Introduction

Colorectal cancer (CRC), which ranks as the second most lethal malignancy and the third most prevalent cancer, is a significant concern in the realm of global health. In the year 2020, it is projected that there will be a total of 1.9 million newly diagnosed cases of CRC worldwide, resulting in approximately 0.9 million fatalities. By 2040, 3.02 million more instances of CRC are anticipated, a significant increase. This enormous impact is anticipated to worsen over the ensuing decades, with 3.2 million new cases by 2040.[1] Different nations and areas display unique patterns of CRC prevalence. While rich countries traditionally have higher incidence rates, westernization and changes in lifestyle are placing an increasing burden on middle- and low-income countries.[2] Alarmingly, the development of early-onset CRC makes the situation worse. Over the next 20 years, China and the United States are anticipated to see the greatest number of new CRC cases. The projected rise in the number of cases in China, from 0.56 million in 2020 to 0.91 million in 2040, and in the US, from 0.16 million to 0.21 million during the same timeframe, serves as evidence of the growing global burden.[1,2]

To address this issue, heightened awareness, the promotion of healthy lifestyle choices, innovative management strategies, and the implementation of effective global screening programs are required. These interventions are crucial for preventing future CRC-related morbidity and mortality. The heterogeneity of CRC emphasizes the need for accurate subtype classification systems, which can contribute to research and clinical outcomes.[2] The CRC can be staged by a special staging called “Duke’s staging.” It can be seen below in Figure 1.

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Figure 1

Duke’s staging for colorectal cancer

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Neoadjuvant therapy is crucial to the all-encompassing management of locally advanced CRC in this scenario. This strategy involves the administration of chemotherapy or chemoradiotherapy before surgery in an effort to enhance outcomes by shrinking tumors, facilitating surgical resection, and potentially reducing the risk of recurrence.[3-8] The significance of neoadjuvant therapy is highlighted by its potential to downstage tumors, improve the feasibility of conservative interventions, and ultimately contribute to higher survival rates.[9]

As the primary cause of cancer-related mortality, CRC requires a multidisciplinary approach for optimal management.[8] Neoadjuvant therapy has shown efficacy in reducing tumor size and increasing the likelihood of attaining complete resection, leading to improved disease control.[3,6] Neoadjuvant chemoradiotherapy has been widely regarded as the preferred treatment modality in various research studies that specifically investigate the management of locally advanced rectal cancer and has numerous benefits.[3-5] It permits early intervention, increases the likelihood of sphincter-preserving surgery, and decreases the risk of incomplete resections.[4,5] Moreover, this strategy has the potential to reduce the need for adjuvant therapy following surgery, potentially mitigating complications and enhancing patient outcomes overall.[3] The changing landscape of CRC treatment highlights the significance of neoadjuvant therapy in maximizing surgical outcomes and long-term survival. This approach has the ability to improve local tumor control, increase the feasibility of conservative interventions, and ultimately contribute to an improved patient prognosis.[3-9] The main pathway for colorectal carcinoma is depicted below in Figure 2.[10]

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Figure 2

Pathways of colorectal carcinoma development

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Methods

This systemic review was carried to describe Novel regimens and treatment strategies in neoadjuvant therapy for CRC and that served as the basis for our investigation. From 20 October of 2023 until 10 December 2023, we searched PubMed, Ovid, Web of Science, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Embase, and Scopus. Filters were not included in the study. The PRISMA 2023 flow diagram in Figure 3 is used to offer information regarding research selection. We chose studies that addressed the use of and treatment strategies for CRC and neoadjyvant therapies. Case studies, case series, cross-sectional research, case-control research, cohort studies, and review papers were all considered. Only English-language articles were taken into consideration. Preprints, publications that were published in languages than English, and articles that were published as grey literature were not included in the study. The complete texts of records for which we had no access, letters to the editor, meeting reports, systematic reviews, cadaver, and animal studies were excluded from the study. Two steps of screening were carried out. We screened by title and abstract in the first step, and then we read the full-text articles in the second. All authors did the screening and tabulation, which they all recorded in an Excel sheet. The authors did not conduct a formal quality evaluation in accordance with the systemic review technique due to the topic’s heterogeneity and the wide variety of study types.

