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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 1  |  Page : 25-29

Quantification of risk of recurrence associated with high risk factors in Stage II colon cancer: A retrospective study from a tertiary cancer institute in India


Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India

Date of Submission20-Jan-2021
Date of Decision21-Feb-2021
Date of Acceptance25-Mar-2021
Date of Web Publication14-Apr-2021

Correspondence Address:
Linu Abraham Jacob
Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Dr. M.H. Marigowda Road, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_4_21

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  Abstract 


Background: Surgery is the primary modality of treatment for Stage II colon cancer, and the role of adjuvant chemotherapy is not well defined. Attempts have been made to find out various high-risk sub-groups within Stage II colon cancer, who might benefit from the adjuvant chemotherapy. Most of these studies do not quantify the risks associated with each of the high-risk factors and the survival benefits conferred by adjuvant chemotherapy based on them. Aim: This study aimed to analyze the prognostic and predictive significance of various high-risk factors among patients with Stage II colon cancer and to define the role of adjuvant chemotherapy among these if any with respect to various high-risk factors. Materials and Methods: An audit on postoperative Stage II colon carcinoma patients was performed retrospectively from the patient database of our hospital, registered over the period from January 2010 to August 2017. Results: A total of 41 pathological Stage II colon carcinoma patients were reviewed. Twelve (29.3%) patients without any high-risk features were spared of adjuvant chemotherapy. Twenty-nine (70.7%) patients had at least one high-risk feature and received adjuvant chemotherapy. Mean disease-free survival (DFS) after a minimum 20-month follow-up period was 26.8 months. On univariate analysis, there was a statistically significant difference in mean DFS according to the T stage (T3 vs. T4; P = 0.04), lympho-vascular invasion (LVI) status (absent vs. present; P < 0.01), perineural invasion status (absent vs. present; P = 0.03) and number of lymph nodes in the histopathology specimen (≥12 vs. <12; P < 0.01). On multivariate analysis, LVI positivity and inadequate lymph node dissection (<12 lymph nodes in the specimen) were independent high-risk factors for recurrence. Conclusion: The presence of LVI, inadequate lymph node dissection, or presence of multiple high-risk factors are associated with higher risks of recurrence even with adjuvant 5-flourouracil-based chemotherapy.

Keywords: Adjuvant chemotherapy, colon cancer, risk factors, Stage II


How to cite this article:
Moharana L, Dasappa L, Babu M C, Lokesh K N, Rudresha A H, Rajeev L K, Saldanha S, Jacob LA. Quantification of risk of recurrence associated with high risk factors in Stage II colon cancer: A retrospective study from a tertiary cancer institute in India. Oncol J India 2021;5:25-9

How to cite this URL:
Moharana L, Dasappa L, Babu M C, Lokesh K N, Rudresha A H, Rajeev L K, Saldanha S, Jacob LA. Quantification of risk of recurrence associated with high risk factors in Stage II colon cancer: A retrospective study from a tertiary cancer institute in India. Oncol J India [serial online] 2021 [cited 2021 May 16];5:25-9. Available from: https://www.ojionline.org/text.asp?2021/5/1/25/313670




  Introduction Top


Colorectal cancer (CRC) is a common cancer worldwide but with a low reported incidence in India. According to GLOBOCAN 2018, colon cancer ranks the 13th in terms of incidence and mortality with 27,605 new cases and 19,548 deaths annually.[1] Stage II colon cancers consist of less than 20% of all colon cancers. These cancers comprise of Stage II A (pT3N0), Stage II B (pT4aN0), and Stage IIC (pT4bN0) tumors. These are tumors, where cancer has not yet spread to lymph nodes. Stage II colon cancers do carry the risk of harboring micrometastatic disease. Adjuvant therapy is used to destroy these micrometastatic diseases before they develop into macrometastasis. In this study, we retrospectively reviewed the profiles of Stage II colon cancer patients to analyze the prognostic and predictive significance of various high-risk factors among these patients to define the role of adjuvant chemotherapy.


  Materials and Methods Top


An audit on postoperative Stage II colon carcinoma patients was performed retrospectively from the patient database of our tertiary care hospital, registered over the period from January 2010 to August 2017. The Institutional Ethics Committee approval was obtained for the study. The database included demographic features, symptoms, basic laboratory investigations, location of the primary tumor, staging information, primary treatment modalities, details of histopathology examination of the resected specimens, details of adjuvant chemotherapy regimens, durations of disease-free interval, pattern of recurrences, treatment modalities followed on recurrences, and overall survival durations. Patients of Stage II colon cancers had undergone upfront radical surgery which includes left, right or sigmoid colectomy, according to the location of the primary tumor, along with lymphadenectomy. The parameters recorded for the histopathological examination of the resected specimen were pathological grade of the tumor, depth of penetration, number of lymph nodes evaluated and number of positive nodes, status of proximal, distal, radial and mesenteric margins, lymphovascular invasion (LVI), perineural invasion (PNI), tumor deposits, and tumor budding. Surgical staging was done according to the AJCC 7th edition. Microsatellite instability (MSI) testing not done due to logistic issues.

