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Huang MY, Huang CW, Wang JY. Surgical treatment following neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Kaohsiung J Med Sci 2020; 36:152-159. [PMID: 31814296 DOI: 10.1002/kjm2.12161] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/11/2019] [Indexed: 01/02/2023] Open
Abstract
Colorectal cancer is a major public health problem worldwide, and locally advanced rectal cancer (LARC) is known for its poor prognosis. A multimodal treatment approach is the only method to achieve satisfactory local recurrence and survival rates in LARC. Determining which therapeutic modality for LARC has the most satisfactory influence on quality of life and disease outcome is still controversial. LARC treatment is subject to continuous advancement due to the development of new and better diagnostic tools, radiotherapy techniques, and chemotherapeutic agents. Herein, we review various therapeutic modalities for LARC from several aspects. In addition to radiotherapy techniques such as neoadjuvant chemoradiotherapy (NCRT), we discuss the progress of chemotherapy, appropriate time interval between NCRT and surgery, relationship between tumor location and NCRT efficacy/safety, wait-and-watch policy, and predictors of treatment response following NCRT. Because of the controversies and unanswered questions regarding NCRT treatments for LARC, additional investigations are required to determine which therapeutic approach is the most feasible for LARC patients.
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Affiliation(s)
- Ming-Yii Huang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jaw-Yuan Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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Yılmaz Rakıcı S, Bedir R, Hatipoğlu C. Are there predictors that can determine neoadjuvant treatment responses in rectal cancer? TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 30:220-227. [PMID: 30459135 DOI: 10.5152/tjg.2018.18179] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS This study aimed to determine a predictive bioindicator that would detect the treatment response of patients diagnosed with rectal cancer and treated with neoadjuvant chemoradiotherapy (nCRT). MATERIALS AND METHODS The data collected from 37 patients receiving nCRT were retrospectively evaluated. The p53 score and gene instability in MLH1 and MSH2, which are among the DNA mismatch repair (MMR) genes, were evaluated using immunohistochemical methods. The neutrophils-leukocytes ratio (NLR), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 values were obtained as hematological parameters from computer records. The pathologic analysis of the therapy response after nCRT was classified according to the modified grading system by Ryan et al. Results: The changes in the NLR, CEA, and CA19-9 values before and after treatment were statistically significant (p<0.001 and p=0.005). A near significant effect of the decrease of the CEA value in the 5th week after treatment was detected on the pathological response score (p=0.075). The p53 mutation score in those patients with any residue was higher than the total response. Overall, 89.2% of the patients exhibited MMR positivity (stability), and 10.8% of the cases with MRM negativity (instability) had a macroscopic residue. Cases with pathological total response were MRM positive. CONCLUSION Consequently, in most of the patients treated with nCRT, the treatment caused tumor and nodal remission. In the prediction of this therapy response, hematological and genetic parameters, such as NLR, P53, MLH1, and MSH2, play a predictive role.
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Affiliation(s)
- Sema Yılmaz Rakıcı
- Department of Radiation Oncology, Recep Tayyip Erdoğan University School of Medicine, Rize, Turkey
| | - Recep Bedir
- Department of Medical Pathology, Recep Tayyip Erdoğan University School of Medicine, Rize, Turkey
| | - Celile Hatipoğlu
- Department of Public Health, Denizli Provincial Directorate of Health, Denizli, Turkey
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Pretreatment Tumor Thickness as a Predictor of Pathologic Complete Response to Neoadjuvant Chemoradiation Therapy for Stage II/III Rectal Adenocarcinoma. Am J Clin Oncol 2019; 41:601-606. [PMID: 27672742 DOI: 10.1097/coc.0000000000000333] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To evaluate pretreatment tumor thickness in predicting pathologic complete response (pCR) of stage II/III rectal adenocarcinoma to neoadjuvant chemoradiation (chemoradiotherapy [CRT]). METHODS We retrospectively analyzed 185 patients who were diagnosed with stage II or III rectal adenocarcinoma from January 2011 to July 2013 and treated with neoadjuvant intensity-modulated radiation therapy (45 Gy in 1.8-Gy fractions to pelvis and 50 Gy in 2-Gy fractions to rectal tumor as an integrated boost) or 3 dimensionally conformal radiation therapy (45 Gy in 1.8-Gy fractions to pelvis followed by an additional 5.4-Gy to rectal tumor) concurrently with two 3-week cycles of chemotherapy (oxaliplatin 130 mg/m on day 1 and capecitabine 825 mg/m, twice per day from day 1 to 14, cycle 2 starts on week 4). One week after CRT, 36% patients received 1 more cycle of the above chemotherapy and 55% received 1 to 2 cycles of FOLFOX6. Tumor response was categorized as pCR and non-pCR. Tumor thickness measured on magnetic resonance imaging was collected. A multivariate logistic regression model was used to evaluate the association of potential predictors and pCR. RESULTS Thirty-eight patients (20.5%) reached pCR. Multivariate analysis found the pretreatment tumor thickness to be associated with higher probability of pCR after adjusting for radiation therapy-surgery interval time and pretreatment carcino-embryonic antigen level. The pretreatment carcino-embryonic antigen level was associated with pCR in the univariate analysis but lost the association in the multivatiate model. The pretreatment T or N stage, tumor volume, distance from tumor to anal verge, craniocaudal length of tumor, radiation therapy technique, and patient age and sex were not associated with pCR. CONCLUSIONS We concluded that pretreatment tumor thickness is an independent predictor for pCR of stage II/III rectal adenocarcinoma to the neoadjuvant CRT.
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Karagkounis G, Kalady MF. Molecular Biology: Are We Getting Any Closer to Providing Clinically Useful Information? Clin Colon Rectal Surg 2017; 30:415-422. [PMID: 29184477 DOI: 10.1055/s-0037-1606373] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Advances in molecular biology and biomarker research have significantly impacted our understanding and treatment of multiple solid malignancies. In rectal cancer, where neoadjuvant chemoradiation is widely used for locally advanced disease, most efforts have focused on the identification of predictors of response in an attempt to appropriately select patients for multimodality therapy. A variety of biomarkers have been studied, including genetic mutations, chromosomal copy number alterations, and single as well as multigene expression patterns. Also, as transanal resection of rectal tumors requires accurate preoperative detection of lymph node metastasis, the identification of biomarkers of regional nodal involvement has been another important field of active research. While preliminary results have been promising, lack of external validation means has a limited translation to clinical use. This review summarizes recent developments in rectal cancer biomarker research, highlighting the challenges associated with their adoption, and evaluating their potential for clinical use.
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Affiliation(s)
- Georgios Karagkounis
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Matthew F Kalady
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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Immunohistochemical Markers as Predictors of Histopathologic Response and Prognosis in Rectal Cancer Treated with Preoperative Adjuvant Therapy: State of the Art. Gastroenterol Res Pract 2017; 2017:2808235. [PMID: 28326100 PMCID: PMC5343286 DOI: 10.1155/2017/2808235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 01/23/2017] [Indexed: 01/18/2023] Open
Abstract
We explain the state of the art of the immunohistochemical markers of response in rectal cancers treated with neoadjuvant medical therapies and its implication with prognosis. Neoadjuvant chemoradiotherapy is widely used to improve the outcome of patients with locally advanced rectal cancer, and the evaluation of the effects of medical therapy is to date based on histomorphological examination by applying four grading systems of response to therapy (tumor regression grade (TRG)). The need to identify immunohistochemical markers that could ensure a better assessment of response and possibly provide additional prognostic information has emerged. We identified p53, p27kip1, Ki67, matrix metalloprotease-9, survivin, Ki67 proliferative index, CD133, COX2, CD44v6, thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase as the most common markers studied in literature to date, and we explained their prognostic potential and their implications in the evaluation of the response to preoperative therapies in rectal cancers.