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Figure 3

Prisma flowchart of included studies

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Results

After filtering out duplicates and items that were irrelevant to our research query from the initial database search’s 510 results, 397 unique articles were found. Eighty-five studies were chosen for additional analysis after the articles underwent two rounds of screening. The PRISMA 2023 flow chart [Figure 3] further explains the procedures and outcomes.

Current Normal Neoadjuvant Treatments

Surgical resection is considered the primary treatment option for CRC and is widely regarded as the cornerstone of therapy. This approach has the ability to cure localized stages (I-III) of the illness and, in some instances, even limited cases of metastatic disease (stage IV). The importance of surgery as a therapeutic modality for localized CRC cannot be emphasized. This therapy strategy is considered a basic therapeutic approach for early-stage CRC, offering a promising outlook for attaining complete tumor eradication and enhancing long-term survival rates.[11] Furthermore, it is worth noting that surgery continues to be a feasible alternative for patients who have limited metastatic disease. In such cases, the removal of the primary tumor alongside metastasectomy can significantly enhance the chances of extended survival.[12,13] Minimally invasive approaches and enhanced recovery protocols, both of which influence clinical outcomes and patient well-being, have influenced the evolution of surgical care. Even so, the decision-making process in Stage IV CRC remains intricate, encompassing not just professional expertise but also patient preferences and considerations for quality of life (QoL). The available information regarding the importance of initial surgery in asymptomatic patients is inconclusive, necessitating the use of clinical judgment in making decisions in these situations.[13]

Consequently, surgical resection remains the mainstay treatment for locally confined CRC, and it can even be beneficial in a subset of metastatic CRC cases. The changing landscape of CRC management highlights the significance of a multidisciplinary approach that takes into account not only the tumor stage but also patient preferences and QoL.[11,13] In recent years, the importance of chemotherapy in neoadjuvant settings for CRC has increased, particularly in locally advanced cases. Neoadjuvant chemotherapy (NACT) refers to the administration of chemotherapy before the primary surgical intervention with the goal of shrinking tumors, improving surgical outcomes, and possibly enhancing long-term survival.

NACT offers a number of prospective advantages in the treatment of CRC. It can target micro metastatic disease early on, potentially resulting in more effective resections and enhanced tolerability of treatment,[3] This strategy is crucial in locally advanced cases where complete resection may be difficult due to tumor size, location, and involvement of adjacent structures.[7] By reducing tumor burden and increasing the likelihood of attaining clear surgical margins, NACT may contribute to improved surgical outcomes and potentially higher R0 resection rates.

The efficacy of NACT in locally advanced colon cancer has been explored in clinical trials and systematic reviews.[7,14] The concept is now under investigation and subject to ongoing debate, with recommendations for its standardized implementation still in a state of development.[7] In general, the use of NACT in CRC shows potential as a beneficial addition to surgical intervention, aiming to improve the likelihood of successful curative resections and potentially enhance patient outcomes. Additional research and continued clinical trials are necessary to determine the most effective medication and further refine its role.

Radiation therapy plays a crucial role in the neoadjuvant treatment strategy for CRC, particularly in the context of rectal cancer. Neoadjuvant radiation is employed to decrease the size of tumors and improve the results of surgical procedures by minimizing the amount of cancerous tissue before curative surgery. The main aim is to attain a comprehensive resection with unambiguous margins, thereby reducing the likelihood of local recurrence and enhancing long-term survival.

