Purpose of Review Rectal cancers are treated with chemotherapy, radiotherapy, and surgery. While trials have illustrated the benefits of radiotherapy for locoregional control, recent investigations have questioned the need in select cases. This review seeks to understand why, how, and when radiation can be omitted from rectal cancer management. Recent Findings Absolute contraindications of radiation include pregnancy, and relative contraindications include fertility concerns, sexual outcomes, autoimmune conditions, and prior radiation. Low-risk features of rectal cancer might warrant the omission of neoadjuvant radiation. MRI-directed therapy, chemotherapy alone, and immunotherapy may offer future ways to omit radiation. Summary While radiation continues to be an essential component for rectal cancer treatment, there may be circumstances that it can be omitted. It is important to educate patients that not receiving radiation is a deviation from standard of care. In the future, we may see developments and changes in the treatment paradigm for rectal cancer.
The surgical management of metastatic colorectal cancer (CRC) has evolved over time. Most often, the management of asymptomatic primary CRC with simultaneous liver metastases (LM) proceeds with neoadjuvant chemotherapy followed by surgical resection. Although the timing of surgical resection has remained controversial, the ability to achieve R0 resection and the importance of patient selection remain widely accepted. Preoperative novel modalities such as portal vein ligation (PVL) or portal vein embolization (PVE) have allowed for improved surgical outcomes and decreased post-surgical morbidity. Combination or hybrid management has also seen increased utility by associating ablation therapies with surgical resection. Finally, patients with significant comorbidities and surgically unresectable disease have benefited greatly from locoregional salvage therapies such as percutaneous ablation and radioembolization. Here we will review pertinent literature associated with surgical management for resectable disease and explore newly developed locoregional salvage therapies for unresectable disease.
Purpose of Review Laparoscopic hemicolectomy (LHC) is widely used to treat benign and malignant colorectal disease. However, the optimal method to restore intestinal continuity is still controversial; hence, this study aims to compare the safety and efficacy of intracorporeal anastomosis (IA) with extracorporeal anastomosis (EA). Recent Findings Current literature comprises largely of retrospective cohort studies and three significant randomized controlled trials examining the differences between IA and EA in mostly right-sided colectomies. The evidence points to superior intraoperative and postoperative outcomes such as reduced incision length, incidence of wound infection and length of stay for IA, but with incongruous findings on outcomes such as anastomotic leakage and lymph node yield. Likewise, existing meta-analyses have reached differing conclusions about some of these key outcomes. Summary This paper provides a timely update to existing reviews and shows that IA is associated with superior intraoperative, postoperative and long-term recovery outcomes. We provide more conclusive evidence that lymph node yield for cancer patients is improved in IA. Furthermore, lymph node yield and lowered readmission rate appeared to be more pronounced in patients with higher BMI through regression analysis. Our key recommendation is for surgeons to acquire a high level of proficiency in performing IA to improve patient outcomes.
The non-operative management of rectal cancer is an area of active research. Dose-escalated radiotherapy may improve sustained local control but toxicity is a concern. Brachytherapy is emerging as a promising boost technique that may confer dosimetric advantages over external beam radiotherapy (EBRT)–based boosts. Preliminary findings from two multicenter prospective randomized phase II/III trials suggest high rates of sustained 2-year local control with a combination of EBRT and either contact X-ray brachytherapy or high dose rate endorectal brachytherapy compared with an EBRT boost. Brachytherapy is a promising technique in the non-operative management of patients with rectal cancer. Further research will be needed to characterize long-term oncologic and toxicity outcomes.
Treatment paradigms for locally advanced rectal cancer have evolved over the last several decades. Patients now have several different “standard” options with different radiation courses, sequencing of treatment modality and in some scenarios potentially avoidance of surgery. In this context, an updated understanding of treatment toxicity is needed to help patients make informed decision regarding their treatment. The RAPIDO study showed no difference in cumulative rate or grade of toxicity between short and long course radiation. Based upon our experience, patients with short course radiation tend to present with acute symptoms 1–2 weeks after completion of radiation, while those receiving long course chemoradiation have symptoms towards the end of treatment. Treatments that may be helpful particularly for short course radiation toxicity include Bentyl (dicycloverine) and steroids. The most common toxicities from radiation are due to bowel and rectal inflammation leading to diarrhea, cramping, and urgency. The combination of surgery and radiation can exacerbate these symptoms. The most common late toxicity in patients receiving doublet chemotherapy is neurotoxicity. Rates of infertility differ in men versus women; all efforts for fertility preservation should be completed prior to initiation of any therapy.
