Current management and controversies in management of T4 cancers of the colon—a narrative review of the literature

Introduction

Colorectal cancer is the third most common malignancy in the world, with approximately 10% of patients with locally advanced disease with peritoneal involvement (T4a) or invasion of adjacent organs (T4b) at the time of diagnosis (1,2) and accounts for third leading cause of cancer related deaths in both genders (3). The prognosis of patients with colon cancer largely correlates to their TNM staging with a 5-year disease specific survival of all T4 tumours being 75% (4), however, there is significant variance within this group with T4a tumours having a significantly higher 5-year survival than T4b tumours (61% vs. 46%) (5,6) underscoring the importance of accurate pre-operative staging. Important questions remain regarding the utilisation of neoadjuvant chemotherapy (NAC) and/or neoadjuvant radiotherapy (NRT) to increase their chances of achieving a R0 resection.

We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/dmr-20-74).

Methods

A literature search was performed for all English articles in this field utilising the MEDLINE (via PubMed) and EMBASE (via OvidSP) databases. Ongoing trails were identified via the clinical trials registry: https://clinicaltrials.gov. All natures of studies; prospective randomised controlled trials, non-randomised prospective trials, retrospective studies, case reports, reviews, meta-analyses and conference abstracts were included. Additional manual searches of relevant articles were also conducted. Key words used included “neoadjuvant chemotherapy”, “neoadjuvant chemoradiotherapy”, “neoadjuvant radiotherapy” in “locally advanced colon cancer”, “high risk T3” and “T4 colon cancer”. Studies referring to locally advanced colon cancer (LACC) with metastases were excluded.

Pre-operative work up

European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) guidelines for preoperative work up include baseline blood tests including carcino-embryonic antigen (CEA), colonoscopy preoperatively if possible, however in an emergent setting this can be performed post operatively, and computed tomography (CT) scan of the chest, abdomen, and pelvis (7). In the case of equivocal CT findings or contraindications to IV contrast, the NCCN recommend positron emission tomography (PET) scan to provide further clarification (8).

Clinically, since T4 tumours are locally advanced, many of them will be diagnosed in an emergent setting with incidence being up to 69% compared with 26% in the elective group (9). In the case of intestinal obstruction or peritonitis due to tumour perforation, preoperative CT scans will adequately describe the lesion responsible but may not accurately discern the full extent of the tumour’s local invasion or the presence of nodal involvement.

In elective cases, a recent meta-analysis by Nerad et al. (10) found that CT overstaged one-third of all patients with an overall sensitivity of 90% in detecting tumour invasion beyond the bowel wall but a specificity of 69%. To date, no studies are able to offer an explanation for the low specificity, however, it is suggested that radiologists, to minimize the risk for under-staging, interpret minimal pericolonic fat stranding due to benign desmoplastic reaction as tumour invasion. This is a widely recognised problem in colorectal staging (11).

Abdominal CT is, however, is very important in detecting distant metastases, especially in T4 colon cancers as the risk of distant metastases is high (up to 45% of the cases), as well as the risk of nodal involvement (up to 65% of the cases) (12,13).

Magnetic resonance imaging (MRI) is well established for pre-operative staging of rectal cancer (14) as it has better soft-tissue contrast than CT allowing for higher resolution imaging of the layers of the bowel wall and its adjacent structures. The diagnostic performance of MRI and CT for LACC has been compared in numerous studies, MRI has been shown to be superior in defining T3 tumours with serosal involvement and T4 tumours as it has a higher specificity and lower false positives compared to those of CT (15-19) allowing for less over-staging. Combined with its known precision in detecting liver metastases and extramural vascular invasion (EMVI) MRI could become the most optimal abdominal staging method for patients with high risk colon cancer (18).