According to previous studies, neoadjuvant radiation therapy has demonstrated efficacy in reducing tumor size and improving the feasibility of surgical resection for patients diagnosed with rectal cancer.[15] The combined use of chemotherapy and radiation therapy, known as chemoradiation, has become the accepted treatment strategy for the treatment of rectal cancer that has advanced locally.[16] The use of a multimodal approach, encompassing chemotherapy as a potential component, aims to enhance the probability of sphincter preservation, diminish local relapse rates, and enhance overall therapeutic outcomes.[17,18] The treatment regimen commonly employed for CRC is presented in Table 1.[19] Nevertheless, the utilization of radiation therapy in neoadjuvant contexts for colon cancer is less common compared to its use in rectal cancer. In specific instances of colon cancer, the utilization of radiation therapy as a neoadjuvant intervention may be contemplated with the intention of reducing the size of tumors before surgical intervention, particularly in cases where the tumor is widespread or has infiltrated neighboring organs.[16] The efficacy of neoadjuvant radiotherapy in downstaging tumors and improving surgical outcomes in rectal cancer has been well documented. However, its role in colon cancer is not as well-established and may be influenced by patient and tumor characteristics. The evolving role of radiation therapy in CRC underscores the necessity for personalized treatment strategies that consider factors such as tumor stage, tumor location, and patient preferences. Figure 3 illustrates many non-adjuvant therapeutic routes in CRC.[20]

Table 1 Commonly treatment regimen used for colorectal cancer

Total Neoadjuvant Therapy (TNT) Methodology

The TNT approach in the management of CRC involves the sequential administration of chemotherapy and radiation therapy before surgical intervention. This therapeutic strategy aims to enhance treatment efficacy and optimize outcomes for individuals diagnosed with locally advanced rectal cancer. The aforementioned comprehensive technique has gained significant traction in the field due to its demonstrated ability to raise the rate of pathological complete response (pCR), facilitate tumor shrinking, and enable sphincter preservation surgery.[19,21] The TNT strategy signifies a fundamental change in the management of locally advanced rectal cancer, as it allows for the integration of systemic chemotherapy at an earlier stage in the treatment process, with the ability to specifically target micro metastases and enhance disease control.[22,23]

The TNT approach addresses the challenge of local recurrence and distant metastases in CRC by administering NACT and radiation therapy before surgery. This approach is particularly applicable in cases of locally advanced rectal cancer, in which reducing tumor burden and enhancing surgical outcomes are essential objectives.[19,21] Utilizing TNT necessitates an individualized treatment strategy that takes into account the disease stage, tumor characteristics, and overall health status of the patient.[25] The ever-changing landscape of neoadjuvant therapies highlights the significance of refining treatment protocols and exploring novel therapeutic combinations to optimize patient outcomes.

The use of TNT might yield many advantages and disadvantages. According to meta-analytic studies, it has been found that the use of TNT results in a notably increased occurrence of enhanced pCR compared to traditional neoadjuvant chemoradiation. Polymerase chain reaction (PCR) has been found to be correlated with improved survival results. Furthermore, it has been observed that TNT has a higher level of disease-free survival (DFS) and overall survival in comparison to conventional therapy, as indicated by previous research.[28] The use of TNT has been shown to enhance the likelihood of sphincter-preserving surgery, hence maintaining the patient’s overall QoL.[4] The systemic chemotherapy component of the treatment known as TNT effectively targets and addresses micro metastases in their early stages, resulting in a decreased probability of the occurrence of distant metastases. The use of TNT has been found to have a positive impact on tumor downstaging, which in turn increases the feasibility of procedures and may even allow for observation instead of surgery in patients who have achieved a complete clinical response.[29]

Concerning disadvantages, the efficacy and safety of TNT remain debatable, with some trials demonstrating benefits and others not.[28] The increased toxicity that may result from TNT’s intensified treatment regimen may impact patient compliance and general health. Neoadjuvant therapy can result in postponed surgery, which may impact patient anxiety and tumor progression. The administration of TNT necessitates multidisciplinary teams that are well-coordinated and sophisticated infrastructure.[29] Personalized decisions are required to determine which patients will gain the greatest benefit from TNT and its optimal sequencing with surgery and other treatments.

