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Martins S, Veiga P, Tralhão JG, Carreira IM, Ribeiro IP. Rectal Cancer: Exploring Predictive Biomarkers Through Molecular Pathways Involved in Carcinogenesis. BIOLOGY 2024; 13:1007. [PMID: 39765674 PMCID: PMC11673418 DOI: 10.3390/biology13121007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 11/29/2024] [Accepted: 12/01/2024] [Indexed: 01/11/2025]
Abstract
In 2022, colorectal cancer (CCR) had the second-highest incidence in Europe, preceded only by breast cancer [...].
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Affiliation(s)
- Sheila Martins
- Portuguese Oncology Institute of Coimbra, 3000-075 Coimbra, Portugal;
| | - Pedro Veiga
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
| | - José Guilherme Tralhão
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
- Surgery Department, Unidade Local de Saúde de Coimbra (ULS Coimbra), 3004-561 Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB) and Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Isabel Marques Carreira
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB) and Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ilda Patrícia Ribeiro
- Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal (J.G.T.); (I.P.R.)
- Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB) and Clinical Academic Center of Coimbra (CACC), University of Coimbra, 3000-548 Coimbra, Portugal
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Lee HH, Chen CH, Huang YH, Chiang CH, Huang MY. Biomarkers of Favorable vs. Unfavorable Responses in Locally Advanced Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy. Cells 2022; 11:cells11101611. [PMID: 35626648 PMCID: PMC9139800 DOI: 10.3390/cells11101611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/27/2022] [Accepted: 05/10/2022] [Indexed: 02/04/2023] Open
Abstract
Colorectal cancer is the second leading cause of cancer death globally. The gold standard for locally advanced rectal cancer (LARC) nowadays is preoperative concurrent chemoradiation (CCRT). Approximately three quarters of LARC patients do not achieve pathological complete response and hence suffer from relapse, metastases and inevitable death. The exploration of trustworthy and timely biomarkers for CCRT response is urgently called for. This review focused upon a broad spectrum of biomarkers, including circulating tumor cells, DNA, RNA, oncogenes, tumor suppressor genes, epigenetics, impaired DNA mismatch repair, patient-derived xenografts, in vitro tumor organoids, immunity and microbiomes. Utilizing proper biomarkers can assist in categorizing appropriate patients by the most efficient treatment modality with the best outcome and accompanied by minimal side effects. The purpose of this review is to inspect and analyze accessible data in order to fully realize the promise of precision oncology for rectal cancer patients.
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Affiliation(s)
- Hsin-Hua Lee
- Ph.D. Program in Environmental and Occupational Medicine, National Health Research Institutes, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chien-Hung Chen
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Radiation Oncology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 801, Taiwan
| | - Yu-Hsiang Huang
- Post-Graduate Year Training, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;
| | - Cheng-Han Chiang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
| | - Ming-Yii Huang
- Ph.D. Program in Environmental and Occupational Medicine, National Health Research Institutes, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; (C.-H.C.); (C.-H.C.)
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 7158)
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Biomarkers and cell-based models to predict the outcome of neoadjuvant therapy for rectal cancer patients. Biomark Res 2021; 9:60. [PMID: 34321074 PMCID: PMC8317379 DOI: 10.1186/s40364-021-00313-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022] Open
Abstract
Rectal cancer constitutes approximately one-third of all colorectal cancers and contributes to considerable mortality globally. In contrast to colon cancer, the standard treatment for localized rectal cancer often involves neoadjuvant chemoradiotherapy. Tumour response rates to treatment show substantial inter-patient heterogeneity, indicating a need for treatment stratification. Consequently researchers have attempted to establish new means for predicting tumour response in order to assist in treatment decisions. In this review we have summarized published findings regarding potential biomarkers to predict neoadjuvant treatment response for rectal cancer tumours. In addition, we describe cell-based models that can be utilized both for treatment prediction and for studying the complex mechanisms involved.
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Abraha I, Aristei C, Palumbo I, Lupattelli M, Trastulli S, Cirocchi R, De Florio R, Valentini V, Cochrane Colorectal Cancer Group. Preoperative radiotherapy and curative surgery for the management of localised rectal carcinoma. Cochrane Database Syst Rev 2018; 10:CD002102. [PMID: 30284239 PMCID: PMC6517113 DOI: 10.1002/14651858.cd002102.pub3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND This is an update of the original review published in 2007.Carcinoma of the rectum is a common malignancy, especially in high income countries. Local recurrence may occur after surgery alone. Preoperative radiotherapy (PRT) has the potential to reduce the risk of local recurrence and improve outcomes in rectal cancer. OBJECTIVES To determine the effect of preoperative radiotherapy for people with localised resectable rectal cancer compared to surgery alone. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library; Issue 5, 2018) (4 June 2018), MEDLINE (Ovid) (1950 to 4 June 2018), and Embase (Ovid) (1974 to 4 June 2018). We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for relevant ongoing trials (4 June 2018). SELECTION CRITERIA We included randomised controlled trials comparing PRT and surgery with surgery alone for people with localised advanced rectal cancer planned for radical surgery. We excluded trials that did not use contemporary radiotherapy techniques (with more than two fields to the pelvis). DATA COLLECTION AND ANALYSIS Two review authors independently assessed the 'Risk of bias' domains for each included trial, and extracted data. For time-to-event data, we calculated the Peto odds ratio (Peto OR) and variances, and for dichotomous data we calculated risk ratios (RR) using the random-effects method. Potential sources of heterogeneity hypothesised a priori included study quality, staging, and the use of total mesorectal excision (TME) surgery. MAIN RESULTS We included four trials with a total of 4663 participants. All four trials reported short PRT courses, with three trials using 25 Gy in five fractions, and one trial using 20 Gy in four fractions. Only one study specifically required TME surgery for inclusion, whereas in another study 90% of participants received TME surgery.Preoperative radiotherapy probably reduces overall mortality at 4 to 12 years' follow-up (4 trials, 4663 participants; Peto OR 0.90, 95% CI 0.83 to 0.98; moderate-quality evidence). For every 1000 people who undergo surgery alone, 454 would die compared with 45 fewer (the true effect may lie between 77 fewer to 9 fewer) in the PRT group. There was some evidence from subgroup analyses that in trials using TME no or little effect of PRT on survival (P = 0.03 for the difference between subgroups).Preoperative radiotherapy may have little or no effect in reducing cause-specific mortality for rectal cancer (2 trials, 2145 participants; Peto OR 0.89, 95% CI 0.77 to 1.03; low-quality evidence).We found moderate-quality evidence that PRT reduces local recurrence (4 trials, 4663 participants; Peto OR 0.48, 95% CI 0.40 to 0.57). In absolute terms, 161 out of 1000 patients receiving surgery alone would experience local recurrence compared with 83 fewer with PRT. The results were consistent in TME and non-TME studies.There may be little or no difference in curative resection (4 trials, 4673 participants; RR 1.00, 95% CI 0.97 to 1.02; low-quality evidence) or in the need for sphincter-sparing surgery (3 trials, 4379 participants; RR 0.99, 95% CI 0.94 to 1.04; I2 = 0%; low-quality evidence) between PRT and surgery alone.Low-quality evidence suggests that PRT may increase the risk of sepsis from 13% to 16% (2 trials, 2698 participants; RR 1.25, 95% CI 1.04 to 1.52) and surgical complications from 25% to 30% (2 trials, 2698 participants; RR 1.20, 95% CI 1.01 to 1.42) compared to surgery alone.Two trials evaluated quality of life using different scales. Both studies concluded that sexual dysfunction occurred more in the PRT group. Mixed results were found for faecal incontinence, and irradiated participants tended to resume work later than non-irradiated participants between 6 and 12 months, but this effect had attenuated after 18 months (low-quality evidence). AUTHORS' CONCLUSIONS We found moderate-quality evidence that PRT reduces overall mortality. Subgroup analysis did not confirm this effect in people undergoing TME surgery. We found consistent evidence that PRT reduces local recurrence. Risk of sepsis and postsurgical complications may be higher with PRT.The main limitation of the findings of the present review concerns their applicability. The included trials only assessed short-course radiotherapy and did not use chemotherapy, which is widely used in the contemporary management of rectal cancer disease. The differences between the trials regarding the criteria used to define rectal cancer, staging, radiotherapy delivered, the time between radiotherapy and surgery, and the use of adjuvant or postoperative therapy did not appear to influence the size of effect across the studies.Future trials should focus on identifying participants that are most likely to benefit from PRT especially in terms of improving local control, sphincter preservation, and overall survival while reducing acute and late toxicities (especially rectal and sexual function), as well as determining the effect of radiotherapy when chemotherapy is used and the optimal timing of surgery following radiotherapy.
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Affiliation(s)
- Iosief Abraha
- Regional Health Authority of UmbriaHealth Planning ServicePerugiaItaly06124
| | - Cynthia Aristei
- University of Perugia and Perugia General HospitalRadiation Oncology Section, Department of Surgical and Biomedical SciencePerugiaItaly
| | - Isabella Palumbo
- University of Perugia and Perugia General HospitalRadiation Oncology Section, Department of Surgical and Biomedical SciencePerugiaItaly
| | | | | | | | - Rita De Florio
- Local Health Unit of PerugiaGeneral MedicineAzienda SanitariaLocale USL 1, Medicina GeneralePerugiaItaly
| | - Vincenzo Valentini
- Fondazione Policlinico Universitario A.Gemelli IRCCSRadiation Oncology DepartmentRomeItaly
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Timmerman C, Taveras LR, Huerta S. Clinical and molecular diagnosis of pathologic complete response in rectal cancer: an update. Expert Rev Mol Diagn 2018; 18:887-896. [PMID: 30124091 DOI: 10.1080/14737159.2018.1514258] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The standard of care for locally advanced rectal cancer includes neoadjuvant chemoradiation with subsequent total mesorectal excision. This approach has shown various degrees of response to neoadjuvant chemoradiation (ranging from complete response to further tumor growth), which have substantial prognostic and therapeutic implications. A total regression of the tumor is a predictor of superior oncologic outcomes compared with partial responders and non-responders. Further, this concept has opened the possibility of nonoperative strategies for complete responders and explains the widespread research interest in finding clinical, radiographic, pathologic, and biochemical parameters that allow for identification of these patients. Areas covered: The present review evaluates the most recent efforts in the literature to identify predictors of patients likely to achieve a complete response following neoadjuvant treatment for the management of rectal cancer. This includes clinical predictors of pathologic complete response such as tumor location, size, and stage, molecular predictors such as tumor biology and microRNA, serum biomarkers such as carcinoembryogenic antigen and nomograms. Expert commentary: There has been significant progress in our ability to predict pathological complete response. However, more high-quality research is still needed to use this concept to confidently dictate clinical management.