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Inomata M, Akagi T, Nakajima K, Etoh T, Tahara K, Matsumoto T, Ogawa T, Fujii K, Shiromizu A, Kitano S. A prospective feasibility study to evaluate neoadjuvant-synchronous S-1 with radiotherapy for locally advanced rectal cancer: A multicentre phase II trial. Mol Clin Oncol 2016; 4:510-514. [PMID: 27073652 DOI: 10.3892/mco.2016.767] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 01/13/2016] [Indexed: 12/28/2022] Open
Abstract
Treatment results of locally advanced rectal cancer without preoperative chemoradiotherapy (CRT) in Japan do not differ from those of Western countries. Preoperative CRT with new anticancer agents may decrease local recurrence rate and prevent distant metastases, thus improving survival. We conducted a trial to evaluate feasibility of neoadjuvant CRT using S-1 in patients with locally advanced rectal cancer. A multi-institutional (17 specialized centres), interventional, phase II trial was conducted from April 2009 to August 2011. Patients fulfilling the following requirements before neoadjuvant CRT were included: histologically proven rectal carcinoma; tumour in the upper or lower rectum; cancer classified as T3-4 N0-3 M0. Neoadjuvant CRT with S-1 (80 mg/m2/day on days 1-5, 8-12, 22-26, and 29-33) and irradiation (total 45 Gy/25 fr, 1.8 Gy/day, on days 1-5, 8-12, 15-19, 22-26, and 29-33) was performed. Total mesorectal excision with D3 lymphadenectomy was performed during weeks 4 and 8 after completion of neoadjuvant CRT. The primary endpoint was completion rate of neoadjuvant CRT. Secondary endpoints were response rate to neoadjuvant CRT, short-term clinical outcomes, curative resection rate, and pathologic response (grade 2/3). Of the 37 patients included, 86.5% completed neoadjuvant CRT (95% CI, 75.5-97.5%), and 10.8% (4) experienced an adverse event (grade 3/4). Response rate (RECIST 1.0) was 56.8% (95% CI, 40.8-72.7%), and pathologic response rate was 48.6% (95% CI, 32.5-64.8%). This study demonstrated that neoadjuvant-synchronous S-1+radiotherapy for locally advanced rectal cancer was feasible in terms of pathologic response and adverse events. Registration number: UMIN-CTR, No. C003396.
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Affiliation(s)
- Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita 879-5593, Japan
| | - Tomonori Akagi
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita 879-5593, Japan
| | - Kentaro Nakajima
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita 879-5593, Japan
| | - Tsuyoshi Etoh
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita 879-5593, Japan
| | - Koichiro Tahara
- Department of Surgery, National Hospital Organization, Oita Medical Center, Oita 879-5593, Japan
| | - Toshifumi Matsumoto
- Department of Gastroenterological Surgery, National Hospital Organization Beppu Medical Center, Beppu 874-0011, Japan
| | - Tadashi Ogawa
- Department of Surgery, Oita Prefectural Hospital, Bunyo 870-8511, Japan
| | - Kyuzo Fujii
- Department of Surgery, Nakatsu Municipal Hospital, Nakatsu 871-8511, Japan
| | - Akio Shiromizu
- Department of Surgery, Oita Red Cross Hospital, Oita 870-0033, Japan
| | - Seigo Kitano
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita 879-5593, Japan
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Kim NK, Hur H. New Perspectives on Predictive Biomarkers of Tumor Response and Their Clinical Application in Preoperative Chemoradiation Therapy for Rectal Cancer. Yonsei Med J 2015; 56:1461-77. [PMID: 26446626 PMCID: PMC4630032 DOI: 10.3349/ymj.2015.56.6.1461] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Indexed: 12/14/2022] Open
Abstract
Preoperative chemoradiation therapy (CRT) is the standard treatment for patients with locally advanced rectal cancer (LARC) and can improve local control and survival outcomes. However, the responses of individual tumors to CRT are not uniform and vary widely, from complete response to disease progression. Patients with resistant tumors can be exposed to irradiation and chemotherapy that are both expensive and at times toxic without benefit. In contrast, about 60% of tumors show tumor regression and T and N down-staging. Furthermore, a pathologic complete response (pCR), which is characterized by sterilization of all tumor cells, leads to an excellent prognosis and is observed in approximately 10-30% of cases. This variety in tumor response has lead to an increased need to develop a model predictive of responses to CRT in order to identify patients who will benefit from this multimodal treatment. Endoscopy, magnetic resonance imaging, positron emission tomography, serum carcinoembryonic antigen, and molecular biomarkers analyzed using immunohistochemistry and gene expression profiling are the most commonly used predictive models in preoperative CRT. Such modalities guide clinicians in choosing the best possible treatment options and the extent of surgery for each individual patient. However, there are still controversies regarding study outcomes, and a nomogram of combined models of future trends is needed to better predict patient response. The aim of this article was to review currently available tools for predicting tumor response after preoperative CRT in rectal cancer and to explore their applicability in clinical practice for tailored treatment.
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Affiliation(s)
- Nam Kyu Kim
- Division of Colorectal Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Hyuk Hur
- Division of Colorectal Surgery, Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Agostini M, Zangrando A, Pastrello C, D'Angelo E, Romano G, Giovannoni R, Giordan M, Maretto I, Bedin C, Zanon C, Digito M, Esposito G, Mescoli C, Lavitrano M, Rizzolio F, Jurisica I, Giordano A, Pucciarelli S, Nitti D. A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients. Cancer Biol Ther 2015; 16:1160-71. [PMID: 26023803 DOI: 10.1080/15384047.2015.1046652] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer.
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Key Words
- CEA, carcinoembryonic antigen
- CRT, Chemoradiotherapy
- DSB, Double-strand breaks
- Gy, Gray
- HT, High throughput
- PPI, Protein-protein interaction
- RC, Rectal cancer
- RIN, RNA integrity number
- SNP, Single nucleotide polymorphism
- SSB, Single-strand breaks
- XRCC3
- biological network
- integrated approach
- mRNA, mRNA
- microarray
- pCRT, Preoperative chemoradiotherapy
- preoperative chemoradiotherapy
- rectal cancer
- siRNA, Small interfering RNA
- treatment response
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Affiliation(s)
- Marco Agostini
- a Department of Surgical , Oncological and Gastroenterological Sciences ; Section of Surgery ; University of Padova ; Padua , Italy
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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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Can a biomarker-based scoring system predict pathologic complete response after preoperative chemoradiotherapy for rectal cancer? Dis Colon Rectum 2014; 57:592-601. [PMID: 24819099 DOI: 10.1097/dcr.0000000000000109] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Numerous molecular markers have been investigated as potential predictors of tumor responses to preoperative chemoradiotherapy (preCRT) for rectal cancer. OBJECTIVE To develop a system in which biomarkers are used to predict the likelihood of a pathologic complete response (pCR) to preCRT. DESIGN & SETTING This is a retrospective analysis of tumor specimens collected prior to preCRT from 81 patients who underwent curative resection for primary rectal adenocarcinoma between June 2008 and February 2012. MAIN OUTCOME MEASURES Using tissue microarrays and immunohistochemistry, expression levels of twelve candidate biomarkers (p53, p21, Bcl2, Bax, EGFR, Cox-2, MLH-1, MSH-2, Ku70, VEGF, TS, Ki-67) were evaluated in paraffin-embedded tumor samples collected before preCRT. The correlation between biomarker expression levels and the pathologic response to preCRT was assessed based on histopathological staging (pTNM) and tumor regression grade (TRG). RESULTS Expression levels of 4 biomarkers (p53, VEGF, p21, Ki67) correlated with pCR. Patients showing low expression of p53 and/or high expression of VEGF, p21, and Ki67 exhibited a significantly greater pCR rate. A scoring system devised so that one point was given for each biomarker whose expression level correlated with pCR (score range: 0-4) showed that 1 of 26 patients with scores of 0 to 1 achieved pCR, whereas 26 of 55 patients with scores of 2 to 4 achieved pCR (3.8% vs. 47.3%, p < 0.001). For prediction of pCR, the scoring system showed 96.3% sensitivity, 46.3% specificity, a 47.3% positive predictive value, and a 96.2% negative predictive value. LIMITATIONS Immunohistochemistry has limitations related to reproducibility and the ability to provide quantitative information. In addition, this study lacks test and validation sets. CONCLUSIONS Expression levels of 4 biomarkers correlated with pCR after preCRT for rectal cancer. A scoring system based on levels of biomarker expression showed good sensitivity and negative predictive value for pCR.
