Muhammad Shadab Khan  ( Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan )
Muhammad Attaullah Khan  ( Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan )
Sana Amir Akbar  ( Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan )
Muhammad Abu Bakar  ( Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan )
Shahid Khattak  ( Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan )
Aamir Ali Syed  ( Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan )

Objective: To explore the importance of serum carcinoembryonic antigen level as a tumour marker in rectal carcinoma.

Method: The retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital, Lahore, Pakistan, and comprised data of patients with rectal carcinoma from January 1996 to December 2015. Serum carcinoembryonic antigen levels were analysed using immulite@2000 system analyser. On the basis of serum carcinoembryonic antigen levels, data of patients was divided into four groups. Group A had normal serum levels both before and after surgical resection; Group B had normal levels pre-surgery but post-surgery levels were raised; Group C had raised levels pre-surgery that went down to normal post-surgery; and Group D had raised levels both before and after surgery. SPSS 23 was used for data analysis.
Results: Of the 401 patients, 267(66.6%) were males, and 204(50.9%) were aged <50 years. Group A had 267(66.6%) patients, Group B 26(6.5%), Group C 79(`9.7) and Group D had 29(7.2%) patients. Stage III disease was the most common 343(85.5%) and it was true across the groups. Overall recurrence was in 141(35.2%) patients. Group D had the highest recurrence rate 26(89.7%), while Group C had the lowest 18(22.8%).

Conclusion: Fluctuating levels of carcinoembryonic antigen affected post-operative outcome.
Keywords: Carcinoembryonic antigen, Rectal carcinoma, Colonoscopy. (JPMA 69: 1442; 2019). doi:10.5455/JPMA.292193
 

Introduction

Rectal carcinoma is one of the common health problems and has serious associated morbidities and mortality issues.1 The degree of penetration of the primary lesion (T stage) and nodal status (N stage) provide a gross overview of tumour stage and possible disease prognosis and relapse of tumour after primary surgery. However, different patients with the same tumour-node-metastasis (TNM) staging behave differently in terms of disease prognosis and relapse. 2  So identification of risk factors for tumour prognosis and relapse is a challenging domain. For this reason it is advisable to check pre-operative parameters other than TNM staging to identify the factors that are responsible for tumour recurrence after curative primary resection of the rectal cancer.3,4 One of the most commonly used tumour markers for colorectal carcinoma is serum carcinoembryonic antigen (CEA). Serum CEA has high expression in adenocarcinoma, it is an easily available, and is a costeffective test. That is why it is the most commonly used tumour marker for surveillance and assessment of disease relapse in rectal cancer patients. 5  Raised pre-operative serum CEA levels have been associated with advanced tumour stage, poor tumour response to neo-adjuvant chemo-radiotherapy and increased risk of recurrence after curative primary resection. 6  It has also been shown in previous studies that raised post-operative serum CEA level has prognostic significance for rectal cancer in terms of disease relapse. 7  Simultaneous evaluation of pre- and post-operative serum CEA levels to have any prognostic significance in rectal cancer is seldom assessed. The current study was planned to explore the importance of serum CEA levels as a tumour marker in predicting clinical outcome, tumour prognosis, tumour relapse, disease-free survival (DFS) and overall survival (OS) for patients with rectal carcinoma.

Materials and Methods

The retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital (SKMC), Lahore, Pakistan, and comprised data of patients with rectal carcinoma who had presented to the Surgical Oncology Department from January 2006 to December 2015. Data of all patients with rectal cancer who had undergone curative surgical resection and in whom serum CEA samplings was performed using IMMULITE@2000 systems Analyzer in pre- and post-operative period was included. Data related to patients with more than one primary cancer and those with missing serum CEA levels was excluded. Staging work-up included full colonoscopy, contrast-enhanced computed tomography (CT) scan of thorax and abdomen, and magnetic resonance imaging (MRI) of pelvis. This had been done in all cases mainly to exclude patients having advanced cancer with distant metastasis. After approval was taken from the institutional review board, clinical data of all patients, including age, gender, clinical presentation, clinical and pathological TNM classification, pre- and post-operative CEA levels at follow-up, histopathological findings, tumour recurrence, DFS and OS, was collected from patient's records. Serum CEA levels had been monitored for a period of one year from the date of primary tumour resection surgery. Depending upon the serum CEA levels in pre- and postoperative period, data of all patients in the study was categorised into four groups. Group A patients had normal serum CEA levels both before and after surgical resection of primary tumour. Group B comprised patients with normal serum CEA levels before surgery while after surgery, serum CEA levels were raised. Group C comprised patients with raised serum CEA levels before surgery which came down to normal after resection of primary tumour. Group D comprised patients with raised serum CEA levels in both before and after the surgery. Serum CEA level of 4.6 was taken as the cut-off upper limit, with levels >4.6 considered to be raised. Data analysis was done using SPSS 23. Mean +/- standard deviation (SD) was used for continuous variables, while frequencies and percentages were used for categorical variables, like recurrence / pre-operative CEA levels / OS etc. Categorical variables were compared using Chi square test or Fisher's exact test when necessary. To estimate survival, Kaplan Meier method was applied, while Log rank test was used for the analysis of survival difference. Statistical significance was defined as twotailed p=0.05.