Numerous clinical trials have been conducted to determine the efficacy of TNT in treating locally advanced rectal cancer. The study revealed a statistically significant correlation between the utilization of TNT and an increased probability of attaining a pathologic complete response (odds ratio [OR], 2.44; 95% confidence interval [CI], 1.99–2.98; I2 = 49%) as well as enhanced DFS (OR, 2.07; 95% CI, 1.03–3.56; I2 = 49%) in comparison to the conventional method of concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy plus A. PCR prevalence was 29.9% (range: 17.2%–38.5%) in the TNT group and 14.9% (range: 4.2%–21.3%) in the CRT plus A group. There were no statistically significant differences between the two approaches in terms of the frequency of sphincter-preserving surgery or the need for ileostomy.[4]

Comparing the efficacy of standard neoadjuvant chemoradiotherapy (CRT) with targeted neoadjuvant therapy (TNT) was the subject of a comprehensive evaluation and synthesis of 15 clinical trials from the existing literature. A twofold increase in the incidence of pCR was observed in the TNT arm compared to the CRT arm. Specifically, the TNT arm had a pCR rate of 25%, while the CRT arm had a rate of 13%. The calculated OR was 2.13, with a CI of 1.71–2.65 and a P > 0.001. At 47%, the heterogeneity statistic (I2) indicated a moderate amount of variation. 3-year rates of DFS were 74.2% in the arm receiving TNT and 69.0% in the arm receiving conventional radiotherapy (CRT) according to a meta-analysis of three studies. The calculated hazard ratio (HR) was 1.31, with a 95% CI ranging from 1.07 to 1.51. In addition, a P = 0.01 was determined. I2, a measurement of heterogeneity, revealed a value of 0%. The user has provided a reference to a number with no accompanying content or context.

The objective of this systematic review and meta-analysis was to compare the relative efficacy of TNT to that of routine neoadjuvant chemoradiotherapy. Eight phase II/III randomized controlled trials were included in the study. The delivery of TNT treatment led to a significant increase in the rate of pCR (OR, 1.77; 95% CI, 1.28–2.40; P = 0.0005). Compared to conventional chemoradiotherapy, the use of trinitrotoluene (TNT) has shown improvements in DFS and overall survival. The calculated HR for DFS was 0.83 (95% CI, 0.72–0.95; P = 0.03). Similarly, the overall survival HR was calculated to be 0.88 (95% CI, 0.74–1.05; P = 0.15). In addition, TNT therapy was associated with a significant reduction in the likelihood of distant metastases (HR = 0.81; 95% CI = 0.68–0.95; P = 0.012).[22] The results depicted in Figure 4 are presented in the following section.

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Figure 4

Non-adjuvant treatment pathways in colorectal cancer

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Novel-targeted Therapies in Neoadjuvant Settings

In the neoadjuvant setting for CRC, targeted therapies have acquired prominence as a valuable strategy. These treatments have the potential to target specific molecular alterations associated with CRC, thereby improving treatment efficacy and patient outcomes. CRC is a prevalent malignancy with differing stages of diagnosis, posing treatment challenges. Traditional methods such as surgery and chemotherapy have been employed, but targeted therapies are emerging as a promising alternative.[24,26,28]

Targeted therapies for CRC include a variety of agents designed to target specific molecular alterations fueling the progression of cancer. By focusing on actionable biomarkers expressed by CRC tumors, these therapies have revolutionized the treatment landscape. Prominent modes of action encompass the utilization of vascular endothelial growth factor (VEGF) Inhibitors, given that VEGF plays a pivotal role in promoting angiogenesis, hence enabling the growth of tumors. Bevacizumab, Ramucirumab, and Ziv-aflibercept are representative examples of targeted pharmacological agents that effectively suppress VEGF, hence impeding the angiogenesis process necessary for tumor sustenance.[28] Epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab, function by inhibiting the signaling of the EGFR, a crucial factor for the proliferation and viability of malignant cells. The aforementioned medicines have demonstrated effectiveness in combating cancers that exhibit mutations or overexpression of the EGFR.[29,30] BRAF inhibitors: The V600E mutation of the BRAF gene promotes the development of CRC. This mutated pathway is inhibited by targeted agents such as encorafenib and binimetinib, thereby limiting tumor progression. Trastuzumab and lapatinib are efficacious against CRC tumors with HER2 amplification or overexpression.[29,31] MEK inhibitors, such as trametinib, are utilized in BRAF-mutated CRC to inhibit tumor growth by blocking the downstream MEK/ERK signaling pathway.[29] The application of immune checkpoint inhibitors (ICIs), such as pembrolizumab and nivolumab, enhances the selective recognition and targeting of cancer cells by the immune system. The therapeutic efficacy of these treatments has been demonstrated in patients afflicted with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) malignancies.[27,31]