Molecular testing, especially for, microsatellite instability (MSI), BRAF and KRAS mutations, is currently routine practice in patients with locally advanced and/or metastatic colon cancer as it not only aids with prognostication, but also, helps guide treatment (8). MSI is a form of genetic instability owing to the deficiency of the DNA mismatch repair (MMR) mechanisms resulting in hypermutability. Those with MSI have a better prognosis than those with microsatellite stability (MSS), this is particularly important as 15–20% of stage II and III colon cancers are MMR-deficient or MSI (20). To date, BRAF mutations have no clear role in guiding treatment decisions, however, are useful in predicting outcomes, and while it has been shown that patients with BRAF-mutant metastatic colon cancer have significantly poor survival (21), its prognostic role in non-metastatic LACCs remains controversial, particularly amongst MSI vs. MSS tumours (22). Targeted therapy is generally given in conjunction with chemotherapy and is largely guided by the tumour’s KRAS mutation status. KRAS mutations predict resistance to epidermal growth factor receptor (EGFR) inhibitors such as cetuximab and panitumumab, resulting in their restricted use in only patients with KRAS wild-type tumours (23). Other targeted monoclonal antibodies include bevacizumab [active against vascular endothelial growth factor (VEGF)] and ramucirumab [active against vascular endothelial growth factor receptor (VEGFR)] (24).

The importance of pre-operative staging is to answer one main question—is the patient a candidate for a potentially extended R0 resection or not?

Treatment strategies

In the elective setting, the NCCN outlines the management of resectable colon cancer based on the presence of obstructing symptoms. Non-obstructing cancers are treated with a colectomy with regional lymphadenectomy, whereas, for obstructed cancers temporary diversion is recommended either at the time of colectomy or before definitive surgery (8). Importantly, in emergent situations where a radical resection is not possible, or difficult to achieve, for example in patients who present with intestinal obstruction without tumour perforation or peritonitis, a defunctioning ostomy should be considered in leu of resection the primary, this not only allows for decompression but also facilitates neoadjuvant therapies.

NAC in LACC

Complete oncologic resection followed by adjuvant chemotherapy (AC) is the current standard treatment for patients with LACC, however, this approach may require extensive en bloc multivisceral resection to achieve negative microscopic margins (25). Despite this aggressive approach, the rate of R0 resections remains underwhelming, varying between 40–90% (25,26) with associated increased postoperative morbidity and mortality (26).

NAC is postulated to enhance tumour regression and aims to downstage tumours (27), improving resectability and promoting higher rates of local control hence, achieving more R0 resections (28-31). This has been proven to be effective in locally advanced oesophageal (32), gastric (33), rectal (34) and breast cancer (35).

To date NAC in LACC has been vastly understudied, however; based largely on emerging data from several phase II trials (36,37), the NCCN have added NAC as a treatment option for patients with clinical T4b disease (8). Table 1 summarises all published randomised control trials investigating NAC in LACC.

The FOxTROT Collaborative Group (36) investigated the feasibility, safety, and efficacy of preoperative chemotherapy for LACC. In this randomised control trial, 150 patients with radiologically staged locally advanced high risk T3 (with ≥5 mm invasion beyond the muscularis propria) or T4 tumours from multiple UK centres were randomly assigned either to 3 cycles of neoadjuvant FOLFOX (folinic acid, fluorouracil and oxaliplatin) followed by surgery with a subsequent 9 cycles as adjuvant therapy or up front oncological resection with a standard 12 cycles of adjuvant FOLFOX. KRAS testing was instituted shortly after the trial had commenced and aimed to randomly assign patients with KRAS wild-type tumours to receive panitumumab (6 weeks) or not, 46 (31%) of the 90 eligible patients received panitumumab. They reported that NAC resulted in significant downstaging compared with the postoperative group (P=0.04), especially in those with apical node involvement (P<0.0001) and exhibited two pathological complete responses. They also found resection margin involvement to be significantly lower in those treated with NAC (P=0.002) and observed significant tumour regression grading (P=0.0001) without incurring significant perioperative morbidity.

