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Ma Z, Tan L, Liu ZL, Xiao JW. Total neoadjuvant therapy or standard chemoradiotherapy for locally advanced rectal cancer: A systematic review and meta-analysis. Front Surg 2022; 9:911538. [PMID: 36090336 PMCID: PMC9458916 DOI: 10.3389/fsurg.2022.911538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 08/10/2022] [Indexed: 11/29/2022] Open
Abstract
Background and Aim The effectiveness of total neoadjuvant therapy (TNT) on patients with locally advanced rectal cancer (LARC) is controversy. This study aims to compare the prognostic value of TNT with standard neoadjuvant chemoradiotherapy (CRT) for LARC. Methods We searched databases (Embase [Ovid], Medline [Ovid], PubMed, Cochrane Library, and Web of Science) for articles published between January 1, 2000, and March 10, 2022. Studies on evaluating the effects of TNT and standard CRT on the prognosis of LARC were included. The primary outcomes were overall survival (OS) and disease-free survival (DFS). Results 19 primary studies, involving 10 randomized controlled trials, 3 prospective studies and 6 retrospective studies, with data on 5,074 patients treated for LARC were included in the meta-analysis. Statistical analyses revealed that, compared with standard CRT, TNT significantly improved OS (hazard ratio [HR]=0.77, 95% confidence interval [CI]=0.65–0.90, I2 = 30%, P = 0.17), DFS (HR = 0.85, 95% CI = 0.74–0.97, I² = 11%, P = 0.35), distant metastases-free survival (DMFS, HR = 0.76, 95% CI = 0.65–0.90, I² = 0%, P = 0.50), pathological complete response rate (pCR, OR = 1.89, 95% CI = 1.61–2.22, I² = 0%, P = 0.47), and R0 resection rate (OR = 1.33, 95% CI = 1.07–1.67, I² = 16%, P = 0.28), but local recurrence-free survival (LRFS, HR = 1.12, 95% CI = 0.90–1.39, I² = 4%, P = 0.37). Conclusions Comprehensive literature research shows that TNT showed excellent short-term efficacy in terms of pCR and R0 resection rate while also improved the long-term outcomes of OS, DFS and DMFS, might become a new standard of treatment in patients with LARC. Even so, more studies and longer follow-up were still warranted.
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Affiliation(s)
- Zhou Ma
- Department of Gastrointestinal Surgery, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Department of Gastrointestinal Surgery, BaZhong Central Hospital, Bazhong, China
| | - Ling Tan
- Department of Urology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing, China
| | - Zi-lin Liu
- Department of Gastrointestinal Surgery, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jiang-wei Xiao
- Department of Gastrointestinal Surgery, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
- Correspondence: Jiang-wei Xiao
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Chitosan-based nanoparticle co-delivery of docetaxel and curcumin ameliorates anti-tumor chemoimmunotherapy in lung cancer. Carbohydr Polym 2021; 268:118237. [PMID: 34127219 DOI: 10.1016/j.carbpol.2021.118237] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 04/25/2021] [Accepted: 05/18/2021] [Indexed: 01/14/2023]
Abstract
The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 μg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.
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Ye W, Shi L, Qian L, Sun Y, Sun X. Feasibility of relatively low neoadjuvant radiation doses for locally advanced rectal cancer: A propensity score-matched analysis. Cancer Rep (Hoboken) 2019; 2:e1188. [PMID: 32721108 DOI: 10.1002/cnr2.1188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 04/24/2019] [Accepted: 04/25/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Neoadjuvant chemoradiation therapy is part of the standard treatment of locally advanced rectal cancer (LARC). Although various options for modifying preoperative radiotherapy protocols have been researched and proposed, there is still no consensus as to the most appropriate dose regimen of neoadjuvant therapy for this disease. AIM To evaluate the effects of relatively low-dose radiation regimens on tumor regression and clinical outcomes in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision. METHODS AND RESULTS We retrospectively analyzed patients with LARC who underwent neoadjuvant concurrent chemoradiation (CCRT) in our hospital from June 2010 to December 2015. A total of 259 consecutive patients were enrolled, receiving 42 to 44 Gy (RLD, n = 31), 46 Gy (SD1, n = 69), or 50 Gy (SD2, n = 159) of CRT, combined with either capecitabine/oxaliplatin or capecitabine only or mFOLFOX6, followed by total mesorectal excision. A 1:4 propensity score matching was employed, and all patients in the RLD group were matched with 124 patients in the SD2 group. Rates of pCR, 3-year local/regional recurrence (LRR), overall survival (OS), and disease-free survival (DFS) in the RLD group were all not significantly different (0.313 for pCR; 0.884 for LRR; and 0.762 for OS; 0.101 for DFS) from those in SD1 and SD2 groups. The RLD group showed a lower incidence of grade 3 to 4 hematologic toxicity than SD2 group (0.019). A propensity score analysis demonstrated no significant differences in the pCR rates and 3-year outcomes between the RLD and SD2 group. CONCLUSION Relatively low-dose regimen (≤44 Gy) of neoadjuvant CRT combined with standard concurrent chemotherapy appears to be both safe and effective in Chinese patients with LARC. Further testing by prospective randomized trials is needed.