Results

Of the 612 patients who presented with rectal carcinoma, 434(71%) had undergone curative resection. Of them, 33(7.6%) were excluded due to missing data, while the remaining 401(92.6%) comprised the final sample. Of the total, 267(66.6%) were males, and 204(50.9%) were aged <50 years. Group A had 267(66.6%) patients, Group B 26(6.5%), Group C 79(`9.7) and Group D had 29(7.2%) patients (p>0.05). Gender had no impact in group comparison (p=0.92). In clinical staging (cTNM), 343(85.5%) patients had stage III disease. On pathological staging (pTNM), 78(19.5%) patients had stage I disease, 84(20.9%) had stage II, 157(39.2%) had stage III and 3(0.7%) had stage IV disease, while 79(19.7%) had no residual tumour showing complete pathological response. Resection margin was positive in 27(6.7%) (Table-1).



On the basis of TNM staging, most patients were stage III in all four groups followed by stage II (Table-2).



Circumferential resection margin was positive in 6(23.1%) patients of group B and 4 (13.8%) of group D (p=0.004). Overall recurrence was found in 141(35.2%) patients, while 206(64.8%) were without any recurrence on long-term follow-up with a mean DFS of 35.63}21.05 months. Group D had the highest recurrence rate 26(89.7%), while Group C had the lowest 18(22.8%). Groups A and C had a higher 5-year DFS compared to groups B and D (Figure-1).



Similarly, OS in groups A and C was much better compared to groups B and D (Figure-2).



Discussion

CEA is a widely used tumour marker for colorectal cancers and it has been evaluated through several studies for its association with disease extent, prognosis, disease recurrence and DFS as well as OS status of the patients. Tumour extension and outcome after surgical resection mostly depends on pre-operative serum CEA levels, while disease recurrence and patient survival status mainly depend on post-operative serum CEA levels.8,9 In some patients, high pre-operative serum CEA levels failed to return to normal after successful surgical resection of the primary tumour with no residual disease behind. Association of pre- and post-operative serum CEA levels and their effects on tumour relapse after curative primary surgical resection were seldom studied.10 Therefore the present study was conducted to explore the importance of serum CEA level as a tumour marker in rectal cancer patients for prognosis in terms of disease recurrence, DFS and OS. There are reports indicating that post-operative serum CEA levels can be influenced by clinical and pathological features like gender, tumour depth and lymph node metastases. 12  European group guidelines on tumour markers also showed that serum CEA levels possessed independent prognostic value for disease relapse and patient survival status. 12  The current study presented a correlation between abnormal pre- and post-operative serum CEA levels with American Joint Committee on Cancer (AJCC) stages. In line with literature, our study also highlighted that advanced stage significantly correlated with higher pre- and post-operative serum CEA levels. For this reason we, together with literature, suggest that serum CEA levels should be added to the current staging system. 13  A high concentration of post-operative serum CEA levels during follow-up predicts an adverse outcome in terms of disease relapse, DFS and OS. Rectal cancerrelated mortality can be significantly reduced with early detection of disease relapse as it will lead to early treatment and, thus, increase the chances of survival. 14  CEA has shown promise as an indicator of residual disease before recurrence becomes clinically apparent, and patients with recurrence might be cured if the residual disease is identified and treated effectively earlier. Studies have reported that in 18-75% cases prior to any clinically observable recurrence, post-operative serum CEA levels rise, and, hence, give a good clue to keeping such patients on close follow-ups and treat such patients effectively at an early stage. 15  This rise has been reported as early as 4 months prior to recurrence 15 and it is possible to detect recurrence at an earlier stage. In the present study, 89.65% patients who had raised pre- and post-operative serum CEA levels and 84.61% patients with normal preoperative but raised post-operative serum CEA levels developed recurrence on follow-up. This showed that a raised serum CEA level in post-operative course is an indication for disease relapse. Goldstein et al. stated that raised pre- and post-operative serum CEA levels are indicative of systemic disease. 16  A study suggested that if pre- and post-operative serum CEA levels remain higher, they may be an indicator of increased risk. 17 These results are similar to those of the current study. The current study showed improved OS in patients who had normal pre- and post-operative serum CEA levels or those in whom pre-operative levels were raised, but postoperatively they returned to normal values. It concluded that patients with raised post-operative CEA levels exhibited poor outcome. In our opinion, rectal cancer patients whose postoperative serum CEA levels continue to remain high should be followed up closely and extensively and should be considered for adjuvant chemotherapy. The current study has its limitations as it is a retrospective study with a small number of patients for analysis at a single institution. We recommend a prospective multicenter study with a large number of patients for analysis to validate the results.