Jakobsen et al. (37) investigated whether NAC could convert high-risk patients (those requiring AC) to a low-risk (not requiring AC). Seventy-seven patients with histologically diagnosed adenocarcinoma, CT scan showing a high risk T3 or T4 tumour with no metastases on staging CT were divided into two groups according to mutational status (wild type vs. mutated + unknown) in this Danish phase II randomised control trial. Patients with KRAS, BRAF, PIK3CA mutation or unknown mutational status received three cycles of neoadjuvant CAPOX (capecitabine and oxaliplatin) while wild-type patients received the same chemotherapy supplemented with panitumumab. All patients then proceeded to oncological resection and were further stratified post histopathological analysis. Those who had high risk T3 tumours defined as having at least one of following factors: (I) <12 lymph nodes in resection specimen, (II) poorly differentiated tumours, (III) vascular, lymphatic or perineural invasion or T4 tumours were deemed ‘non-converts’ and received a further five cycles of the CAPOX without panitumumab. The study’s primary end point was ‘converted’ patients i.e., those not fulfilling the criteria for AC and this cohort was offered follow up only. The overall conversion rate from high risk patients to low risk patients was 42% in the wild-type group compared to 51% in patients with a mutation. Secondary end points were recurrence rate and disease-free survival (DFS). The group reported a cumulative recurrence rate in converted versus unconverted patients of 6% vs. 32% (P=0.005) with a 3-year DFS of 94% vs. 63% (P=0.005). Jakobsen et al. concluded that NAC is feasible in LACC and acknowledged that the study partly relies on an elimination of lymph node metastases and that conversion rates should be interpreted with caution as pre-operative CT may not show nodal involvement that may subsequently be found in the resection specimen.

A phase II multicentre French randomized controlled trial (PRODIGE 22) (38) evaluated the efficacy and safety of NAC in patients with locally advanced non-metastatic colon cancer. One hundred and twenty patients with resectable high risk T3 or T4 tumour and/or N2 nodal involvement were randomised to receive either eight cycles of adjuvant FOLFOX after colectomy or four cycles neoadjuvant FOLFOX ± cetuximab (depending on RAS mutation status) followed by colectomy and subsequent eight more cycles of the same chemotherapy post operatively. Importantly, at interim analysis, the FOLFOX + cetuximab arm was ceased due to lack of efficacy and hence this arm was excluded from statistical analysis. While, of the 104 patients analysed, the group did not observe any major pathological response (TRG1) in the NAC arm they did find a significant pathological regression 44% vs. 8%, P<0.001 in the NAC arm compared to the control arm with a trend to tumour downstaging without significant difference in overall mortality and morbidity rates.

Table 2 depicts two Chinese single arm phase II prospective trials (39,40) investigating the feasibility, safety and tumour response of NAC in LACC have also reported significant tumour regression and downstaging with acceptable toxicity and perioperative morbidity. Additionally, multiple retrospective propensity-score matched cohort analysis studies exploring patients with T4 colon cancer treated with NAC have shown significant radiological and pathological regression (41-43) with a higher 3-year overall survival (OS) (44).

In a recent presentation at the ESMO Congress 2019, the FOxTROT Collaborative Group presented an interim analysis of a further 1,053 patients across 98 hospitals in the UK, Denmark and Sweden (45). Of the 699 patients allocated to the NAC arm, 88% completed the three cycles of neoadjuvant FOLFOX and had marked histological downstaging after NAC with a lower pT and pN stage (P<0.0001 for both). A small subset of NAC arm patients displayed a complete (3.8%) and near-complete (4.6%) tumour regression. Serious perioperative complications, prolonged hospital stays and re-operation rates were lower in NAC group.

In summary, it appears that NAC is a safe, feasible and well tolerated therapy in LACC, current evidence, although still emerging, suggests NAC can cause significant tumour regression and downstaging with minimal adverse outcomes and perioperative morbidity.

NRT for LACC

The role of NRT in LACC remains unclear and while there is ongoing research evaluating its safety and efficacy (46,47), there is relative paucity of definitive data supporting its use in this patient population. Theoretical benefits of NRT include downsizing and decreased risk of tumour cell shedding, making surgical outcomes more favourable in terms of achieving R0 resections. NRT also potentially carries a lower side effect profile and toxicity as healthy tissues with preserved tissue oxygenation and blood supply allow for better penetration to neoplastic tissue compared to fibrosed post-operative tissue. There is however, emerging evidence validating these theoretical benefits.

Krishnamurty et al. (48) conducted a cohort analysis to determine the outcomes of NRT on patients with non-metastatic T4 colon cancer. Patients were divided into two groups, those who received NRT and those who did not, all patients proceeded to oncological resections with the primary outcomes being R0 resection and OS. Of the 131 patients included in the study 23 patients (17.4%) received NRT. They found a non-statistically significant improvement in R0 resection rate and local recurrence with a median follow up for 52.6 months. There was, however, a statistically significant difference in tumour downstaging (P=0.007) and an improved 5-year OS (P=0.03) in the NRT cohort. There were several limitations to this study, including small sample size, selection bias, and although pre-treatment factors in both the two cohorts were similar, there was inconsistency in radiation technique/dose and chemotherapy regimen amongst the groups. Additionally, 91% of those in the NRT group received NAC compared to 3% of those in the non-NRT group which may further confound results.

