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Shi W, Chen J, Yao N, Wu T, Suo X, Wang Q, Liu J, Yu G, Zhang K. The prognostic ability of radiotherapy of different colorectal cancer histological subtypes and tumor sites. Sci Rep 2023; 13:11758. [PMID: 37474552 PMCID: PMC10359278 DOI: 10.1038/s41598-023-38853-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 07/16/2023] [Indexed: 07/22/2023] Open
Abstract
The prognostic significance of radiotherapy (RT) for colorectal cancer (CRC) has shown conflicting results, particularly among different pathological subtypes, including adenocarcinoma (AC), mucinous adenocarcinoma (MC), and signet-ring cell carcinoma (SR). This study analyzed the prognosis of three pathological CRC types and focused on the prognostic significance of RT on three CRC histological subtypes. Patients diagnosed with AC (n = 54,174), MC (n = 3813), and SR (n = 664) in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database (2010-2017) were evaluated. Cox regression models and competitive risk models were built to assess the effect of RT on the risk of CRC-associated death. Potential interactions between RT and stratified variables including age, sex, and tumor location were examined by multiplicative models. Compared with AC patients, SR patients had the worst overall survival (OS) among 3 subtypes of CRC (log-rank test, p < 0.001). Compared with patients who did not receive radiotherapy, RT was associated with a 1.09-fold (HR = 1.09, 95%[CI]: 1.03, 1.15) elevated risk of death among AC patients. In the SR group, RT significantly reduced the risk of death by 39% (HR = 0.61, 95%[CI]: 0.39-0.95). However, RT did not appear to independently influence survival in the MC group (HR = 0.96, 95%[CI]: 0.77, 1.21). In the subgroup analysis, tumor location (colon and rectum) significantly modified the association between RT and the risk of death among the AC and SR patients (p for interaction < 0.05). SR patients exhibited a worse OS (overall survival) than AC patients, and the effect of RT varied according to CRC histological subtypes. This can ultimately lead to more personalized and effective treatment strategies for CRC patients.
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Affiliation(s)
- Wenzai Shi
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Jianfei Chen
- Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Ninth School of Clinical Medicine, Peking University, Beijing, 100038, China
- School of Oncology, Capital Medical University, Beijing, 100038, China
| | - Nan Yao
- Department of General Surgery, Aerospace Center Hospital, Beijing, 100089, China
| | - Tiantian Wu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Xiaopeng Suo
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Qiang Wang
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Jun Liu
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China
| | - Guoyong Yu
- Department of Nephrology, Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital, East 4th North Street 279, Dongcheng District, Beijing, 100007, China.
| | - Keming Zhang
- Department of Hepatobiliary Surgery, Peking University International Hospital, Life Park Road No.1 Life Science Park of Zhong Guancun, Chang Ping District, Beijing, 102206, China.
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Development of a method for digital assessment of tumor regression grade in patients with rectal cancer following neoadjuvant therapy. J Pathol Inform 2022; 13:100152. [PMID: 36605115 PMCID: PMC9808016 DOI: 10.1016/j.jpi.2022.100152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/07/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Neoadjuvant chemo-radiotherapy (nCRT) followed by surgical resection is the standard treatment strategy in patients with locally advanced rectal cancer (RC). The pathological effect of nCRT is assessed by determining the tumor regression grade (TRG) of the resected tumor. Various methods exist for assessing TRG and all are performed manually by the pathologist with an accompanying risk of interobserver variation. Automated digital image analysis could be a more objective and reproducible approach to evaluate TRG. This study aimed at developing a digital method to assess TRG in RC following nCRT, and correlate the results to the currently used Mandard method. A deep learning-based semi-automatic Epithelium-Tumor area Percentage (ETP) algorithm enabling quantification of tumor regression by determining the percentage of residual tumor epithelium out of the total tumor area was developed. The ETP was quantified in 50 cases treated with nCRT and 25 cases with no prior nCRT served as controls. Median ETP was 39.25% in untreated compared with 6.64% in patients who received nCRT (P < .001). The ETP of the resected tumors treated with nCRT increased along with increasing Mandard grade (P < .001). As new treatment strategies in RC are emerging, performing an accurate and reproducible evaluation of TRG is important in the assessment of treatment response and prognosis. TRG is often used as an outcome point in clinical trials. The ETP algorithm is capable of performing a precise and objective value of tumor regression.
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DI Tommaso M, Rosa C, Caravatta L, Augurio A, Borzillo V, DI Santo S, Perrotti F, Taraborrelli M, Cianci R, Innocenti P, DI Sebastiano P, Colasante A, Angelucci D, Basti M, Sindici G, Mazzola L, Pizzicannella G, DI Bartolomeo N, Marchioni M, DI Nicola M, Genovesi D. Treatment Intensification for Locally Advanced Rectal Cancer: Impact on Pathological Complete Response and Outcomes. In Vivo 2021; 34:1223-1233. [PMID: 32354913 DOI: 10.21873/invivo.11896] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 01/14/2023]
Abstract
AIM Pathological complete response (pCR) and clinical outcomes [overall survival (OS), disease-free survival (DFS), locoregional control (LC)] were evaluated in a single-institution experience of different schedules of neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC). PATIENTS AND METHODS Data for 322 patients with LARC were retrospectively analyzed. pCR was evaluated according to Mandard tumor regression grade (TRG). The Kaplan-Meier method was used to estimate OS, DFS and LC. RESULTS Three hundred and three (94.1%) patients underwent surgery. pCR was observed in 81 patients (26.7%), with TRG1-2 rate of 41.8%. The 5- and 10-year OS, DFS and LC rates were 82.5%±2.5% and 65.5%±3.8%, 81.2%±2.4% and 79.3%±2.9%, 93.1%±1.7% and 90.5%±2.1%, respectively. CONCLUSION Neoadjuvant CRT in LARC patients resulted in favorable long-term oncological outcomes, with a high pCR rate and acceptable toxicity.