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Leibold T, Hui VW, Shia J, Ruby JA, Riedel ER, Guillem JG. p27 expression in post-treatment rectal cancer: a potential novel approach for predicting residual nodal disease. Am J Surg 2014; 208:228-34. [PMID: 24814310 DOI: 10.1016/j.amjsurg.2014.02.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 01/14/2014] [Accepted: 02/06/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Expression profiles of p21, p27, p53, Ki-67, and thymidylate synthase may be associated with response to neoadjuvant chemoradiation. The relationship between post-treatment protein expression and regional lymph node involvement has not been fully explored. METHODS Tumor cores from 126 rectal cancer patients underwent immunohistochemical analysis for the aforementioned proteins. Staining indices (SIs) using percentage of stained cells and staining intensity were calculated for 10 tumor cores per patient. SI for each marker was compared between node negative and node positive patients. RESULTS Twenty-six (20.6%) cancer patients had a pathologic complete response and 37 had inadequate tissue or cancer cells, leaving 63 for analysis. Thirty-seven (58.7%) cancer patients were node negative and 26 (41.3%) were node positive. There was an association between increased p27 SI and nodal positivity (P = .04). CONCLUSION Increased p27 expression in post-treatment rectal cancer is associated with nodal positivity and may determine which patients are suitable for local excision.
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Affiliation(s)
- Tobias Leibold
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Vanessa W Hui
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Jeannine A Ruby
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Elyn R Riedel
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - José G Guillem
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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p27 and BCL2 expression predicts response to chemotherapy in head and neck squamous cell carcinomas. Oral Oncol 2014; 50:128-34. [DOI: 10.1016/j.oraloncology.2013.10.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 10/06/2013] [Accepted: 10/26/2013] [Indexed: 11/17/2022]
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Milgrom SA, Garcia-Aguilar J. Molecular biomarkers as predictors of response to neoadjuvant chemoradiation therapy in rectal cancer. SEMINARS IN COLON AND RECTAL SURGERY 2013. [DOI: 10.1053/j.scrs.2013.03.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Gantt GA, Kalady MF. Molecular markers for targeted neoadjuvant rectal cancer therapy. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.35] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Neoadjuvant chemoradiotherapy is the standard of care for locally advanced rectal cancer. While neoadjuvant chemoradiation has been demonstrated to improve oncological outcomes, there is a wide spectrum of responses to therapy. The ability to predict who will respond favorably or unfavorably to neoadjuvant therapy could prevent unnecessary morbidity and potentially lead to novel therapeutic targets. A number of individual biomarkers and multigene signatures have been investigated as potential means of predicting response to neoadjuvant chemoradiation. While promising, none of these predictive biomarkers have yet been introduced clinically. This review summarizes both individual and multigene biomarkers for rectal cancer response to neoadjuvant chemoradiation.
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Affiliation(s)
- Gerald A Gantt
- Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Matthew F Kalady
- Department of Stem Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
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Tsai HL, Wang JY. Predictors of response in locally advanced rectal cancer following concurrent chemoradiotherapy. BIOMARKERS AND GENOMIC MEDICINE 2013; 5:18-22. [DOI: 10.1016/j.gmbhs.2013.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
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16
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Restivo A, Zorcolo L, Cocco IMF, Manunza R, Margiani C, Marongiu L, Casula G. Elevated CEA levels and low distance of the tumor from the anal verge are predictors of incomplete response to chemoradiation in patients with rectal cancer. Ann Surg Oncol 2012; 20:864-71. [PMID: 23010737 DOI: 10.1245/s10434-012-2669-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND The objective of this study was to evaluate pretreatment clinical parameters as predictive factors for complete pathological response after long-term chemoradiotherapy (RCT) for rectal cancer. Tumor downstaging after RCT for rectal cancer can be obtained in half of cases, whereas a complete pathological response (CPR) is reported to range between 15 and 30%. It is not possible to foresee before therapies who will respond. METHODS Patients with stage II-III rectal cancer that had undergone RCT and rectal resection between January 1995 and October 2010 were considered. Patients were divided in those who achieved a CPR, "CR" group, and those who did not achieve a CPR, "NCR" group. Univariate and multivariate analyses between groups were performed considering the clinical parameters: gender, age, ASA score, preoperative hematic CEA, tumor grading; distance of the tumor from the anal verge, maximum tumor diameter, TNM stage, and neoadjuvant treatment details. RESULTS Among 260 patients, 43 (16.5%) achieved a CPR. The two groups resulted homogeneous for age, sex, pretreatment status, and tumor stage. A CEA <5 ng/dl and distance from anal verge >5 cm were correlated with CPR at multivariate analysis. Patients with both these conditions presented a significantly higher CPR rate (30.6%) as well as improved 5-year survival. CPR was also correlated with improved survival. CONCLUSIONS Very low tumors with a high serum CEA are very unlikely to reach a CPR. The predictive value of these easily available clinical factors should not be underestimated, and better therapeutic strategies for these tumors are needed.
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Affiliation(s)
- Angelo Restivo
- Department of Surgery, Colorectal Surgery Center, University of Cagliari, Cagliari, Italy.
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Akiyoshi T, Kobunai T, Watanabe T. Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer. Surg Today 2012; 42:713-9. [PMID: 22706722 DOI: 10.1007/s00595-012-0223-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 10/19/2011] [Indexed: 12/25/2022]
Abstract
Preoperative radiotherapy or chemoradiotherapy (CRT) has become a standard treatment for patients with locally advanced rectal cancer. However, there is a wide spectrum of responses to preoperative CRT, ranging from none to complete. There has been intense interest in the identification of molecular biomarkers to predict the response to preoperative CRT, in order to spare potentially non-responsive patients from unnecessary treatment. However, no specific molecular biomarkers have yet been definitively proven to be predictive of the response to CRT. Instead of focusing on specific factors, microarray-based gene expression profiling technology enables the simultaneous analysis of large numbers of genes, and might therefore have immense potential for predicting the response to preoperative CRT. We herein review published studies using a microarray-based analysis to identify gene expression profiles associated with the response of rectal cancer to radiation or CRT. Although some studies have reported gene expression signatures capable of high predictive accuracy, the compositions of these signatures have differed considerably, with little gene overlap. However, considering the promising data regarding gene profiling in breast cancer, the microarray analysis could still have potential to improve the management of locally advanced rectal cancer. Increasing the number of patients analyzed for more accurate prediction and the extensive validation of predictive classifiers in prospective clinical trials are necessary before such profiling can be incorporated into future clinical practice.
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Affiliation(s)
- Takashi Akiyoshi
- Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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18
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Edden Y, Wexner SD, Berho M. The use of molecular markers as a method to predict the response to neoadjuvant therapy for advanced stage rectal adenocarcinoma. Colorectal Dis 2012; 14:555-61. [PMID: 21689364 DOI: 10.1111/j.1463-1318.2011.02697.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The response to combined neoadjuvant therapy for advanced stage rectal adenocarcinoma is predictive of outcome. In addition to both clinical and pathological features, the expression of a variety of molecules may provide another method of identifying tumour responsiveness to pre-operative therapy. The aim of this study was to evaluate several markers in the apoptotic pathway as well as expression of Cox-2 and vascular endothelial growth factor (VEGF) to determine their ability to predict response to neoadjuvant therapy. METHOD In total, 152 patients with advanced rectal adenocarcinoma were treated with neoadjuvant therapy followed by resection. Paraffin-embedded sections obtained before and after therapy were assessed by immunohistochemical staining for Cox-2, VEGF, p53, p21, p27, Bax, BCL-2 and apoptosis protease-activating factor 1 (APAF-1). These stains were correlated with tumour regression grade, complete pathological response and T-downstaging of the surgical specimen. Clinical and pathological data were also collected. Data were analysed using the χ2 and Spearman's correlation tests. RESULTS Pathological complete response was seen in 24.5% of patients. Amongst the apoptosis-associated markers, only APAF-1 expression was found to be significantly associated with tumour regression grade (P<0.001), complete pathological response (P<0.031) and T-downstaging (P<0.004). On multivariate analysis, APAF-1 expression was found to be independently associated with good tumour regression grade. In contrast, overexpression of Cox-2 and VEGF in pretreatment biopsies was related to less tumour regression (P<0.003) and less likelihood of T-downstaging (P<0.03). CONCLUSION Immunohistochemical evaluation of initial biopsy specimens of rectal cancer with APAF-1, Cox-2 and VEGF may predict tumour response to neoadjuvant therapy in patients with advanced rectal adenocarcinoma. Those with an expected limited response may be considered for other investigational neoadjuvant protocols.