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Affiliation(s)
- Corey Timmerman
- a University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Luis R Taveras
- a University of Texas Southwestern Medical Center , Dallas , TX , USA
| | - Sergio Huerta
- a University of Texas Southwestern Medical Center , Dallas , TX , USA.,b VA North Texas Healthcare System , Dallas , TX , USA
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Luppi G, Santantonio M, Bertolini F, Fiorica F, Zanelli F, Gavioli M, Balli M, Silingardi V. Preoperative Concomitant Radiotherapy and Chemotherapy in Ultrasound-Staged T3 and T4 Rectal Cancer. TUMORI JOURNAL 2018; 89:152-6. [PMID: 12841662 DOI: 10.1177/030089160308900209] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background To analyze early results of a single institution's experience using neoadjuvant chemoradiotherapy in locally advanced, ultrasound-staged rectal cancer. Patients and methods Since 1998, 67 consecutive patients (36 males and 31 females; mean age, 59.5) have received preoperative combined treatment for T3 or T4 rectal cancer. All patients were staged by endorectal ultrasound and computed tomography, and all had a pathology-demonstrated invasive adenocarcinoma of the rectum. Patients were treated preoper-atively with concomitant radiochemotherapy: pelvic irradiation (50 Gy in 25 fractions) and protracted-venous-infusion 5-fluorouracil (225 mg/m2/d, 7 days per week). Patients were restaged within 4 weeks, then submitted to surgery within 6-7 weeks after the end of therapy. Adjuvant postoperative chemotherapy with 5-fluorouracil plus folinic acid - the “de Gramont” schedule – for 24 weeks was purposed to all patients. Results Radiotherapy was completed in all cases; only one patient required suspension of the treatment for grade 4 toxicity (diarrhea). Instead, chemotherapy was interrupted in 3 cases (2 for central venous catheter thrombosis and 1 for grade IV diarrhea). Sixty-six patients underwent surgical resection (1 patient died before surgical treatment). Radical surgery was performed in 94%, and 46% of the 26 patients with distal rectal cancer had a conservative sphincter-sparing surgery. A complete pathologic response (defined as no evidence of viable tumor cells) was obtained in 22%. At a median follow-up of 17 months, distant metastases have been observed in 10 patients, and 3 of them developed a local recurrence. The actuarial estimations of 4-year overall survival, disease-free survival, local and distant control are 79%, 61%, 94% and 61%, respectively. Conclusions Preoperative chemoradiotherapy seems to be an effective and well-tolerated treatment with a low complication rate. The high percentage of downstaging and sphincter sparing, also in distal rectal cancer, shows the efficacy of the treatment, which could significantly influence the incidence of relapses and quality of life.
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Meng WJ, Pathak S, Ding ZY, Zhang H, Adell G, Holmlund B, Li Y, Zhou ZG, Sun XF. Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer. Cancer Biol Ther 2016; 16:1738-45. [PMID: 26528635 DOI: 10.1080/15384047.2015.1095408] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasn't been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer.
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Affiliation(s)
- Wen-Jian Meng
- a Department of Gastrointestinal Surgery ; West China Hospital; Sichuan University ; Chengdu , China.,b Department of Oncology and Department of Clinical and Experimental Medicine ; Linköping University ; Linköping , Sweden
| | - Surajit Pathak
- b Department of Oncology and Department of Clinical and Experimental Medicine ; Linköping University ; Linköping , Sweden
| | - Zhen-Yu Ding
- c Cancer Center and State Key Laboratory of Biotherapy; West China Hospital; Sichuan University ; Chengdu , China
| | - Hong Zhang
- d School of Medicine; Örebro University ; Örebro , Sweden
| | - Gunnar Adell
- e Department of Oncology ; County Council of Östergötland ; Linköping , Sweden
| | - Birgitta Holmlund
- e Department of Oncology ; County Council of Östergötland ; Linköping , Sweden
| | - Yuan Li
- f Institute of Digestive Surgery; State Key Laboratory of Biotherapy and Cancer Center; West China Hospital; Sichuan University ; Chengdu , China
| | - Zong-Guang Zhou
- a Department of Gastrointestinal Surgery ; West China Hospital; Sichuan University ; Chengdu , China.,f Institute of Digestive Surgery; State Key Laboratory of Biotherapy and Cancer Center; West China Hospital; Sichuan University ; Chengdu , China
| | - Xiao-Feng Sun
- b Department of Oncology and Department of Clinical and Experimental Medicine ; Linköping University ; Linköping , Sweden.,f Institute of Digestive Surgery; State Key Laboratory of Biotherapy and Cancer Center; West China Hospital; Sichuan University ; Chengdu , China
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Han Y, Oh S, Choi M, Lee S, Jang H, Lee M, Kim JG. Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation. Diagn Interv Imaging 2016; 97:843-50. [DOI: 10.1016/j.diii.2016.05.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 05/03/2016] [Accepted: 05/17/2016] [Indexed: 01/01/2023]
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Loftas P, Arbman G, Sun XF, Edler D, Syk E, Hallbook O. FXYD-3 expression in relation to local recurrence of rectal cancer. Radiat Oncol J 2016; 34:52-8. [PMID: 27104167 PMCID: PMC4831969 DOI: 10.3857/roj.2016.34.1.52] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 02/17/2016] [Accepted: 03/14/2016] [Indexed: 01/07/2023] Open
Abstract
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.
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Affiliation(s)
- Per Loftas
- Division of Surgery, Department of Clinical and Experimental Medicine, Linkoping University, Norrkoping, Sweden
| | - Gunnar Arbman
- Division of Surgery, Department of Clinical and Experimental Medicine, Linkoping University, Norrkoping, Sweden
| | - Xiao-Feng Sun
- Division of Oncology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
| | - David Edler
- Department of Surgery, Karolinska Institute, Stockholm, Sweden
| | - Erik Syk
- Department of Surgery, Ersta Hospital, Stockholm, Sweden
| | - Olof Hallbook
- Division of Surgery, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden
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Patel PM, Harris K, Huerta S. Clinical and molecular diagnosis of pathologic complete response in rectal cancer. Expert Rev Mol Diagn 2015; 15:1505-16. [DOI: 10.1586/14737159.2015.1091728] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Ramzan Z, Nassri AB, Huerta S. Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer. World J Gastrointest Oncol 2014; 6:194-210. [PMID: 25024812 PMCID: PMC4092337 DOI: 10.4251/wjgo.v6.i7.194] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/19/2014] [Accepted: 05/08/2014] [Indexed: 02/05/2023] Open
Abstract
Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer.
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Gasinska A, Adamczyk A, Niemiec J, Biesaga B, Darasz Z, Skolyszewski J. Gender-related differences in pathological and clinical tumor response based on immunohistochemical proteins expression in rectal cancer patients treated with short course of preoperative radiotherapy. J Gastrointest Surg 2014; 18:1306-18. [PMID: 24756926 DOI: 10.1007/s11605-014-2526-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 04/07/2014] [Indexed: 01/31/2023]
Abstract
BACKGROUND Prognostic value of pretreatment expression of proteins in rectal cancer for early pathological tumor response (pTR), clinical tumor response (CTR) to preoperative radiotherapy (RT), and the potential difference between these parameters depending on patient gender is not established. MATERIAL AND METHODS One hundred eleven patients were treated with short preoperative course of RT (SCRT) with 5 Gy dose per fraction during 5 days, followed by surgery 3 to 53 days (mean, 21 days) later. Expression of CD34, Ki-67, GLUT-1, Ku70, BCL-2, and P53 proteins was assessed immunohistochemically. RESULTS There were 76 men and 35 women. There were 27, 69, and 15 clinical tumor-node-metastasis (cTNM) tumor stages I, II, and III, respectively. Significant differences in Ki-67, GLUT-1, Ku 70, and BCL-2 expressions between male and female tumors were observed for pathological TNM (pTNM) stage and grade. Association between proteins expression and pTNM, pTR, and CTR was analyzed separately for short (≤15 days) and long (>15 days) break between RT and surgery and males and female patients. For SCRT with short break, no protein was significantly related to pTNM; for pTR, higher Ki-67 and lower BCL-2 expression were correlated with pTR. In the male subgroup, BCL-2 overexpression was predictive. For SCRT with long break, none of the proteins was predictive for pTR, but Ki-67, Ku70 (in female subgroup), and BCL-2 expressions were positively correlated with pTNM. BCL-2 overexpression was associated with CTR in the females only. CONCLUSION In SCRT, long break in the treatment should be avoided because correlation between Ki-67, KU70, and BCL-2 expressions and pTNM after RT might indicate tumor progression.
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Affiliation(s)
- Anna Gasinska
- Department of Applied Radiobiology, Oncology Center, Maria Sklodowska-Curie Memorial Institute, Garncarska 11, 31-115, Cracow, Poland,
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Kotti A, Holmqvist A, Albertsson M, Sun XF. SPARCL1 expression increases with preoperative radiation therapy and predicts better survival in rectal cancer patients. Int J Radiat Oncol Biol Phys 2014; 88:1196-202. [PMID: 24661672 DOI: 10.1016/j.ijrobp.2013.12.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 12/20/2013] [Accepted: 12/24/2013] [Indexed: 12/31/2022]
Abstract
PURPOSE The secreted protein acidic and rich in cysteine-like 1 (SPARCL1) is expressed in various normal tissues and many types of cancers. The function of SPARCL1 and its relationship to a patient's prognosis have been studied, whereas its relationship to radiation therapy (RT) is not known. Our aim was to investigate the expression of SPARCL1 in rectal cancer patients who participated in a clinical trial of preoperative RT. METHODS AND MATERIALS The study included 136 rectal cancer patients who were randomized to undergo preoperative RT and surgery (n=63) or surgery alone (n=73). The expression levels of SPARCL1 in normal mucosa (n=29), primary tumor (n=136), and lymph node metastasis (n=35) were determined by immunohistochemistry. RESULTS Tumors with RT had stronger SPARCL1 expression than tumors without RT (P=.003). In the RT group, strong SPARCL1 expression was related to better survival than weak expression in patients with stage III tumors, independent of sex, age, differentiation, and margin status (P=.022; RR = 18.128; 95% confidence interval, 1.512-217.413). No such relationship was found in the non-RT group (P=.224). Further analysis of interactions among SPARCL1 expression, RT, and survival showed statistical significance (P=.024). In patients with metastases who received RT, strong SPARCL1 expression was related to better survival compared to weak expression (P=.041) but not in the non-RT group (P=.569). CONCLUSIONS SPARCL1 expression increases with RT and is related to better prognosis in rectal cancer patients with RT but not in patients without RT. This result may help us to select the patients best suited for preoperative RT.