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Affiliation(s)
- Wenyuan Ye
- Department of Radiation Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liming Shi
- Department of Radiation Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liwen Qian
- Department of Radiation Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yikan Sun
- University of New South Wales, Sydney, New South Wales, Australia
| | - Xiaonan Sun
- Department of Radiation Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Yang YJ, Cao L, Li ZW, Zhao L, Wu HF, Yue D, Yang JL, Zhou ZR, Liu SX. Fluorouracil-based neoadjuvant chemoradiotherapy with or without oxaliplatin for treatment of locally advanced rectal cancer: An updated systematic review and meta-analysis. Oncotarget 2018; 7:45513-45524. [PMID: 27322422 PMCID: PMC5216738 DOI: 10.18632/oncotarget.9995] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 06/03/2016] [Indexed: 12/27/2022] Open
Abstract
To measure the safety and efficacy of oxaliplatin (OX) application in neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC), EMBASE, PubMed, Cochrane Library, and Web of Science were used for a literature search. Cochrane's risk of bias tool of randomized controlled trials (RCTs) was used for quality evaluation. The statistical analyses were performed using RevMan 5.3. In addition, 95% confidence intervals (CIs) and pooled risk ratios (RRs) were calculated. Seven RCTs were included in our meta-analysis. After adding OX to fluoropyrimidine (FU), a marginal significant improvement in disease-free survival was noted compared with FU alone (RR = 0.89, 95% CI: 0.78–1.00; P = 0.05). Neoadjuvant CRT with OX significantly decreased the distant metastasis rate (RR = 0.79, 95% CI: 0.67–0.94, P = 0.007). However, no improvement in the local recurrence rate (RR = 0.86, 95% CI: 0.68–1.08; P = 0.19) was noted. In addition, neoadjuvant CRT with OX also significantly increased the pathologic complete response (RR = 1.24, 95% CI: 1.02–1.51; P = 0.03). Grade 3–4 acute toxicity and grade 3–4 diarrhea was considerably higher for OX/FU compared with FU alone. In conclusion, the use of OX on the basis of FU/capecitabine in preoperative CRT is feasible. LARC patients are likely to benefit from CRT regimens with OX.
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Affiliation(s)
- Yong-Jing Yang
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
| | - Ling Cao
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
| | - Zhi-Wen Li
- Department of Anesthesiology, The First Hospital Affiliated to Jilin University, Changchun, 130012, People's Republic of China
| | - Ling Zhao
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
| | - Hong-Fen Wu
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
| | - Dan Yue
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
| | - Jin-Lei Yang
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
| | - Zhi-Rui Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China
| | - Shi-Xin Liu
- Department of Radiation Oncology, Cancer Hospital of Jilin Province, Changchun, 130012, People's Republic of China
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Xu BH, Chi P, Guo JH, Guan GX, Tang TL, Yang YH, Chen MQ, Song JY, Feng CY. Pilot Study of Intense Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: Retrospective Review of a Phase II Study. TUMORI JOURNAL 2018; 100:149-57. [DOI: 10.1177/030089161410000206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Aims and Background Locally advanced rectal adenocarcinoma is typically treated with neoadjuvant chemoradiotherapy and surgery. We assessed the effect of an additional cycle of capecitabine/oxaliplatin chemotherapy before surgery in 57 patients with T3/4, N+/- or T1/2, N+ rectal cancer. Materials and Study Design Radiotherapy (total dose, 50.4 Gy) was combined with three cycles of chemotherapy (two cycles concomitant with radiotherapy), and each cycle consisted of oxaliplatin (130 mg/m2 on day 1) and capecitabine (825 mg/m2, twice per day from day 1 to day 14) for 21 days. In addition to assessing the safety of this treatment, the primary endpoint was pathological complete response (pCR). The secondary endpoint was the change in primary tumor and node stage from pre-treatment to post-surgery. Results Eleven patients (19%) experienced complete tumor regression and 23 patients (40%) experienced tumor regression grade 3. Tumor down-staging occurred in 31 patients (54.4%) and down-staging of nodes occurred in 25 patients (43.9%). There was a significant difference in tumor stage between pre-treatment and post-surgery (P <0.001). Patients with less advanced N stages had significantly better recurrence-free survival but similar metastasis-free survival and overall survival. Tumor regression grade was not associated with overall survival, recurrence-free survival or metastasis-free survival. The most common adverse events were pulmonary infection (n = 6, 10.5%) and intestinal obstruction (n = 6, 10.5%). Conclusions An additional cycle of chemotherapy given after chemoradiotherapy and before surgery provided good efficacy and had a satisfactory safety profile in patients with locally advanced rectal cancer.
