This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnston, P. G. Search for Related Content PubMed Articles by Johnston, P. G.

Prognostic Markers of Local Relapse in Rectal Cancer: Are We Any Further Forward?

Centre for Cancer Research & Cell Biology, Queen's University Belfast, Belfast City Hospital, Belfast, United Kingdom

Rectal cancer is a major health problem affecting more than 100,000 patients in the United States and Europe each year.¹ Although it is a highly treatable and often curable disease when localized to the bowel, the prognosis for locally advanced disease varies, with local recurrence rates ranging from 4% to 40%; local recurrence often is the cause of severe morbidity and poor mortality in this disease.² Therefore, clinical approaches to prevent early recurrence are one of the major goals in the treatment of rectal cancer.

The treatment for patients with clinically resectable, locally invasive rectal cancer has begun to evolve away from more radical surgical approaches such as abdominoperitoneal resection toward attempts at preservation of the anal sphincter and maintenance of anorectal function.³ In the postoperative setting, there is clear evidence that adjuvant fluorouracil (FU) -based chemotherapy combined with radiotherapy significantly improves disease-free survival and overall survival in patients with rectal cancer.⁴ More recently, several groups clearly have shown the benefit in reducing local recurrence rates and toxicity using neoadjuvant preoperative chemotherapy/radiotherapy combinations as opposed to adjuvant treatment.^5,6

One such study, the German CAO/ARO/AIO-94 rectal cancer group trial, randomly assigned 823 patients with T3/4 and/or node-positive rectal cancer to receive preoperative versus postoperative combined-modality therapy consisting of FU on weeks 1 and 5 and 50.4 Gy of concurrent radiation therapy.⁴ There was a significant improvement in local recurrence rates (6% in the preoperative group v 13% in the postoperative group) as well as improvements in acute and long-term toxicity. Moreover, in the preoperative group, 39% of the patients initially requiring an abdominoperitoneal resection were able to undergo a sphincter-sparing operation, whereas in the postoperatively treated group only 19% were eligible for a sphincter-sparing procedure. Although there was no difference in overall survival between the two groups, the preoperative combined-modality approach significantly improved the chances of sphincter preservation and also led to a significant reduction in local recurrence.

The identification of patients with rectal cancer at high risk for both local and distant recurrence is an active area of clinical investigation. Traditionally, it has depended on pathologic features such as depth of bowel wall penetration, lymph node involvement, and adherence to, or invasion of, adjacent organs.^7,8 Preoperative staging with ultrasound and computed tomography or magnetic resonance imaging allows for a selective patient approach based on the stage and pathologic characteristics of a patient's tumor.⁸ However, these preoperative staging methods and the ways of identifying patients at high risk for recurrence have proven to be unreliable, with wide variability in relapse rates making it difficult to provide detailed predictions of individual patient outcomes. The advent of neoadjuvant chemoradiation therapy followed by local excision approaches has the advantage of allowing patients to be selected for local excision or radical surgery based on the pathologically defined tumor response, and provides the opportunity to incorporate other biologic markers for assessment.

In this issue of the Journal of Clinical Oncology, Liersch et al⁹ present their analyses of the time to relapse in a cohort of 40 patients with stage II and III rectal cancer. These patients had a median follow-up of 49 months after receiving neoadjuvant chemotherapy according to the CAO/ARO/AIO-94 trial. They compared the time to relapse versus level of primary tumor downsizing and downstaging as well as lymph node status and the expression of several molecular biomarkers. Only those patients who were downstaged had a significantly improved disease-free survival and overall survival compared with those who were not. All of the patients who developed recurrent disease were noted to have evidence of lymph node disease in the surgically resected specimen 4 to 6 weeks after a neoadjuvant treatment. In addition to assessing histopathologic parameters, the study also examined gene expression levels of several biomarkers (thymidylate synthase [TS], thymidine phosphorylase, and dihydropyrimidine dehydrogenase) in the post-treatment surgical specimen using quantitative techniques based on reverse transcriptase polymerase chain reaction. They found that patients whose residual tumors had high TS gene expression levels had a significantly shorter time to disease recurrence. Their findings suggest that the persistence of lymph node disease and the presence of high TS levels in the primary tumor after neoadjuvant chemoradiotherapy treatment potentially may be important predictors of a high likelihood of early relapse.⁹