Conclusion

Isolated pre-operative serum CEA levels, if elevated, had no association with recurrence and disease prognosis but if pre- and post-operative serum CEA levels were higher or postoperative serum CEA levels increased in a patient with normal pre-operative serum CEA levels, it had a poor prognosis and worse outcome.

Disclaimer: None.

Conflict of Interest: None.
Source of Funding: None.

References

1. Holt A, Nelson RA, Lai L. Surveillance with serial serum carcinoembryonic levels detect colorectal cancer recurrences in patients who are initial nonsecretors. Am Surg. 2010; 76:1100-3.

2. Verberne CJ, Wiggers T, Vermeulen KM, De Jong KP. Detection of recurrences during follow-up after liver surgery for colorectal metastases: both carcinoembryonic antigen (CEA) and imaging are important. Ann Surg Oncol. 2013; 20:457-63.

3. Verberne C, Doornbos PM, Grossmann I, De Bock GH, Wiggers T. Intensified follow-up in colorectal cancer patients using frequent carcino-embryonic antigen (CEA) measurements and CEAtriggered imaging. Eur J Surg Oncol. 2015; 41:1188-96.

4. Primrose JN, Perera R, Gray A, Rose P, Fuller A, Corkhill A, et al. Effect of 3 to 5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: the FACS randomized clinical trial.. JAMA. 2014; 311:263-70.

5. Mazilu L, Ciufu N, Galan M, Suceveanu AI, Suceveanu AP, Parepa

IR, et al. Postherapeutic follow-up of colorectal cancer patients treated with curative intent. Chirurgia (Bucur). 2012; 107:55-8.

6. Primrose JN, Perera R, Gray A, Rose P, Fuller A, Corkhill A, et al. Effect of 3-5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial. JAMA. 2014; 311:263-70.

7. May DJ, Richardson JRC, Saunders BW, Miles AJG. Intensive long term follow-up after T1 and T2 node negative colorectal cancer is not necessary. Colorectal Disease. 2012; 14:22-3.

8. Su BB, Shi H, Wan J. Role of serum carcinoembryonic antigen in the detection of colorectal cancer before and after surgical resection. World J Gastroenterol. 2012; 18:2121-6.

9. Friederichs J, Gertler R, Rosenberg R, Dahm M, Nekarda H, Holzmann B, et al. Correlation of CK-20-positive cells in peripheral venous blood with serum CEA levels in patients with colorectal carcinoma. World J Surg. 2007; 31:2329-34.

10. Hara M, Sato M, Takahashi H, Takayama S, Takeyama H. Accuracy

of monitoring serum carcinoembryonic antigen levels in postoperative stage III colorectal cancer patients is limited to only the first postoperative year. Surg Today. 2011; 41:1357-62.

11. Fora AA, Patta AM, Attwood K, Wilding GE, Fakih M. Intensive radiographic and CEA screening and salvage resection in patients with stage II and III colorectal cancer. J Clin Oncol. 2012; 30: 405.

12. Makis W, Kurzencwyg D, Hickeson M. 18F-FDG PET/CT superior to serum CEA in detection of colorectal cancer and its recurrence. Clin Imaging. 2013; 37:1094-7.

13. Levy M, Lipska L, Visokai V, Veskrna K, Simsa J. Tumour markers in

colorectal cancer relapse. Tumour Bio. 2012; 33:S15-S80.
14. Wang JY, Lin SR, Wu DC, Lu CY, Yu FJ, Hsieh JS, et al. Multiple molecular markers as predictors of colorectal cancer in patients with normal perioperative serum carcinoembryonic antigen levels. Clin Cancer Res. 2007; 13:2406-13.

15. Kerr NA, Jha B, Edwards T, Karnati G, Mackey PM. The detection of colorectal cancer recurrence following curative resection. Colorectal Disease. 2012; 14:12-40.

16. Leventakos K, Lu SS, Perry DJ. Intensive CT scan surveillance for patients who have undergone curative intent treatment for colorectal cancer: The Medstar Washington Hospital Center experience. J Clin Oncol. 2013; 31: e14675.

17. Farquharson AL, Genever AV, Belfield J, Hersey N, Amin SN, De Noronha R. PET-CT scan is a specific test for the detection of recurrent colorectal cancer but has limitations for patients with mucinous tumours. Colorectal Disease. 2012; 14:1-11.