The high-risk features for triaging patients for adjuvant treatment were pT4 tumor stage, high grade or poorly differentiated tumor, presence of LVI and PNI, positive margins, <12 lymph nodes resected, presence of tumor budding in the histopathology, those who had presented to emergency with bowel obstruction or perforation or who had elevated carcinoembryonic antigen (CEA) level before surgery. Those patients who had any one high-risk feature were planned for adjuvant chemotherapy. One of the following two chemotherapy regimens was used in the eligible patients.

Capecitabine

Tab Capecitabine 1000 mg/m2 twice daily, day 1 to day 14: Cycles repeated every 3 weeks for eight cycles.

5-flourouracil+Leucovorin

Injection leucovorin 500 mg/m2 intravenous infusion over 2 h followed by injection 5-flourouracil (5-FU) 500 mg/m2 intravenous bolus on day 1, every week for 6 weeks: Cycle repeated every 8 weeks for 4 cycles.

During the course of chemotherapy, patients were evaluated for possible toxicities. Hemogram, liver and kidney function tests ordered before every cycle of chemotherapy and at the clinicians' discretion. Chemotherapy was put on hold for Grade III or IV hematological toxicities or hand foot syndrome, until toxicity grades recover to Grade I or less. Dose modifications were allowed taking into account patients' performance status and toxicity profiles in the previous cycles. Prophylactic growth factors were not allowed. Primary endpoint was disease-free survival (DFS), which was calculated from the date of surgery to the date of imaging with confirmation of recurrence.

SPSS for Windows, Version 16.0. Chicago, SPSS Inc; 2007 was used for the statistical analysis. Kaplan–Meier test was used to find the mean and median survivals. Cox-regression analysis was used to compare the variables and to find out the hazards.


  Results Top


A total of 41 patients of pathological Stage II colon carcinoma were retrospectively reviewed during the study period. The basic characteristics of the study population is mentioned in [Table 1]. The median age of presentation was 58 years (range: 23–81 years). There was male predominance with a male-to-female ratio of 1.73. The average duration of symptoms of presentation was 2 months (range: 1–4 months). Two (4.9%) patients had presented with intestinal obstruction. Thirty-seven (90.2%), 3 (7.3%), and 1 (2.5%) patient had Stage IIA, IIB, and IIC disease, respectively. Twenty-eight (68.3%) patients had left-sided tumors (splenic flexure, descending, and sigmoid colon). Thirteen (31.7%) patients had right sided tumor (cecum, ascending colon, and hepatic flexure and proximal 2/3rd of transverse colon). Fifteen (36.6%), 18 (43.9%), and 8 (19.5%) patients had Grade I, II, and III tumors, respectively. Margins were negative in 25 (61%) patients, in 3 (7.3%) circumferential margins were positive, 13 (31.7%) patients had indeterminate or close (<1mm) circumferential margins. LVI and PNI were present in 6 (14.6%) and 8 (19.5%) patients, respectively. Three (7.3%) patients had tumor budding identified at the tumor margin. The mean number of lymph nodes identified in the resected specimens was 13.5 (range: 6–20). Twenty-nine (70.7%) patients had 12 or more lymph nodes identified in the specimen. Nine (22.0%) patients had elevated CEA before surgery. Twelve (29.3%) patients had none of the high-risk features and were spared of any adjuvant chemotherapy. Twenty-nine (70.7%) patients had at least one of the high-risk features and received adjuvant chemotherapy. Among them, 14 (48.3%) and 15 (51.7%) patients had received single agent Capecitabine and 5FU+Leucovorin-based chemotherapy regimens, respectively.
Table 1: Patient characteristics

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Mean DFS after a minimum follow-up period of 20 months was 26.8 months. On univariate analysis, there was significant difference in mean DFS according to the T stage (T3 vs. T4: 27.5 months vs. 17.5 months; P = 0.04), LVI status (absent vs. present: 28.9 months vs. 14.7 months; P < 0.01), PNI status (absent vs. present: 27.9 months vs. 23.1 months; P = 0.03) and number of lymph nodes in the histopathology specimen (≥12 vs. <12: 29.3 months vs 20.7 months; P < 0.01). On the contrary grade of the tumor, margin status, preoperative CEA level, presence or absence of tumor budding, or whether or not patient presented with bowel obstruction or perforation, did not impact significantly on DFS in the univariate analysis [Table 2].
Table 2: Univariate analysis of disease-free survival