A larger 2019 study by Hawkins and colleagues (49) analysed the National Cancer Database (United States of America and Puerto Rico) for use of NRT in patients with stage T4 LACC. The 15,207 patients with clinical T4 disease who underwent resection were included in the study of which 195 patients (1.3%) underwent NRT. The team reported that NRT was associated with a non-statistically significant improvement in R0 resection rates but an improvement in 5-year OS (P<0.001). Furthermore, a subgroup analysis of only patients with clinical T4b disease revealed that this group was more likely to undergo NRT with an improved 5-year OS (P=0.002). A major limitation of this study is incomplete data collection in terms of preoperative staging, tumour location, organs involved in either tumour extension or multivisceral resection, radiation dosing, fields, and side effects. As there was no randomisation for consideration of NRT, significant selection bias may exist. Additionally, a key outcome of NRT is local recurrence which was not captured by this database.

Neoadjuvant chemoradiotherapy for LACC

The use of combined neoadjuvant chemoradiotherapy for LACC has only been reported in case reports and three small case series (50-52). These studies (Table 3), while severely limited by sample size and length of follow up, reported encouragingly high rates of achieving R0 resection and pathological complete response.

Surgical treatment

LACC presents a surgical challenge as the tumour, especially T4 tumours, can extend, adhere and even invade into adjacent organs. These adhesions present an exceptionally high risk of being malignant, this combined with the fact that intraoperative assessment of nature of adhesions is often inaccurate (53), guidelines recommend en bloc multi-visceral resections for treatment of these tumours. Multiple studies have validated extended resections improve the likelihood of negative resection margins and are associated with a better improved OS (8,54,55).

The most frequent organs involved are the bladder and loops of small bowel (25,53,56), however, dependant on the location of the tumour, it may also invade the abdominal wall, pancreaticoduodenal region, liver, stomach, spleen and/or urinary tract (kidney, ureters).

Anterior invasion (small bowel, bladder, prostate, seminal vesicles, vagina)

Tumour invasion of small bowel loops can be solved by an en bloc enterectomy while invasion of other parts of colon may require extended colectomy or even a subtotal colectomy.

In cases where the tumour has invaded into the bladder, without distant metastases, an en bloc resection would require a full thickness excision of the bladder wall with a 2–3 cm margin (57-59). While primary reconstruction of the bladder is achievable in the majority of cases, the decision to perform total rather than partial cystectomy should be based on the anatomic location of the tumour, with tumours invading the dome of the bladder, as is the case with most LACCs, necessitating only a partial cystectomy ensuring adequate radial margins macroscopically (60) as the local recurrence and survival rates of both procedures seems to be comparable given negative resection margins (61).

Superior invasion (stomach, duodenum, pancreas, gallbladder, spleen)

An en-bloc resection of a T4 transverse colon cancer that invades into the stomach involves either a wedge resection of the greater curvature or a distal gastrectomy dependent on level of invasion (62). An invasive splenic flexure cancer may require a splenectomy or even a splenopancreatectomy, if the tail of the pancreas is involved (63), whereas, an invasive hepatic flexure cancer likely necessitates a cholecystectomy and a wedge or segmental liver resection (62,64). Right sided colon cancers can invade into duodenum and/or head of pancreas, and as such can be surgically challenging. Limited duodenal invasion generally requires a partial duodenectomy with primary suture closure, if possible, or a duodenojejunostomy in defect is too large (65). When the pancreatic head is involved, selected patients may undergo a curative pancreaticoduodenectomy (66).

Posterior invasion (major vessels, kidneys, ureters)

Tumour involving superior mesenteric or common iliac artery are commonly deemed unresectable (67), however, with recent advances in vascular interposition grafts, femoral-femoral bypasses and primary anastomoses this is no longer the case (68). Right or left T4 colon cancers can invade the kidney and/or the ureter which can be solved with an en bloc nephrectomy and/or ureterectomy (69,70). If the contralateral kidney has abnormal function, an uretero-ureteral anastomosis may be possible (71), however, if there is adequate ureteric length remaining and a nephrectomy was not indicated in the oncological resection, reimplantation of the ureter into the bladder via a Boari flap with or without a psoas hitch can maintain baseline renal function (71,72).