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Affiliation(s)
- Y Edden
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, Florida 33331, USA
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Vallböhmer D, Krieg A, Stoecklein NH, Knoefel WT. Response prediction in the multimodality therapy of locally advanced rectal cancer. COLORECTAL CANCER 2012. [DOI: 10.2217/crc.11.5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Neoadjuvant therapies have been established in the multimodality treatment of locally advanced rectal cancer. Radiation with concurrent 5-fluorouracil-based chemotherapy followed by surgical resection is considered to be the standard of care in advanced rectal cancer. However, recent studies revealed that patients with complete histopathologic response seem to benefit most from neoadjuvant therapies. Consequently, predictive markers to allow individualization of multimodality therapy in locally advanced rectal cancer are mostly required to identify those who will benefit the most. Unfortunately, there is still an immense lack of factors for response assessment in patients with rectal cancer undergoing multimodality treatment. While conventional diagnostic tools lack sufficient accuracy to provide information for response assessment, newer techniques such as [18F]-fluorodeoxyglucose-PET and diffusion-weighted MRI show promising results. In addition, studies on molecular factors for response assessment in rectal cancer are encouraging but still do not provide a reliable instrument for utilization in clinical practice.
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Affiliation(s)
| | - Andreas Krieg
- Department of General, Visceral & Pediatric Surgery, University of Dusseldorf, Moorenstrasse 540225 Dusseldorf, Germany
| | - Nikolas H Stoecklein
- Department of General, Visceral & Pediatric Surgery, University of Dusseldorf, Moorenstrasse 540225 Dusseldorf, Germany
| | - Wolfram T Knoefel
- Department of General, Visceral & Pediatric Surgery, University of Dusseldorf, Moorenstrasse 540225 Dusseldorf, Germany
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20
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Qiu HZ, Wu B, Xiao Y, Lin GL. Combination of differentiation and T stage can predict unresponsiveness to neoadjuvant therapy for rectal cancer. Colorectal Dis 2011; 13:1353-60. [PMID: 21689282 DOI: 10.1111/j.1463-1318.2011.02570.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIM The study aimed to identify the factors predictive for extreme unresponsiveness to neoadjuvant therapy for rectal cancer. METHOD Ninety-six patients with rectal cancer received neoadjuvant therapy (41 were treated with radiotherapy and 55 with chemoradiotherapy) before surgery. Tumour response, downstaging, pathological complete response (pCR) and disease-free survival were evaluated. RESULTS Tumour response, downstaging and pCR occurred in 70 (72.9%), 47 (49.0%) and 14 (14.6%) patients, respectively. Univariate analyses showed that a large tumour size, T4 stage, elevated serum tumour markers, poor differentiation, radiotherapy alone and mucinous tumour were indicators of poor tumour response and/or downstaging. On multivariate analysis, chemoradiotherapy was found to be predictive for tumour response and downstaging, whereas mucinous type and T4 stage negatively affected tumour response. No variable was found to be associated with pCR, but poor differentiation and T4 stage together predicted extreme unresponsiveness with a high specificity and a high positive predictive value. Very poor disease-free survival was also observed in patients simultaneously carrying these phenotypes. CONCLUSION Neoadjuvant chemoradiotherapy is superior to radiotherapy alone in producing a response of rectal cancer. Unresponsiveness was most likely to occur in patients with poor differentiation and T4 disease.
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Affiliation(s)
- H-Z Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.
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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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Grimminger PP, Shi M, Barrett C, Lebwohl D, Danenberg KD, Brabender J, Vigen CLP, Danenberg PV, Winder T, Lenz HJ. TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials. THE PHARMACOGENOMICS JOURNAL 2011; 12:404-11. [PMID: 21788964 DOI: 10.1038/tpj.2011.29] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy.
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Affiliation(s)
- P P Grimminger
- Department of Molecular Biology and Biochemistry, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA
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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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24
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Grimminger PP, Brabender J, Warnecke-Eberz U, Narumiya K, Wandhöfer C, Drebber U, Bollschweiler E, Hölscher AH, Metzger R, Vallböhmer D. XRCC1 gene polymorphism for prediction of response and prognosis in the multimodality therapy of patients with locally advanced rectal cancer. J Surg Res 2010; 164:e61-6. [PMID: 20863523 DOI: 10.1016/j.jss.2010.08.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 07/04/2010] [Accepted: 08/02/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND Neoadjuvant treatment strategies have been developed to improve survival of patients with locally advanced rectal cancer. Since mainly patients with major histopathologic response benefit from this therapy, predictive markers are needed. The gene polymorphism of the X-ray-repair-cross complementing (XRCC1-) gene (rs25487) was analyzed to predict response to neoadjuvant radiochemotherapy and prognosis in patients with locally advanced rectal cancer. PATIENTS AND METHODS 81 patients (51 male; 30 female; median age 59 years) with locally advanced rectal cancer were included in this study. All patients received a neoadjuvant radiochemotherapy (50.4 Gy, 5-FU) followed by surgical therapy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% viable tumor cells (n = 28) and minor response when more than 10% viable tumor cells (n = 53) were detected in the surgical specimen. Genomic DNA was extracted from paraffin-embedded tissues of all study patients. Allelic discrimination was performed by real-time polymerase chain reaction. Two allele-specific TaqMan probes in competition were used for amplification of the XRCC1 gene. Allelic genotyping was correlated with therapy response and prognosis. RESULTS Single-nucleotide polymorphism XRCC1 A399G (rs25487) was predictive for therapy response (P = 0.039). Within the AG genotype group, 17 (53%) patients showed a minor response and 15 (47%) patients a major response. In contrast, 39 (78%) of the patients with homogeneous AA or GG genotype were minor responders and only 11 (22%) major responders. No prognostic value was revealed for the XRCC1 A399G (rs25487) gene polymorphism in the multimodality therapy. CONCLUSION Our data supports the role of XRCC1 as a predictive marker for therapy response in the multimodality therapy of patients with locally advanced rectal cancer. Single-nucleotide polymorphism XRCC1 A399G (rs25487) could be applied to individualize treatment strategies.
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Affiliation(s)
- Peter P Grimminger
- Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany
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25
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Cuadrado M, Gutierrez-Martinez P, Swat A, Nebreda AR, Fernandez-Capetillo O. p27Kip1 stabilization is essential for the maintenance of cell cycle arrest in response to DNA damage. Cancer Res 2009; 69:8726-32. [PMID: 19843869 DOI: 10.1158/0008-5472.can-09-0729] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
One of the current models of cancer proposes that oncogenes activate a DNA damage response (DDR), which would limit the growth of the tumor in its earliest stages. In this context, and in contrast to studies focused on the acute responses to a one-time genotoxic insult, understanding how cells respond to a persistent source of DNA damage might become critical for future studies in the field. We here report the discovery of a novel damage-responsive pathway, which involves p27(Kip1) and retinoblastoma tumor suppressors and is only implemented after a persistent exposure to clastogens. In agreement with its late activation, we show that this pathway is critical for the maintenance, but not the initiation, of the cell cycle arrest triggered by DNA damage. Interestingly, this late response is independent of the canonical ataxia telangiectasia mutated-dependent and ataxia telangiectasia mutated and Rad3-related-dependent DDR but downstream of p38 mitogen-activated protein kinase. Our results might help to reconcile the oncogene-induced DNA damage model with the clinical evidence that points to non-DDR members as the most important tumor suppressors in human cancer.