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Patients with no high-risk factors had significantly longer DFS than patients who had any (33.9 months vs. 23.0 months, respectively; P < 0.01). Patients with multiple high-risk factors fared poorly in comparison to patients with single high-risk factor of recurrence [Table 3].
Table 3: Mean disease-free survival according to the number of high-risk factors present

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On multivariate analysis [Table 4], of the whole cohort, LVI positivity was associated with highest risk of recurrence (hazard ratio [HR] = 19.2, 95% confidence interval [CI] = 0.11–0.24; P < 0.01). Other than LVI, <12 lymph nodes in the specimen were associated significantly with higher risk of recurrence (HR = 2.84, 95% CI = 1.20–6.73; P = 0.01).
Table 4: Multivariate analysis of hazards of recurrence

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  Discussion Top


Colon cancer is a common cancer worldwide, with a majority of cases occurring in the developed countries. India has a low prevalence of CRC.[1] The overall age-adjusted incidence of CRC in all races was 48.9 per 100,000 for males and 37.1 per 100,000 for females in 2008–2012. The risk of CRC increases with age; the median age at diagnosis for colon cancer is 68 in men and 72 in women.[2] The median age of presentation in our study cohort was 58 years (23–81 years). In a meta-analysis, Sargent et al. analyzed 18 randomized trials and had concluded that most of the relapses in colon cancer occur within 2 years of surgery.[3] In our study, minimum follow-up period was 20 months. A total of 33 (80.5%) patients had an event. At 20 months, recurrence-free survival in QUASAR trial is >90%.[4] Higher recurrence rate in our study population could be attributed to the following few reasons. First, our study population is different from the other study populations. Second, 32 of our study patients had undergone surgery outside in the peripheral health centers and not by onco- or gastro-surgeons. Third possible reason could be because of harboring occult nodal micro-metastasis, recurrence rates are higher. Our study focused on DFS rather than overall survival, as our aim was to identify Stage II colon cancer patients at high risk of recurrence who might benefit from dose intensification with an oxaliplatin-based doublet chemotherapy regimen rather than 5-FU-based single-agent chemotherapy alone, in an adjuvant setting.

The standard treatment for colon cancer involves a combination of surgical resection and chemotherapy. The recommended treatment for Stage II colon cancer after surgery is either observation or chemotherapy depending on the presence of risk factors for recurrence and MSI status. Patients with Stage II colon cancer are often recommended to undergo adjuvant chemotherapy if they have low MSI and have any of the high-risk factors. Various high-risk factors have been described by different bodies such as NCCN, ASCO, and ESMO. They are pT4 tumor T stage, poorly differentiated tumor, presentation with perforation of bowel, presence of lymphovascular, and PNI. Apart from these, close, indeterminate, or positive margins as described by NCCN and less than 12 resected lymph nodes as described by ASCO are considered other high-risk factors necessitating use of adjuvant chemotherapy in Stage II colon cancer patients. In randomized studies comparing surgical resection versus surgical resection followed by adjuvant chemotherapy for patients with stage II and III colon cancers, 5-year OS for patients with Stage II colon cancer after curative surgery alone has been around 80%.[5],[6],[7] In a SEER analysis, 5-year OS for patients with Stages IIA, IIB, and IIC colon cancer was 66.7%, 60.6%, and 45.7%, respectively.[5] These findings suggest that patients with Stage II colon cancer represent a heterogeneous population that includes some patients who might derive meaningful benefit from adjuvant chemotherapy and others for whom adjuvant chemotherapy after surgery is likely to provide minimal, if any, benefit.[6]