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Affiliation(s)
- Ben-hua Xu
- Department of Radiation Oncology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Pan Chi
- Department of General Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Jin-hua Guo
- Department of Radiation Oncology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Guo-xian Guan
- Department of General Surgery, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Tian-lan Tang
- Department of Radiation Oncology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Ying-hong Yang
- Department of Pathology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Ming-qiu Chen
- Department of Radiation Oncology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Jian-yuan Song
- Department of Radiation Oncology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Chang-yin Feng
- Department of Pathology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
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Musio D, Raffetto N, Dionisi F, Iannacone E, Dipalma B, Caparrotti F, Meaglia I, Caiazzo R, Bangrazi C, Banelli E. Comparison between Intensified Neoadjuvant Treatment and Standard Preoperative Chemoradiation for Rectal Cancer. TUMORI JOURNAL 2018; 96:11-6. [DOI: 10.1177/030089161009600102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Objectives The aim of the current study was to compare a neoadjuvant regimen containing oxaliplatin with standard preoperative treatment for rectal cancer. Methods From December 2006 to December 2007, 20 patients with rectal cancer were treated at our Institution with the weekly addition of oxaliplatin (50 mg/m2) to radiotherapy (50.4–54.0 Gy in 28–30 daily fractions) and continuous infusion of 5-fluorouracil (200 mg/m2). The results of the regimen were compared with a historical control group including 21 consecutive patients previously treated with standard 5-fluorouracil treatment from December 2004 to October 2006. Results Both the rate of sphincter preservation in low rectal cancer (91.7% vs 36.4%, P = 0.009) and the rate of downstaging (84.2% vs 47.6%, P = 0.023) were higher in the oxaliplatin group than in the control group. Pathological complete response was achieved in 8 patients (42.1%) in the oxaliplatin group and in 4 patients (19.0%) in the control group (P = 0.172). When ypT0-pT1 stages were analyzed together, the P value was 0.051. Acute toxicity was increased in the oxaliplatin group, with a higher incidence of G3 diarrhea and pelvic pain than in the control group (30.0% vs 14.3%, P = NS). Conclusions Our data seem to correlate the addition of oxaliplatin to the standard treatment for rectal cancer with higher rates of sphincter preservation, down-staging and complete response. Toxicity is increased and requires careful monitoring. However, our results refer to a retrospective comparison of a small series of patients and need to be validated by the large, phase III randomized trial currently ongoing.