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Affiliation(s)
- Myriam Cuadrado
- Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain
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26
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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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Grade M, Gaedcke J, Wangsa D, Varma S, Beckmann J, Liersch T, Hess C, Becker H, Difilippantonio MJ, Ried T, Ghadimi BM. Chromosomal copy number changes of locally advanced rectal cancers treated with preoperative chemoradiotherapy. CANCER GENETICS AND CYTOGENETICS 2009; 193:19-28. [PMID: 19602460 PMCID: PMC2714587 DOI: 10.1016/j.cancergencyto.2009.03.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Accepted: 03/23/2009] [Indexed: 11/30/2022]
Abstract
Standard treatment of rectal cancer patients comprises preoperative chemoradiotherapy followed by radical surgery. However, clinicians are faced with the problem that response rates vary from one individual to another. Predictive biomarkers would therefore be helpful. To identify genomic imbalances that might assist in stratifying tumors into responsive or nonresponsive categories, we used metaphase comparative genomic hybridization to prospectively analyze pretherapeutic biopsies from 42 patients with locally advanced rectal cancers. These patients were subsequently treated with 5-fluorouracil-based preoperative chemoradiotherapy. Based on downsizing of the T-category, 21 rectal cancers were later classified as responsive, while the other 21 were nonresponsive. Comparing these two groups, we could show that gains of chromosomal regions 7q32 approximately q36 and 7q11 approximately q31, as well as amplifications of 20q11 approximately q13, were significantly associated with responsiveness to preoperative chemoradiotherapy (P<0.05). However, the probability of detecting these copy number changes by chance is high (P=0.21). Our primary results suggest that pretherapeutic evaluation of chromosomal copy number changes may be of value for response prediction of rectal cancers to preoperative chemoradiotherapy. This will require validation in a larger cohort of patients.
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Affiliation(s)
- Marian Grade
- Department of General and Visceral Surgery, University Medicine, Göttingen, Germany
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A
| | - Jochen Gaedcke
- Department of General and Visceral Surgery, University Medicine, Göttingen, Germany
| | - Danny Wangsa
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A
| | - Sudhir Varma
- Biometrics Research Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A
| | - Jaje Beckmann
- Department of General and Visceral Surgery, University Medicine, Göttingen, Germany
| | - Torsten Liersch
- Department of General and Visceral Surgery, University Medicine, Göttingen, Germany
| | - Clemens Hess
- Department of Radiation Oncology and Radiotherapy, University Medicine, Göttingen, Germany
| | - Heinz Becker
- Department of General and Visceral Surgery, University Medicine, Göttingen, Germany
| | | | - Thomas Ried
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A
| | - B. Michael Ghadimi
- Department of General and Visceral Surgery, University Medicine, Göttingen, Germany
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Gao X, Saha D, Kapur P, Anthony T, Livingston EH, Huerta S. Radiosensitization of HT-29 cells and xenografts by the nitric oxide donor DETANONOate. J Surg Oncol 2009; 100:149-58. [PMID: 19507186 DOI: 10.1002/jso.21318] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Mechanisms of radioresistance in rectal cancer remain unclear. OBJECTIVES To determine mechanisms of radioresistance in rectal cancer cells and to assess the role of the nitric oxide donor DETANONOate as a radiosensitizing agent. METHODS Survival was determined by clonogenic assays, apoptosis by PARP-1 cleavage, and phenotypic differences by Western blot analysis. SCID mice bearing HT-29 xenografts were treated with ionizing radiation (IR) [2.0 Gy x 5], DETANONOate [0.4 mg/kg i.p.], or combination treatment. RESULTS Colorectal cancer HT-29-p53-null cells were resistant and HCT-116-p53 wild-type cells sensitive to IR, which correlated with cleaved PARP-1. Increased levels of p21 occurred in HCT-116 cells, while Bcl-2 and survivin were elevated in HT-29 cells. Radiosensitization was achieved with a substantial elevation of cleaved PARP-1 in DETANONOate-HT-29-treated versus control cells, which was accompanied by elevation of p21, p27, and BAX, and a concomitant decrease in Bcl-2. SCID mice bearing HT-29 xenografts demonstrated a 37.6%, 51.1%, and 70.1% inhibition in tumor growth in mice receiving IR, DETANONOate, and combination treatment versus control, respectively. CONCLUSIONS Radioresistant HT-29 cells are p53-null and have substantially decreased levels of p21. DETANONOate radiosensitized HT-29 cells in vitro and in vivo by an additive effect in apoptosis.
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Affiliation(s)
- Xiaohuan Gao
- Department of Surgery, Dallas VA Medical Center, University of Texas Southwestern, Dallas, Texas, USA
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Biomarkers for response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys 2009; 74:673-88. [PMID: 19480968 DOI: 10.1016/j.ijrobp.2009.03.003] [Citation(s) in RCA: 180] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 02/27/2009] [Accepted: 03/03/2009] [Indexed: 02/06/2023]
Abstract
Locally advanced rectal cancer (LARC) is currently treated with neoadjuvant chemoradiation. Although approximately 45% of patients respond to neoadjuvant therapy with T-level downstaging, there is no effective method of predicting which patients will respond. Molecular biomarkers have been investigated for their ability to predict outcome in LARC treated with neoadjuvant chemotherapy and radiation. A literature search using PubMed resulted in the initial assessment of 1,204 articles. Articles addressing the ability of a biomarker to predict outcome for LARC treated with neoadjuvant chemotherapy and radiation were included. Six biomarkers met the criteria for review: p53, epidermal growth factor receptor (EGFR), thymidylate synthase, Ki-67, p21, and bcl-2/bax. On the basis of composite data, p53 is unlikely to have utility as a predictor of response. Epidermal growth factor receptor has shown promise as a predictor when quantitatively evaluated in pretreatment biopsies or when EGFR polymorphisms are evaluated in germline DNA. Thymidylate synthase, when evaluated for polymorphisms in germline DNA, is promising as a predictive biomarker. Ki-67 and bcl-2 are not useful in predicting outcome. p21 needs to be further evaluated to determine its usefulness in predicting outcome. Bax requires more investigation to determine its usefulness. Epidermal growth factor receptor, thymidylate synthase, and p21 should be evaluated in larger prospective clinical trials for their ability to guide preoperative therapy choices in LARC.
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Could the surgeon trust to radiotherapy help in rectal cancer? ACTA ACUST UNITED AC 2008; 55:55-9. [PMID: 19069693 DOI: 10.2298/aci0803055v] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
When the surgeon analyzes the ongoing literature on the evidence of the neoadjuvant approaches to rectal cancer finds a true paradox: from one side they seem to offer a relative less relevant contribute through the time, in fact whereas in the Swedish trial preoperative radiation yielded a significant improvement of local control and survival, after the introduction of TME the contribution of preoperative chemoradiation is relegate to local control with no or poor influence on survival, even if the absolute 5-year survival rate moved from 40% of the '70 to 60-65% of the latest years. From other side the growing evidence of an incidence of pCR approaching to 30%, seems to identify a subset of patients with more favourable prognosis to neoadjuvant treatments. Furthermore, the overall evidence that 30-35% of rectal cancer patients treated with multimodality therapy still die from cancer namely by distant metastases in spite of the 4-8% of absolute benefit of adjuvant 5Fu based adjuvant chemotherapy, seems to vanish the efforts of the further optimization of the local treatments (surgery and radiotherapy) and of the ongoing modality of delivery the chemotherapeutic agents. We would like to address the main evidences from the literature and the main uncertainties that the surgeon could face to propose a combined treatment to his rectal cancer patient.