Immunotherapy for Neoadjuvant Cancer Treatment

The application of immunotherapy has emerged as a potentially effective therapeutic strategy for CRC, especially in cases of metastatic disease. The CRC ranks as the third most prevalent type of cancer and is the second leading cause of cancer-related mortality on a global scale.[32] In instances of metastatic disease, standard therapeutic techniques, including chemotherapy, radiation therapy, and surgery, may produce less than optimum outcomes.[33] In recent years, there have been notable advancements in the field of immunotherapy, which have showcased its capacity to augment the immune system’s aptitude for discerning and eradicating cancerous cells in a targeted manner. In the realm of CRC, the utilization of ICIs, particularly those that selectively bind to programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1), constitutes a noteworthy immunotherapeutic strategy. Various types of tumors, such as CRC, have demonstrated enduring responses to inhibitors,[34] particularly in cases marked by dMMR or MSI-H. The aforementioned molecular features are observed in around 5% of instances of CRC.[2] The challenge lies in the observation that a significant proportion, specifically 95%, of CRC instances demonstrate a proficient mismatch repair (pMMR) or microsatellite stable phenotype. The present phenotype is correlated with a reduced tumor mutation burden and less infiltration of tumor lymphocytes.[34]

The primary emphasis of ongoing research is directed at resolving the challenges associated with immune tolerance and evasion in the tumor microenvironment. At present, there is a concerted endeavor to ascertain biomarkers that might accurately predict the response to immunotherapy, as well as to formulate innovative therapeutic approaches. The prognostic and predictive relevance of the immunological tumor microenvironment (TME) in CRC is attributed to its intricate and heterogeneous nature. Although immune checkpoint drugs have demonstrated therapeutic effectiveness, individuals with pMMR or MSS CRC necessitate the implementation of efficacious immunotherapy approaches. This requires a deeper understanding of the immune system’s role in the tumor microenvironment and the need to design combination therapies that can augment the immune response against tumors.[35] The utilization of immunotherapy has significant promise in transforming the management of CRC, particularly in instances characterized by the presence of metastatic disease. The efficacy of ICIs has been found to be outstanding, particularly in cases characterized by the dMMR/MSI-H phenotype. However, current research endeavors to expand the advantages of immunotherapy to the majority of CRC cases characterized by the pMMR/MSS phenotype. This is being achieved by the identification of predictive biomarkers and the development of innovative therapeutic approaches.[36]

Biomarker-Informed Neoadjuvant Interventions

Emerging CRC biomarkers

The identification of emerging biomarkers for CRC is crucial to improve early detection, prognosis, and treatment approaches. Biomarkers play a crucial role in tailoring therapy to specific patients and enhancing patient outcomes. Advancements in genomics and molecular pathology have led to the identification of potential biomarkers.[34] These biomarkers have the potential to enhance the customization of therapy and facilitate the prediction of prognosis. It is important to highlight that the utilization of molecular testing to identify gene mutations, including KRAS, BRAF, and p53, together with the assessment of microsatellite instability and epigenetic modifications, holds significant significance in the advancement and advancement of CRC.[38]

Furthermore, scientists are also examining cell surface indicators as a means of identifying diverse colorectal tumors at an early stage. The purpose of these biomarkers is to enhance the sensitivity of colonoscopy, which is widely regarded as the most reliable method for detecting CRC.[36] The next figures, Figures 5 and 6, illustrate the mutation of BRAF and HER2, as well as their progression and signaling pathways in CRC.[39-43]

