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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 102-107

Adjuvant chemotherapy for stage II colon cancer: Whom to treat?


Department of Radiation Oncology, Action Cancer Hospital, New Delhi, India

Date of Submission03-Jun-2021
Date of Acceptance12-Oct-2021
Date of Web Publication23-Feb-2022

Correspondence Address:
Dr. Deep S Pruthi
Department of Radiation Oncology, Action Cancer Hospital, A-4, Paschim Vihar, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jco.jco_20_21

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  Abstract 

The treatment of choice in stage II colon cancer is surgery, which alone has shown a high cure rate (about 80%). The role of adjuvant chemotherapy is still a matter of debate. This clinical issue leads to the need for identifying patients who may benefit from postoperative chemotherapy based on their risk of recurrence. Patients with stage II colon cancer need to be stratified according to risk factors, which can be either clinical or pathological. In this review article, we analyzed various risk factors individually and try to quantify the relative contribution of each factor. We also analyzed various chemotherapy regimens and their duration as well.

Keywords: Adjuvant, chemotherapy, colon cancer, stage II


How to cite this article:
Pruthi DS, Pandey MB, Nagpal P. Adjuvant chemotherapy for stage II colon cancer: Whom to treat?. J Curr Oncol 2021;4:102-7

How to cite this URL:
Pruthi DS, Pandey MB, Nagpal P. Adjuvant chemotherapy for stage II colon cancer: Whom to treat?. J Curr Oncol [serial online] 2021 [cited 2022 Nov 30];4:102-7. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2021/4/2/102/338052




  Introduction Top


Colon cancer is the fourth most common cancer in the world and the fifth leading cause of cancer mortality.[1] The incidence rates of both large and small bowel malignancies are low in India. The incidence rates of colon cancer in eight population registries vary from 3.7 to 0.7/100,000 among men and from 3 to 0.4/100,000 among women. Colon cancer is the eighth most common cancer among men and the ninth most common cancer among women.[2] Its incidence is growing in some countries, which may be due to certain factors such as obesity, physical inactivity, alcohol consumption, high red meat intake, and cigarette smoking.[3] Some risk factors include increased age, medical history of adenoma, colon cancer or inflammatory bowel disease, family history of colon cancer or adenoma, or cancer syndromes such as familial adenomatous polyposis or Lynch syndrome.[4]

A complete colonoscopy and biopsy for histopathological confirmation is recommended for diagnosis in the absence of bowel obstruction or massive hemorrhage. In addition to blood investigations and tumor marker carcinoembryonic antigen (CEA), contrast-enhanced computed tomography scan (thorax, abdomen, and pelvis) is done to see the local and distant extent of colon cancer. A contrast-enhanced magnetic resonance imaging may be done for better local soft tissue extent.[5]

The treatment of choice is surgery, with the aim of wide local excision of the involved bowel segment along with its lymphatic drainage.[6] The minimum resection margin is 5 cm on either side, and a minimum of 12 lymph nodes should be dissected. Obstructive lesions can be treated in two stages: colostomy first followed by resection.[7] The postoperative histopathological specimen should include the following details: specimen description, tumor site and size, macroscopic tumor perforation, histological type and grade, extension into the bowel wall and adjacent organs, distance of cancer from resected margins (proximal, distal, and radial), presence or absence of tumor deposits, lymph vascular and/or perineural invasion (PNI), tumor budding, site and number of removed and involved regional lymph nodes, and mismatch repair/microsatellite instability (MMR/MSI) status as per immunohistochemistry (IHC).[8]

The risk of relapse after colon cancer resection is estimated by combining the clinicopathological features of the tumor with the molecular marker MMR/MSI status.[9] TNM staging remains the most relevant histological criteria for risk assessment after surgery of colon cancer. The reported five-year survival rates after surgical resection alone are 99% for stage I, 68%–83% for stage II, and 45%–65% for stage III disease.[10]

The adjuvant treatment of choice is chemotherapy depending on stage, prognostic factors, and performance status. There are various options among the regimen of chemotherapy and the number of cycles given. There exists a lot of dilemma in the adjuvant chemotherapy for stage II colon cancer, which will the focus of this review article.