Peritoneal invasion

For selected patients with low volume peritoneal metastasis, the NCCN recommend consideration of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) (8). This is largely based on the results of a randomised control trial by Verwaal et al. (73) that evaluated systemic 5-fluorouracil (5-FU) alone versus cytoreduction and HIPEC with mitomycin C, the team demonstrated a doubling of survival (22.3 vs. 12.6 months) in those that underwent cytoreduction and HIPEC compared to systemic therapy alone. The controversial PRODIGE 7 trial (74) compared cytoreductive surgery plus HIPEC and perioperative oxaliplatin against cytoreductive surgery alone, and while the team did not meet its primary endpoint of OS with the addition of perioperative oxaliplatin to cytoreductive surgery and HIPEC, they did find while that cytoreductive surgery alone showed satisfactory OS, the addition of HIPEC may potentially delay initial recurrence.

Adjuvant radiotherapy for LACC

The role of adjuvant radiotherapy in LACC is poorly defined, to date, there has been only one randomized control trial (Intergroup-0130) (47) which sought to evaluate the role of AC and radiotherapy compared with AC alone in patients with LACC. The trial was unfortunately terminated prematurely due to poor accrual, however, the study did show 5-year OS and DFS were comparable in both groups with patients in the chemoradiotherapy arm experiencing higher toxicity. A recent sizable propensity score matched retrospective cohort analysis by Sebastian et al. (75) found no statistically significant difference in OS between patients with T4 colon cancer treated with or without adjuvant radiation but highlighted that it may be useful in those with T4b lesions and/or positive margins following resection, this was further echoed by smaller retrospective observational studies (46,76).

Conclusions

Even with the considerable advancements in imaging modalities of late in preoperative staging, accurate diagnosis of T4 colon cancer remains a difficult task, this is due to the significant percentage of cases that present with acute bowel obstruction or tumour perforation and the inability of these imaging modalities to accurately predict the true level of malignant invasion. There is increasing literature defining the role of NAC and radiotherapy to improve R0 resections and survival in T4 colon cancer however, is not yet widely recommended by either NCCN or ESMO guidelines. Extended multi-visceral en bloc resections are imperative in T4 colon cancers and carry an acceptable postoperative morbidity and mortality as achieving R0 resections may offer the chance for a cure.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Eva Segelov) for the series “Colorectal Cancer” published in Digestive Medicine Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/dmr-20-74