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Affiliation(s)
- Angeliki Kotti
- Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, County Council of Östergötland, University of Linköping, Linköping, Sweden.
| | - Annica Holmqvist
- Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, County Council of Östergötland, University of Linköping, Linköping, Sweden
| | - Maria Albertsson
- Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, County Council of Östergötland, University of Linköping, Linköping, Sweden
| | - Xiao-Feng Sun
- Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, County Council of Östergötland, University of Linköping, Linköping, Sweden.
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Ding ZY, Zhang H, Adell G, Olsson B, Sun XF. Livin expression is an independent factor in rectal cancer patients with or without preoperative radiotherapy. Radiat Oncol 2013; 8:281. [PMID: 24295240 PMCID: PMC3904757 DOI: 10.1186/1748-717x-8-281] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2013] [Accepted: 11/17/2013] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND This study was aimed to investigate the expression significance of Livin in relation to radiotherapy (RT), clinicopathological and biological factors of rectal cancer patients. METHODS This study included 144 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative radiotherapy. Tissue microarray samples from the excised primary rectal cancers, normal mucosa and lymph node metastases were immunostained with Livin antibody. The proliferation of colon cancer cell lines SW620 and RKO was assayed after Livin knock-down. RESULTS The expression of Livin was significantly increased from adjacent (P = 0.051) or distant (P = 0.028) normal mucosa to primary tumors. 15.4% (2/13) and 39.7% (52/131) patients with Livin-negative and positive tumors died at 180 months after surgery, and the difference tended to be statistically significant (P = 0.091). In multivariate analyses, the difference achieved statistical significance, independent of TNM stage, local and distant recurrence, grade of differentiation, gender, and age (odds ratio = 5.09, 95% CI: 1.01-25.64, P = 0.048). The in vitro study indicated colon cancer cells with Livin knock-down exhibited decreased proliferation compared with controls after RT. CONCLUSIONS The expression of Livin was was independently related to survival in rectal cancer patients, suggesting Livin as a useful prognostic factor for rectal cancer patients.
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Affiliation(s)
| | | | | | | | - Xiao-Feng Sun
- Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Country Council of Östergötland, University of Linköping, Linköping, Sweden.
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15
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Chan J, Kinsella MT, Willis JE, Hu H, Reynolds H, Delaney C, McCulla A, Deharo S, Ahdesmäki M, Allen WL, Johnston PG, Kinsella TJ. A Predictive Genetic Signature for Response to Fluoropyrimidine-Based Neoadjuvant Chemoradiation in Clinical Stage II and III Rectal Cancer. Front Oncol 2013; 3:288. [PMID: 24324931 PMCID: PMC3839295 DOI: 10.3389/fonc.2013.00288] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 11/11/2013] [Indexed: 01/29/2023] Open
Abstract
PURPOSE Pre-operative chemoradiation (CRT) is currently the standard of care for patients with clinical stage II and III rectal cancer but only about 45% of patients achieve tumor downstaging and <20% of patients achieve a pathologic complete response. Better methods to stratify patients according to potential neoadjuvant treatment response are needed. We used microarray analysis to identify a genetic signature that correlates with a pathological complete response (pCR) to neoadjuvant CRT. We performed a gene network analysis to identify potential signaling pathways involved in determining response to neoadjuvant treatment. PATIENTS AND METHODS We identified 31 T3-4 N0-1 rectal cancer patients who were treated with neoadjuvant fluorouracil-based CRT. Eight patients were identified to have achieved a pCR to treatment while 23 patients did not. mRNA expression was analyzed using cDNA microarrays. The correlation between mRNA expression and pCR from pre-treatment tumor biopsies was determined. Gene network analysis was performed for the genes represented by the predictive signature. RESULTS A genetic signature represented by expression levels of the three genes EHBP1, STAT1, and GAPDH was found to correlate with a pCR to neoadjuvant treatment. The difference in expression levels between patients who achieved a pCR and those who did not was greatest for EHBP1. Gene network analysis showed that the three genes can be connected by the gene ubiquitin C (UBC). CONCLUSION This study identifies a 3-gene signature expressed in pre-treatment tumor biopsies that correlates with a pCR to neoadjuvant CRT in patients with clinical stage II and III rectal cancer. These three genes can be connected by the gene UBC, suggesting that ubiquitination is a molecular mechanism involved in determining response to treatment. Validating this genetic signature in a larger number of patients is proposed.
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Affiliation(s)
- Jason Chan
- Department of Radiation Oncology, Brown University, Providence, RI, USA
| | - Michael T. Kinsella
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joseph E. Willis
- Department of Pathology, Case Medical Center, Cleveland, OH, USA
| | - Huankai Hu
- Department of Pathology, Case Medical Center, Cleveland, OH, USA
| | - Harry Reynolds
- Department of Surgery, Case Medical Center, Cleveland, OH, USA
| | - Conor Delaney
- Department of Surgery, Case Medical Center, Cleveland, OH, USA
| | | | | | | | - Wendy Louise Allen
- Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK
| | - Patrick G. Johnston
- Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK
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Ozden SA, Ozyurt H, Ozgen Z, Kilinc O, Oncel M, Gul AE, Karadayi N, Serakinci N, Kan B, Orun O. Prognostic role of sensitive-to-apoptosis gene expression in rectal cancer. World J Gastroenterol 2011; 17:4905-10. [PMID: 22171132 PMCID: PMC3235634 DOI: 10.3748/wjg.v17.i44.4905] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 06/21/2011] [Accepted: 06/28/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between prognosis of rectal cancer treated with chemoradiotherapy (CRT) and expression of sensitive-to-apoptosis (SAG), B-cell lymphoma-extra large (Bcl-XL) and Bcl-2 homologous antagonist/killer (Bak).
METHODS: Real-time quantitative polymerase chain reaction was used to determine the expression of proteins of interest, namely SAG, Bcl-XL, Bak and β-actin, in rectal carcinoma patients who had a follow-up period of 3 years after CRT. Biopsy specimens were excised from the rectal tumor preceding CRT.
RESULTS: SAG, Bcl-XL and Bak proteins showed significant correlations with each other. In multivariate analysis, patients with high vs low SAG expression showed a statistically significant difference in 2-year survival rates: 56% vs 73%, respectively (P = 0.056). On the other hand, there were no significant correlations between the expression levels of all three genes and metastatic rates or tumor responses to CRT. Mean overall survival in the patients with elevated SAG expression was 27.1 mo ± 3.9 mo [95% confidence interval (CI): 19.3-34.9], and in patients with reduced expression, it was 32.1 mo ± 2.5 mo (95% CI: 27.3-36.9). The corresponding values for Bcl-XL were 28.0 mo ± 4.1 mo (95% CI: 19.9-36.1) and 31.7 mo ± 2.9 mo (95% CI: 26.0-37.5), and those for Bak were 29.8 mo ± 3.7 mo (95% CI: 22.5-37.2) and 30.6 mo ± 2.4 mo (95% CI: 25.5-35.0), respectively.
CONCLUSION: Two-year survival rates significantly correlated with low SAG expression, and SAG may be a candidate gene for good prognosis, independent of therapeutic response of different individuals.
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Endosialin expression in relation to clinicopathological and biological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy. BMC Cancer 2011; 11:89. [PMID: 21362178 PMCID: PMC3056834 DOI: 10.1186/1471-2407-11-89] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Accepted: 03/01/2011] [Indexed: 11/10/2022] Open
Abstract
Background The importance of changes in tumour-associated stroma for tumour initiation and progression has been established. Endosialin is expressed in fibroblasts and pericytes of blood vessels in several types of tumours, and is involved in the progression of colorectal cancer. In order to see whether endosialin was related to radiotherapy (RT) response, and clinicopathological and biological variables, we investigated endosialin expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative RT. Methods Endosialin was immunohistochemically examined in normal mucosa, including distant (n = 72) and adjacent (n = 112) normal mucosa, and primary tumours (n = 135). Seventy-three of 135 patients received surgery alone and 62 received additional preoperative RT. Results Endosialin expression in the stroma increased from normal mucosa to tumour (p < 0.0001) both in RT and non-RT group. In the RT group, endosialin expression in the stroma was positively associated with expression of cyclooxygenase-2 (Cox-2) (p = 0.03), p73 (p = 0.01) and phosphates of regenerating liver (PRL) (p = 0.002). Endosialin expression in the tumour cells of both in the RT group (p = 0.01) and the non-RT group (p = 0.06) was observed more often in tumours with an infiltrative growth pattern than in tumours with an expansive growth pattern. In the RT group, endosialin expression in tumour cells was positively related to PRL expression (p = 0.02), whereas in the non-RT group, endosialin expression in tumour cells was positively related to p73 expression (p = 0.01). Conclusions Endosialin expression may be involved in the progression of rectal cancers, and was related to Cox-2, p73 and PRL expression. However, a direct relationship between endosialin expression and RT responses in patients was not found.