There is a growing consensus that oligometastatic disease-directed treatment is associated with improved oncologic outcomes in patients with colorectal cancer; however,the optimal local management of pulmonary oligometastases remains controversial. While surgery has traditionally been recognized as the gold standard local treatment for pulmonary metastases, there is no prospective data supporting a significant benefit of pulmonary metastasectomy (PME) compared to other local treatment modalities, such as stereotactic ablative radiotherapy (SABR) or radiofrequency ablation (RFA). There has been increasing utilization of SABR for pulmonary oligometastases—particularly for patients who are not candidates for PME, with comparable survival, local control, and toxicity observed. There remains an unmet need for high-quality prospective data to optimally guide patient selection for local treatment modalities of pulmonary oligometastases. Given the evolving complexity of oligometastatic disease states and multitude of local and systemic treatment factors, multidisciplinary clinical discussion is essential.
Purpose of Review To discuss the emerging technologies in the field of Interventional radiology (IR) for the management of metastatic colorectal cancer (mCRC). We review the field of selective internal radiation therapy (SIRT), and well-known IR treatments, with a more focused investigation of radioembolization with Yttrium-90 (Y-90). Recent Findings State-of-the-art treatment modalities for unresectable hepatic malignancies are crucial to increased patient survival. There are many options for the treating physician to manage and potentially cure patient’s disease, with Y-90 as the cornerstone of liver neoplasm treatment. Additionally, current research in the fields of dosimetry and radiomics may allow for more optimized patient specific radiation doses. Summary Continued advancements in colorectal surgery and interventional radiology have improved survival outcomes for patients with mCRC. Current treatment options are numerous and often include partial hepatectomy and SIRT. We review current literature and discuss our experiences in treating patients with advanced liver malignancies.
Colorectal cancer is the third most common malignancy in the USA with 20% of patients presenting with metastatic disease. While first line agents include cytotoxic chemotherapy regimens, targeted therapies have an increasing role in the management of metastatic colorectal cancer (mCRC). Next Generation Sequencing (NGS) has expanded the ability to identify HER2 variations and is crucial to the next steps in personalized medicine. Anti-HER2 therapies provide a promising treatment option for patients who have exhausted traditional regimens including those who have failed prior anti-HER2 therapy. This is in accordance with the 2021 addition of trastuzumab-deruxtecan to the National Comprehensive Cancer Center Guidelines as a subsequent therapy in eligible patients based on the results of the DESTINY-CRC01 trial. Various anti-HER2 therapies are approved alone or in combination for patients with mCRC and HER2–amplified tumors. Further investigation into the role of HER2–directed therapy in mutated mCRC is an unmet need, as is the wider use of NGS and ctDNA to explore mechanisms of resistance.
The goal of this review is to summarize recent evidence linking behavioral risk factors to early-onset colorectal cancer (EO-CRC) as the incidence continues to rise by 2% annually in the USA. The potential mechanisms linking these risk factors to EO-CRC are also discussed. Obesity and sedentary behavior have been associated with an increased risk of EO-CRC in women through a large cohort study, while the data is inconclusive for men. Diabetes was also associated with an increased risk of EO-CRC in a large Swedish cohort study. While the evidence for metabolic syndrome and diet comes from cross-sectional studies, they still point to an association with EO-CRC. The mechanisms underlying these risk factors include inflammation, gut dysbiosis, and aberrant mitogenic signaling. The etiology of EO-CRC likely involves a multifactorial mechanism that will require a multidisciplinary approach. Existing consortia and new data harmonization of multiple studies will be useful in re-evaluating the role of established lifestyle/genetic risk factors of CRC in EO-CRC. Future investigations should prospectively collect information on exposures and biospecimens, particularly during early life, to further elucidate risk factors and contributors to the rising incidence of EO-CRC.