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Affiliation(s)
- Daniela Musio
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | - Nicola Raffetto
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | - Francesco Dionisi
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | - Eva Iannacone
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | | | | | - Ilaria Meaglia
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | - Rossella Caiazzo
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | - Caterina Bangrazi
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
| | - Enzo Banelli
- Department of Radiation Oncology, University “Sapienza”, Rome, Italy
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Hüttner FJ, Probst P, Kalkum E, Hackbusch M, Jensen K, Ulrich A, Büchler MW, Diener MK. Addition of platinum derivatives to neoadjuvant single-agent fluoropyrimidine chemoradiotherapy in patients with stage II/III rectal cancer: protocol for a systematic review and meta-analysis (PROSPERO CRD42017073064). Syst Rev 2018; 7:11. [PMID: 29357929 PMCID: PMC5778669 DOI: 10.1186/s13643-018-0678-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 01/11/2018] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is to assess the efficacy, safety, and quality of life resulting from adding a platinum derivative to neoadjuvant single-agent fluoropyrimidine-based chemoradiotherapy in patients with Union for International Cancer Control stage II and III rectal cancer. METHODS MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials will be systematically searched to identify all randomized controlled trials comparing single-agent fluoropyrimidine-based chemoradiotherapy to combined neoadjuvant therapy including a platinum derivative. Predefined data on trial design, quality, patient characteristics, and endpoints will be extracted. Quality of included trials will be assessed according to the Cochrane Risk of Bias Tool, and the GRADE recommendations will be applied to judge the quality of the resulting evidence. The main outcome parameter will be survival, but also treatment toxicity, perioperative morbidity, and quality of life will be assessed. DISCUSSION The findings of this systematic review and meta-analysis will provide novel insights into the efficacy and safety of combined neoadjuvant chemoradiotherapy including a platinum derivative and may form a basis for future clinical decision-making, guideline evaluation, and research prioritization. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42017073064.
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Affiliation(s)
- Felix J. Hüttner
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
- The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
| | - Pascal Probst
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
- The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
| | - Eva Kalkum
- The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
| | - Matthes Hackbusch
- Institute of Medical Biometry and Informatics (IMBI), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
| | - Katrin Jensen
- Institute of Medical Biometry and Informatics (IMBI), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Markus W. Büchler
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
| | - Markus K. Diener
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany
- The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
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Teo MTW, McParland L, Appelt AL, Sebag-Montefiore D. Phase 2 Neoadjuvant Treatment Intensification Trials in Rectal Cancer: A Systematic Review. Int J Radiat Oncol Biol Phys 2017; 100:146-158. [PMID: 29254769 DOI: 10.1016/j.ijrobp.2017.09.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 08/23/2017] [Accepted: 09/21/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE Multiple phase 2 trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals, but these have not translated into improved cancer outcomes in phase 3 trials. Improvements in phase 2 trial design are needed to reduce these false-positive signals. This systematic review evaluated the design of phase 2 trials of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification in locally advanced rectal cancer. METHODS AND MATERIALS The PubMed, EMBASE, MEDLINE, and Cochrane Library databases were searched for published phase 2 trials of neoadjuvant treatment intensification from 2004 to 2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta-regression analysis of pathologic complete response (pCR) was conducted. RESULTS We identified 92 eligible trials. Patients with American Joint Committee on Cancer stage II and III equivalent disease were eligible in 87 trials (94.6%). In 43 trials (46.7%), local staging on magnetic resonance imaging was mandated. Only 12 trials (13.0%) were randomized, with 8 having a standard-treatment control arm. Just 51 trials (55.4%) described their statistical design, with 21 trials (22.8%) failing to report their sample size derivation. Most trials (n=84, 91.3%) defined a primary endpoint, but 15 different primary endpoints were used. All trials reported pCR rates. Only 38 trials (41.3%) adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5% (95% confidence interval, 15.7%-19.4%) across treatment arms of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification and substantial heterogeneity among the reported effect sizes (I2 = 55.3%, P<.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiation therapy doses (adjusted P=.025). CONCLUSIONS Improvement in the design of future phase 2 rectal cancer trials is urgently required. A significant increase in randomized trials is essential to overcome selection bias and determine novel schedules suitable for phase 3 testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer.
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Affiliation(s)
- Mark T W Teo
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK
| | - Lucy McParland
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Ane L Appelt
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK
| | - David Sebag-Montefiore
- Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK; Leeds Cancer Centre, St James University Hospital, Leeds, UK.