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Terrin L, Rampazzo E, Pucciarelli S, Agostini M, Bertorelle R, Esposito G, DelBianco P, Nitti D, De Rossi A. Relationship Between Tumor and Plasma Levels of hTERT mRNA in Patients with Colorectal Cancer: Implications for Monitoring of Neoplastic Disease. Clin Cancer Res 2008; 14:7444-51. [DOI: 10.1158/1078-0432.ccr-08-0478] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Evidence and research in rectal cancer. Radiother Oncol 2008; 87:449-74. [PMID: 18534701 DOI: 10.1016/j.radonc.2008.05.022] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Revised: 05/14/2008] [Accepted: 05/15/2008] [Indexed: 12/20/2022]
Abstract
The main evidences of epidemiology, diagnostic imaging, pathology, surgery, radiotherapy, chemotherapy and follow-up are reviewed to optimize the routine treatment of rectal cancer according to a multidisciplinary approach. This paper reports on the knowledge shared between different specialists involved in the design and management of the multidisciplinary ESTRO Teaching Course on Rectal Cancer. The scenario of ongoing research is also addressed. In this time of changing treatments, it clearly appears that a common standard for large heterogeneous patient groups have to be substituted by more individualised therapies based on clinical-pathological features and very soon on molecular and genetic markers. Only trained multidisciplinary teams can face this new challenge and tailor the treatments according to the best scientific evidence for each patient.
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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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Ojima E, Inoue Y, Miki C, Mori M, Kusunoki M. Effectiveness of gene expression profiling for response prediction of rectal cancer to preoperative radiotherapy. J Gastroenterol 2007; 42:730-6. [PMID: 17876542 DOI: 10.1007/s00535-007-2089-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2006] [Accepted: 06/19/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND Our aim was to determine whether the expression levels of specific genes could predict clinical radiosensitivity in human colorectal cancer. METHODS Radioresistant colorectal cancer cell lines were established by repeated X-ray exposure (total, 100 Gy), and the gene expressions of the parent and radioresistant cell lines were compared in a microarray analysis. To verify the microarray data, we carried out a reverse transcriptase-polymerase chain reaction analysis of identified genes in clinical samples from 30 irradiated rectal cancer patients. RESULTS A comparison of the intensity data for the parent and three radioresistant cell lines revealed 17 upregulated and 142 downregulated genes in all radioresistant cell lines. Next, we focused on two upregulated genes, PTMA (prothymosin alpha) and EIF5a2 (eukaryotic translation initiation factor 5A), in the radioresistant cell lines. In clinical samples, the expression of PTMA was significantly higher in the minor effect group than in the major effect group (P = 0.004), but there were no significant differences in EIF5a2 expression between the two groups. CONCLUSIONS We identified radiation-related genes in colorectal cancer and demonstrated that PTMA may play an important role in radiosensitivity. Our findings suggest that PTMA may be a novel marker for predicting the effectiveness of radiotherapy in clinical cases.
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Affiliation(s)
- Eiki Ojima
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, 514-8507, Japan
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Lin LC, Lee HH, Hwang WS, Li CF, Huang CT, Que J, Lin KL, Lin FC, Lu CL. p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy. Surg Oncol 2006; 15:211-216. [PMID: 17360176 DOI: 10.1016/j.suronc.2007.01.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Revised: 12/12/2006] [Accepted: 01/08/2007] [Indexed: 01/02/2023]
Abstract
Our aim was to examine whether certain molecular markers, specifically p53, p21, p27, and Bcl-2, could be used to predict the tumor response of rectal cancer to neoadjuvant therapy and determine the overall and disease-free survival rates of patients following neoadjuvant therapy. Seventy-seven patients with rectal cancers were used in this study. All of them received neoadjuvant therapy and 53 of them were given radical surgery. Immunohistochemical tests were performed for the four markers mentioned above using biopsy specimens obtained from 70 of the patients prior to radiation. The identical tests were performed for the same markers using excised specimens from the patients after radical surgery. For the pre-radiation specimens, the positive rate for having p27 and Bcl-2 markers was 32.7% and 16.6%, respectively. This rate increased to 73.5% and 41.6% (p=0.001 and 0.012, respectively) in the specimens obtained after the surgery. With respect to "fair response (FR)" of patients, the pre-radiation biopsy specimens showed significant difference for the p53 (-) and p27 (+) markers (p=0.006). Patients with a 3-year overall survival rate were found to have, from their surgical specimens, 92% of the p27 (+) and 75% of p27 (-) markers (p=0.0058). Our study showed: first, the rate of positive identification of molecular markers, p27 and Bcl-2, increased following neoadjuvant therapy. Second, either the p53 (-) or p27 (+) status was a good predictor for FR in the pre-radiation biopsy specimens. Third, patients with p27 (+) markers in the surgical specimens lived longer at 3 years.
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Affiliation(s)
- Li-Ching Lin
- Department of Radiation Oncology, Chi-Mei Foundation Medical Center, No. 901 Junghua Rd., Yungkang City, Tainan 710, Taiwan, ROC.
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Rengan R, Paty PB, Wong WD, Guillem JG, Weiser M, Temple L, Saltz L, Minsky BD. Ten-year results of preoperative radiation followed by sphincter preservation for rectal cancer: increased local failure rate in nonresponders. Clin Colorectal Cancer 2006; 5:413-21. [PMID: 16635280 DOI: 10.3816/ccc.2006.n.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND The primary objective of this study was to determine the long-term outcome of sphincter preservation with preoperative radiation therapy (RT) and surgical resection in the treatment of distal rectal adenocarcinoma. PATIENTS AND METHODS Between April 1988 and December 1996, 36 (cT2, n=9; cT3, n=27) patients with rectal adenocarcinoma were enrolled on a phase I/II trial of preoperative RT followed by surgical resection. All patients had distal tumors that were clinically judged to require an abdominoperineal resection and received preoperative RT (50.4 Gy) followed by surgery. The median follow-up was 94.5 months (range, 4-187 months). RESULTS Of the 35 patients in this study who underwent resection, 77% were able to undergo sphincter preservation after preoperative RT. The pathologic complete response rate for these patients was 14%. The 10-year rates of overall survival and local failure for patients undergoing sphincter preservation were 54% and 21%, respectively. The 10-year local failure was 26% in patients with cT3 disease who underwent sphincter preservation. All local failures in this study occurred in patients with cT3 disease undergoing sphincter preservation; however, none of the patients with cT3 disease that was downstaged by preoperative RT experienced local failure. In contrast, 10-year local failure was 67% in the patients with cT3 disease that was not downstaged by RT. Sphincter function was good or excellent in 85% of patients at the time of last follow-up. CONCLUSION This approach provides excellent long-term results in all patients with cT2 disease and those with cT3 disease that is downstaged by RT. However, patients with cT3 disease that is not downstaged by RT have an increased risk of local failure. These data underscore the impact of tumor response to radiation on long-term oncologic outcome.