Purpose of Review This review describes recent data supporting locoregional ablative radiation in the treatment of oligometastatic colorectal cancer liver metastases. Recent Findings Stereotactic body radiotherapy (SBRT) demonstrates high rates of local control in colorectal cancer liver metastases when a biologically equivalent dose of > 100 Gy is delivered. Future innovations to improve the efficacy of SBRT include MRI-guided radiotherapy (MRgRT) to enhance target accuracy, systemic immune activation to treat extrahepatic disease, and genomic customization. Selective internal radiotherapy (SIRT) with y-90 is an intra-arterial therapy that delivers high doses to liver metastases internally which has shown to increase liver disease control in phase 3 trials. Advancements in transarterial radioembolization (TARE) dosimetry could improve local control and decrease toxicity. Summary SBRT and SIRT are both promising options in treating unresectable metastatic colorectal cancer liver metastases. Identification of oligometastatic patients who receive long-term disease control from either therapy is essential. Future advancements focusing on improving radiation design and customization could further improve efficacy and toxicity.
The trimodal treatment for LARC—surgery, radiotherapy, and chemotherapy—has been the standard of care for more than 30 years but is facing fresh challenges. Major contemporary developments include the delivery of full systemic chemotherapy in the preoperative period, with or without chemoradiation (total neoadjuvant therapy or “TNT”), and the withholding of surgery for patients who achieve a complete clinical response (cCR) to initial treatment (“watch-and-wait”). We review the historical development of these trends and propose an approach to LARC treatment that integrates newly emerging protocols with the traditional standard of care. Data from the recent randomized trials PRODIGE 23 and CAO/ARO/AIO-12 show that patients with LARC treated with TNT have a higher frequency of cCR, longer disease-free survival, and increased ability to tolerate chemotherapy. Preliminary results of the prospective OPRA study indicate that a watch-and-wait approach may permit sphincter preservation for a high proportion of patients without compromising survival. The increasing adoption of TNT to treat LARC is due to high rates of cCR, low levels of toxicity, a superior ability to deliver full-dose chemotherapy, and better preservation of quality of life. Based on current evidence, the combination of preoperative systemic chemotherapy and non-surgical management is appropriate for selected patients who have achieved a cCR and face a high risk of sphincter loss or dysfunction with surgery.
Colorectal cancer (CRC) is the most common gastrointestinal neoplasm. Imaging plays a key role in the primary diagnosis, risk stratification and prognosis, therapy planning, treatment response assessment, follow-up, and, to some extent, also in prevention of CRC. The most used imaging modalities for the evaluation of these tumours are computed tomography (CT) and magnetic resonance imaging (MRI). We review the literature and, drawed on our own experience, evaluate recent innovations in hardware, software (including artificial intelligence), and analytic tools that are opening new possibilities to CT and MRI imaging in CRC. Finally, we examine the advantages and disadvantages of these techniques. Advances in CT technology have improved image quality and reduced radiation exposure to patients and have allowed a paradigm shift from an imaging modality that provided solely anatomical data to one that can also provide functional information. In addition, technological improvements in MRI have made possible a faster and more robust imaging technique and the generation of new data of tumour phenotype. All these advances have expanded the clinical capabilities of these techniques in colorectal tumours. Recent developments and emerging technologies in CT and MRI are changing the management of CRC patients in many clinical scenarios. Current evidence supports the clinical application of many of them. In other cases, such as quantitative imaging, multiparametric assessment, and radiomics/radiogenomics, important problems of standardization and reproducibility of these techniques persist that limit their introduction in daily clinical practice.
The current standard treatment for locally advanced or metastatic colorectal cancer often includes radiotherapy delivered under computed tomography (CT)–based image guidance. Magnetic resonance–guided radiotherapy (MRgRT) offers a substantial improvement in target and adjacent organ visualization and allows for real-time imaging throughout treatment to ensure target accuracy with each fraction. However, this technology is in its relative infancy, with many open questions regarding how to maximize the potential of this new treatment modality. We review the literature and share our institutional experience to highlight the strengths and limitations of MRgRT for treatment of colorectal cancer. MRgRT is safe and effective in both the locally advanced and metastatic settings. Dose can be safely escalated in locally advanced cases, potentially improving rates of pathologic complete response. Functional imaging offers insight into treatment response dynamics, opening the possibility for nonoperative management of select cases. Liver metastases can be treated to ablative doses with high rates of local control. MRgRT has the potential to shift the paradigm of treatment for locally advanced and metastatic colorectal cancer. Improved target accuracy and real-time gating allows for dose prescriptions beyond what has been achievable with CT-based imaging, allowing for higher rates of tumor control with no significant increase in toxicity. Future work will focus on optimal dose fractionation schemes and functional radiographic assessment of tumor response.
