; P < 0.0001). Similar results were observed in patients with stage II and III CRC, where DFS was 33.5% in the ctDNA-positive group compared to 89.3% in the negative group (HR: 12.05; 95%CI: 9.46 to 15.34; P < 0.0001)[47].

A significant advancement in the use of ctDNA is its potential as a predictive biomarker in mCRC. Monitoring ctDNA levels can help predict response to chemotherapy and the emergence of resistance[48]. However, although ctDNA was proven to be a powerful prognostic biomarker, it has yet to be established as a definitive predictive marker for therapeutic decision-making. Trials like ALTAIR and VEGA are investigating this aspect in depth, which will be important for its future application in treatment personalization and improving clinical outcomes in CRC patients[49].

Finally, it is anticipated that the personalization of surgery will benefit from the use of biomarkers such as ctDNA. This will allow surgical treatments to be adapted to the molecular characteristics of each tumor, representing a significant advance in the precision and effectiveness of surgical interventions[50].

CONCLUSION

The management of CRC has significantly advanced as a result of a better understanding of tumor biology and the development of surgical techniques and personalized therapies. TNT is more accepted every day, while RT remains crucial for local disease control and shows potential for treating metastases. Systemic treatments, including monoclonal antibodies and immunotherapy, have proven effective in advanced and metastatic cases, especially in tumors with specific molecular characteristics. Incorporating biomarkers such as ctDNA could change the decision-making, with applications in the detection of residual disease, assessment of therapeutic response, and long-term prognosis. ctDNA shows a good potential for use in personalized treatments and improving clinical outcomes in CRC patients. Future artificial intelligence applications and new technologies like fluorescence-guided surgery will offer more precise and customized treatments.