Peer Review File: Available at http://dx.doi.org/10.21037/dmr-20-74

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/dmr-20-74). The series “Colorectal Cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Xue L, Williamson A, Gaines S, et al. An update on colorectal cancer. Curr Probl Surg 2018;55:76-116. [Crossref] [PubMed]
2. Larkin JO, O'Connell PR. Multivisceral resection for T4 or recurrent colorectal cancer. Dig Dis 2012;30:96-101. [Crossref] [PubMed]
3. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020;70:145-64. [Crossref] [PubMed]
4. Ueno H, Mochizuki H, Akagi Y, et al. Optimal colorectal cancer staging criteria in TNM classification. J Clin Oncol 2012;30:1519-26. [Crossref] [PubMed]
5. Gao P, Song YX, Wang ZN, et al. Is the prediction of prognosis not improved by the seventh edition of the TNM classification for colorectal cancer? Analysis of the surveillance, epidemiology, and end results (SEER) database. BMC Cancer 2013;13:123.
6. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.
7. Pellino G, Warren O, Mills S, et al. Comparison of Western and Asian Guidelines concerning the management of colon cancer. Dis Colon Rectum 2018;61:250-9. [Crossref] [PubMed]
8. Benson AB, Venook AP, Al-Hawary MM, et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Compr Canc Netw 2018;16:359-69. [Crossref] [PubMed]
9. Grossmann I, Klaase JM, Avenarius JK, et al. The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer. BMC Cancer 2011;11:433. [Crossref] [PubMed]
10. Nerad E, Lahaye MJ, Maas M, et al. Diagnostic accuracy of CT for local staging of colon cancer: a systematic review and meta-analysis. AJR Am J Roentgenol 2016;207:984-95. [Crossref] [PubMed]
11. Dighe S, Purkayastha S, Swift I, et al. Diagnostic precision of CT in local staging of colon cancers: a meta-analysis. Clin Radiol 2010;65:708-19. [Crossref] [PubMed]
12. Takano S, Kato J, Yamamoto H, et al. Identification of risk factors for lymph node metastasis of colorectal cancer. Hepatogastroenterology 2007;54:746-50. [PubMed]
13. Engelmann BE, Loft A, Kjaer A, et al. Positron emission tomography/computed tomography for optimized colon cancer staging and follow up. Scand J Gastroenterol 2014;49:191-201. [Crossref] [PubMed]
14. Balyasnikova S, Brown G. Optimal imaging strategies for rectal cancer staging and ongoing management. Curr Treat Options Oncol 2016;17:32. [Crossref] [PubMed]
15. Dam C, Lindebjerg J, Jakobsen A, et al. Local staging of sigmoid colon cancer using MRI. Acta Radiol Open 2017;6:2058460117720957. [Crossref] [PubMed]
16. Hunter C, Siddiqui M, Georgiou Delisle T, et al. CT and 3-T MRI accurately identify T3c disease in colon cancer, which strongly predicts disease-free survival. Clin Radiol 2017;72:307-15. [Crossref] [PubMed]
17. Liu LH, Lv H, Wang ZC, et al. Performance comparison between MRI and CT for local staging of sigmoid and descending colon cancer. Eur J Radiol 2019;121:108741. [Crossref] [PubMed]
18. Nerad E, Lambregts DM, Kersten EL, et al. MRI for local staging of colon cancer: can MRI become the optimal staging modality for patients with colon cancer? Dis Colon Rectum 2017;60:385-92. [Crossref] [PubMed]
19. Park SY, Cho SH, Lee MA, et al. Diagnostic performance of MRI- versus MDCT-categorized T3cd/T4 for identifying high-risk stage II or stage III colon cancers: a pilot study. Abdom Radiol (NY) 2019;44:1675-85. [Crossref] [PubMed]
20. Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009;100:266-73. [Crossref] [PubMed]
21. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014;371:1609-18. [Crossref] [PubMed]
22. Blons H, Emile JF, Le Malicot K, et al. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. Ann Oncol 2014;25:2378-85. [Crossref] [PubMed]
23. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011;22:1535-46. [Crossref] [PubMed]
24. Ohhara Y, Fukuda N, Takeuchi S, et al. Role of targeted therapy in metastatic colorectal cancer. World J Gastrointest Oncol 2016;8:642-55. [Crossref] [PubMed]
25. Lehnert T, Methner M, Pollok A, et al. Multivisceral resection for locally advanced primary colon and rectal cancer: an analysis of prognostic factors in 201 patients. Ann Surg 2002;235:217-25. [Crossref] [PubMed]
26. Croner RS, Merkel S, Papadopoulos T, et al. Multivisceral resection for colon carcinoma. Dis Colon Rectum 2009;52:1381-6. [Crossref] [PubMed]