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Huerta S, Hrom J, Gao X, Saha D, Anthony T, Reinhart H, Kapur P. Tissue microarray constructs to predict a response to chemoradiation in rectal cancer. Dig Liver Dis 2010; 42:679-84. [PMID: 20227932 DOI: 10.1016/j.dld.2010.02.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Revised: 01/26/2010] [Accepted: 02/02/2010] [Indexed: 12/11/2022]
Abstract
PURPOSE To identify, using tissue microarray (TMA), an immunohistochemical panel predictive of response to ionizing radiation (IR) in rectal cancer. METHODS TMA constructs were prepared from archived stage II/III rectal tumors and matching adjacent mucosa (n=38) from patients treated with pre-operative chemoradiation. Immunohistochemistry (IHC) was performed for MIB, Cyclin E, p21, p27, p53, survivin, Bcl-2, and BAX. Immunoreactivity along with clinical variables was subjected to univariate and forward stepwise logistic regression analyses. RESULTS Pathological complete response (pCR) was 23.9%. The number of positive lymph nodes obtained in the resected specimen was associated with pCR. Immunoreactivity for MIB (Sn 15%, Sp 65%, OR 0.33), p53 (Sn 3%, Sp 84%, OR 0.16), Bcl-2 (Sn 11%, Sp 74%, OR 0.35), and BAX (Sn 92%, Sp 80%, OR 46) was associated with pathological response (all p's<0.001). Forward stepwise logistic regression analysis demonstrated that MIB was an independent predictor of a response to chemoradiation (p=0.001). CONCLUSIONS A combined panel of mediators of apoptosis alone or combined with clinical factors is a feasible approach that can be applied to rectal tumor biopsies to predict a response to chemoradiation. The most sensitive factor was BAX; while MIB independently predicted a response to chemoradiation.
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Affiliation(s)
- Sergio Huerta
- Department of Surgery, University of Texas Southwestern Medical Center, United States.
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Nam TK, Lee JS, Kim HR, Ahn SJ, Song JY, Yoon MS. Molecular prognostic factors in rectal cancer treated by preoperative chemoradiotherapy. Oncol Lett 2010; 1:23-29. [PMID: 22966250 DOI: 10.3892/ol_00000004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Accepted: 09/24/2009] [Indexed: 12/30/2022] Open
Abstract
The present study evaluated the expression of p53, pRb, hMLH1 and MDM2 prior to preoperative chemoradiotherapy (CRT) in patients with rectal cancer, and attempted to determine any correlation with treatment outcome. Forty-five patients with available pretreatment biopsy tissues and who received preoperative CRT were enrolled in this study. Preoperative CRT consisted of a median 50.4 Gy and 2 cycles of concurrent administration of 5-fluorouracil + leucovorin. Surgery was performed approximately seven weeks after CRT. Protein expression in formalin-fixed paraffin-embedded biopsy specimens was assessed by immunohistochemistry. A positive expression of p53, pRb, hMLH1 and MDM2 was found in 40, 46.7, 40 and 66.7% of the tissue specimens, respectively. The 5-year overall (OS), disease-free (DFS) and locoregional recurrence-free survival (LRFS) rates for patients included in the study were 71.3, 66.1 and 60.9%, respectively. p53 expression presented a significantly different OS (positive vs. negative, 45.8 vs. 86.2%; p=0.02). However, the expression of pRb, hMLH1 and MDM2 was not significant for OS. The expression of p53 was a borderline significant prognostic factor for DFS and for LRFS. Age, p53 and MDM2 expression were significant factors in the multivariate analysis performed for OS with 12 covariates, including 8 clinicopathological parameters and 4 proteins. No significant factor affected DFS or LRFS in the multivariate analysis. We suggest that the expression of p53 is a potential marker of survival. Determinations of this protein expression may be useful for selecting candidates from rectal cancer patients for more tailored treatment.
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Affiliation(s)
- Taek-Keun Nam
- Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea
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20
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Holmqvist A, Gao J, Adell G, Carstensen J, Sun XF. The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy. Ann Oncol 2009; 21:512-517. [PMID: 19889620 DOI: 10.1093/annonc/mdp486] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Lymphangiogenesis and angiogenesis are essential for tumour development and progression. The lymphatic vessel density (LVD) and blood vessel density (BVD) and their relationship to outcome have been studied extensively, however the clinical significance of the location of LVD/BVD in tumour is not known. In the present study, the location and degree of LVD/BVD and their relationship to preoperative radiotherapy (RT), clinicopathological, histopathological and biological factors were studied in rectal cancer patients participating in a Swedish clinical trial of preoperative RT. PATIENTS AND METHODS The location and degree of LVD/BVD were analysed in primary tumours (n = 138/140) and in their subgroups of non-RT (n = 74) and RT (n = 64/66). Further, the degree of LVD/BVD was examined in the corresponding distant normal mucosa (n = 35/31) and adjacent normal mucosa (n = 72/91). All sections were immunohistochemically examined by using D2-40 and CD34 antibodies. RESULTS In the whole series of the patients, a higher LVD at the periphery was related to negative p53 expression (P = 0.03) and favourable survival independent of tumour-node-metastasis stage, differentiation and p53 expression (P = 0.03). LVD was increased in p53-negative tumours after RT (P = 0.01). CONCLUSION LVD at the periphery of the tumour was an independent prognostic factor in rectal cancer patients.
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Affiliation(s)
- A Holmqvist
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine.
| | - J Gao
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine
| | - G Adell
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine
| | - J Carstensen
- Department of Health and Society, Faculty of Arts and Sciences, Linköping University, Linköping, Sweden
| | - X-F Sun
- Department of Medical Oncology, Institute of Clinical and Experimental Medicine
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Huerta S, Gao X, Saha D. Mechanisms of resistance to ionizing radiation in rectal cancer. Expert Rev Mol Diagn 2009; 9:469-80. [PMID: 19580431 DOI: 10.1586/erm.09.26] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
While patients with breast cancers are not subjected to the adverse side effects of tamoxifen or trastuzumab if their tumors are negative for estrogen, progesterone or Her-2/Neu, neoadjuvant ionizing radiation with concurrent chemotherapeutic agents is administered almost universally to patients with stage II/III rectal cancers. There is, however, a tremendously wide range of response to this preoperative modality from complete pathological response to continuous tumor growth in patients receiving the same form of treatment. The specific phenotype of the tumor plays a major role in rendering tumor cells survival advantage to the cytotoxic effects of chemoradiation. Pathways such as proliferation, cell cycle, apoptosis and hypoxia have been investigated under a variety of conditions in preirradiated tissues and postirradiated tumors. This article reviews the current evidence available to identify a molecular profile predictive of the best response to ionizing radiation.
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Affiliation(s)
- Sergio Huerta
- Department of Surgery, University of Texas Southwestern Medical Center/Dallas VA Medical Center, 4500 Lancaster Road, Dallas, TX 75216, USA.
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Lööf J, Pfeifer D, Adell G, Sun XF. Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy. Radiother Oncol 2009; 92:215-20. [DOI: 10.1016/j.radonc.2009.06.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2008] [Revised: 05/26/2009] [Accepted: 06/08/2009] [Indexed: 11/28/2022]
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Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells. J Cancer Res Clin Oncol 2009; 135:1583-92. [PMID: 19504123 DOI: 10.1007/s00432-009-0606-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Accepted: 05/18/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE To study expression of proteins previously connected to radiotherapy response in rectal cancer patients, namely, p53, TAp73, DeltaNp73, survivin and PRL-3, after irradiation in colon cancer cells to gain standing ground for further studies of pathways and mechanisms. METHODS Three colon cancer cell lines (KM12C, KM12SM and KM12L4a) with one origin were radiated with gamma-radiation. Radiosensitivity was determined with cell cycle, survival fraction at 5 Gy (SF5) and apoptosis analysis and protein expression by Western blot. RESULTS Following irradiation, KM12C showed no cell cycle arrest, and low SF5 and apoptosis, whilst KM12L4a showed high SF5 and apoptosis. KM12SM had moderate radiosensitivity. After irradiation, the anti-apoptotic DeltaNp73 and mitosis-factor PRL-3 increased in KM12C and the radioresistance factor survivin increased in KM12L4a. CONCLUSIONS The cell lines seem to have evolved different protein patterns regarding the studied proteins and partly therefore developed different resistance mechanisms, less apoptosis for KM12C and continued proliferation for KM12L4a, after gamma-irradiation.
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Martinez CAR, Priolli DG, Cardinalli IA, Pereira JA, Portes AV, Margarido NF. Influência da localização do tumor na expressão tecidual da proteína p53 em doentes com câncer colorretal: estudo de 100 casos. Rev Col Bras Cir 2008. [DOI: 10.1590/s0100-69912008000400006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
OBJETIVO: O objetivo do presente estudo foi verificar, se existem diferenças na expressão tecidual da proteína p53 segundo a localização do tumor em doentes com câncer colorretal. MÉTODO: Foram estudados 100 doentes (54 mulheres), com média de idade de 59,8 anos com adenocarcinoma colorretal. A expressão da proteína p53 foi analisada por imunoistoquímica, com anticorpo monoclonal anti-p53 pela técnica da estreptavidina-biotina-peroxidase. A expressão tecidual da proteína p53 foi relacionada às variáveis: gênero, idade, grau histológico, tipo histológico, tamanho do tumor, estadiamento TNM, profundidade de invasão da parede intestinal, comprometimento linfonodal, invasão angiolinfática, localização do tumor no intestino grosso em relação à flexura esplênica. Na avaliação estatística da relação entre expressão da proteína p53 e as variáveis consideradas empregou-se o teste qui-quadrado, estabelecendo-se nível de significância de 5% (p<0,05). RESULTADOS: A proteína p53 foi positiva em 77% dos casos. Com relação as diferentes variáveis consideradas verificou-se maior tendência de expressão da proteína mutante quando se considerava a idade (p=0,001), grau histológico (p=0,001), tipo histológico (p=0,001), estádios tardios da classificação TNM (p=0,001), maior profundidade de invasão na parede cólica (p=0,001), comprometimento linfonodal (p=0,001), invasão angiolinfática (p=0,02), localização após a flexura esplênica (p=0,001), não se encontrando relação com gênero (p=0,49) e tamanho do tumor (p=0,08). CONCLUSÃO: Os resultados do presente estudo permitem concluir que a expressão da proteína p53 mutante ocorre com maior freqüência nos tumores localizados a partir da flexura esplênica.