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Affiliation(s)
- Monica DI Tommaso
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Consuelo Rosa
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Luciana Caravatta
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Antonietta Augurio
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Valentina Borzillo
- Department of Radiation Therapy, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Sara DI Santo
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Francesca Perrotti
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Maria Taraborrelli
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Roberta Cianci
- Department of Radiology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
| | - Paolo Innocenti
- Division of Surgery, Villa Serena Clinic, Città S. Angelo, Italy
| | - Pierluigi DI Sebastiano
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University, Chieti, Italy
| | | | | | - Massimo Basti
- Division of Surgery III, Santo Spirito Hospital, Pescara, Italy
| | - Giulia Sindici
- Division of Pathology, Santo Spirito Hospital, Pescara, Italy
| | | | | | | | - Michele Marchioni
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, G. D'Annunzio University, Chieti, Italy
| | - Marta DI Nicola
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, G. D'Annunzio University, Chieti, Italy
| | - Domenico Genovesi
- Department of Radiation Oncology, SS. Annunziata Hospital, G. D'Annunzio University, Chieti, Italy
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Tabchouri N, Buggisch J, Demtröder CR, Thiery J, Rezniczek G, Tempfer CB, Fischer B, Dogan C, Lecomte T, Ouaissi M, Giger-Pabst U. Pressurized Intraperitoneal Aerosol Chemotherapy for Colorectal Peritoneal Metastases. Ann Surg Oncol 2021; 28:5275-5286. [PMID: 33471267 DOI: 10.1245/s10434-020-09508-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/01/2020] [Indexed: 01/29/2023]
Abstract
BACKGROUND The benefit of repetitive PIPAC specifically in CPM patients has yet to be demonstrated in terms of oncological and functional outcomes. OBJECTIVE The aim of this study was to evaluate the outcome of patients with non-resectable colorectal peritoneal metastases (CPM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). METHODS We conducted an analysis of a prospective single-center database of all CPM patients who underwent PIPAC with oxaliplatin 92 mg/m2 body surface (PIPAC-Ox). The outcome criteria were adverse events (Common Terminology Criteria for Adverse Events version 4.0), Peritoneal Regression Grading Score (PRGS), and survival. RESULTS Overall, 102 patients with a median age of 64 years (33-88) were scheduled for PIPAC-Ox. Access to the abdominal cavity for the first application failed in 22/102 (21.6%) patients. A total of 185 PIPACs were performed, with 26/102 (25.5%), 20/102 (19.6%), 17/102 (16.7%), and 17/102 (16.7%) patients undergoing one, two, three, and four or more PIPACs, respectively. Perioperative overall morbidity/mortality Grade I-V occurred in 14 (7.6%), 29 (15.8%), 6 (3.2%), 1 (0.5%), and 1 (0.5%) patient without significant differences between each cycle. Of 27 patients who underwent three or more PIPACs, 20/102 (19.6%) had major/complete CPM regression (PRGS 1-2). In a multivariate analysis, independent predictive factors for > 12 months' survival following the first PIPAC-Ox administration were three or more PIPACs (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.35-15.2; p = 0.014) and younger patient age (OR 1.058, 95% CI 1.00-1.12; p = 0.039). CONCLUSIONS Repetitive PIPAC-Ox for CPM patients, alone or combined with perioperative systemic chemotherapy, is feasible. Our data suggest that three or more consecutive PIPAC-Ox cycles for advanced CPM can improve survival.
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Affiliation(s)
- Nicolas Tabchouri
- Department of Digestive Oncological, Endocrine, Hepato-Biliary, Pancreatic and Liver Transplant Surgery, Trousseau Hospital, Chambray Les Tours, France
| | - Jonathan Buggisch
- Department of General-, Visceral- and Transplant Surgery, University Hospital of Münster, Münster, Germany
| | - Cédric Rémy Demtröder
- Department of Surgery and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany.,Department of General and Visceral Surgery, Therapy Center for Metabolic and Bariatric Surgery, St. Martinus Hospital Düsseldorf, Düsseldorf, Germany
| | - Julien Thiery
- Department of Digestive Oncological, Endocrine, Hepato-Biliary, Pancreatic and Liver Transplant Surgery, Trousseau Hospital, Chambray Les Tours, France
| | - Günther Rezniczek
- Department of Obstetrics and Gynecology, and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany
| | - Clemens B Tempfer
- Department of Obstetrics and Gynecology, and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany
| | - Britta Fischer
- Department of Surgery and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany
| | - Can Dogan
- Department of Obstetrics and Gynecology, and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany
| | - Thierry Lecomte
- Department of Hepatogastroenterology and Digestive Oncology, University Hospital Trousseau, Tours, France
| | - Mehdi Ouaissi
- Department of Digestive Oncological, Endocrine, Hepato-Biliary, Pancreatic and Liver Transplant Surgery, Trousseau Hospital, Chambray Les Tours, France. .,Colorectal Surgery Unit, Trousseau Hospital, Avenue de la République, Chambray Les Tours, France.
| | - Urs Giger-Pabst
- Department of General-, Visceral- and Transplant Surgery, University Hospital of Münster, Münster, Germany.,Department of Surgery and Therapy Center for Peritoneal Carcinomatosis, Marien Hospital Herne, Ruhr-Universität Bochum, Herne, Germany
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Petresc B, Lebovici A, Caraiani C, Feier DS, Graur F, Buruian MM. Pre-Treatment T2-WI Based Radiomics Features for Prediction of Locally Advanced Rectal Cancer Non-Response to Neoadjuvant Chemoradiotherapy: A Preliminary Study. Cancers (Basel) 2020; 12:cancers12071894. [PMID: 32674345 PMCID: PMC7409205 DOI: 10.3390/cancers12071894] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/30/2020] [Accepted: 07/09/2020] [Indexed: 12/24/2022] Open
Abstract
Locally advanced rectal cancer (LARC) response to neoadjuvant chemoradiotherapy (nCRT) is very heterogeneous and up to 30% of patients are considered non-responders, presenting no tumor regression after nCRT. This study aimed to determine the ability of pre-treatment T2-weighted based radiomics features to predict LARC non-responders. A total of 67 LARC patients who underwent a pre-treatment MRI followed by nCRT and total mesorectal excision were assigned into training (n = 44) and validation (n = 23) groups. In both datasets, the patients were categorized according to the Ryan tumor regression grade (TRG) system into non-responders (TRG = 3) and responders (TRG 1 and 2). We extracted 960 radiomic features/patient from pre-treatment T2-weighted images. After a three-step feature selection process, including LASSO regression analysis, we built a radiomics score with seven radiomics features. This score was significantly higher among non-responders in both training and validation sets (p < 0.001 and p = 0.03) and it showed good predictive performance for LARC non-response, achieving an area under the curve (AUC) = 0.94 (95% CI: 0.82–0.99) in the training set and AUC = 0.80 (95% CI: 0.58–0.94) in the validation group. The multivariate analysis identified the radiomics score as an independent predictor for the tumor non-response (OR = 6.52, 95% CI: 1.87–22.72). Our results indicate that MRI radiomics features could be considered as potential imaging biomarkers for early prediction of LARC non-response to neoadjuvant treatment.