  What is the Dilemma? Top


Surgery alone has a high cure rate in stage II colon cancer. An estimated 75% of people with stage II colon cancer will be cancer-free five years later, without adjuvant chemotherapy, but 25% will not be. Some of these patients may benefit from having chemotherapy after surgery.[11] The small benefit with chemotherapy is due to the fact that most of the patients with stage II colon cancer have a very good long-term survival, leaving a relatively small risk to be reduced by adjuvant therapy.[12] So the challenge is to identify a small percentage of patients who are actually in a higher risk category and who may obtain benefit with adjuvant chemotherapy treatment. The other question is what type of chemotherapy is recommended for such patients (monotherapy vs. doublet therapy) along with the number of cycles. According to international guidelines, patients with stage II colon cancer should be stratified into low and high risk of recurrence.[13],[14]


  What Are the Prognostic Factors? Top


Major prognostic parameters for stage II include lymph nodes number, T stage, including perforation and microsatellite status. Minor prognostic parameters for stage II colon cancer include high-grade tumor, vascular invasion, lymphatic invasion, PNI, tumor presentation with obstruction, and high preoperative CEA levels.[9] Several analyses of adjuvant trials have shown that stage II disease with one or more of these features have a disease-free survival (DFS) benefit from adjuvant chemotherapy.[15],[16]

T stage

T stage means the grade of penetration in the bowel wall. A pT3 tumors means that there is invasion of muscularis propria into peri-colorectal tissues and pT4 represents the involvement of the serosa, the penetration the visceral peritoneum (T4a), or the invasion of adjacent organs (T4b).[17] pT3 N0, pT4a N0, and pT4b N0 are classified as stage IIA, IIB, and IIC, respectively. The deeper the invasion, the higher the risk of relapse. As per ESMO guidelines, pT4 is a poor prognostic factor that is to be considered in stage II.[9] The five-year OS rate in stage II with surgery alone ranged between 85% and 88% for pT3 and between 70% and 75% for pT4. The prognosis is worsened if the stage increases from pT4a to pT4b, with the five-year OS being 79.6% and 58.4%, respectively.[18] It is also very peculiar to note that stage IIB (pT4N0M0) has a poorer prognosis as compared with stage IIIA (T1-2N1M0), with a lower five-year OS.[19] pT4 seems to be one of the major indications for adjuvant chemotherapy. pT3 is a relative indication for chemotherapy; however, other prognostic factors need to be looked at while deciding the need for adjuvant chemotherapy. These will be discussed subsequently.

Remark

pT4 stage should be considered for postoperative chemotherapy.

Lymph node status

Inadequate lymph node dissection is considered as a poor prognostic factor. The five-year OS rates do differ according to the number of lymph nodes sampled in stage II patients: With one to seven retrieved lymph nodes (LNs), the five-year OS rate was 49.8%; with 8–12 LNs, it was 56.2%; and with >13 LNs, it was 63.4%.[20] The Intergroup 0089 study found a 14% higher absolute five-year OS for stage II patients, with >20 negative lymph nodes examined compared with <10 negative lymph nodes examined.[7] Another study showed a five-year OS benefit of 10%–20% if 13–15 lymph nodes are dissected compared with zero to six lymph nodes in stage II, with a major survival advantage for T4 cancer. The theory behind this is that when a lesser number of lymph nodes are dissected, there is a chance that a higher number of lymph nodes may go undiagnosed. The minimum number of lymph nodes to be dissected is 12.[21]

Remark

Inadequate lymph node dissection should be considered for adjuvant chemotherapy


  Grade Top


A high grade indicates a poorly differentiated disease and is another common feature of poor prognosis.[22] In the SEER analyses on 119,363 patients diagnosed with colon adenocarcinoma, it was shown that the subgroup with high-grade tumors represents about 20% of the cases.[19] The presence of grade III tumors in colon cancer is variable with respect to stage. A more frequent incidence of grade 3 tumors has been observed in stage IIB colon cancer than in stage IIIA: In an analysis conducted by Kim et al., a high-grade tumor was found in twice as many cases of T4N0 than T1–2 N1.[23] The analysis by Gill et al. on 3,302 patients with stage II and stage III colon cancer showed lower five-year DFS and five-year OS in high-grade disease. In particular, high-grade compared with low-grade disease is associated with a loss of 8%–9% in five-year DFS in T3N0 and T4N0 tumors (65% vs. 73% and 51% vs. 60%, respectively).[24]

Remark

High-grade tumors should be considered for adjuvant chemotherapy.


  Clinical Features Top


Bowel perforation or obstruction is linked to a higher rate of micro-metastases, surgical morbidity, and recurrence.[25] An emergency colectomy for perforation or obstruction is a stronger prognostic factor than a pathological finding of perforation.[26]

Remark

Patients with bowel perforation or obstructive features should be considered for adjuvant chemotherapy.