A 2015 meta-analysis of 25 studies showed that there is no significant DFS benefit, with adjuvant chemotherapy in Stage II colon cancer patients (5-year DFS with adjuvant chemotherapy vs no adjuvant chemotherapy: 79.3% vs 81.4%). On the other hand, there was significant benefit of adjuvant chemotherapy in Stage III patients (5-year DFS: 63.6% vs. 49.0%), suggesting that benefits of adjuvant chemotherapy are greater in patients with positive nodes.[8] Benefits if any of adding oxaliplatin in adjuvant therapy in Stage II colon cancers was addressed in MOSAIC trial. It showed no DFS benefit of FOLFOX over 5FU+ Leucovorin in stage II patients at 6 years (HR = 0.84; 95% CI, 0.62–1.14; P = 0.258). Moreover, no difference in 10-year OS (79.5% vs. 78.4%; HR, 1.00; P = 0.98).[9] QUASAR trial showed a small but significant 2-year recurrence-free survival benefit with 5FU+Leucovorin adjuvant chemotherapy in Stage II colon cancers (relative risk of recurrence at 2 years: 0.71; 95% CI, 0.54–0.92; P = 0.01) over surgery alone.[4] Several studies have shown the benefits of adjuvant chemotherapy among patients with Stage II colon cancer with high-risk features. However, most of these studies do not quantify the risks associated with each of the high-risk factors, and the survival benefits conferred by adjuvant chemotherapy based on the individual high-risk factors. Verhoeff et al.[10] concluded that among the high-risk factors, only for pT4, chemotherapy could result in better OS, and Babcock et al.[11] also reported similar result. Kumar et al. reported in their study that, adjuvant chemotherapy improved disease specific and recurrence-free survival only in patients withT4 tumors and not in the less than 12 lymph nodes examined or the LVI groups.[12] In our study there was significant difference in DFS between T3 and T4 tumors on univariate analysis but not on multivariate analysis. Stage migration because of under reporting of T4 diseases might be a possible reason behind the same. As only four patients had T4 disease, it is not possible to draw any conclusions out of it. PNI positivity was associated with shorter DFS, which was statistically significant on univariate analysis but not on multivariate analysis. In our study, LVI positivity and less than 12 lymph nodes in the histopathology specimen were the high-risk factors, associated with early recurrence in both univariate and multivariate analysis, which were statistically significant. High-grade tumors had numerically shorter but statistically nonsignificant difference in mean DFS in the univariate analysis. Same was the case for other risk factors such as bowel obstruction, margin positivity, presence of tumor budding, or elevated preoperative serum CEA level. The presence of occult nodal disease could be one reason behind the possible stage migration and ultimately leading to higher risk of recurrence and lesser DFS. Hence, there could be a subset of patients in Stage II colon cancer who could actually benefit from oxaliplatin based more intensive doublet chemotherapy regimens instead of single agent fluropyrimidine-based therapy. According to our study, LVI or resection of less than 12 lymph nodes could be the independent risk factors which may predict occult nodal disease. Moreover, these patients may benefit more from oxaliplatin-based doublet adjuvant chemotherapy. The presence of multiple risk factors was found to confer higher risk of recurrence in comparison to the presence of a single risk factor, even when adjuvant chemotherapy is used. Hence, the presence of multiple risk factors could be another subset which may benefit from an intensive doublet regimen. The present study has the inherent limitations of being a retrospective study and having a small sample size. Therefore, further investigation is required to reach a concrete conclusion.


  Conclusion Top


The presence of LVI, <12 lymph nodes in the resected specimen, or presence of multiple high-risk factors are associated with higher risks of recurrence even with adjuvant 5-FU based chemotherapy, may be because of occult nodal disease. Therefore, the addition of oxaliplatin may have a role, if at all, in these patient populations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
2.
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al., editors. SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, MD; 2020 Available from: https://seer.cancer.gov/csr/1975_2017/. [Last accessed on 2020 Apr 15].  Back to cited text no. 2
    
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Sargent D, Sobrero A, Grothey A, O'Connell MJ, Buyse M, Andre T, et al. Evidence for cure by adjuvant therapy in colon cancer: Observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2009;27:872-7.  Back to cited text no. 3
    
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Quasar Collaborative Group, Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: A randomised study. Lancet 2007;370:2020-9.  Back to cited text no. 4
    
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Gunderson LL, Jessup JM, Sargent DJ, Greene FL, Stewart AK. Revised TN categorization for colon cancer based on national survival outcomes data. J Clin Oncol 2010;28:264-71.  Back to cited text no. 5
    
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International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999;17:1356-63.  Back to cited text no. 6
    
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Gill S, Loprinzi CL, Sargent DJ, Thome SD, Alberts SR, Haller DG, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol 2004;22:1797-806.  Back to cited text no. 7
    
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Böckelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B. Risk of recurrence in patients with colon cancer stage II and III: A systematic review and meta-analysis of recent literature. Acta Oncol 2015;54:5-16.  Back to cited text no. 8
    
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André T, de Gramont A, Vernerey D, Chibaudel B, Bonnetain F, Tijeras-Raballand A, et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol 2015;33:4176-87.  Back to cited text no. 9
    
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Verhoeff SR, van Erning FN, Lemmens VE, de Wilt JH, Pruijt JF. Adjuvant chemotherapy is not associated with improved survival for all high-risk factors in stage II colon cancer. Int J Cancer 2016;139:187-93.  Back to cited text no. 10
    
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Babcock BD, Aljehani MA, Jabo B, Choi AH, Morgan JW, Selleck MJ, et al. High-risk stage II colon cancer: Not all risks are created equal. Ann Surg Oncol 2018;25:1980-5.  Back to cited text no. 11
    
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Kumar A, Kennecke HF, Renouf DJ, Lim HJ, Gill S, Woods R, et al. Adjuvant chemotherapy use and outcomes of patients with high-risk versus low-risk stage II colon cancer. Cancer 2015;121:527-34.  Back to cited text no. 12
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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