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Affiliation(s)
- Bianca Petresc
- Department of Radiology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (B.P.); (M.M.B.)
- Department of Radiology, Emergency Clinical County Hospital Cluj-Napoca, 400006 Cluj-Napoca, Romania;
| | - Andrei Lebovici
- Department of Radiology, Emergency Clinical County Hospital Cluj-Napoca, 400006 Cluj-Napoca, Romania;
- Department of Radiology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania
- Correspondence: (A.L.); (C.C.)
| | - Cosmin Caraiani
- Department of Medical Imaging, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania
- Department of Radiology, Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400158 Cluj-Napoca, Romania
- Correspondence: (A.L.); (C.C.)
| | - Diana Sorina Feier
- Department of Radiology, Emergency Clinical County Hospital Cluj-Napoca, 400006 Cluj-Napoca, Romania;
- Department of Radiology, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania
| | - Florin Graur
- Department of Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania;
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology “Prof. Dr. Octavian Fodor”, 400158 Cluj-Napoca, Romania
| | - Mircea Marian Buruian
- Department of Radiology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540139 Târgu Mureș, Romania; (B.P.); (M.M.B.)
- Department of Radiology, Emergency Clinical County Hospital Târgu Mureș, 540136 Târgu Mureș, Romania
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Yu Y, Li Y, Xu C, Zhang Z, Zhang X. Comparison of long course and short course preoperative radiotherapy in the treatment of locally advanced rectal cancer: a systematic review and meta-analysis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 111:17-27. [PMID: 30284906 DOI: 10.17235/reed.2018.5674/2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND rectal cancer (RC) is one of the most prevalent malignancies worldwide and different preoperative radiotherapies may lead to different outcomes. This meta-analysis aimed to compare the effectiveness of long-course (LC) and short-course radiotherapy (SC), with or without chemotherapy, for locally advanced rectal cancer. METHODS studies published up to March 31st 2018 were retrieved from PubMed, Medline, Cochrane and EMABSE. Randomized control or consort control trials that reported the outcomes of short or long course radiotherapy were eligible. Either a fixed or random effects model was used to access the overall combined risk estimates. RESULTS sixteen studies with a total of 2,773 RC patients were included in the analysis. There were no significant differences between LC and SC therapies with regard to the following: pathological complete response (PCR) (I2 = 78%, p < 0.05, RR = 0.54, 95% CI: 0.26-1.10); tumor downstaging (I2 = 79%, p < 0.05, RR = 0.83, 95% CI: 0.58-1.17); local recurrences (I2 = 22%, p = 0.27, RR = 0.55, 95% CI: 0.26-1.16); distant metastases (I2 = 29%, p = 0.22, RR = 1.03, 95% CI: 0.77-1.37); mortality (I2 = 0%, p = 0.78, RR = 0.95, 95% CI: 0.78-1.15) and serious late toxicity (I2 = 74%, p = 0.01, RR = 1.10, 95% CI: 0.37-3.26). In the subgroup analysis, LC had a better PCR and tumor downstaging rate compared with SC in the RCT subgroup. Besides, LC also presented a better PCR rate compared with SC without chemotherapy. CONCLUSIONS LC and SC are both effective in the preoperative treatment of RC with regard to PCR, tumor downstaging, local recurrences, distant metastases, mortality and serious late toxicity. Furthermore, chemotherapy may enhance the efficacy of preoperative treatment.
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Affiliation(s)
- Yongjun Yu
- Department 8 of colorectal surgery, Tianjin Union Medical Center, China
| | - Yuwei Li
- Department 8 of colorectal surgery, Tianjin Union Medical Center
| | - Chen Xu
- Department 8 of colorectal surgery, Tianjin Union Medical Center, China
| | - Zhao Zhang
- Department 7 of colorectal surgery, Tianjin Union Medical Center, China
| | - Xipeng Zhang
- Department 7 of colorectal surgery, Tianjin Union Medical Center, China
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How to measure tumour response in rectal cancer? An explanation of discrepancies and suggestions for improvement. Cancer Treat Rev 2020; 84:101964. [PMID: 32000055 DOI: 10.1016/j.ctrv.2020.101964] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 01/06/2020] [Accepted: 01/07/2020] [Indexed: 02/06/2023]
Abstract
Various methods categorize tumour response after neoadjuvant therapy, including down-staging and tumour regression grading. Response categories allow comparison of different treatments within clinical trials and predict outcome. A reproducible response categorization could identify subgroups with high or low risk for the most appropriate subsequent treatments, like watch and wait. Lack of standardization and interpretation difficulties currently limit the usability of these approaches. In this review we describe these difficulties for the evaluation of chemoradiation in rectal cancer. An alternative approach of tumour response is based on patterns of residual disease, including fragmentation. We summarise the evidence behind this alternative method of response categorisation, which explains a number of very relevant clinical discrepancies. These issues include differences between downstaging and tumour regression, high local regrowth in advanced tumours during watchful waiting procedures, the importance of resection margins, the limited value of post-treatment biopsies and the relatively poor outcome of patients with a near complete pathological response. Recognition of these patterns of response can allow meaningful development of novel biomarkers in the future.