  Mismatch Repair Status Top


Approximately 15% of all colorectal cancers have abnormalities in the DNA MMR pathway. DNA MMR is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base–base mismatches and insertion/deletion, which are generated during DNA replication and recombination.[27] Sporadic or inherited mutations in genes associated with DNA mismatch repair processes are found in about 15% of colon cancers.[28] As a consequence of defective DNA mismatch repair activity, segments of DNA in which a short motif is repeated several times, which are termed as microsatellites, are prone to mutations, a genetic signature termed MSI.[29] It is possible to distinguish two groups of colorectal cancer: MSI-high (or deficiency of the mismatch repair, dMMR) and MSI-low (or proficiency of the mismatch repair, pMMR).

Deficient DNA MMR status can be identified by IHC, detecting loss of MMR protein expression (MLH1, MSH2, MSH6, or PMS2) or by polymerase chain reaction (PCR) assays of MSI status (microsatellite mutations).[21] The dMMR was predominantly seen in women, especially older women, compared with men, and in parts of the colon proximal to the splenic flexure, including the transverse colon.

Untreated patients with stage II dMMR tumors have an improved survival rate (90%) compared with patients with a pMMR status (66%).[30] Patients with MSI-H carry a better prognosis. Sargent et al. showed how the effect of adjuvant chemotherapy in terms of OS changes on the basis of MMR status. They found that five-year OS decreased in MSI-H stage II patients treated with fluoropyrimidines compared with those undergoing surgery alone.[31] Other studies have shown that even the combination with oxaliplatin does not improve the benefit in DFS or OS in these patient subgroups.[32]

In a retrospective study done by Ribic et al., patients who did not receive adjuvant chemotherapy, those with MSI-H tumor had a significantly better OS than the patients with microsatellite stable (MSS) tumor. At the same time, patients who had MSS tumors showed a benefit in OS with adjuvant chemotherapy and no benefit was seen in the patients with MSI-H tumors.[33]

MSI also has a role in determining genetic predisposition. MSI/MMR status determination is important to rule out Lynch syndrome. The presence of MSH2 and/or MSH6 loss by IHC indicates suspicion of Lynch syndrome, whereas MLH1 and PMS2 loss needs to be investigated further by determining BRAF mutation or hypermethylation of the promoter region of hMLH1.[21]

Remark

MSI status is an important prognostic factor that needs to be checked routinely. This factor not only helps in deciding the prognosis but can also guide the treatment regarding whether to keep the patient on follow-up or help decide the regimen of chemotherapy.


  Lymphovascular and Perineural Invasion Top


The presence of tumor cells in the space surrounding lymphatic or blood vessels defines the pathological feature of lymphovascular invasion. Similarly, the involvement of nerve fibers depicts the PNI. Their presence is associated with a worse prognosis, which was noted in a study that showed that five-year OS decreased by about 6% with lymphovascular invasion and about 10% with PNI compared with patients without these features.[34] In a prospective study by Quah et al., they demonstrated a loss of DFS by 12% in those patients with lympho-vascular or PNI.[35]

Remark

Lymphovascular space invasion and PNI are poor prognostic factors and if present should be considered for adjuvant chemotherapy.


  Choice and Duration of Chemotherapy? Top


5FU as single agent

The most commonly used is adjuvant chemotherapy. Various trials have compared the use of adjuvant chemotherapy with surgery alone. The benefit of adjuvant fluorouracil compared with surgery in terms of five-year OS was 2% in the IMPACT B2 analysis, 5% in the Intergroup analysis, 4% in the QUASAR trial, and 1% in the ACCENT pooled analysis.[36],[37],[38] DFS benefit at five years was 4% in the Intergroup analysis and ACCENT trial, whereas the IMPACT B2 trial reported an event-free survival (EFS) of 3% at five years.

Remark

The benefit of adjuvant chemotherapy does not improve survival statistics by more than 5%.

Doublet chemotherapy

The combination chemotherapy of oxaliplatin and 5FU for stage II colon cancer has been studied in various trials. Neither MOSAIC trial nor NSABP-C07 trial showed a benefit in OS and DFS when combination chemotherapy was used in the adjuvant setting.[39],[40] However, the MOSAIC exploratory analysis in high-risk stage II patients showed an absolute benefit of 7.7% in DFS at five years with no difference in OS.

Remark

Combination chemotherapy (FOLFOX) is recommended in those with high-risk features and not for patients with low risk/favorable factors.