The ability to accurately predict the risk of recurrence in rectal cancer after neoadjuvant therapy has major implications because it may help more accurately define that subgroup of patients who should not be selected for sphincter preservation surgery after preoperative combined-modality therapy and those who possibly should be targeted for alternative postoperative chemotherapy regimens. Unfortunately, clinical assessment and radiologic examination after preoperative treatment have been of limited benefit to date in this regard. Physical examination by the surgeon after preoperative therapy is able to predict pathologic complete remission in only 25% of patients.^7,8 Radiologic techniques such as rectal ultrasound, computed tomography, magnetic resonance imaging, or positron emission spectroscopy scanning are not accurate enough to correctly predict complete remission.⁸

Molecular markers such as K-ras, TS, and p53 cellular proliferation have been assessed and correlated with clinical outcome in rectal cancer, but with limited success.^10-14 One of the more promising markers in rectal cancer to date has been TS, which is an enzyme responsible for the provision of thymidylate required for DNA synthesis and repair.^15,16 TS is also the primary intracellular target for FU. Both preclinical and clinical investigations have demonstrated the importance of intracellular TS levels as a determinant of sensitivity to FU, and multiple clinical investigations have demonstrated an improved response to fluoropyrimidine-containing regimens in patients with low levels of TS in their cancers when compared with the response in patients whose cancers overexpress TS.¹⁷

TS was first demonstrated to have prognostic value in patients with locally advanced rectal cancer treated on the National Surgical Adjuvant Breast and Bowel Project R-01, which was designed to test the utility of the addition of methotrexate, vincristine, and FU (MOF) chemotherapy or radiation therapy to standard surgical resection in patients with rectal cancer.¹⁵ This study, which used the monoclonal antibody TS 106, demonstrated that patients whose tumors contained high levels of TS had a worse clinical outcome when compared with those whose tumors contained low levels of TS. A subsequent study by Edler et al¹⁶ confirmed the independent prognostic value of TS in patients with locally advanced rectal cancer. Although the study size in this current investigation⁹ is small, it is interesting that intratumoral TS levels in the post-treatment sample now also seem to predict for relapse in the neoadjuvant setting. This would suggest that measurement of TS might be important in patients undergoing surgery after neoadjuvant therapy for rectal cancer. It is interesting to postulate whether the TS levels seen in post-treatment rectal cancers are directly related to treatment or intrinsic to the biology of the disease. Although the current investigation suggests that TS levels are lower in tumors resected after chemoradiotherapy compared with those removed by primary surgery, this conclusion will require much more rigorous investigation in a larger series.

Another recent and interesting approach has been the use of gene expression profiling as a method for the prediction of response to neoadjuvant therapy in rectal cancer.¹⁸ In 30 patients treated as part of the same CAO/ARO/AIO-94 German trial, Ghadimi et al¹⁸ showed that gene expression profiling using a 54-gene set could stratify responders clinically from nonresponders with 86% specificity and 78% sensitivity. Their results suggested that pretherapeutic gene expression profiling might be a useful method to assist in the prediction of response to neoadjuvant chemoradiotherapy treatment in this disease.

In conclusion, this interesting study has demonstrated that assessment of lymph node status and TS gene expression levels may have significant prognostic significance for patients with stage II and III rectal carcinoma after neoadjuvant chemoradiotherapy. Given that an increasing number of patients with rectal cancer are being treated with a neoadjuvant approach, the evaluation of these parameters could be incorporated as part of the management of the patient with rectal cancer. This would allow us to identify more precisely that group of patients at highest risk of recurrence and also that group of rectal cancer patients who are benefiting from neoadjuvant FU-based therapies. It may be that it is in this group that other therapies such as oxaliplatin, irinotecan, and some of the newer biologic agents may have a more beneficial effect.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Jemal A, Tiwari RC, Murray T, et al: Cancer Statistics 2004. CA Cancer J Clin 54:8-29, 2004[Abstract/Free Full Text]

2. Midgley R, Kerr D: Colorectal cancer. Lancet 353:391-399, 1999[CrossRef][Medline]

3. Rengan R, Paty P, Wong WD, et al: Distal cT2N0 rectal cancer: Is there an alternative to abdominoperitoneal resection? J Clin Oncol 23:4905-4912, 2005[Abstract/Free Full Text]