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High MUC2 immunohistochemical expression is a predictor of poor response to preoperative radiochemotherapy (RCT) in rectal adenocarcinoma. Appl Immunohistochem Mol Morphol 2008; 16:227-31. [PMID: 18301248 DOI: 10.1097/pai.0b013e3181545944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The purpose of this study is to establish if mucoid differentiation is associated with responsiveness to preoperative radiochemotherapy (RCT) in rectal adenocarcinomas. Thirty-two patients with rectal adenocarcinomas were preoperatively treated with 44 to 46 Gy in 22 to 23 fractions and with 5-fluorouracil (200 to 225 mg/m) before surgery. Mucoid differentiation was searched for both in pre-RCT biopsies with anti-MUC2 antiserum and in postoperative specimens. To evaluate the responsiveness to preoperative RCT, a regression grading was used (grades 0 to 4). Statistical analysis showed a significant negative correlation between immunohistochemical expression of MUC2 in pre-RCT biopsies and regression grade in postoperative specimens (r=-0.529; P=0.002). A significant cutoff value of 60% of MUC2 positive neoplastic cells in pre-RCT biopsies was observed (P=0.018): 13 cases with more than 60% exhibited a poor response to RCT (grade 0 in 5/13, grade 1 in 4/13, grade 2 in 4/13), whereas 19 cases with less than 60% showed a better response to RCT (grade 1 in 6/19, grade 2 in 9/19, grade 3 in 3/19, grade 4 in 1/19).
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Abstract
Patients with stage II and III rectal cancer benefit from a multidisciplinary approach to treatment. Studies of postoperative adjuvant therapy consistently demonstrate decreases in locoregional recurrence with the use of radiation therapy. The use of postoperative chemotherapy results in improved disease-free survival and overall survival in certain studies. Preoperative radiation therapy decreases locoregional recurrence and in one study demonstrated an improvement in survival. The addition of chemotherapy to preoperative radiation results in improved locoregional control, but not survival. Preoperative chemoradiation is the standard of care for patients with clinical stage II and III rectal cancer in the United States due to improved local recurrence, acute and late toxicity, and sphincter preservation compared with postoperative chemoradiation. Promising approaches include the incorporation of new chemotherapeutic and biologic agents into chemoradiation and adjuvant chemotherapy regimens; new radiation techniques, such as the use of intraoperative radiation therapy and an accelerated concomitant radiation boost; and gene and protein expression profiling, to better predict response to treatment and prognosis.
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Affiliation(s)
- Smitha S. Krishnamurthi
- Department of Medicine, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
- Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Yuji Seo
- Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Timothy J. Kinsella
- Case Comprehensive Cancer Center, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
- Department of Radiation Oncology, University Hospitals Case Medical Center and Case Western Reserve University School of Medicine, Cleveland, Ohio
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Zhang ZY, Zhao ZR, Adell G, Jarlsfelt I, Cui YX, Kayed H, Kleeff J, Wang MW, Sun XF. Expression of MAC30 in rectal cancers with or without preoperative radiotherapy. Oncology 2007; 71:259-65. [PMID: 17657172 DOI: 10.1159/000106449] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2007] [Accepted: 05/26/2007] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Meningioma-associated protein (MAC30) is overexpressed in several types of cancers, but its therapeutic implication in the patients has not been studied. We examined the relationship of MAC30 with clinicopathological and biological factors in rectal cancer patients with or without radiotherapy (RT). METHODS MAC30 was immunohistochemically examined in 75 distant and 91 adjacent normal mucosa specimens, 132 primary tumours and 39 lymph node metastases from rectal cancer patients participating in a clinical trial of preoperative RT. RESULTS In the RT group, MAC30 was or tended to be positively correlated with infiltrated growth pattern (p = 0.02), PRL (phosphatase of regenerating liver, p = 0.01) and Ki-67 expression (p = 0.06). MAC30 at the invasive margin of the metastasis was related to poor survival (p = 0.02) in the whole group of patients. MAC30 in primary tumours was not related to recurrence and survival in the non-RT or RT group. CONCLUSIONS MAC30 expression in metastasis was an indicator for poor survival. After RT, MAC30 seemed to be more related to aggressive morphological and biological factors; however, we did not find direct evidence that MAC30 expression was related to the outcome of patients with or without RT.
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Affiliation(s)
- Zhi-Yong Zhang
- Department of Oncology, Institute of Biomedicine and Surgery, Linkoping University, Linkoping, Sweden
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Wong RKS, Tandan V, De Silva S, Figueredo A. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev 2007:CD002102. [PMID: 17443515 DOI: 10.1002/14651858.cd002102.pub2] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Preoperative radiotherapy (PRT) has become part of standard practice offered to improve treatment outcomes in patients with rectal cancer. OBJECTIVES To determine if PRT improves outcome for patients with localized resectable rectal cancer and how it compared with other adjuvant or neoadjuvant strategies. SEARCH STRATEGY A computerized search was performed December 2006 on MEDLINE (from 1966 to December 2006) and the Cochrane Central Register of Controlled Trials (CENTRAL), conference proceedings, using MeSH and textwords where appropriate to identify randomized trials in PRT and rectal cancer. In addition, MetaRegister of Clinical Trials was searched for ongoing trials. SELECTION CRITERIA Randomized trials with a PRT arm versus surgery alone, or other neoadjuvant or adjuvant (NA/A) strategies, targeted patients with localized rectal cancer planned for radical surgery were included. DATA COLLECTION AND ANALYSIS Trials were selected, data extracted and quality assessed by 2 authors. Quality was assessed using a 14 point checklist. Summary statistics included Hazard ratios and variances (for the outcomes: overall (OA) mortality, cause specific (CS) mortality, any recurrence and local recurrences (LR)) and Odds Ratio (OR) for other outcomes. Potential sources of heterogeneity hypothesized a priori included study quality, biological effective dose (BED), radiotherapy RT technique, and total mesorectal excision (TME) surgery. MAIN RESULTS Nineteen trials compared PRT versus surgery alone. Overall (OA) mortality was marginally improved HR 0.93 [95% CI -0.87-1](absolute difference is 2% if the expected survival rate is 60%). Local recurrence (LR) was improved but the magnitude of benefit was heterogeneous across trials. Sensitivity analyses suggested greater benefits in patients treated with BED>30Gy(10) and multiple field RT techniques. There was significantly more pelvic or perineal wound infection, late rectal and sexual dysfunction. Nine trials compared PRT vs. other NA/A. Available evidence did not support an OA mortality or sphincter preserving benefit with the use of combined chemoradiotherapy (CRT) or selective postoperative RT. CRT provides incremental benefit for local control compared with PRT, which was independent of the timing of the CT. There was no significant difference in outcome for different intervals between RT and surgery (2 vs. 8 wk). Dose escalation with endocavitary boost showed significant effect on sphincter preservation. AUTHORS' CONCLUSIONS Optimal PRT improves LR, OA mortality, but no increase in sphincter sparing procedure. CRT further increases local control. If the objective is to increase the incidence of sphincter sparing surgery, endocavitary boost showed the most promise. Strategies with the potential to improve outcomes, especially OAS and sphincter sparing while reducing acute and late toxicities (rectal and sexual function) are needed to guide future strategy designs.
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Affiliation(s)
- R K S Wong
- University Health Hetwork, University of Toronto, Radiation Medicine Program, Princess Margaret Hospital, 610 University Avenue, Toronto, Canada, M5G 2M9.
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Kim NK, Baik SH, Min BS, Pyo HR, Choi YJ, Kim H, Seong J, Keum KC, Rha SY, Chung HC. A comparative study of volumetric analysis, histopathologic downstaging, and tumor regression grade in evaluating tumor response in locally advanced rectal cancer following preoperative chemoradiation. Int J Radiat Oncol Biol Phys 2006; 67:204-10. [PMID: 17084555 DOI: 10.1016/j.ijrobp.2006.08.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2006] [Revised: 08/04/2006] [Accepted: 08/15/2006] [Indexed: 01/20/2023]
Abstract
PURPOSE To compare tumor volume reduction rate, histopathologic downstaging, and tumor regression grade (TRG) among tumor responses in rectal cancer after preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS Between 2002 and 2004, 30 patients with locally advanced rectal cancer underwent preoperative CRT, followed by surgical resection. Magnetic resonance volumetry was performed before and after CRT. Histopathologic tumor staging and tumor regression were reviewed. We compared pre- and post-CRT tumor volume and percent of volume reduction, according to histopathologic downstaging and TRG. RESULTS The tumor volume reduction rates ranged from 14.6% to 100%. Mean pre- and post-CRT tumor volumes were significantly smaller in patients who showed T downstaging than in those who did not (p = 0.040, 0.014). The mean tumor volume reduction was 66.4% vs. 55.2% (p = 0.361). However, the mean pre- and post-CRT tumor volume and mean tumor volume reduction rate between patients who showed N downstaging and those who did not were not statistically different (p = 0.176, 0.767, and 0.899). With respect to TRG, the mean pre- and post-CRT tumor volumes were not statistically significant (p = 0.108, 0.708, and 0.120). CONCLUSION Tumor volume reduction rate does not correlate with histopathologic downstaging and TRG. It might be hazardous to evaluate tumor response with respect to volume reduction and to select the surgical method on this basis.
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Affiliation(s)
- Nam Kyu Kim
- Colorectal Cancer Clinic Severance Hospital, Yonsei University Medical Center, Seoul, Republic of Korea.
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Pfeifer D, Gao J, Adell G, Sun XF. Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy. Int J Radiat Oncol Biol Phys 2006; 65:1143-8. [PMID: 16750334 DOI: 10.1016/j.ijrobp.2006.02.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2005] [Revised: 02/08/2006] [Accepted: 02/09/2006] [Indexed: 11/26/2022]
Abstract
PURPOSE To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers. METHODS AND MATERIALS p73 was immunohistochemically examined on biopsies (unirradiated, n=102), distant (from the large bowel, n=82), and adjacent (adjacent to primary tumor, n=89) normal mucosa samples, primary tumors (n=131), and lymph node metastasis (n=32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT. RESULTS Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (p<or=0.0001). Nuclear (p=0.02) and cytoplasmic (p=0.003) p73 was higher in irradiated distant mucosa samples than in unirradiated ones, and nuclear p73 tended to be increased in irradiated primary tumors compared with unirradiated ones (p=0.06). p73 was positively related to cyclooxygenase-2 expression in irradiated tumors (p=0.03). p73-negative tumors tended to have a lower local recurrence after RT compared with unirradiated cases (p=0.06). CONCLUSIONS Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT.