Duration

The results of the pooled analysis of the four IDEA studies in 3,273 stage II patients showed that three months of adjuvant capecitabine plus oxaliplatin (CAPOX) were as beneficial as six months (five-year DFS of 81.7% vs. 82%), with considerably less toxicity. By contrast, six months of FOLFOX yielded better efficacy than three months of the same regimen (five-year DFS of 79.2% vs. 86.5%), however, with significantly more toxicity.[12]

Age

The usual cutoff for classifying a patient as elderly is 70 years. In MOSAIC trial, two different chemotherapeutic regimens were compared (FOLFOX and 5FU/Leucovorin) and five-year OS and DFS were similar in both groups.[39] Similar results were obtained in NSABP–C07 trial as well.[40] These post hoc analyses of elderly patients in combined populations of stage II colon cancer demonstrate limited benefit of oxaliplatin in elderly patients.

Addition of irinotecan

The role of irinotecan in the adjuvant setting was explored in a few trials, with negative results.[41]


  Markers Top


CEA is a complex glycoprotein produced by 90% of colorectal cancers and contributes to the malignant characteristics of a tumor.[42] It can be measured in serum quantitatively, and its level in plasma can be useful as a marker of disease. Due to its lack of sensitivity in the early stages of colorectal cancer, CEA measurement is an unsuitable modality for mass population screening. However, it is a prognostic and predictive marker in patients with colon cancer. During the treatment course of colon cancer, an elevated preoperative CEA is a poor prognostic sign and correlates with reduced overall survival after surgical resection. A failure of the CEA to return to normal levels after surgical resection is indicative of inadequate resection of occult systemic disease. After treatment, frequent monitoring of CEA postoperatively may enable the identification of patients with metastatic disease for whom surgical resection or other localized therapy might be potentially beneficial.[42] Coming to stage II colon cancer in particular, there was a review done by Spindler et al. in which they hypothesized that CEA can improve preoperative risk stratification for stage II colon cancer. They included more than 40,000 patients with available CEA reports from the National Cancer Database. Chemotherapy administration was similar between normal and elevated CEA groups (23.8% vs. 25.1%). The five-year overall survival in patients with normal CEA was improved as compared with patients with elevated CEA (74.5% vs. 63.4%, P < 0.001). Restratification incorporating CEA resulted in reclassification of 6,912 patients (16.9%) from average to high risk.[43]

Other molecular markers have been also investigated as prognostic candidate biomarkers. DNA ploidy, KRAS, TP53 mutations, thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, loss of heterozygosity on chromosome 18q, MSI, and V600E mutation in the BRAF gene have been widely investigated. In a study done by Donada et al. with 120 patients of stage II colon cancer, the presence of the V600E mutation in the BRAF gene was a poor prognostic factor for disease-free and overall survival. Adjuvant therapy significantly improved survival in patients with high TYMS levels.[44] Tumors with mild to moderate p53 expression are associated with more frequent proximal location, undifferentiated histology, lower N category, extraglandular mucin production, MSI, CIMP-P1, CK7 expression, and decreased CDX2 expression. A study showed that p53-mild expression status was found to be an independent prognostic marker in adjuvant FOLFOX-treated patients with stage III and high-risk stage II CRC.[45]

Genome classifiers such as Oncotype DX and ColoPrint have been proposed in stage II colon cancer (similarly in breast cancer). These can help identify patients who can be managed without chemotherapy, independently of other clinical risk factors.[46]


  Discussion Top


Stage II colon cancer represents a unique challenge for the clinician. The patient must be carefully assessed in regard to decisions regarding adjuvant chemotherapy. In this review article, we have analyzed various prognostic factors, both histologically and clinically. High-risk patients are classified as those with an incidence of recurrence >20%. Those patients with pT4 tumors or inadequate lymph node sampling have the highest risk, in the range of 30%–40%. With this size of risk, adjuvant chemotherapy is strongly recommended with six months of fluoropyrimidines alone or three months of CAPOX. MMR testing helps in the decision between two recommended chemotherapy regimens. Importantly, fluoropyrimidine-only adjuvant chemotherapy should not be given to patients with dMMR within this high-risk group. Patients with dMMR (about 15% of all stage II colon cancers) do not benefit from adjuvant fluoropyrimidines alone and should only be followed up with no adjuvant treatment. In the presence of other poor prognostic factors, the MSI status should be used as guidance for further treatment. The evaluation of available data does not give enough support regarding the prognostic weight of the association of two or more prognostic factors compared with the assessment of every single factor.

It is important to integrate genomic and molecular-based prognostic factors with currently used clinical and pathological prognostic factors in a search for an even more tailored prognostication of stage II colon cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
What is the Dilemma?
What Are the Pro...
Grade
Clinical Features
Mismatch Repair ...
Lymphovascular a...
Choice and Durat...
Markers
Discussion
References

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