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Kane C, Glynne-Jones R. Should we favour the use of 5 × 5 preoperative radiation in rectal cancer. Cancer Treat Rev 2019; 81:101908. [DOI: 10.1016/j.ctrv.2019.101908] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/20/2022]
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Ma B, Gao P, Song Y, Huang X, Wang H, Xu Q, Zhao S, Wang Z. Short-Course Radiotherapy in Neoadjuvant Treatment for Rectal Cancer: A Systematic Review and Meta-analysis. Clin Colorectal Cancer 2018; 17:320-330.e5. [DOI: 10.1016/j.clcc.2018.07.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 07/23/2018] [Accepted: 07/28/2018] [Indexed: 02/07/2023]
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Yan H, Wang R, Zhu K, Zhao W, Jiang S, Feng R, Xu X, Meng X, Sun H, Zhang H, Mu D, Xu Z. Predictors of Sensitivity to Preoperative Chemoradiotherapy of Rectal Adenocarcinoma. TUMORI JOURNAL 2018; 97:717-23. [DOI: 10.1177/030089161109700607] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Objectives The purpose of the study was to identify predictive factors of tumor response to preoperative chemoradiotherapy for rectal adenocarcinoma. Methods Ninety-eight patients with nonmetastatic rectal adenocarcinoma received preoperative concurrent chemoradiotherapy and underwent mesorectal excision. After treatment, tumor response according to tumor regression grade were evaluated. The correlation of clinicopathologic factors to tumor response was analyzed. Results The results from a univariate analysis indicated that pretreatment carcinoembryonic antigen level ≤3.0 ng/ml (P = 0.002), non-fixed tumor (P = 0.001), and tumor circumferential extent ≤50% (P = 0.001) were associated significantly with a good tumor response. They also indicated that pretreatment positive lymph nodes (P = 0.032) were associated significantly with a poor tumor response. In multivariate analysis, the results indicated that pretreatment carcinoembryonic antigen level (hazard ratio, 2.930; P = 0.003), tumor mobility (hazard ratio, 2.651; P = 0.002) and circumferential extent of tumor (hazard ratio, 2.394; P = 0.019) independently predicted a good pathologic response rate. Pretreatment positive lymph nodes were not significantly associated with a good response (hazard ratio, 0.361; P = 0.191). Conclusions Pretreatment carcinoembryonic antigen level, tumor mobility and circumferential extent of tumor may be helpful in predicting responsiveness in rectal adenocarcinoma to preoperative chemoradiotherapy, although the results should be confirmed in larger, more homogeneous studies.
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Affiliation(s)
- Hongjiang Yan
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Renben Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Kunli Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Wei Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Shumei Jiang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Rui Feng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Xiaoqing Xu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Xiangjiao Meng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Huiying Sun
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Haiqin Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Dianbin Mu
- Department of Pathology, Shandong Cancer Hospital and Institute, Jinan, PR China
| | - Zhongfa Xu
- Department of General Surgery, Shandong Cancer Hospital and Institute, Jinan, PR China
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Mullen TD, Kim EY, Apisarnthanarax S. Short-Course Radiation Therapy Versus Long-Course Chemoradiation in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer: New Insights from Randomized Trials. CURRENT COLORECTAL CANCER REPORTS 2017. [DOI: 10.1007/s11888-017-0359-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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12
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Hill EJ, Roberts C, Franklin JM, Enescu M, West N, MacGregor TP, Chu KY, Boyle L, Blesing C, Wang LM, Mukherjee S, Anderson EM, Brown G, Dutton S, Love SB, Schnabel JA, Quirke P, Muschel R, McKenna WG, Partridge M, Sharma RA. Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer. Clin Cancer Res 2016; 22:1922-31. [PMID: 26861457 PMCID: PMC4835023 DOI: 10.1158/1078-0432.ccr-15-1489] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 12/28/2015] [Indexed: 01/13/2023]
Abstract
PURPOSE Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach. EXPERIMENTAL DESIGN Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD). RESULTS There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in medianKtrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P= 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG). CONCLUSIONS This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow.
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Affiliation(s)
- Esme J Hill
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Corran Roberts
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Jamie M Franklin
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Monica Enescu
- Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom
| | - Nicholas West
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom
| | - Thomas P MacGregor
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Kwun-Ye Chu
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Lucy Boyle
- Oncology Clinical Trials Office (OCTO), Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Claire Blesing
- Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom
| | - Lai-Mun Wang
- Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom
| | - Somnath Mukherjee
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Ewan M Anderson
- Oxford University Hospitals NHS Trust, Churchill Hospital, Oxford, United Kingdom
| | - Gina Brown
- Radiology Department, Royal Marsden Hospital, Sutton, Surrey, United Kingdom
| | - Susan Dutton
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Sharon B Love
- Centre for Statistics in Medicine, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
| | - Julia A Schnabel
- Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford, United Kingdom
| | - Phil Quirke
- Section of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, United Kingdom
| | - Ruth Muschel
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - William G McKenna
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Michael Partridge
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Ricky A Sharma
- Oxford Cancer Imaging Centre and NIHR Oxford Biomedical Research Centre, Department of Oncology, University of Oxford, Oxford, United Kingdom.
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Abstract
The discussion of pathology results is one of the important items in the multidisciplinary meeting. These results describe not only the adequacy of earlier treatments (neoadjuvant therapy, surgery), but guide subsequent treatment decisions by providing staging information and additional prognostic and predictive factors. In the era of next-generation sequencing, every so often the emphasis is put on the molecular background of tumours, but the information that can be retrieved from the resection specimen remains essential for optimal patient care. In the current review the different surgical approaches will be described, together with the relevant macroscopic evaluations. Microscopic features will be addressed, giving an overview that is aimed at optimal information exchange in the multidisciplinary meeting. Finally, special requirements for reporting local excisions and specimen after neoadjuvant therapy will be discussed.
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Affiliation(s)
- Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
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14
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Zhou ZR, Liu SX, Zhang TS, Chen LX, Xia J, Hu ZD, Li B. Short-course preoperative radiotherapy with immediate surgery versus long-course chemoradiation with delayed surgery in the treatment of rectal cancer: A systematic review and meta-analysis. Surg Oncol 2014; 23:211-21. [DOI: 10.1016/j.suronc.2014.10.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 10/17/2014] [Indexed: 01/14/2023]
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15
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Nagtegaal ID, West NP, van Krieken JHJM, Quirke P. Pathology is a necessary and informative tool in oncology clinical trials. J Pathol 2014; 232:185-9. [PMID: 24037805 DOI: 10.1002/path.4261] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 09/02/2013] [Accepted: 09/07/2013] [Indexed: 02/01/2023]
Abstract
Clinical trials are essential for the improvement of cancer care. The complexity of modern cancer care and research require careful design, for which input from all disciplines is necessary. Pathologists should play a key role in the design and execution of modern cancer trials, with special attention to the eligibility, stratification and evaluation of response to therapy. In the current review all these aspects are discussed, with examples from colorectal cancer trials. We describe critical issues in biomarker evaluation and development and emphasize the importance of the role of the pathologist in quality control of cancer treatment.