27. Nelson H, Petrelli N, Carlin A, et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001;93:583-96. [Crossref] [PubMed]
28. Bosset JF, Calais G, Mineur L, et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results--EORTC 22921. J Clin Oncol 2005;23:5620-7. [Crossref] [PubMed]
29. de Bruin AF, Nuyttens JJ, Ferenschild FT, et al. Preoperative chemoradiation with capecitabine in locally advanced rectal cancer. Neth J Med 2008;66:71-6. [PubMed]
30. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-40. [Crossref] [PubMed]
31. Gérard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24:4620-5. [Crossref] [PubMed]
32. Allum WH, Stenning SP, Bancewicz J, et al. Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol 2009;27:5062-7. [Crossref] [PubMed]
33. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. [Crossref] [PubMed]
34. Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010;11:835-44. [Crossref] [PubMed]
35. Eltahir A, Heys SD, Hutcheon AW, et al. Treatment of large and locally advanced breast cancers using neoadjuvant chemotherapy. Am J Surg 1998;175:127-32. [Crossref] [PubMed]
36. Foxtrot Collaborative Group. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol 2012;13:1152-60. [Crossref] [PubMed]
37. Jakobsen A, Andersen F, Fischer A, et al. Neoadjuvant chemotherapy in locally advanced colon cancer. A phase II trial. Acta Oncol 2015;54:1747-53. [Crossref] [PubMed]
38. Karoui M, Rullier A, Piessen G, et al. Perioperative FOLFOX 4 versus FOLFOX 4 plus cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a phase II multicenter randomized controlled trial (PRODIGE 22). Ann Surg 2020;271:637-45. [Crossref] [PubMed]
39. Liu F, Yang L, Wu Y, et al. CapOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: a prospective single-arm phase II trial. Chin J Cancer Res 2016;28:589-97. [Crossref] [PubMed]
40. Zhou H, Song Y, Jiang J, et al. A pilot phase II study of neoadjuvant triplet chemotherapy regimen in patients with locally advanced resectable colon cancer. Chin J Cancer Res 2016;28:598-605. [Crossref] [PubMed]
41. de Gooyer JM, Verstegen MG, 't Lam-Boer J, et al. Neoadjuvant chemotherapy for locally advanced T4 colon cancer: a nationwide propensity-score matched cohort analysis. Dig Surg 2020;37:292-301. [Crossref] [PubMed]
42. Arredondo J, Baixauli J, Pastor C, et al. Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery. Clin Transl Oncol 2017;19:379-85. [Crossref] [PubMed]
43. Arredondo J, Gonzalez I, Baixauli J, et al. Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy. J Gastrointest Oncol 2014;5:104-11. [PubMed]
44. Dehal A, Graff-Baker AN, Vuong B, et al. Neoadjuvant chemotherapy improves survival in patients with clinical T4b colon cancer. J Gastrointest Surg 2018;22:242-9. [Crossref] [PubMed]
45. Morton D. FOxTROT: An international randomised controlled trial in 1053 patients evaluating neoadjuvant chemotherapy (NAC) for colon cancer. On behalf of the FOxTROT Collaborative Group. Ann Oncol 2019;30:V198. [Crossref]
46. Ludmir EB, Arya R, Wu Y, et al. Role of adjuvant radiotherapy in locally advanced colonic carcinoma in the modern chemotherapy era. Ann Surg Oncol 2016;23:856-62. [Crossref] [PubMed]
47. Martenson JA Jr, Willett CG, Sargent DJ, et al. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 2004;22:3277-83. [Crossref] [PubMed]
48. Krishnamurty DM, Hawkins AT, Wells KO, et al. Neoadjuvant radiation therapy in locally advanced colon cancer: a cohort analysis. J Gastrointest Surg 2018;22:906-12. [Crossref] [PubMed]
49. Hawkins AT, Ford MM, Geiger TM, et al. Neoadjuvant radiation for clinical T4 colon cancer: A potential improvement to overall survival. Surgery 2019;165:469-75. [Crossref] [PubMed]
50. Huang CM, Huang MY, Ma CJ, et al. Neoadjuvant FOLFOX chemotherapy combined with radiotherapy followed by radical resection in patients with locally advanced colon cancer. Radiat Oncol 2017;12:48. [Crossref] [PubMed]
51. Qiu B, Ding PR, Cai L, et al. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer. Chin J Cancer 2016;35:65. [Crossref] [PubMed]
52. Cukier M, Smith AJ, Milot L, et al. Neoadjuvant chemoradiotherapy and multivisceral resection for primary locally advanced adherent colon cancer: a single institution experience. Eur J Surg Oncol 2012;38:677-82. [Crossref] [PubMed]
