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      Current Approaches and Challenges for Monitoring Treatment Response in Colon and Rectal Cancer

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          Abstract

          Introduction: With the advent of multidisciplinary and multimodality approaches to the management of colorectal cancer patients, there is an increasing need to define how we monitor response to novel therapies in these patients. Several factors ranging from the type of therapy used to the intrinsic biology of the tumor play a role in tumor response. All of these can aid in determining the ideal course of treatment, and may fluctuate over time, pending down-staging or progression of disease. Therefore, monitoring how disease responds to therapy requires standardization in order to ultimately optimize patient outcomes. Unfortunately, how best to do this remains a topic of debate among oncologists, pathologists, and colorectal surgeons. There may not be one single best approach. The goal of the present article is to shed some light on current approaches and challenges to monitoring treatment response for colorectal cancer.

          Methods: A literature search was conducted utilizing PubMed and the OVID library. Key-word combinations included colorectal cancer metastases, neoadjuvant therapy, rectal cancer, imaging modalities, CEA, down-staging, tumor response, and biomarkers. Directed searches of the embedded references from the primary articles were also performed in selected circumstances.

          Results: Pathologic examination of the post-treatment surgical specimen is the gold standard for monitoring response to therapy. Endoscopy is useful for evaluating local recurrence, but not in assessing tumor response outside of the limited information gained by direct examination of intra-lumenal lesions. Imaging is used to monitor tumors throughout the body for response, with CT, PET, and MRI employed in different circumstances. Overall, each has been validated in the monitoring of patients with colorectal cancer and residual tumors.

          Conclusion: Although there is no imaging or serum test to precisely correlate with a tumor's response to chemo- or radiation therapy, these modalities, when used in combination, can aid in allowing clinicians to adjust medical therapy, pursue operative intervention, or (in select cases) identify complete responders. Improvements are needed, however, as advances across multiple modalities could allow appropriate selection of patients for a close surveillance regimen in the absence of operative intervention.

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          Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years.

          Preoperative chemoradiotherapy (CRT) has been established as standard treatment for locally advanced rectal cancer after first results of the CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] trial, published in 2004, showed an improved local control rate. However, after a median follow-up of 46 months, no survival benefit could be shown. Here, we report long-term results with a median follow-up of 134 months. A total of 823 patients with stage II to III rectal cancer were randomly assigned to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or the same schedule of CRT used postoperatively. The study was designed to have 80% power to detect a difference of 10% in 5-year overall survival as the primary end point. Secondary end points included the cumulative incidence of local and distant relapses and disease-free survival. Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT. According to intention-to-treat analysis, overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P = .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P = .048). No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P = .9) and disease-free survival. There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. Integrating more effective systemic treatment into the multimodal therapy has been adopted in the CAO/ARO/AIO-04 trial to possibly reduce distant metastases and improve survival.
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            Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer.

            Following neoadjuvant chemoradiotherapy (CRT) and interval proctectomy, 15-20 per cent of patients are found to have a pathological complete response (pCR) to combined multimodal therapy, but controversy persists about whether this yields a survival benefit. This systematic review evaluated current evidence regarding long-term oncological outcomes in patients found to have a pCR to neoadjuvant CRT. Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The systematic review included all original articles reporting long-term outcomes in patients with rectal cancer who had a pCR to neoadjuvant CRT, published in English, from January 1950 to March 2011. A total of 724 studies were identified for screening. After applying inclusion and exclusion criteria, 16 studies involving 3363 patients (1263 with pCR and 2100 without) were included (mean age 60 years, 65·0 per cent men). Some 73·4 per cent had a sphincter-saving procedure. Mean follow-up was 55·5 (range 40-87) months. For patients with a pCR, the weighted mean local recurrence rate was 0·7 (range 0-2·6) per cent. Distant failure was observed in 8·7 per cent. Five-year overall and disease-free survival rates were 90·2 and 87·0 per cent respectively. Compared with non-responders, a pCR was associated with fewer local recurrences (odds ratio (OR) 0·25; P = 0·002) and less frequent distant failure (OR 0·23; P < 0·001), with a greater likelihood of being alive (OR 3·28; P = 0·001) and disease-free (OR 4·33, P < 0·001) at 5 years. A pCR following neoadjuvant CRT is associated with excellent long-term survival, with low rates of local recurrence and distant failure. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.
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              Morphologic predictors of lymph node status in rectal cancer with use of high-spatial-resolution MR imaging with histopathologic comparison.

              To evaluate signal intensity and border characteristics of lymph nodes at high-spatial-resolution magnetic resonance (MR) imaging in patients with rectal cancer and to compare these findings with size in prediction of nodal status. Forty-two patients who underwent total mesorectal excision of the rectum to determine if they had rectal carcinoma were studied with preoperative thin-section MR imaging. Lymph nodes were harvested from 42 transversely sectioned surgical specimens. The slice of each lymph node was carefully matched with its location on the corresponding MR images. Nodal size, border contour, and signal intensity on MR images were characterized and related to histologic involvement with metastases. Differences in sensitivity and specificity with border or signal intensity were calculated with CIs by using method 10 of Newcombe. Of the 437 nodes harvested, 102 were too small (<3 mm) to be depicted on MR images, and only two of these contained metastases. In 15 (68%) of 22 patients with nodal metastases, the size of normal or reactive nodes was equal to or greater than that of positive nodes in the same specimen. Fifty-one nodes were above the area imaged, and seven of these contained metastases. The diameter of benign and malignant nodes was similar; therefore, size was a poor predictor of nodal status. If a node was defined as suspicious because of an irregular border or mixed signal intensity, a superior accuracy was obtained and resulted in a sensitivity of 51 (85%) of 60 (95% CI: 74%, 92%) and a specificity of 216 (97%) of 221 (95% CI: 95%, 99%). Prediction of nodal involvement in rectal cancer with MR imaging is improved by using the border contour and signal intensity characteristics of lymph nodes instead of size criteria. Copyright RSNA, 2003
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                Author and article information

                Journal
                J Cancer
                J Cancer
                jca
                Journal of Cancer
                Ivyspring International Publisher (Sydney )
                1837-9664
                2014
                1 January 2014
                : 5
                : 1
                : 31-43
                Affiliations
                1. Department of Surgery, Swedish Medical Center, Seattle, WA, USA
                2. Department of Surgery, Madigan Army Center, Tacoma, WA, USA
                3. Division of Colorectal Surgery, UMass Medical Center, Worcester, MA, USA
                4. Department of Surgery, Division of Surgical Oncology, Walter Reed National Military Medical Center, Bethesda, MD, USA
                5. Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                6. Bon Secours Cancer Institute, Richmond, VA, USA
                Author notes
                ✉ Corresponding author: Scott R. Steele, MD, Madigan Army Medical Center, Department of Surgery, 9040a Fitzsimmons Dr., Tacoma, WA 98431. Phone: 253-968-2200; Fax: 253-968-0232; Email: harkersteele@ 123456me.com

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                jcav05p0031
                10.7150/jca.7987
                3881219
                24396496
                fdfc3105-b024-46fe-a418-6cc7a29d9dbf
                © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                History
                : 1 October 2013
                : 25 November 2013
                Categories
                Review

                Oncology & Radiotherapy
                neoadjuvant therapy,imaging modalities,pet,ct,mri,erus,down-staging,colorectal cancer,treatment response,cea

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