The aim of this paper is to summarize the current treatment landscape in metastatic colorectal cancer, as well as those on the horizon in the third-line and beyond settings. Herein, recent data regarding TAS-102, regorafenib, and novel anti-angiogenic agents are described. Data on chemotherapy re-challenge and EGFR re-challenge is reviewed. A summary of data on the use of BRAF-targeted therapies, HER-2-targeted therapies, rare fusions (NTRK, RET), MET amplification, and KRAS G12C is included, as well as a brief review on the current role of immune checkpoint inhibitors in metastatic colorectal cancer. Multiple new agents are on the horizon. There is increasing relevance of next generation sequencing to look for rare targets, and potentially to assess tumor mutational burden. ctDNA appears to be a valuable asset which may guide the use of therapies in the re-challenge setting.
Early response prediction for locally advanced rectal cancer (LARC) provides an opportunity for response-tailored treatment management. The goal of this review is to summarize recent advances in applying functional MRI, such as diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI), to predict treatment response for LARC patients, as well as to discuss the associated limitations and future directions. Many recent studies incorporated advanced data analysis methods, such as radiomics and deep learning, to enhance prediction performance. Multi-parametric imaging has also become a trend that utilizes complementary information from each technique. However, there are wide variations in patient enrollment, imaging time points, scan parameters, and treatment response endpoint definitions, which leads to a range of findings among these studies. Moreover, small sample size and lack of independent validation of most studies also weaken conclusions. Functional MRI has been shown as a potential early biomarker for rectal cancer treatment response estimation. To incorporate functional MRI into clinical workflow, future work with large standardized data are warranted.
The application of advanced genomic testing to develop tumor-specific molecular profiles is essential to facilitating precision medicine pharmacotherapy. These approaches are highly relevant in colorectal cancer, where tumors frequently contain druggable molecular mutations, as well as the potential to respond to immunotherapy. Here we review the literature characterizing biomarker-driven pharmacotherapy for colorectal cancer, and highlight the pivotal ongoing trials that will help inform future treatment of this disease. Both prospective and retrospective studies have confirmed that the benefit from adding anti-epidermal growth factor receptor therapy is limited to patients with stage IV disease, RAS wild-type tumors, and left-sided primary tumors. Furthermore, patients with BRAF-mutated tumors derive significantly less benefit from the addition anti-epidermal growth factor receptor therapy. The use of BRAF inhibitors in the second-line setting is associated with a relatively high response rate, and regimens incorporating first-line treatment with BRAF inhibitors may soon become standard of care for patients with BRAF-mutated tumors. In the relapsed setting, the use of targeted agents and immunotherapy should be prioritized for patients with respective tumor profiles. There has been significant advancement in the understanding of how to utilize molecular profiling and tumor biomarkers to tailor pharmacotherapy in colorectal cancer. Future studies should continue to incorporate these tests at enrollment to further define patient cohorts deriving the greatest benefit from precision medicine, characterize ideal sequence of therapy, and advance understanding of drug resistance mechanisms.
Despite mounting interest in the non-operative management (NOM, also known as watchful waiting) of rectal adenocarcinoma, limited guidance exists regarding appropriate patient selection and procedures. In this literature review targeting patients with operable adenocarcinoma of the rectum, we sought to evaluate NOM in terms of patient selection, management approaches, and outcomes with regard to both quality of life (QoL) and oncologic outcomes. Despite a lack of randomized evidence comparing NOM (performed via active surveillance following neoadjuvant chemotherapy and radiation) to neoadjuvant therapy followed by planned surgery, given that the vast majority of local, regional, and distant recurrences occur early in follow-up, the available evidence points to similar oncologic outcomes and possible QoL improvement. Due to the high chance of surgical salvage in the case of locoregional recurrence, close multidisciplinary follow-up is essential. Under the care of an experienced multidisciplinary lower gastrointestinal team, NOM is feasible, is safe, and has the potential for improved QoL. A potential algorithm for clinically implementing NOM is described within this review.