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Affiliation(s)
- Iris D Nagtegaal
- Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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16
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Prognostic significance of partial tumor regression after preoperative chemoradiotherapy for rectal cancer: a meta-analysis. Dis Colon Rectum 2013; 56:1093-101. [PMID: 23929020 DOI: 10.1097/dcr.0b013e318298e36b] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Complete tumor regression after preoperative chemoradiotherapy for rectal cancer has been associated with better disease-free and overall survival. The survival experience for patients with partial tumor regression is less clear. OBJECTIVE The aim of this meta-analysis was to evaluate the prognostic significance of partial response after preoperative chemotherapy on disease-free survival in rectal cancer patients. DATA SOURCES Relevant studies were identified by a search of MEDLINE and EMBASE databases with no restrictions to October 31, 2012. STUDY SELECTION We included long-course radiotherapy that reported the association between degree of tumor regression and disease-free survival of rectal cancer. INTERVENTIONS Direct, indirect, and graph methods were used to extract HRs. MAIN OUTCOME MEASURES Study-specific HRs on the disease-free survival were pooled using a random-effects model. Eleven articles in total were selected. Analysis was performed first among the 6 studies that separated partial response from the complete response and later among all 11 of the studies. RESULTS Pooled HR was 0.49 (95% CI, 0.28-0.85) for the 6 studies that compared partial response with poor response. It was 0.41 (95% CI, 0.25-0.67) when all 11 of the studies were analyzed together. LIMITATIONS The studies were limited by not being prospective, randomized trials, and the tumor regression grades were not uniform. CONCLUSIONS Partial tumor response is associated with a 50% improvement in disease-free survival and should be considered as a favorable prognostic factor.
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17
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Bohac GC, Guaqueta D, Cheng DM, Aschengrau A, Hartshorn KL. Disparity in the use of combined modality therapy for rectal cancer in the older adult. J Geriatr Oncol 2012; 4:90-7. [PMID: 24071497 DOI: 10.1016/j.jgo.2012.10.173] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 08/10/2012] [Accepted: 10/03/2012] [Indexed: 01/10/2023]
Abstract
OBJECTIVES The standard treatment strategy for patients with rectal adenocarcinoma having T3 or T4 tumors or positive lymph nodes includes concurrent chemoradiation, surgery and chemotherapy. Population based studies show relatively low rates of usage of standard therapy for rectal cancer in the older adult. MATERIALS AND METHODS Two decades of cases of stage II and stage III rectal cancer from two academic teaching hospitals were reviewed. Comparisons were made of subjects ≤70 or ≥71years with regard to initiation and completion of radiation, chemotherapy and surgery. RESULTS Subjects ≥71years of age had significantly lower proportions of surgical resection (84 vs. 94%) and of initiation of all three component of standard therapy (49 vs. 66%) compared to those ≤70years of age. Subjects ≥71years had significantly more co-morbidities; however, the difference in initiation of therapy remained after adjusting for stage, treating hospital, co-morbid status, race or sex in multivariable analysis. The odds for initiation of therapy were reduced by ≈22% in older adults in the adjusted analysis. Among all patients who started therapy only 56% completed it without dose reduction or delay. There were trends to increased completion among those receiving neo-adjuvant vs. post-operative chemoradiation and among those with stage III as opposed to stage II cancer. CONCLUSIONS Our study indicates that a major disparity in the use of standard therapy for rectal cancer in the older adult exists in academic hospital settings. It will be important for oncologists to reconsider increasing the usage of curative therapy in these patients.
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Affiliation(s)
- Gerald C Bohac
- Boston University School of Medicine, Department of Medicine, Boston MA, USA
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18
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Saigusa S, Tanaka K, Toiyama Y, Matsushita K, Kawamura M, Okugawa Y, Hiro J, Inoue Y, Uchida K, Mohri Y, Kusunoki M. Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy. Oncol Rep 2012; 28:855-61. [PMID: 22711167 DOI: 10.3892/or.2012.1863] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 05/18/2012] [Indexed: 02/02/2023] Open
Abstract
Tumor regression grading (TRG) reportedly has prognostic value in rectal cancer patients after pre-operative chemoradiotherapy (CRT). The aim of this retrospective study was to differentiate gene expression profiles based on TRG in residual cancer cells after CRT. We evaluated pathological response using the criteria of four TRG systems: the Japanese Society for the Cancer of Colon and Rectum (JSCCR), Mandard, Dworak and Rödel. Total RNA was obtained using microdissection from 52 locally advanced rectal cancer specimens from patients who underwent pre-operative CRT to examine the expression levels of 20 genes [PCNA, MKI67, CDKN1A (p21Cip1), CDK2, CHEK1, PDRG1, LGR5, PROM1 (CD133), CD44, SOX2, POU5F1 (OCT4), LKB1, VEGF, EGFR, HGF, MET, HIF1, GLUT1, BAX and BCL2] using real-time quantitative RT-PCR. Gene expression was compared across the four TRG systems. LGR5 gene expression levels in CRT non-responders were significantly higher than in responders in all four grading systems. Patients with elevated PDRG1 and GLUT1 gene expression had poor pathological response in three TRG systems (JSCCR, Dworak and Rödel). MKI67 gene expression in non-responders was significantly higher than in responders in two grading systems (JSCCR and Rödel). While, BAX gene expression in responders was significantly higher than in non-responders in the Mandard TRG system. The results of this study suggest that TRG may reflect characteristics, such as proliferative activity, stemness potency and resistance to hypoxia, of residual cancer cells following pre-operative CRT.
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Affiliation(s)
- Susumu Saigusa
- Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Mie 514-8507, Japan.
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19
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Molinari C, Ballardini M, Teodorani N, Giannini M, Zoli W, Emiliani E, Lucci E, Passardi A, Rosetti P, Saragoni L, Guidoboni M, Amadori D, Calistri D. Genomic alterations in rectal tumors and response to neoadjuvant chemoradiotherapy: an exploratory study. Radiat Oncol 2011; 6:161. [PMID: 22099067 PMCID: PMC3236016 DOI: 10.1186/1748-717x-6-161] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 11/18/2011] [Indexed: 12/17/2022] Open
Abstract
Background Neoadjuvant chemoradiotherapy is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods Forty-eight candidates for neoadjuvant chemoradiotherapy were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade. Results Both Hidden Markov Model and Smoothing approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 3q29, 7p22-21, 7q21, 7q36, 8q23-24, 10p14-13, 13q12, 13q31-34, 16p13, 17p13-12 and 18q23 chromosomal regions. Conclusions This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information on response to neoadjuvant chemoradiotherapy and could help to optimize therapy in rectal cancer patients. The data discussed in this study are available on the NCBI Gene Expression Omnibus [GEO: GSE25885].