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Affiliation(s)
- Daniella Pfeifer
- Department of Oncology, Institute of Biomedicine and Surgery, Linköping University, Linköping, Sweden
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31
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Pachkoria K, Zhang H, Adell G, Jarlsfelt I, Sun XF. Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy. Int J Radiat Oncol Biol Phys 2005; 63:739-44. [PMID: 16199309 DOI: 10.1016/j.ijrobp.2005.02.031] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2004] [Revised: 02/07/2005] [Accepted: 02/24/2005] [Indexed: 10/25/2022]
Abstract
PURPOSE Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. METHODS AND MATERIALS Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. RESULTS Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p < or = 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. CONCLUSION Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.
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Affiliation(s)
- Ketevan Pachkoria
- Department of Oncology, Institute of Biomedicine and Surgery, University of Linköping, Linköping, Sweden
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Ince WL, Jubb AM, Holden SN, Holmgren EB, Tobin P, Sridhar M, Hurwitz HI, Kabbinavar F, Novotny WF, Hillan KJ, Koeppen H. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst 2005; 97:981-9. [PMID: 15998951 DOI: 10.1093/jnci/dji174] [Citation(s) in RCA: 253] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin (IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab. METHODS Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53. Nuclear P53 expression was determined by immunohistochemistry. Hazard ratios and 95% confidence intervals (CI) for overall survival were estimated using Cox regression analysis. RESULTS In all biomarker subgroups, estimated hazard ratios for risk of death were less than 1 for bevacizumab-treated patients as compared with those for placebo-treated patients. Mutations in k-ras and/or b-raf were observed in 88 of 213 patients (41%). Hazard ratios for death among patients with tumors with wild-type k-ras/b-raf status, as compared with those of patients with mutations in one or both genes, were 0.51 (95% CI = 0.28 to 0.95) among those treated with IFL plus bevacizumab and 0.66 (95% CI = 0.37 to 1.18) among those treated with IFL plus placebo. Mutations in p53 were found in 139 of 205 patients (68%), and P53 was overexpressed in 191 of 266 patients (72%); neither p53 mutation nor P53 overexpression was statistically significantly associated with survival. CONCLUSIONS We did not find a statistically significant relationship between mutations of k-ras, b-raf, or p53 and the increase in median survival associated with the addition of bevacizumab to IFL in metastatic colorectal cancer.
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Affiliation(s)
- William L Ince
- Department of Pathology, Genentech Inc., San Francisco, CA, USA
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Lebe B, Sarioğlu S, Sökmen S, Ellidokuz H, Füzün M, Küpelioğlu A. The clinical significance of p53, p21, and p27 expressions in rectal carcinoma. Appl Immunohistochem Mol Morphol 2005; 13:38-44. [PMID: 15722792 DOI: 10.1097/00129039-200503000-00007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Many checkpoint proteins that are involved in the control of the cell cycle and apoptosis have been investigated, but only a few studies have evaluated the prognostic significance of multiple factors only in rectal carcinomas. The aim of this study was to determine the role of p53, p21, and p27 protein expression as a prognostic factor in rectal carcinomas. Formalin-fixed, paraffin-embedded tissue blocks from 45 rectal adenocarcinomas with appropriate clinical and prognostic data were examined. The standard streptavidin-biotin immunoperoxidase method was used for immunostaining with p53 protein, p21 WAF1/Cip1 protein, and p27 Kip1 protein. The extent of positive p53, p21, and p27 staining was graded semiquantitatively. The clinicopathologic and prognostic features were statistically analyzed. No significant association was found between p53 status and p21 or p27 protein expression (chi2 test, P=0.42 and P=0.18 respectively). There was no correlation between the expressions of p53, p21, and p27, and conventional clinicopathologic features. The mean time interval to recurrence was 25.7+/-24.7 months (range, 0-54 months). p53, p21, and p27 expression was not associated significantly with recurrence and distant metastasis. However, a significant relationship was found between the expression of p27 protein and hepatic metastasis (independent samples t-test, P=0.007). The authors concluded that p53, p27, and p21 protein expression was not related to the clinicopathologic parameters, tumor aggressiveness, metastatic potential, and survival in rectal carcinomas. Further studies are needed to evaluate the predictors of outcome in rectal cancer, considering a variety of prognosticators.
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Affiliation(s)
- Banu Lebe
- Department of Pathology, Dokuz Eylul University, School of Medicine, Izmir, Turkey.
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Knutsen A, Adell G, Sun XF. Survivin expression is an independent prognostic factor in rectal cancer patients with and without preoperative radiotherapy. Int J Radiat Oncol Biol Phys 2004; 60:149-55. [PMID: 15337550 DOI: 10.1016/j.ijrobp.2004.02.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2003] [Revised: 02/02/2004] [Accepted: 02/03/2004] [Indexed: 01/26/2023]
Abstract
PURPOSE Survivin, as an inhibitor of apoptosis, is undetectable in normal tissues but expressed in tumors. Survivin expression in rectal cancer patients who have undergone preoperative radiotherapy (RT) alone has not been studied. We analyzed the relationships of survivin expression to RT, clinicopathologic variables, apoptosis, and p53 expression in rectal cancer patients who participated in a trial of preoperative RT. METHODS AND MATERIALS Survivin was immunohistochemically examined in 98 rectal tumors (74 had adjacent normal mucosa). Of 98 patients, 57 underwent surgery alone and 41 underwent RT before surgery. RESULTS Survivin positivity was related to worse survival, independent of Dukes' stage, local and distant recurrence, differentiation, gender, age, apoptosis, and p53 expression (p = 0.02). Survivin was not associated with survival in the patients without (p = 0.08) or with (p = 0.19) RT. After RT, survivin tended to be increased in adjacent normal mucosa (p = 0.057) but not in tumors (p = 0.71). CONCLUSION Survivin was independently related to survival in rectal cancer patients who participated in a trial of preoperative RT, but not in either treatment group (surgery alone or surgery plus RT). Whether the effect of survivin on tumors is associated with RT and further related to patient survival needs to be investigated in a larger number of patients.
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Affiliation(s)
- Annica Knutsen
- Department of Oncology, Institute of Biomedicine and Surgery, Linköping University, S-58185 Linköping, Sweden
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Günther K, Dimmler A, Rödel F, Reulbach U, Merkel S, Bittorf BR, Matzel KE, Papadopoulos T, Hohenberger W, Sauer R, Rödel C. P27 does not predict histopathological response to radiochemotherapy in rectal cancer. J Surg Res 2003; 113:179-88. [PMID: 12957127 DOI: 10.1016/s0022-4804(03)00049-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Tumor response to radiochemotherapy (RCT) varies considerably, even among patients treated in accordance with the same protocol. The aim of the present study was to test the predictive value of the cell-cycle inhibitor p27kip1 with regard to neoadjuvant RCT response in rectal cancer. MATERIALS AND METHODS P27kip1 was evaluated by immunohistochemistry in pretreatment biopsy material obtained from 42 patients with rectal cancer treated uniformly in accordance with an identical prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Four expression patterns (staining intensity [-,+,++,+++] and the percentage of positive cells, evaluated separately for nuclei and cytoplasm) of p27kip1 were investigated for correlation with tumor response, which was assessed in the resected surgical specimen using a histopathological five-point grading system. Additionally, p27(kip1) expression was investigated for correlation with several pathological features, overall survival, and disease-free survival. RESULTS p27kip1 expression was as follows: nuclear intensity: -: 8, +: 19, ++: 11, +++: 4 cases, median percentage of positive cells: 18.75%; cytoplasmic intensity: -: 0, +: 25, ++: 12, +++: 3 cases, median percentage of positive cells: 70%. Histopathological tumor regression was acceptable in 30 patients (3 complete; 27 good) and inadequate in 12 patients (7 moderate; 5 minimal). No tumor failed to show some regression. No significant correlation was found between any of the p27kip1 expression patterns and RCT response, tumor differentiation (low grade versus high grade), cT- and ypT-category, UICC stage, overall survival, and disease-free survival. CONCLUSIONS p27kip1 cannot aid the individualization of multimodal treatment strategies in rectal cancer, nor can it serve as a predictor of survival.
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Affiliation(s)
- Klaus Günther
- Institute of Pathology, University of Erlangen, Erlangen, Germany.
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Magné N, Fischel JL, Formento P, Etienne MC, Dubreuil A, Marcié S, Lagrange JL, Milano G. Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status. Oncology 2003; 64:280-7. [PMID: 12697970 DOI: 10.1159/000069308] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVES AND METHODS The association oxaliplatin (OXA)-5-fluorouracil/folinic acid (FUFA) is currently a standard first-line treatment for advanced colorectal cancer. The main objective of this experimental study was to examine the cytotoxic effects resulting from the addition of ionizing radiation (Rgamma) to the combination OXA-FUFA on 2 human colon cancer cell lines (SW403, p53 wild type and WiDr, p53 mutated). A clinically relevant drug sequence was used consisting in OXA during 2 h followed by FUFA over 24 h. The impact of the position of radiation (1 and 4 Gy) was tested: radiation 2 h before drug application, in the middle of the drug application or 24 h after the drug application. RESULTS Both cell lines exhibited similar dose response curves to Rgamma alone, WiDr being more radio-sensitive than SW403 (IC50: 4.8 Gy and 7 Gy, respectively). The effects of Rgamma-drug combinations were assessed using a conventional isobolographic method and by computing a potentiation factor (F) defined as the ratio of IC50 drug combinations/IC50 drug combinations combined with Rgamma. The results from both calculation methods concurred: the combination of OXA-FUFA with Rgamma led to additive-antagonistic effects for the p53 mutated cell line (WiDr), whatever the sequence. In contrast, for the p53 wild type cell line (SW403), additive-synergistic effects were observed with, in this case, an optimal position for Rgamma occurring when applied before or at mid-drug application. CONCLUSIONS These results could be taken into consideration for an optimal design of clinical protocols associating Rgamma and OXA-FUFA.