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Affiliation(s)
- Ramesh Rengan
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
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Ferrigno R, Novaes PERDS, Silva MLG, Nishimoto IN, Nakagawa WT, Rossi BM, Ferreira FDO, Lopes A. Neoadjuvant radiochemotherapy in the treatment of fixed and semi-fixed rectal tumors. Analysis of results and prognostic factors. Radiat Oncol 2006; 1:5. [PMID: 16722598 PMCID: PMC1459184 DOI: 10.1186/1748-717x-1-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2005] [Accepted: 03/28/2006] [Indexed: 12/21/2022] Open
Abstract
PURPOSE To report the retrospective analysis of patients with locally advanced rectal cancer treated with neodjuvant radiochemotherapy. METHODS AND MATERIALS From January 1994 to December 2003, 101 patients with fixed (25%) or semi-fixed (75%) rectal adenocarcinoma were treated by preoperative radiotherapy with a dose of 45 Gy at the whole pelvis and 50.4 Gy at primary tumor, concomitant to four weekly chemotherapies with 5-Fluorouracil (425 mg/m2) and Leucovorin (20 mg/m2). In 71 patients (70.3%) the primary tumor was located up to 6 cm from the anal verge and in 30 (29.7%) from 6.5 cm to 10 cm. Age, gender, tumor fixation, tumor distance from the anal verge, clinical response, surgical technique, and postoperative TNM stage were the prognostic factors analyzed for overall survival (OS), disease-free survival (DFS), and local control (LC) at five years. RESULTS Median follow-up time was 38 months (range, 2-141). Complete response was observed in eight patients (7.9%), partial in 54 (53.4%) and absence in 39 (38.7%). OS, DFS and LC were 52.6%, 53.8%, and 75.9%, respectively. Distant metastasis occurred in 40 (39.6%) patients, local recurrence in 20 (19.8%) and both in 16 (15.8%). Patients with fixed tumors had lower OS (17% Vs 65.6%; p < 0.001), DFS (31.2% Vs 60.9%; p = 0.005), and LC (58% Vs 82%; p = 0.004). Patients with tumors more than 6 cm above the anal verge had better LC (93% Vs 69%; p = 0.04). The postoperative TNM stage was a significant factor for DFS (I:64.1%, II:69.6%, III:35.2%, IV:11.1%; p < 0.001) and for LC (I:75.7%, II: 92.9%, III:54.1%, IV:100%; p = 0.005). Patients with positive lymph nodes had worse OS (37.9% Vs 70.4%, p = 0.006), DFS (32% Vs 72.7%, p < 0.001) and LC (56.2% Vs 93.4%; p < 0.001). CONCLUSION This study suggests that the neoadjuvant treatment employed was effective for local control. Fixation of the lesion and lymph nodes metastasis were the main adverse prognostic factors. Distant failures were frequent, supporting the need of new drugs for adjuvant chemotherapy.
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Affiliation(s)
- Robson Ferrigno
- Department of Radiation Oncology, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
| | | | - Maria Letícia Gobo Silva
- Department of Radiation Oncology, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
| | - Ines Nobuko Nishimoto
- Department of Biostatistics, Fundação Antonio Prudente, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
| | - Wilson Toshihiko Nakagawa
- Department of Pelvic Surgery, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
| | - Benedito Mauro Rossi
- Department of Pelvic Surgery, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
| | - Fábio de Oliveira Ferreira
- Department of Pelvic Surgery, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
| | - Ademar Lopes
- Department of Pelvic Surgery, Hospital do Câncer A. C. Camargo, Rua Prof. Antonio Prudente, 211, São Paulo, SP 01509-900, Brazil
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Park YA, Sohn SK, Seong J, Baik SH, Lee KY, Kim NK, Cho CW. Serum CEA as a predictor for the response to preoperative chemoradiation in rectal cancer. J Surg Oncol 2006; 93:145-50. [PMID: 16425302 DOI: 10.1002/jso.20320] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES Recent data suggest that good responders to preoperative chemoradiation (CRT) have a favorable prognosis in rectal cancer patients. The aim of this study was to investigate the predictive value of serum carcinoembryonic antigen (CEA) levels for the tumor response to preoperative CRT in rectal cancer patients. METHODS The study comprised 141 rectal adenocarcinoma patients who underwent preoperative radiotherapy with 5-fluorouracil (FU) based chemotherapy, followed by radical surgery. The staging workup was consisted of endorectal ultrasound, abdominopelvic computed tomography scan, or magnetic resonance imaging. The outcome parameters were cancer-specific survival and disease-free survival. Pre-CRT clinicopathologic features, including age, gender, location of the tumor, clinical tumor (cT) classification, clinical nodal (cN) classification, and serum CEA levels were investigated as possible predictors for the response to preoperative CRT. RESULTS Pathologic complete or near complete responses (good responders, GR) occurred in 26 (19%) patients, while partial or no response (poor responders, PR) occurred in the remaining 115 (81%) patients. GR showed better cancer-specific survival (P = 0.028) and disease-free survival rates (P = 0.011) than PR. Univariate analysis revealed that positive cN and elevated (>5 ng/ml) pre-CRT serum CEA levels are associated with poor tumor response to preoperative CRT. Using logistic regression analysis, elevated pre-CRT serum CEA levels were the only significant predictor for the poor response to CRT (Odd ratio = 2.876, 95% confidence interval = 1.04-7.46, P = 0.041). CONCLUSIONS Our data suggest that elevated pre-CRT serum CEA levels are associated with poor tumor response to CRT. Therefore, pre-CRT serum CEA levels provide useful information about tumor response to preoperative CRT in rectal cancer patients.
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Affiliation(s)
- Yoon-Ah Park
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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40
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Minsky BD. Treatment of Unresectable/Recurrent Rectal Cancer with External Beam and/or Intraoperative Radiation Techniques. SEMINARS IN COLON AND RECTAL SURGERY 2005. [DOI: 10.1053/j.scrs.2005.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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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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Ghadimi BM, Grade M, Difilippantonio MJ, Varma S, Simon R, Montagna C, Füzesi L, Langer C, Becker H, Liersch T, Ried T. Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 2005; 23:1826-38. [PMID: 15774776 PMCID: PMC4721601 DOI: 10.1200/jco.2005.00.406] [Citation(s) in RCA: 263] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE There is a wide spectrum of tumor responsiveness of rectal adenocarcinomas to preoperative chemoradiotherapy ranging from complete response to complete resistance. This study aimed to investigate whether parallel gene expression profiling of the primary tumor can contribute to stratification of patients into groups of responders or nonresponders. PATIENTS AND METHODS Pretherapeutic biopsies from 30 locally advanced rectal carcinomas were analyzed for gene expression signatures using microarrays. All patients were participants of a phase III clinical trial (CAO/ARO/AIO-94, German Rectal Cancer Trial) and were randomized to receive a preoperative combined-modality therapy including fluorouracil and radiation. Class comparison was used to identify a set of genes that were differentially expressed between responders and nonresponders as measured by T level downsizing and histopathologic tumor regression grading. RESULTS In an initial set of 23 patients, responders and nonresponders showed significantly different expression levels for 54 genes (P < .001). The ability to predict response to therapy using gene expression profiles was rigorously evaluated using leave-one-out cross-validation. Tumor behavior was correctly predicted in 83% of patients (P = .02). Sensitivity (correct prediction of response) was 78%, and specificity (correct prediction of nonresponse) was 86%, with a positive and negative predictive value of 78% and 86%, respectively. CONCLUSION Our results suggest that pretherapeutic gene expression profiling may assist in response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. The implementation of gene expression profiles for treatment stratification and clinical management of cancer patients requires validation in large, independent studies, which are now warranted.