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Affiliation(s)
- Chiara Molinari
- Biosciences Laboratories, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy
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20
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Pretreatment CD133 and cyclooxygenase-2 expression as the predictive markers of the pathological effect of chemoradiotherapy in rectal cancer patients. Dis Colon Rectum 2011; 54:1098-106. [PMID: 21825889 DOI: 10.1097/dcr.0b013e3182218155] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND CD133 confers chemoradioresistance properties to cells and has recently been used to identify cancer-initiating cells. OBJECTIVE We investigated whether the overexpression of CD133 and cyclooxygenase-2 can be used as predictive markers of tumor response to preoperative chemoradiotherapy in patients with rectal cancer. SETTING The study was conducted at the National Defense Medical College Hospital in Japan. PATIENTS We recruited 96 patients who underwent a single regimen of preoperative short-term chemoradiotherapy (20 Gy in 5 fractions with 400 mg/day Tegafur/Uracil for 1 week) and radical resection. DESIGN This was a retrospective study. We obtained pretreatment biopsy specimens of these patients and immunostained these specimens with antibodies for CD133, cyclooxygenase-2, p53, p27, p21, and epidermal growth factor receptor. The resected primary tumor was evaluated according to 2 different tumor regression grading systems that were based on the degrees of fibrosis and cytological alterations. RESULTS Positivity for CD133 or cyclooxygenase-2 expression was associated with chemoradioresistance, which was determined by the degree of fibrosis, in both univariate (P = .02 and P = .0003) and multivariate (P = .03 and P = .001) analyses. Univariate and multivariate analyses of the degree of cytological alterations also revealed a significant association between chemoradioresistance and the expression of CD133 (P = .005 and P = .003) and cyclooxygenase-2 (P = .005 and P = .03), whereas other markers failed to associate. LIMITATIONS The information on patients' outcome was not available. CONCLUSIONS Our study revealed the independent predictive values of CD133 and cyclooxygenase-2 expressions in histological tumor regression after preoperative chemoradiotherapy.
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21
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Casado E, García VM, Sánchez JJ, Blanco M, Maurel J, Feliu J, Fernández-Martos C, de Castro J, Castelo B, Belda-Iniesta C, Sereno M, Sánchez-Llamas B, Burgos E, García-Cabezas MÁ, Manceñido N, Miquel R, García-Olmo D, González-Barón M, Cejas P. A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer. Clin Cancer Res 2011; 17:4145-54. [PMID: 21467161 DOI: 10.1158/1078-0432.ccr-10-2257] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies. EXPERIMENTAL DESIGN We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2-3-4 vs. 0-1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome. RESULTS In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2-15.75, P = 0.02), in which it remained the only statistically significant prognostic factor. CONCLUSIONS A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies.
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Affiliation(s)
- Enrique Casado
- Unidad de Oncología; Unidad de Gastroenterología, Hospital Infanta Sofía, Spain.
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22
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Veenhof AAFA, Bloemena E, Engel AF, van der Peet DL, Meijer OWM, Cuesta MA. The relationship of histological tumor regression grade (TRG) and two different time intervals to surgery following radiation therapy for locally advanced rectal cancer. Int J Colorectal Dis 2009; 24:1091-6. [PMID: 19415307 DOI: 10.1007/s00384-009-0722-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/16/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND The objective of this study was to assess the effect of two different time intervals between radiation therapy and surgery for rectal cancer on the histological tumor regression grade (TRG) in the resected specimen. METHODS Between 1995 and 2000, patients undergoing preoperative radiation therapy and TME for locally advanced (T3N0 and T3N1) mid and low rectal tumors treated in the VU University Medical Center or the Zaans Medical Center were entered into this study. All patients received identical radiation treatment (5 x 5 Gy) in the VU University medical center and were subsequently operated on within 2 weeks in the Zaans Medical Center (SI group) and after 6-8 weeks in the VU University Medical Center (LI group). All available histological material was reevaluated for TRG and correlated to survival. RESULTS Sixty-seven patients were included in the present study, 28 in the LI group and 39 in the SI group. Patient gender was comparable for both groups with 21 (75%) male patients in the LI group versus 26 (67%) male patients in the SI group (p = 0.46). A T3N0 preoperative tumor stage was found in 21 (75%) patients in the LI group and in 33 (85%) patients in the SI group (p = 0.36). All tumors were histologically proven adenocarcinoma. Patients in the SI group were significantly older (67 vs. 58 years). In the LI group, a significantly more pronounced histological tumor regression was found. A complete response (TRG1), combined with a near complete histological response (TRG 2), were present in 12 patients in the LI group and in four patients in the SI group (p = 0.002). Radicality of resection was comparable for both groups. With a follow-up of over 60 months, there were no statistically significant differences between the SI and LI groups regarding local control, overall, or disease-free survival. CONCLUSION Although histological tumor regression is significantly more pronounced following a long interval between radiation therapy and surgery, in the present study, this is not reflected in a better radical resection rate, local control or better overall and disease-free survival.
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Affiliation(s)
- A A F A Veenhof
- Department of Surgery, VU University Medical Center, Postbus 7057, de Boelelaan 1117, 1007 MB Amsterdam, The Netherlands.
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23
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The future of TNM staging in rectal cancer: The era of neoadjuvant therapy. CURRENT COLORECTAL CANCER REPORTS 2008. [DOI: 10.1007/s11888-008-0024-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Jacques AET, Rockall AG, Alijani M, Hughes J, Babar S, Aleong JAC, Cottrill C, Dorudi S, Reznek RH. MRI demonstration of the effect of neoadjuvant radiotherapy on rectal carcinoma. Acta Oncol 2008; 46:989-95. [PMID: 17851843 DOI: 10.1080/02841860701317865] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND PURPOSE In patients with locally advanced rectal cancer, neoadjuvant long course (45-54 Gy in 25-30 fractions) chemoradiotherapy (CRT) may reduce tumour size and result in downstaging. In patients with primary resectable tumour short course (25 Gy in 5 fractions) radiotherapy (SCRT) reduces local recurrence but downstaging the disease or altering tumour size has not been described. We aimed to assess change in tumour size on MRI after SCRT or CRT. MATERIALS AND METHODS Nineteen patients with rectal carcinoma underwent MRI before and after SCRT or CRT. In each case, tumour length and width were documented and number of locoregional lymph nodes recorded. Total mesorectal excision was performed in 15 patients and MR findings correlated with histopathology. RESULTS Ten patients received SCRT and nine CRT. Tumour length reduced by 19% overall (15% following SCRT, 23% following CRT). Greater than 30% reduction (partial response) in maximum tumour thickness was seen in 4/10 (40%) following SCRT and 5/9 (56%) following CRT. CONCLUSIONS Significant reduction in tumour size can be achieved with preoperative long course CRT and SCRT. This unexpected finding following SCRT has not been previously described.