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Affiliation(s)
- Nicolas Magné
- Oncopharmacology Laboratory, Centre Antoine Lacassagne, 33 Avenue de Valombrose, F-06189 Nice Cedex 2, France
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Díez M, Ramos P, Medrano MJ, Mugüerza JM, Villeta R, Lozano O, Escribano J, Noguerales F, Ruíz A, Granell J. Preoperatively irradiated rectal carcinoma: analysis of the histopathologic response and predictive value of proliferating cell nuclear antigen immunostaining. Oncology 2003; 64:213-9. [PMID: 12697960 DOI: 10.1159/000069307] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVES To investigate the relationship between the histopathologic effects of preoperative chemoradiotherapy in rectal cancer and the proteins, proliferating cell nuclear antigen (PCNA) and p53. METHODS Samples from 73 tumors were examined. The histopathologic effects observed in the resected specimens induced by preoperative chemoradiotherapy were correlated with the inmunohistochemical expression of PCNA and p53 in biopsies obtained by rectoscopy before chemoradiotherapy. RESULTS Thirty-five tumors showed a high PCNA index (48%). Nuclear accumulation of p53 protein was detected in 53 tumors (72%). Specimens were assigned one of four grades based on the amount of residual viable tumor. Three neoplasms (4%) showed complete regression; 8 other carcinomas (11%) showed only small numbers of tumor cells scattered within the field of stromal reaction. In these cases, it was considered that the tumor had responded significantly to radiotherapy. Tumors with a high PCNA index responded to chemoradiotherapy more frequently (8/35; 72%) than tumors with a low index (3/38; 43%) (p = 0.07). p53-negative tumors responded more frequently (4/20; 20%) than positive tumors (7/53; 13.2%) (p = 0.50). When pathologic and immunohistochemical characteristics of the tumors were included in a logistic regression model, only high PCNA index (odds ratio 5.35, 95% confidence interval 1.07-26.7) (p = 0.04) was significantly associated with the histologic response to preoperative chemoradiotherapy. CONCLUSION High proliferative activity of rectal cancer, as determined by PCNA immunostaining, is predictive of the response to preoperative chemoradiotherapy.
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Affiliation(s)
- M Díez
- Department of Surgery and Morphological Sciences, General Surgery, Hospital Príncipe de Asturias, University of Alcalá de Henares, E-28805 Madrid, Spain.
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Araujo SEA, da Silva eSousa AH, de Campos FGCM, Habr-Gama A, Dumarco RB, Caravatto PPDP, Nahas SC, da Silva J, Kiss DR, Gama-Rodrigues JJ. Conventional approach x laparoscopic abdominoperineal resection for rectal cancer treatment after neoadjuvant chemoradiation: results of a prospective randomized trial. REVISTA DO HOSPITAL DAS CLINICAS 2003; 58:133-40. [PMID: 12894309 DOI: 10.1590/s0041-87812003000300002] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The aims of this study were to evaluate the safety and efficacy of laparoscopic abdominoperineal resection compared to conventional approach for surgical treatment of patients with distal rectal cancer presenting with incomplete response after chemoradiation. METHOD Twenty eight patients with distal rectal adenocarcinoma were randomized to undergo surgical treatment by laparoscopic abdominoperineal resection or conventional approach and evaluated prospectively. Thirteen underwent laparoscopic abdominoperineal resection and 15 conventional approach. RESULTS There was no significant difference (p<0,05) between the two studied groups regarding: gender, age, body mass index, patients with previous abdominal surgeries, intra and post operative complications, need for blood transfusion, hospital stay after surgery, length of resected segment and pathological staging. Mean operation time was 228 minutes for the laparoscopic abdominoperineal resection versus 284 minutes for the conventional approach (p=0.04). Mean anesthesia duration was shorter (p=0.03) for laparoscopic abdominoperineal resection when compared to conventional approach : 304 and 362 minutes, respectively. There was no need for conversion to open approach in this series. After a mean follow-up of 47.2 months and with the exclusion of two patients in the conventional abdominoperineal resection who presented with unsuspected synchronic metastasis during surgery, local recurrence was observed in two patients in the conventional group and in none in the laparoscopic group. CONCLUSIONS We conclude that laparoscopic abdominoperineal resection is feasible, similar to conventional approach concerning surgery duration, intra operative morbidity, blood requirements and post operative morbidity. Larger number of cases and an extended follow-up are required to adequate evaluation of oncological results for patients undergoing laparoscopic abdominoperineal resection after chemoradiation for radical treatment of distal rectal cancer.
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Affiliation(s)
- Sergio Eduardo Alonso Araujo
- Digestive Surgery Department, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
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Reerink O, Verschueren RCJ, Szabo BG, Hospers GAP, Mulder NH. A favourable pathological stage after neoadjuvant radiochemotherapy in patients with initially irresectable rectal cancer correlates with a favourable prognosis. Eur J Cancer 2003; 39:192-5. [PMID: 12509951 DOI: 10.1016/s0959-8049(02)00557-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Initial treatments of locally advanced rectal cancers focus on local control, as local relapse of a rectal cancer is correlated with a high morbidity and mortality. We studied the effect of neoadjuvant radiochemotherapy on advanced rectal cancer patients in relation to downstaging, local relapse and survival. Post-treatment pathological staging, local relapse and survival were analysed in 66 patients from a single institution. 43 patients had irresectable cancer as determined by laparatomy (n=42) or rectal examination (n=1). These 43 patients received 45-56 Gy preoperatively with 5-fluorouracil (5-FU) and leucovorin (350/20 mg/m(2)x5 day (d)) in weeks 1 and 5 during the radiation therapy. 23 patients had primary resectable tumours with a T1-2 stage. Of the initially irresectable tumours 79% became macroscopically resectable, in 74% a R0 resection was performed. In 6 of 34 (18%) surgical specimens, no tumour was found (pT0), 7 patients had small tumour remnants (pT1-2). In these pT0-2 tumours, no local relapses occurred (observation period of median 4.5 years, range 18-87 months). In the 21 patients with pT3-4 tumours 3 local relapses were seen. In the 23 patients with primary resectable T1-2 tumours the relapse rate was 4%. Downstaging of an initially irresectable rectal tumour to pT2 or less results in a local relapse rate and overall survival that correspond with the rates in primary resectable cancer with the same T classification.
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Affiliation(s)
- O Reerink
- Department of Radiation Oncology, University Hospital Groningen, 9700 RB, Groningen, The Netherlands
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Grann A, Zauber P. Is there a predictive value for molecular markers in predicting response to radiation and chemotherapy in rectal cancer? Int J Radiat Oncol Biol Phys 2002; 54:1286-7. [PMID: 12419459 DOI: 10.1016/s0360-3016(02)03024-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Rebischung C, Gérard JP, Gayet J, Thomas G, Hamelin R, Laurent-Puig P. Prognostic value of P53 mutations in rectal carcinoma. Int J Cancer 2002; 100:131-5. [PMID: 12115559 DOI: 10.1002/ijc.10480] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The influence of p53 mutations on the response to ionizing radiation and survival was retrospectively evaluated in patients treated with preoperative radiotherapy for rectal carcinoma. From 1989 to 1991, 86 rectal cancer patients treated by preoperative radiotherapy were included in this series. For all patients, endorectal sonography (to define ultrasonography TNM [uTNM]) was performed before treatment; 19 patients were classified as stage 1, 27 as stage 2 and 40 as stage 3. Response to radiotherapy (39 Gy in 13 fractions delivered in 17 days) was assessed by comparing the uT and the T obtained by histologic examination of the resected specimen (TNM classification). A rectal cancer biopsy was performed before treatment and enabled the search for p53 mutations by denaturing gradient gel electrophoresis (DGGE) and sequencing. The status of the p53 gene was correlated with the response to radiotherapy and survival. Forty-nine percent of the tumors presented abnormal DGGE profiles. The prevalence of p53 mutations was significantly higher in patients who did not respond to radiotherapy (63%) than in those who did respond (34%) (p < 0.01). Presence of a p53 mutation was associated with significantly shorter 5-year survival compared to patients without mutations (p < 0.02). In a multivariate analysis, p53 mutation status remained a prognostic factor independent of tumor posttreatment staging (p < 0.05). p53 status is an independent prognostic factor of response to radiotherapy and survival in rectal carcinoma.
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Fernebro E, Dictor M, Bendahl PO, Fernö M, Nilbert M. Evaluation of the tissue microarray technique for immunohistochemical analysis in rectal cancer. Arch Pathol Lab Med 2002; 126:702-5. [PMID: 12033959 DOI: 10.5858/2002-126-0702-eottmt] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Immunohistochemical staining for tumor-associated proteins is widely used for the identification of novel prognostic markers. Recently, a tissue-conserving, high-throughput technique, tissue microarray, has been introduced. This technique uses 0.6-mm tissue core biopsy specimens, 500 to 1000 of which are brought into a new paraffin array block, which can be sectioned up to 100 times. METHODS We evaluated the tissue microarray technique for immunohistochemical analysis in 20 rectal cancers. Immunohistochemical staining was performed for the proliferation marker Ki-67 and the tumor suppressor protein p53 in whole tissue sections and in tissue core biopsy specimens. RESULTS The whole tissue sections were assessed by counting all cells in 10 high-power fields (x40), which resulted in a mean fraction of Ki-67-expressing tumor cells of 0.81 (range, 0.54-1.0). p53 expression assessed in whole tissue sections showed nuclear staining in 15 (75%) of 20 rectal carcinomas. For the tissue microarray technique, a median of 3 (range, 3-5) 0.6-mm tissue core biopsy specimens were studied from each of the 20 tumor specimens. The tissue microarray method gave a mean Ki-67 expression of 0.85 (range, 0.50-1.0) in tumor cell nuclei and showed p53 protein expression in the same 15 of 20 tumors as in the whole tissue sections. CONCLUSION We conclude that the tissue microarray technique for immunohistochemical staining in rectal cancer yields staining of good quality and expression data for Ki-67 and p53 comparable to those obtained with whole tissue staining. The feasibility of tissue microarray thus enables time- and tissue-preserving studies of multiple markers in large tumor series.
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Affiliation(s)
- Eva Fernebro
- Department of Oncology, University Hospital, Lund, Sweden.