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Affiliation(s)
- B Michael Ghadimi
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg 50, Rm 1408, 50 South Dr, Bethesda, MD 20892-8010, USA
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Pucciarelli S, Toppan P, Friso ML, Russo V, Pasetto L, Urso E, Marino F, Ambrosi A, Lise M. Complete pathologic response following preoperative chemoradiation therapy for middle to lower rectal cancer is not a prognostic factor for a better outcome. Dis Colon Rectum 2004; 47:1798-807. [PMID: 15622571 DOI: 10.1007/s10350-004-0681-1] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The aim of this study was to evaluate factors associated with pathologic tumor response following pre-operative chemoradiation therapy, and the prognostic impact of pathologic response on overall and disease-free survival. METHODS Between 1994 and 2002, 132 patients underwent chemoradiation therapy followed by surgery for middle to lower rectal cancer. After excluding 26 cases (metastatic cancer, n = 13; nonradical surgery, n = 6; local excision procedure, n = 4; non-5-fluorouracil-based chemotherapy, n = 2; incomplete data on preoperative chemoradiation therapy regimen used, n = 1), the remaining 106 patients were included in the study. Variables considered were the following: age, gender, tumor location, pretreatment T and N stage, modality of 5-fluorouracil administration, total radiotherapy dose delivered, chemoradiation therapy regimen used (Regimen A: chemotherapy (bolus of 5-fluorouracil and leucovorin, days 1-5 and 29-33) + radiotherapy (45 Gy/25 F/1.8 Gy/F); Regimen B: chemotherapy (5-fluorouracil continuous venous infusion +/- weekly bolus of carboplatin or oxaliplatin) + radiotherapy (50.4 Gy/28 F/1.8 Gy/F)), time interval between completion of chemoradiation therapy and surgery, postoperative chemotherapy administration, surgical procedures, pT, pN, and pTNM stage, and response to chemoradiation therapy defined as tumor regression grade, scored from 1 (no tumor on surgical specimen) to 5 (absence of regressive changes). Statistical analysis was performed by means of logistic regression analysis (Cox's model for overall and disease-free survival). RESULTS Median age of the 106 patients was 60 (range, 31-79) years and the male:female ratio, 66:40. Median distance of tumor from the anal verge was 6 (range, 1-11) cm. Pretreatment TNM stage, available in 104 patients, was cT3T4N0, n = 41; cT2N1, n = 9; cT3N1, n = 39; and cT4N1, n = 17. The median radiotherapy dose delivered was 50.4 (range, 40-56) Gy; 58 patients received 5-fluorouracil by continuous venous infusion, and carboplatin with oxaliplatin was added to the chemotherapy schedule in 71 cases. Patients were given Regimen A in 47 cases and Regimen B in 59. The median interval between chemoradiation therapy and surgery was 42.5 (range, 19-136) days, and 94 patients underwent a sphincter-saving procedure. Tumor regression grade, available in 104 cases, was 1, n = 19; 2, n = 18; 3, n = 15; 4, n = 13; and 5, n = 39. At a median follow-up of 42 (range, 1-110) months, 11 patients had died, and 95 were alive. None of the patients had local recurrences, but 13 had distant recurrences. At logistic regression analysis, the chemoradiation therapy regimen used was the only independent predictor of tumor response following preoperative chemoradiation therapy (odds ratio = 0.29, 95% confidence interval = 0.13-0.67, P = 0.003). At Cox's regression analysis, pretreatment T stage was the only independent prognostic factor for both disease-free survival (relative risk = 7.13, 95% confidence interval = 2.3-21.8, P = 0.001) and overall survival (relative risk = 4.83, 95% confidence interval = 1.1-19.9, P = 0.029). CONCLUSIONS Tumor response following preoperative chemoradiation therapy is mainly related to the preoperative regimen used. For patients receiving preoperative chemoradiation therapy, pretreatment T stage, but not tumor response to preoperative chemoradiation therapy, is prognostic for outcome (both disease-free and overall survival).
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Affiliation(s)
- Salvatore Pucciarelli
- Dipartimento di Scienze Oncologiche e Chirurgiche, Padova University, Padova, Italy.
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Baldus SE, Mönig SP, Schröder W, Metzger R, Lang S, Zirbes TK, Thiele J, Müller RP, Dienes HP, Hölscher AH, Schneider PM. Regression von �sophaguskarzinomen nach neoadjuvanter Radiochemotherapie. DER PATHOLOGE 2004; 25:421-7. [PMID: 15168076 DOI: 10.1007/s00292-004-0697-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Following surgical resection locally advanced oesophageal carcinomas exhibit a bad prognosis and therefore neoadjuvant therapeutic strategies were developed. Because success of therapy is associated with the extent of tumor regression in this context, the introduction of objective histopathological criteria seems to be very important. This study included 67 patients with oesophageal carcinomas (cT2-cT4 cNx cM0) that were treated with a cisplatin- and 5-fluorouracil-containing simultaneous radiochemotherapy. In 43 patients squamous cell, in 24 cases adenocarcinomas were diagnosed. After completion of therapy, a surgical resection and a histopathological examination of the tissue specimens were performed. The extent of tumor regression was histologically evaluated and therapy-induced alterations were graded semiquantitatively. Thereby, a significantly favorable prognosis was observed in the group of patients that showed a regression of carcinomas of 90% or more. Additionally, the extent of a resorptive-histiocytic reaction, giant cells and lymphocytic infiltrates correlated with the grade of regression. These results underline the importance of an exact examination and histomorphological evaluation of the response for the assessment of survival probability after neoadjuvant radiochemotherapy of oesophageal carcinomas.
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Affiliation(s)
- S E Baldus
- Institut für Pathologie, Universität zu Köln, Joseph-Stelzmann-Strasse 9, 50931 Köln.
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Moore HG, Shia J, Klimstra DS, Ruo L, Mazumdar M, Schwartz GK, Minsky BD, Saltz L, Guillem JG. Expression of p27 in residual rectal cancer after preoperative chemoradiation predicts long-term outcome. Ann Surg Oncol 2004; 11:955-61. [PMID: 15525823 DOI: 10.1245/aso.2004.03.095] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Compared with surgery alone, preoperative radiotherapy and 5-fluorouracil-based chemotherapy (combined-modality therapy; CMT) improves outcomes in patients with locally advanced rectal cancer. Although numerous studies have focused on identifying molecular markers of prognosis in the primary rectal cancer before CMT, our aim was to identify markers of prognosis in residual rectal cancer after preoperative CMT. METHODS Sixty-seven patients with locally advanced (T3-4 and/or N1) rectal cancer were treated with preoperative radiotherapy (median, 5040 cGy) with or without 5-fluorouracil-based chemotherapy. Residual tumor in the resected specimen, available for 52 patients, was analyzed for tumor-node-metastasis stage, lymphovascular and/or perineural invasion, and immunohistochemical expression of p27, p21, p53, Ki-67, retinoblastoma gene, cyclin D1, and bcl-2. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared by the log-rank test. RESULTS With a median follow-up of 69 months, the overall 5-year RFS was 74%. RFS was significantly worse for patients with positive p27 expression (P = .005), T3-4 tumors (P = .02), and positive lymph nodes (P = .04) in the irradiated specimen. On multivariate analysis, positive p27 expression remained an independent negative prognostic factor for RFS (P = .04). None of the other proteins was significantly associated with RFS. CONCLUSIONS Our results indicate that positive p27 expression in rectal cancer after preoperative chemoradiation is an independent negative predictor of RFS. Expression of p27 in the residual rectal cancer may therefore identify patients with disease likely to be refractory to standard therapy and for whom investigational approaches should be strongly considered.
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Affiliation(s)
- Harvey G Moore
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-1077, New York, NY 10021, USA
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Minsky BD. Combined-Modality Therapy of Rectal Cancer with Oxaliplatin-Based Regimens. Clin Colorectal Cancer 2004; 4 Suppl 1:S29-36. [PMID: 15212703 DOI: 10.3816/ccc.2004.s.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
There are 2 conventional treatments for clinically resectable rectal cancer. First is surgery and, if the tumor is stage T3 and/or N1/2, this is followed by postoperative combined modality therapy. The second is preoperative combined modality therapy followed by surgery and postoperative combined modality therapy if the tumor is stage uT3/4 and/or node-positive. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of these new chemotherapeutic agents in combination with pelvic radiation therapy, most commonly in the preoperative setting are in progress and suggest higher complete response rates. There is considerable interest in integrating oxaliplatin into preoperative combined modality therapy regimens for rectal cancer. Based on results from phase I/II trials, the recommended regimen for patients who receive oxaliplatin-based combined modality therapy is continuous infusion 5-fluorouracil or capecitabine with pelvic radiation.
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Affiliation(s)
- Bruce D Minsky
- Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY 10021-6007, USA.
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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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Minsky BD. Combined modality therapy for rectal cancer. ACTA ACUST UNITED AC 2003; 21:803-16. [PMID: 15338775 DOI: 10.1016/s0921-4410(03)21038-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Affiliation(s)
- Bruce D Minsky
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
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Abstract
The two conventional treatments for clinically resectable rectal cancer are surgery followed by postoperative combined modality therapy and preoperative combined modality therapy followed by surgery and postoperative chemotherapy. Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhanced sphincter preservation. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy are in progress.
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Affiliation(s)
- Bruce D Minsky
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
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