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Figure 5

Comparison of outcomes total neoadjuvant therapy versus CRT

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Figure 6

BRAF mutation and pathway in colorectal cancer

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In Neoadjuvant Settings, Combination Therapies

Reducing Treatment Toxicity and Managing Adverse Reactions

Emerging Strategies and Future Paths

Obstacles and Restrictions in Neoadjuvant Therapy

Challenges and limitations in neoadjuvant therapy for CRC involve a complex interplay of factors that influence treatment outcomes, patient compliance, and bridging the research-to-clinical practice gap. To maximize the efficacy of neoadjuvant approaches, these obstacles must be addressed.[66]

Recent Clinical Trials

Following recent clinical trials done in the past 10 years of how different neoadjuvant therapies have worked for CRC are mentioned below in Table 2.

Table 2 Recent clinical trials performed in the past 10 years

Conclusion

This review has provided a thorough examination of novel regimens and treatment strategies in CRC neoadjuvant therapy. The investigation of diverse approaches encompassing neoadjuvant radiotherapy, chemotherapy, immunotherapy, and combination therapies demonstrates the expanding potential to improve patient outcomes and transform the landscape of CRC treatment. Neoadjuvant therapy has evolved beyond conventional approaches, demonstrating the capacity to downstage locally advanced disease, facilitate more effective resections, and enhance treatment tolerability. Neoadjuvant radiotherapy, especially for rectal cancer, has demonstrated efficacy in reducing tumor burden before curative surgery, and its benefits are best realized through multidisciplinary collaboration and careful patient selection.[15] Similarly, NACT has demonstrated promise in the treatment of colon cancer, and ongoing research aims to uncover its complete potential and refine its administration.[82] The integration of ICIs into neoadjuvant therapy for MSI-H CRC has initiated a novel era and revolutionized the approach to managing this particular subtype of the disease. The emergence of precision medicine based on the unique biological characteristics of each individual’s CRC has paved the way for targeted therapies,[84] in which therapeutic approaches are tailored to the tumor’s specific characteristics. The prospective impact on patient outcomes is substantial as the field advances. The incorporation of innovative strategies can result in enhanced disease management, improved surgical outcomes, and increased organ preservation. Nevertheless, obstacles such as patient selection, treatment toxicity, and balancing the benefits and risks of neoadjuvant interventions require careful consideration and ongoing research.[83] Figure 7 illustrate HER 2 mutation, therapy, and signaling pathway in colorectal cancer.

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Figure 7

HER 2 mutation, therapy, and signaling pathway in colorectal cancer

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Future prospects for the advancement of neoadjuvant approaches are promising. Current clinical trials investigate the duration, sequencing, and combination of various therapeutic modalities. The objective is to refine neoadjuvant strategies, identify predictive biomarkers, and optimize patient selection to achieve the best outcomes possible while minimizing treatment-related morbidity.[85] The rapidly changing landscape of neoadjuvant therapy for CRC offers numerous opportunities to enhance patient care. Adoption of novel regimens and strategies, implementation of precision medicine, and the emergence of immunotherapy all have the potential to improve outcomes, redefine treatment paradigms, and continue the trend toward more effective and individualized treatments for CRC. As research advances, it is crucial to maintain a patient-centered perspective, balancing innovation with careful consideration of patient requirements and QoL.

Patient’s Consent Statement

Not applicable.

Availability of Data and Material

The data presented in this article are available with the corresponding author and will be provided on reasonable request.

Competing Interests

None.

Funding Statement

None.

Authors’ Contributions

Yamama Al-Khazraji, Muhammad Ali Muzammil, Saman Javid,: Conceptualization, methodology, software, data curation, validation, writing-original draft preparation. Adarsh Vardhan Tangella, Namra Vinay Gohil, Hanya Saifullah, Sai Gautham Kanagala: Writing- reviewing and editing, project administration. Sai Gautham Kanagala, Ali Shariq: Writing- reviewing and editing, supervision.