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Affiliation(s)
- Audrey E T Jacques
- Academic Department of Radiology, St. Bartholomews' Hospital, London, UK.
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Valentini V, Coco C, Minsky BD, Gambacorta MA, Cosimelli M, Bellavita R, Morganti AG, La Torre G, Trodella L, Genovesi D, Portaluri M, Maurizi-Enrici R, Barbera F, Maranzano E, Lupattelli M. Randomized, multicenter, phase IIb study of preoperative chemoradiotherapy in T3 mid-distal rectal cancer: raltitrexed + oxaliplatin + radiotherapy versus cisplatin + 5-fluorouracil + radiotherapy. Int J Radiat Oncol Biol Phys 2007; 70:403-12. [PMID: 17919844 DOI: 10.1016/j.ijrobp.2007.06.025] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2007] [Revised: 06/14/2007] [Accepted: 06/19/2007] [Indexed: 01/06/2023]
Abstract
PURPOSE To prospectively compare the rates of pathologic response, acute toxicity, and sphincter preservation with two different schedules of preoperative chemoradiotherapy in patients with cT3 mid-distal rectal cancer. METHODS AND MATERIALS Patients with cT3 and/or N+ resectable rectal carcinoma were randomized to receive one of the two following chemoradiotherapy regimens: cisplatin, 5-fluorouracil, and radiotherapy (PLAFUR) or raltitrexed, oxaliplatin, and radiotherapy (TOMOX-RT). For PLAFUR, cisplatin (60 mg/m(2)) was given on Days 1 and 29, with a prolonged infusion of 5-fluorouracil (1,000 mg/m(2)) on Days 1-4 and 29-32, plus concurrent radiotherapy (50.4 Gy in 1.8-Gy fractions daily). For TOMOX-RT, raltitrexed (3 mg/m(2)) and oxaliplatin (130 mg/m(2)) was given on Days 1, 19, and 38 with the same radiotherapy regimen as used for PLAFUR. Surgery was performed 6-8 weeks after completion of chemoradiotherapy. All pathologic specimens were reviewed by a designated expert pathologist. The primary endpoint of this study was pathologic tumor downstaging (defined as tumor regression grade 1-2). Secondary endpoints included the incidence of ypT0, clinical tumor downstaging, sphincter-saving surgery, and acute treatment-related toxicity. RESULTS Between 2002 and 2005, 164 patients were accrued in 10 Italian centers, 83 patients in the PLAFUR arm and 81 in the TOMOX-RT arm. Overall, tumor regression grade 1-2 was observed in 76 patients (46.4%) and ypT0 in 49 (29.9%). The tumor regression grade 1-2 rate was 41.0% vs. 51.9% (p = 0.162) and the ypT0 rate was 24.1% vs. 35.8% (p = 0.102) for the PLAFUR vs. TOMOX-RT arm, respectively. The overall rate of tumor regression grade 1 and ypN+ was 4.6%. The occurrence of ypT downstaging was significantly greater in the TOMOX-RT arm (p = 0.035). Grade 3-4 acute toxicity occurred in 19 patients (11.6%): 7.1% in the PLAFUR arm vs. 16.4% in the TOMOX-RT arm. Sphincter-saving surgery was performed in 143 patients (87.2%) overall: 87.9% in the PLAFUR arm and 86.4% in the TOMOX-RT arm. CONCLUSIONS Compared with the PLAFUR regimen, TOMOX-RT achieved a greater incidence of downstaging but was associated with a correspondingly greater rate of acute Grade 3+ toxicity. With longer follow-up, the local control and survival rates might offer additional guidance as to the choice of regimen.
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Affiliation(s)
- Vincenzo Valentini
- Department of Radiation Therapy, Università Cattolica Sacro Cuore, Rome, Italy.
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Kobayashi H, Hashiguchi Y, Ueno H, Shinto E, Kajiwara Y, Mochizuki H. Absence of cyclooxygenase-2 protein expression is a predictor of tumor regression in rectal cancer treated with preoperative short-term chemoradiotherapy. Dis Colon Rectum 2007; 50:1354-62. [PMID: 17308999 DOI: 10.1007/s10350-006-0881-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Neoadjuvant chemoradiotherapy followed by total mesorectal excision has become the standard of care for patients with locally advanced rectal cancer. This study was designed to determine whether pretreatment cyclooxygenase-2 and p53 protein expression were predictors of histopathologic response in patients with rectal cancer treated with preoperative short-term chemoradiotherapy. METHODS Fifty-two patients with low rectal cancer received short-term preoperative chemoradiotherapy (20 Gy given in 5 daily doses of 4 Gy and concurrent administration of Tegafur/Uracil 400 mg/day), followed by total mesorectal excision. Cyclooxygenase-2 and p53 protein expression were measured by immunohistochemistry before and at the time of resection. Tumor regression grading was evaluated according to the criteria by Rodel (Grade 4, complete regression; Grade 3, regression >50 percent; Grade 2, 25-50 percent; Grade 1,<25 percent; and Grade 0, no regression). RESULTS Two patients had a pathologic complete response. Good response (Grade 3 + 4) was found in 57.7 percent of the resected specimens. Cyclooxygenase-2 was expressed in 80.8 percent of patients before chemoradiotherapy and in 100 percent after chemoradiotherapy. The rates of good response (Grade 3 + 4) were significantly associated with lack of cyclooxygenase-2 expression before chemoradiotherapy (P = 0.021). However, there was no correlation between p53 protein expression and tumor regression grading. CONCLUSIONS Patients with tumor lacking cyclooxygenase-2 expression before chemoradiotherapy are more likely to demonstrate good response to treatment. Cyclooxygenase-2 protein expression may be a marker for response to chemoradiotherapy in patients with rectal cancer.
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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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Klautke G, Fietkau R. Intensified neoadjuvant radiochemotherapy for locally advanced rectal cancer: a review. Int J Colorectal Dis 2007; 22:457-65. [PMID: 17072624 DOI: 10.1007/s00384-006-0204-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND The rate of local recurrence of locally advanced rectal cancer (stage III and IV according to the criteria of Union Internationale Contre Le Cancer) is still high, and also the rate of distant metastases. There are a lot of phase I/II trails of intensified neoadjuvant radiochemotherapy with different chemotherapeutic agents and current protocols to radiotherapy. AIM The objective of this review of literature was to evaluate the necessity, the results, and comparability of the different regimes and to evaluate a potential impact on later adjuvant chemotherapy.