53. Gezen C, Kement M, Altuntas YE, et al. Results after multivisceral resections of locally advanced colorectal cancers: an analysis on clinical and pathological t4 tumors. World J Surg Oncol 2012;10:39. [Crossref] [PubMed]
54. Otchy D, Hyman NH, Simmang C, et al. Practice parameters for colon cancer. Dis Colon Rectum 2004;47:1269-84. [Crossref] [PubMed]
55. Tjandra JJ, Kilkenny JW, Buie WD, et al. Practice parameters for the management of rectal cancer (revised). Dis Colon Rectum 2005;48:411-23. [Crossref] [PubMed]
56. López-Cano M, Mañas MJ, Hermosilla E, et al. Multivisceral resection for colon cancer: analysis of prognostic factors. Dig Surg 2010;27:238-45. [Crossref] [PubMed]
57. Woranisarakul V, Ramart P, Phinthusophon K, et al. Accuracy of preoperative urinary symptoms, urinalysis, computed tomography and cystoscopic findings for the diagnosis of urinary bladder invasion in patients with colorectal cancer. Asian Pac J Cancer Prev 2014;15:7241-4. [Crossref] [PubMed]
58. Delacroix SE Jr, Winters JC. Bladder reconstruction and diversion during colorectal surgery. Clin Colon Rectal Surg 2010;23:113-8. [Crossref] [PubMed]
59. Fujisawa M, Nakamura T, Ohno M, et al. Surgical management of the urinary tract in patients with locally advanced colorectal cancer. Urology 2002;60:983-7. [Crossref] [PubMed]
60. Carne PW, Frye JN, Kennedy-Smith A, et al. Local invasion of the bladder with colorectal cancers: surgical management and patterns of local recurrence. Dis Colon Rectum 2004;47:44-7. [Crossref] [PubMed]
61. Talamonti MS, Shumate CR, Carlson GW, et al. Locally advanced carcinoma of the colon and rectum involving the urinary bladder. Surg Gynecol Obstet 1993;177:481-7. [PubMed]
62. Kapoor S, Das B, Pal S, et al. En bloc resection of right-sided colonic adenocarcinoma with adjacent organ invasion. Int J Colorectal Dis 2006;21:265-8. [Crossref] [PubMed]
63. Diaconescu M, Burada F, Mirea CS, et al. T4 colon cancer - current management. Curr Health Sci J 2018;44:5-13. [PubMed]
64. Qu K, Liu C, Mansoor AM, et al. Pyogenic liver abscess as initial presentation in locally advanced right colon cancer invading the liver, gallbladder, and duodenum. Front Med 2011;5:434-7. [Crossref] [PubMed]
65. Cirocchi R, Partelli S, Castellani E, et al. Right hemicolectomy plus pancreaticoduodenectomy vs partial duodenectomy in treatment of locally advanced right colon cancer invading pancreas and/or only duodenum. Surg Oncol 2014;23:92-8. [Crossref] [PubMed]
66. Zhang J, Leng JH, Qian HG, et al. En bloc pancreaticoduodenectomy and right colectomy in the treatment of locally advanced colon cancer. Dis Colon Rectum 2013;56:874-80. [Crossref] [PubMed]
67. Shibata D, Paty PB, Guillem JG, et al. Surgical management of isolated retroperitoneal recurrences of colorectal carcinoma. Dis Colon Rectum 2002;45:795-801. [Crossref] [PubMed]
68. Abdelsattar ZM, Mathis KL, Colibaseanu DT, et al. Surgery for locally advanced recurrent colorectal cancer involving the aortoiliac axis: can we achieve R0 resection and long-term survival? Dis Colon Rectum 2013;56:711-6. [Crossref] [PubMed]
69. Stief CG, Jonas U, Raab R. Long-term follow-up after surgery for advanced colorectal carcinoma involving the urogenital tract. Eur Urol 2002;41:546-50. [Crossref] [PubMed]
70. Stief CG, Raab R. Interdisciplinary abdomino-urological surgery for advanced colorectal carcinoma involving the urogenital tract. BJU Int 2002;89:496-503. [Crossref] [PubMed]
71. Elenkov C, Draganov K, Donkov I, et al. Extrinsic obstruction of the ureter in colorectal cancer--aspects of pathogenesis, diagnosis and treatment. Khirurgiia (Sofiia) 2006;36-40. [PubMed]
72. Lazar AM, Bratucu E, Straja ND, et al. Primitive retroperitoneal tumors. Vascular involvement--a major prognostic factor. Chirurgia (Bucur) 2012;107:186-94. [PubMed]
73. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737-43. [Crossref] [PubMed]
74. Quénet F. Colorectal peritoneal carcinomatosis: what is the future of HIPEC? Eur J Surg Oncol 2018;44:1847-8. [Crossref] [PubMed]
75. Sebastian NT, Tan Y, Miller ED, et al. Surgery with and without adjuvant radiotherapy is associated with similar survival in T4 colon cancer. Colorectal Dis 2020;22:779-89. [Crossref] [PubMed]
76. Willett CG, Fung CY, Kaufman DS, et al. Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol 1993;11:1112-7. [Crossref] [PubMed]