4. Tepper JE, O'Connell MJ, Petroni GR, et al: Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: Initial results of Intergroup 0114. J Clin Oncol 15:2030-2039, 1997[Abstract/Free Full Text]

5. Sauer R, Becker H, Hohenberger W, et al: Preoperative chemo/radiotherapy as compared with post-operative chemo/radiotherapy for locally advanced rectal cancer. N Engl J Med 351:1731-1740, 2004[Abstract/Free Full Text]

6. Minsky BD, Cohen AM, Kemeny N, et al: Preoperative combined 5-FU with low dose leucovorin and sequential radiotherapy for unresectable rectal cancer. Int J Radiat Oncol Biol Phys 25:821-827, 1993[Medline]

7. Hiotis SP, Weber SM, Cohen AM, et al: Assessing the predictive value of clinical complete response to neoadjuvant therapy of rectal cancer: An analysis of 488 patients. J Am Coll Surg 194:131-136, 2002[CrossRef][Medline]

8. Vecchio FM, Valentini V, Minsky BD, et al: The relationship of pathologic tumour regression grade and outcome after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys 62:752-760, 2005[CrossRef][Medline]

9. Liersch T, Langer C, Ghadimi, et al: Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoadjuvant fluorouracil-based chemoradiotherapy. J Clin Oncol 24:4062-4068, 2006[Abstract/Free Full Text]

10. Kahn H, Alexander A, Rakinic J, et al: Preoperative staging of irradiated rectal cancers using digital rectal examination, computed tomography, endorectal ultrasound, and magnetic resonance imaging does not accurately predict T0N0 pathology. Dis Colon Rectum 40:140-144, 1997[CrossRef][Medline]

11. Luna-Perez P, Segura J, Alvarado I, et al: Specific C-K-ras gene mutations as a tumor response marker in locally advanced rectal cancer treated with preoperative chemo/radiotherapy. Ann Surg Oncol 7:727-773, 2000[Abstract]

12. Adell G, Zhang H, Jansson A, et al: Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer. Int J Radiat Oncol Biol Phys 50:659-663, 2001[CrossRef][Medline]

13. Saw RPM, Morgan M, Koorey D, et al: P53, deleted in colorectal cancer gene, and thymidylate synthase as predictors of histopathologic response and survival in low, locally advanced, rectal cancer treated with preoperative adjuvant therapy. Dis Colon Rectum 46:192-202, 2003[CrossRef][Medline]

14. Kandioler D, Zwertek R, Ludwig C, et al: TP53 genotype but not p53 immunohistochemical results predicts response to preoperative short term radiotherapy in rectal cancer. Ann Surg 235:493-498, 2002[CrossRef][Medline]

15. Johnston PG, Fisher ER, Rockette HE, et al: The role of thymidylate synthase expression in prognosis and outcome to adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 12:2640-2647, 1994[Abstract/Free Full Text]

16. Edler D, Hallstrom M, Johnston PG, et al: Thymidylate synthase expression: An independent prognostic factor for local recurrence, distant metastasis, disease-free and overall survival in rectal cancer. Clin Cancer Res 6:1378-1384, 2000[Abstract/Free Full Text]

17. Johnston PG, Lenz HJ, Leichman CG, et al: Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in colorectal and gastric tumors. Cancer Res 55:1407-1412, 1995[Abstract/Free Full Text]

18. Ghadimi BM, Grade M, Difilppantonio MJ, et al: Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23:1826-1838, 2005[Abstract/Free Full Text]

This article has been cited by other articles:

				B. D. Minsky Adjuvant Management of Rectal Cancer: The More We Learn, the Less We Know J. Clin. Oncol., October 1, 2007; 25(28): 4339 - 4340. [Full Text] [PDF]

				L. Collette, J.-F. Bosset, M. den Dulk, F. Nguyen, L. Mineur, P. Maingon, L. Radosevic-Jelic, M. Pierart, and G. Calais Patients With Curative Resection of cT3-4 Rectal Cancer After Preoperative Radiotherapy or Radiochemotherapy: Does Anybody Benefit From Adjuvant Fluorouracil-Based Chemotherapy? A Trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group J. Clin. Oncol., October 1, 2007; 25(28): 4379 - 4386. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnston, P. G. Search for Related Content PubMed Articles by Johnston, P. G.