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Affiliation(s)
- Gunther Klautke
- Klinik und Poliklinik für Strahlentherapie der Universität Rostock, Rostock, Germany.
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Liszka L, Zielińska-Pajak E, Pajak J, Gołka D, Starzewski J, Lorenc Z. Usefulness of two independent histopathological classifications of tumor regression in patients with rectal cancer submitted to hyperfractionated pre-operative radiotherapy. World J Gastroenterol 2007; 13:515-24. [PMID: 17278216 PMCID: PMC4065972 DOI: 10.3748/wjg.v13.i4.524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the usefulness of two independent histopathological classifications of rectal cancer regression following neo-adjuvant therapy.
METHODS: Forty patients at the initial stage cT3NxM0 submitted to preoperative radiotherapy (42 Gy during 18 d) and then to radical surgical treatment. The relationship between “T-downstaging” versus regressive changes expressed by tumor regression grade (TRG 1-5) and Nasierowska-Guttmejer classification (NG 1-3) was studied as well as the relationship between TRG and NG versus local tumor stage ypT and lymph nodes status, ypN.
RESULTS: Complete regression (ypT0, TRG 1) was found in one patient. “T-downstaging” was observed in 11 (27.5%) patients. There was a weak statistical significance of the relationship between “T-downstaging” and TRG staging and NG stage. Patients with ypT1 were diagnosed as TRG 2-3 while those with ypT3 as TRG5. No lymph node metastases were found in patients with TRG 1-2. None of the patients without lymph node metastases were diagnosed as TRG 5. Patients in the ypT1 stage were NG 1-2. No lymph node metastases were found in NG 1. There was a significant correlation between TRG and NG.
CONCLUSION: Histopathological classifications may be useful in the monitoring of the effects of hyperfractionated preoperative radiotherapy in patients with rectal cancer at the stage of cT3NxM0. There is no unequivocal relationship between “T-downstaging” and TRG and NG. There is some concordance in the assessment of lymph node status with ypT, TRG and NG. TRG and NG are of limited value for the risk assessment of the lymph node involvement.
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Affiliation(s)
- Lukasz Liszka
- Department of Pathology, Medical University of Silesia, ul. Medykow 14, Katowice 40-754, Poland
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Vironen JH, Kairaluoma M, Aalto AM, Kellokumpu IH. Impact of functional results on quality of life after rectal cancer surgery. Dis Colon Rectum 2006; 49:568-78. [PMID: 16583289 DOI: 10.1007/s10350-006-0513-6] [Citation(s) in RCA: 170] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE Quality of life is an important outcome measure that has to be considered when deciding treatment strategy for rectal cancer. The aim of this study was to find out the impact of surgery-related adverse effects on quality of life. METHODS The RAND-36 questionnaire and questionnaires assessing urinary, sexual, and bowel dysfunction were administered to 94 patients with no sign of recurrence a minimum of one year after curative surgery. Results were compared with age-matched and gender-matched general population. RESULTS Eighty-two (87 percent) patients answered the questionnaires. Major bowel dysfunction was as common after high anterior resection as after low anterior resection. Urinary complaints occurred as often after anterior resection as after abdominoperineal resection, but sexual dysfunction was more common after abdominoperineal resection. Overall, the patients reported better general health perception but poorer social functioning than population controls. In particular, elderly patients reported a significantly better quality of life in many dimensions than their population controls. There was no significant difference in quality of life between treatment groups. Major bowel dysfunction after anterior resection impaired social functioning compared with that of patients without such symptoms. Urinary dysfunction impaired social functioning and impotence impaired physical and social functioning. CONCLUSIONS Quality of life after rectal cancer surgery is not worse than that of the general population. The major adverse impact of bowel and urogenital dysfunction is on social functioning. These adverse effects need to be discussed with the patient and preoperative function needs to be taken into account when choosing between treatment options. Permanent colostomy is not always the factor that disrupts a person's quality of life most.
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Affiliation(s)
- Jaana H Vironen
- Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland
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Ceelen W, Pattyn P, Boterberg T, Peeters M. Pre-operative combined modality therapy in the management of locally advanced rectal cancer. Eur J Surg Oncol 2006; 32:259-68. [PMID: 16443345 DOI: 10.1016/j.ejso.2005.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2005] [Accepted: 12/07/2005] [Indexed: 12/19/2022] Open
Abstract
AIMS To review the use of pre-operative combined modality therapy (CMT, chemotherapy with radiotherapy) in the management of resectable rectal cancer. METHODS A systematic search was performed on pre-operative CMT and rectal cancer. Additional information was retrieved from hand searching the literature and from relevant congress proceedings. We addressed the following issues: Phase II studies of pre-operative CMT, pre-operative radiotherapy (RT) alone vs pre-operative CMT, pre-operative vs post-operative CMT, functional outcome and pathologic downstaging after CMT, prediction and importance of complete response to CMT. RESULTS Pre-operative CMT results in an average pathological complete response (pCR) rate of 18.5% in Phase II studies. Compared with pre-operative RT alone, the addition of CT significantly improves tumour response but not overall survival while acute toxicity increases and the effect on sphincter preservation is at present unclear. Pre-operative CMT has been proven to be superior to post-operative CMT in a German multicenter randomized trial. The scarce available data suggest that the addition of CT might worsen anorectal function compared to pre-operative RT alone. Although a significant pathological response is prognostically favourable, the clinical and imaging tools available at present do not allow to accurately predict pCR in clinical complete responders confirming the indication for surgery in this subgroup. CONCLUSIONS Pre-operative CMT enhances tumour response and could therefore, have a role in patients with possibly invaded resection margins or low lying cancers, although both acute toxicity and anorectal function are worse compared to RT alone. The final results of ongoing randomized trials will more accurately establish the role of pre-operative CMT in resectable rectal cancer patients.
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Affiliation(s)
- W Ceelen
- Department of Surgery, University Hospital, 2K12 IC, De Pintelaan 185, B-9000 Ghent, Belgium.
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Roels S, Haustermans K, Grégoire V, Withers HR. In regard to Ciernik et al.: Automated Functional Image-Guided Radiation Treatment Planning for Rectal Cancer (Int J Radiat Oncol Biol Phys 2005;62:893–900). Int J Radiat Oncol Biol Phys 2006; 64:1611-2; author reply 1612-3. [PMID: 16580510 DOI: 10.1016/j.ijrobp.2005.11.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2005] [Revised: 10/03/2005] [Accepted: 11/18/2005] [Indexed: 11/25/2022]
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