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Kandioler D, Zwrtek R, Ludwig C, Janschek E, Ploner M, Hofbauer F, Kührer I, Kappel S, Wrba F, Horvath M, Karner J, Renner K, Bergmann M, Karner-Hanusch J, Pötter R, Jakesz R, Teleky B, Herbst F. TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer. Ann Surg 2002; 235:493-8. [PMID: 11923604 PMCID: PMC1422463 DOI: 10.1097/00000658-200204000-00006] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To evaluate and compare the predictive power of p53 gene analysis versus p53 immunohistochemical staining in terms of response to preoperative short-term radiotherapy using 25 Gy in operable rectal cancer. SUMMARY BACKGROUND DATA Recent studies show that p53 may be a determinant of radiosensitivity being required for induction of apoptosis in case of radiation-induced DNA damage. METHODS Preirradiation biopsy samples of 64 patients with rectal carcinoma were analyzed. Genetic alterations of the p53 gene were detected by complete direct sequencing of exons 2 to 10. Expression of the nuclear phosphoprotein p53 was assessed by immunohistochemical staining. Results were correlated with histopathology of resected specimens and follow-up data, respectively. RESULTS Mutations of the p53 gene were present in 45% of tumors. Patients with a normal p53 gene had a significant survival advantage. Comparing pre- and postradiotherapy T category, a reduction was seen in patients with normal p53 genotype only. A mutant p53 genotype was highly specific in indicating stable disease concerning T category after irradiation. Protein overexpression was detected in 61%. Overexpression of the p53 protein was not related to survival or response. The concordance between immunohistochemistry and sequencing was only 0.51. CONCLUSIONS The authors show that downstaging after short-term radiation may occur but is seen in tumors with normal p53 gene only. Moreover, p53 genotype but not p53 immunohistochemistry is predictive for response to preoperative short-term radiotherapy and patient survival.
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Abstract
The most common neo-adjuvant therapy for rectal cancer is chemotherapy and concurrent radiation therapy. In general, it is delivered pre-operatively for patients with clinical evidence of T(3-4) disease or post-operatively in patients who have undergone surgery and have T(3) and/or N(1-2) disease. This chapter reviews the rationale and results for neo-adjuvant therapy, the selection process for pre-operative versus post-operative treatment, and new approaches and controversies.
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Affiliation(s)
- Bruce D Minsky
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, Cornell University, USA
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Cascinu S, Graziano F, Catalano V, Staccioli MP, Rossi MC, Baldelli AM, Barni S, Brenna A, Secondino S, Muretto P, Catalano G. An analysis of p53, BAX and vascular endothelial growth factor expression in node-positive rectal cancer. Relationships with tumour recurrence and event-free survival of patients treated with adjuvant chemoradiation. Br J Cancer 2002; 86:744-9. [PMID: 11875737 PMCID: PMC2375295 DOI: 10.1038/sj.bjc.6600155] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2001] [Revised: 12/12/2001] [Accepted: 12/14/2001] [Indexed: 02/03/2023] Open
Abstract
Tumours of patients with node-positive rectal cancer were studied by immunohistochemistry for p53, BAX and vascular endothelial growth factor expressions. Results were correlated to the relapse rate, the pattern of relapse and the event-free survival after radical surgery and adjuvant chemoradiation. After a median follow-up of 60 months, 39 patients remained disease-free and 40 patients relapsed (18 local relapses and 22 distant metastases). The majority of disease-free patients showed p53 negative and vascular endothelial growth factor negative tumours. Local relapses occurred more frequently in patients with p53 overexpressing tumours (P<0.01), while distant metastases were in patients with vascular endothelial growth factor positive tumours (P<0.003). Patients with p53 negative or vascular endothelial growth factor negative tumours showed better event-free survival than patients with p53 positive or vascular endothelial growth factor positive tumours. BAX analysis did not show any association with patients' outcome and it was unrelated to the p53 status. Adjuvant treatment strategies for node-positive rectal cancer may be improved by identifying categories of high-risk patients. In this study, vascular endothelial growth factor and p53 expressions correlated with recurrent disease, pattern of relapse and poor event-free survival.
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Affiliation(s)
- S Cascinu
- Division of Medical Oncology, Hospital of Parma, Italy.
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46
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Marijnen CAM, Kapiteijn E, Nagtegaal ID, Mulder-Stapel AA, van de Velde CJH, Schrier PI, Peltenburg LTC, van Krieken JHJM. p53 expression in human rectal tissue after radiotherapy: upregulation in normal mucosa versus functional loss in rectal carcinomas. Int J Radiat Oncol Biol Phys 2002; 52:720-8. [PMID: 11849795 DOI: 10.1016/s0360-3016(01)02674-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE In vitro, ionizing radiation of epithelial cells leads to upregulation of wild-type p53 and subsequent induction of p21(waf1). The effect of radiotherapy (RT) on the expression of these proteins in patients is unknown. We assessed the influence of RT on the expression of p53 and p21(waf1) in normal mucosa and rectal carcinomas in vivo. METHODS Tumor and normal tissue samples were derived from rectal cancer patients randomized in a clinical trial in which the value of preoperative RT was evaluated. p53 and p21(waf1) expression was determined in 51 irradiated and 52 nonirradiated patients using immunohistochemistry. RESULTS In normal mucosa, both p53 and p21(waf1) were strongly upregulated after RT compared with the expression in unirradiated normal tissue (p <0.001). In tumor cells, no significant difference in the expression of p53 or p21(waf1) was found in the irradiated vs. nonirradiated group. In the few rectal tumors with wild-type p53, induction of p53 after RT did not necessarily lead to upregulation of p21(waf1). CONCLUSION These findings demonstrate that in normal mucosa, a functional p53-p21(waf1) pathway is present, whereas in tumor cells it is defective in almost all cases because of either p53 mutation or down- or upstream disruption in tumors with wild-type p53. Therefore, we believe that the role of p53 expression as a single prognostic marker in rectal cancer needs reconsideration.
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Affiliation(s)
- Corrie A M Marijnen
- Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
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47
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Rödel C, Grabenbauer GG, Papadopoulos T, Bigalke M, Günther K, Schick C, Peters A, Sauer R, Rödel F. Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys 2002; 52:294-303. [PMID: 11872273 DOI: 10.1016/s0360-3016(01)02643-8] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor shrinkage by preoperative radiochemotherapy (RCT) can markedly improve surgery in locally advanced (T4) rectal cancer with clear resection margins and may enable sphincter preservation in low-lying tumors. However, tumor response varies considerably, even among tumors treated according to the same protocol. If one is able to identify patients with highly radio-responsive tumors at the time of diagnosis, a selective and individualized policy of preoperative RCT might be pursued. METHODS The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 44 patients treated uniformly according to a prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Treatment response was assessed histopathologically in the resected surgical specimen, using a five-point grading system. Expression of each marker was correlated with tumor response and relapse-free survival after curative surgery. RESULTS Tumors with complete (n = 3) or good (n = 28) response to RCT showed significantly higher pretreatment levels of apoptosis (mean AI: 2.06%) than tumors with moderate (n = 7), minimal (n = 5), or no regression (n = 1) from RCT (AI: 1.44%, p = 0.003). The AI was significantly related to Ki-67 (p = 0.05), but not to p53 and bcl-2 status. Tumor regression and AI best predicted relapse-free survival after combined modality treatment and curative surgery. CONCLUSION Spontaneous apoptosis in rectal cancer may serve as an important predictor of tumor regression from RCT in rectal cancer and as a significant prognosticator of relapse-free survival. Thus, this molecular marker may finally help to tailor therapy with regard to (neo-) adjuvant treatment of rectal cancer.
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Affiliation(s)
- Claus Rödel
- Department of Radiation Therapy, University of Erlangen, Erlangen, Germany.
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48
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Minsky BD. Management of Locally Unresectable Rectal Cancer. COLORECTAL CANCER 2002. [DOI: 10.1007/978-1-59259-160-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Villafranca E, Okruzhnov Y, Dominguez MA, García-Foncillas J, Azinovic I, Martínez E, Illarramendi JJ, Arias F, Martínez Monge R, Salgado E, Angeletti S, Brugarolas A. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J Clin Oncol 2001; 19:1779-86. [PMID: 11251009 DOI: 10.1200/jco.2001.19.6.1779] [Citation(s) in RCA: 230] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17). CONCLUSION This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.
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Affiliation(s)
- E Villafranca
- Department of Oncology, Clínica Universitaria, University of Navarre, Pamplona, Spain.
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Petersen S, Thames HD, Nieder C, Petersen C, Baumann M. The results of colorectal cancer treatment by p53 status: treatment-specific overview. Dis Colon Rectum 2001; 44:322-33; discussion 333-4. [PMID: 11289276 DOI: 10.1007/bf02234727] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Both negative and positive influences of mutant p53 on treatment outcome have been reported, and we present here a meta-analysis of published studies where outcome was reported for defined treatment groups. METHODS We identified articles on the effect of p53 status by treatment modality, excluding those not stratified by method of treatment. A common hazard ratio was estimated from studies that reported a multivariate analysis. We also estimated the numbers of patients expressing the endpoint at the mean or median follow-up time and calculated a pooled odds ratio. RESULTS Twenty-eight articles were evaluable (23 using immunohistochemistry to detect overexpression of p53 and 8 using DNA sequencing), for a total of 4,416 patients. For patients treated with surgery only, the immunohistochemistry studies showed a significant influence of p53 status on disease-free survival and a marginally significant influence on overall survival. In the studies using DNA sequencing, by contrast, there was a significant influence of p53 mutations on overall survival, but not disease-free survival. For patients treated with surgery and radiotherapy, the influence of p53 status on disease-free survival was either insignificant or marginally significant, depending on test used; there was no influence on overall survival. CONCLUSIONS Although this pooled analysis of published studies where treatment was accounted for shows that there is a borderline significant hazard associated with p53 overexpression or mutation vs. p53 wild-type, it is unlikely that p53 can be applied in a routine clinical setting alongside factors such as T stage, nodal status, and residual tumor, whose prognostic value is much stronger.
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Affiliation(s)
- S Petersen
- Department of Experimental Radiation Oncology The University of Texas, M.D. Anderson Cancer Center, Houston, USA
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