Purpose of Review This review provides an overview of the current role of biologics, anti-vascular endothelial growth factor (VEGF) inhibitors and anti-epidermal growth factor receptor (EGFR) inhibitors, in the perioperative treatment of colorectal liver metastases as well as a discussion of their future trends. Recent Findings Over the past decade, a number of clinical trials have suggested that the use of biologics with cytotoxic agents may increase median overall survival in certain subsets of patients with colorectal liver metastases. The benefit of these agents is limited to borderline resectable and unresectable hepatic metastases and is not seen in upfront resectable disease. In the RAS wild-type population, the difference in efficacy of VEGF and EGFR inhibitors in combination with chemotherapy is minimal. These agents perform differently depending on primary tumor location; bevacizumab has greater efficacy in right-sided tumors, whereas cetuximab has greater efficacy in left-sided tumors. While biologics benefit patients in the neoadjuvant setting, studies have not shown similar results in the adjuvant setting. Summary Given the variability of patient presentations as well as the risk of treatment-related toxicity, the addition of biologics requires careful consideration of patient’s medical fitness, surgical risk, and tumor profile.
Purpose of Review The currently established standard of care treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) and adjuvant fluorouracil and oxaliplatin. The body of evidence that supports this treatment has grown over the last 20 years. However, recent advances and ongoing studies seek to further evaluate the role of neoadjuvant chemotherapy with and without radiation and total neoadjuvant therapy (TNT). In this article, we review the current literature as well as investigate the emerging role of TNT for patients with LARC and comment on updates utilizing combination neoadjuvant chemotherapy in early-stage rectal cancer. Recent Findings Evidence for the current standard of neoadjuvant CRT comes from well-established randomized phase III trials as well as emerging evidence on merits of TNT. There is a growing body of literature including retrospective analysis and ongoing clinical trials that look at upfront induction chemotherapy in addition to CRT prior to surgical resection leading to more effective delivery of systemic therapy and increases in response to treatment. Neoadjuvant combination chemotherapy is also being investigated in early-stage low rectal tumors to see if rates of local excision will increase compared to radical excision. Summary Current evidence continues to support neoadjuvant CRT as the standard treatment for LARC. There is an increasing body of evidence to support TNT in LARC as an effective treatment strategy that better ensures delivery of systemic therapy leading to higher rates of complete response (CR) and is encouraging for the development of non-operative protocols. There is ongoing evaluation looking at the benefit of novel sensitizers added to neoadjuvant therapy and ongoing investigation into upfront combination chemotherapy with selective use of radiation in upper rectal cancers.
The investigation of total neoadjuvant therapy has increased significantly in recent years, with a number of approaches being utilized in ongoing prospective studies, including (1) induction neoadjuvant chemotherapy (INCT), (2) consolidation neoadjuvant chemotherapy (CNCT), and (3) short-course radiation therapy (SC-RT) for locally advanced rectal cancer (LARC). Significant questions remain regarding the ideal sequence of a total neoadjuvant therapy (TNT) approach. Multiple prospective multi-institutional trials have evaluated the addition of multi-agent chemotherapy before or after neoadjuvant rectal cancer chemoradiation. In 2019, a multi-center randomized phase II trial from Germany, CAO/ARO/AIO-12, demonstrated better compliance and lower toxicities with CNCT in comparison to INCT. The OPRA study recently reported in ASCO 2020 improved organ preservation for CNCT, and similar 3-year disease-free survival (DFS) and distant metastasis-free survival (DMFS). RAPIDO reports higher rates of pathologic complete response (pCR) and lower rates of 3-year distant metastases (DM) for TNT compared to traditional treatment sequencing. Recent literature on TNT for LARC highlights the potential of this approach to enhance compliance, increase distant control and survival rates, and reduce toxicities. Further research is important to tailor treatment approaches to patients with LARC.
