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Response to neoadjuvant treatment in rectal cancer surgery
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Norrköping.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.

Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.

Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.

Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.

Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 66 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1553
National Category
Cancer and Oncology Surgery Clinical Laboratory Medicine Urology and Nephrology Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-132759DOI: 10.3384/diss.diva-132759ISBN: 9789176856383 (Print)OAI: oai:DiVA.org:liu-132759DiVA: diva2:1049033
Public defence
2016-12-15, Hasselqvistsalen, Växthuset, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2016-11-24Bibliographically approved
List of papers
1. EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
Open this publication in new window or tab >>EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
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2009 (English)In: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, ISSN 0360-3016, Vol. 75, no 1, 137-142 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: FXYD-3 (MAT-8) is overexpressed in several types of cancers; however, its clinical relevance in rectal cancers has not been studied. Therefore, we examined FXYD-3 expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative radiotherapy (RT) to determine whether FXYD-3 was overexpressed in rectal cancers and correlated with RT, survival, and other clinicopathologic variables. Methods and Materials: The study included 140 rectal cancer patients who participated in a clinical trial of preoperative RT, 65 with and 75 without RT before surgery. FXYD-3 expression was immumohistochemically examined in distant (n = 70) and adjacent (n = 101) normal mucosa, primary tumors (n = 140), and lymph node metastasis (n = 36). Results: In the whole cohort, strong FXYD-3 expression was correlated with infiltrative tumor growth (p = 0.02). In the RT group, strong FXYD-3 expression alone (p = 0.02) or combined with phosphatase of regenerating liver was associated with an unfavorable prognosis (p = 0.02), independent of both TNM stage and tumor differentiation. In tumors with strong FXYD-3 expression, there was less tumor necrosis (p = 0.02) and a trend toward increased incidence of distant metastasis (p = 0.08) after RT. None of these effects was seen in the non-RT group. FXYD-3 expression in the primary tumors tended to he increased compared with normal mucosa regardless of RT. Conclusion: FXYD-3 expression was a prognostic factor independent of tumor stage and differentiation in patients receiving preoperative RT for rectal cancer.

Keyword
FXYD-3, Rectal cancer, Radiotherapy, Prognosis, Immunohistochemistry
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20598 (URN)10.1016/j.ijrobp.2008.10.076 (DOI)
Available from: 2009-09-16 Created: 2009-09-15 Last updated: 2016-11-24
2. FXYD-3 expression in relation to local recurrence of rectal cancer
Open this publication in new window or tab >>FXYD-3 expression in relation to local recurrence of rectal cancer
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2016 (English)In: Radiation Oncology Journal, ISSN 2234-1900 (print), 2234-3156 (online), Vol. 34, no 1, 52-58 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: In a previous study, the transmembrane protein FXYD-3 was suggested as a biomarker for a lower survival rate and reduced radiosensitivity in rectal cancer patients receiving preoperative radiotherapy. The purpose of preoperative irradiation in rectal cancer is to reduce local recurrence. The aim of this study was to investigate the potential role of FXYD-3 as a biomarker for increased risk for local recurrence of rectal cancer.

Materials and Methods: FXYD-3 expression was immunohistochemically examined in surgical specimens from a cohort of patients with rectal cancer who developed local recurrence (n = 48). The cohort was compared to a matched control group without recurrence (n = 81).

Results: Weak FXYD-3 expression was found in 106/129 (82%) of the rectal tumors and strong expression in 23/129 (18%). There was no difference in the expression of FXYD-3 between the patients with local recurrence and the control group. Furthermore there was no difference in FXYD-3 expression and time to diagnosis of local recurrence between patients who received preoperative radiotherapy and those without.

Conclusion: Previous findings indicated that FXYD-3 expression may be used as a marker of decreased sensitivity to radiotherapy or even overall survival. We were unable to confirm this in a cohort of rectal cancer patients who developed local recurrence.

Place, publisher, year, edition, pages
Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea, 2016
Keyword
Rectal cancer, Human FXYD3 protein, Local recurrence
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-132758 (URN)10.3857/roj.2016.34.1.52 (DOI)27104167 (PubMedID)
Available from: 2016-11-23 Created: 2016-11-23 Last updated: 2016-11-29Bibliographically approved
3. Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer
Open this publication in new window or tab >>Nodal involvement in luminal complete response after neoadjuvant treatment for rectal cancer
2016 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 42, no 6, 801-807 p.Article in journal (Refereed) Published
Abstract [en]

Background: Pathological complete response (pCR) after neoadjuvant therapy in rectal cancer is correlated with improved survival. There is limited knowledge on the incidence of pCR at a national level with uniform guidelines. The aim of this prospective register-based study was to investigate the incidence and outcome of pCR in relation to neoadjuvant therapy in a national cohort. Method: All patients abdominally operated for rectal cancer between 2007 and 2012 (n = 7885) were selected from The Swedish Colorectal Cancer Register. Twenty-six per cent (n = 2063) had neoadjuvant therapy with either long or short course radiotherapy with amp;gt;4 weeks delay with the potential to achieve pCR. The primary endpoints were pCR and survival in relation to neoadjuvant therapy. Results: Complete eradication of the luminal tumor, ypTO was found in 161 patients (8%). In 83% of the ypTO the regional lymph nodes were tumor negative (ypTONO), 12% had 1-3 positive lymph nodes (ypTON1) and 4% had more than three positive lymph nodes (ypTON2). There was significantly greater survival with ypTO compared to ypT+ (hazard ratio 0.38 (C.I 0.25-0.58)) and survival was significantly greater in patients with ypTONO compared to ypT0N1-2 (hazard ratio 0.36 (C.I 0.15-0.86)). In ypTO, cT3-4 tumors had the greater risk of node-positivity. The added use of chemotherapy resulted in 10% ypTO compared to 5.1% in the group without chemotherapy (p amp;lt; 0.00004). Conclusion: Luminal pathological complete response occurred in 8%, 16% of them had tumor positive nodes. The survival benefit of luminal complete response is dependent upon nodal involvement status. (C) 2016 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2016
Keyword
Rectal cancer; Complete response; Lymph nodes; Neoadjuvant treatment
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130432 (URN)10.1016/j.ejso.2016.03.013 (DOI)000379559300007 ()27146960 (PubMedID)
Available from: 2016-08-07 Created: 2016-08-05 Last updated: 2016-11-24

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Division of Clinical SciencesFaculty of Medicine and Health SciencesDepartment of Surgery in Norrköping
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