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Resende HM, Jacob LFP, Quinellato LV, Matos D, da Silva EMK. Combination chemotherapy versus single-agent chemotherapy during preoperative chemoradiation for resectable rectal cancer. Cochrane Database Syst Rev 2015; 10:CD008531. [PMID: 35658163 PMCID: PMC8947000 DOI: 10.1002/14651858.cd008531.pub2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Colorectal cancer represents 10% of all cancers and is the third most common cause of death in women and men. Almost two-thirds of all bowel cancers are cancers of the colon and over one-third (34%) are cancers of the rectum, including the anus. Surgery is the cornerstone for curative treatment of rectal cancer. Mesorectal excision decreases the rate of local recurrences; however, it does not improve the overall survival of people with locally advanced rectal cancer. There have been significant research efforts since the mid-1990s to optimise the treatment of rectal cancer. Based on the findings of clinical trials, people with T3/T4 or N+ rectal tumours are now being treated preoperatively with radiation and chemotherapy, mainly fluoropyrimidine. However, the incidence of distant metastases remains as high as 30%. Combination chemotherapy regimens, similar to those used in metastatic disease with the addition of oxaliplatin and irinotecan, have been tested to improve the prognosis of people with rectal cancer. OBJECTIVES To compare outcomes (including overall survival, disease-free survival and toxicity) between two 5-fluorouracil-containing chemotherapy regimens in people with stage II and III rectal cancer who are receiving preoperative chemoradiation. SEARCH METHODS We searched the Cochrane Colorectal Cancer Group Specialised Register (January 2015), the Cochrane Central Register of Controlled Trials (2015, Issue 1), Ovid MEDLINE (1950 to January 2015), Ovid EMBASE (1974 to January 2015) and LILACS (1982 to January 2015). We reviewed the reference lists of included studies, checked clinical trials registers and handsearched relevant journal proceedings. We applied no language or publication restrictions. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing single-agent chemotherapy (fluoropyrimidine) versus combination chemotherapy (fluoropyrimidine plus another agent including, but not limited to, oxaliplatin) during preoperative radiochemotherapy in people with resectable rectal cancer. DATA COLLECTION AND ANALYSIS Two review authors (HMR, EMKS) independently extracted data and assessed trial quality. When necessary, we requested additional information and clarification of published data from the authors of individual trials. MAIN RESULTS We included four RCTs involving 3875 people with resectable rectal cancer. In the preoperative period, the participants of these studies were randomised to receive chemoradiation either with a single fluoropyrimidine agent (capecitabine or 5-fluorouracil) or with a combination of drugs (fluoropyrimidine plus oxaliplatin). The only study that reported overall survival and disease-free survival found no significant differences between the intervention and control groups; we considered this evidence very low quality. For pathological complete response after preoperative treatment (ypCR) there was high quality evidence favouring the intervention group (odds ratio (OR) 1.23, 95% confidence interval (CI) 1.04 to 1.46), but there was also moderate quality evidence suggesting a higher risk for early toxicity in the intervention group (OR 2.07, 95% CI 1.31 to 3.27). Moderate to high quality evidence suggested that the control group had better compliance to radiotherapy (OR 0.32, 95% CI 0.14 to 0.75). There were no significant differences between groups in postoperative mortality within 60 days, postoperative morbidity, resection margins, abdominoperineal resection and Hartmann procedures. AUTHORS' CONCLUSIONS There was very low quality evidence that people with resectable rectal cancer who receive combination preoperative chemotherapy have no improvements in overall survival or disease-free survival. There was high quality evidence that suggested that combination chemotherapy with oxaliplatin may improve local tumour control in people with resectable rectal cancer, but this regimen also caused more toxicity. The review included four RCTs but only one reported survival; therefore, we cannot make robust conclusions or useful clinical recommendations. The publication of more survival data from these studies will contribute to future analyses.
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Affiliation(s)
- Heloisa M Resende
- Escola Paulista de Medicina, Universidade Federal de São PauloPost‐Graduation Program Emergency Medicine and Evidence Based Medicine of the Federal University of São Paulo (UNIFESP)Rua Borges Lagoa 564 cj 64Vl. ClementinoSão PauloBrazil04038‐000
| | | | | | - Delcio Matos
- Escola Paulista de Medicina, Universidade Federal de São PauloDepartment of Gastroenterological SurgeryRua Edison 278, Apto 61Campo BeloSão PauloSão PauloBrazil04618‐031
| | - Edina MK da Silva
- Universidade Federal de São PauloEmergency Medicine and Evidence Based MedicineRua Borges Lagoa 564 cj 64Vl. ClementinoSão PauloSão PauloBrazil04038‐000
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10
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Jones RG, Tan D. How can we determine the best neoadjuvant chemoradiotherapy regimen for rectal cancer? COLORECTAL CANCER 2015. [DOI: 10.2217/crc.15.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY The current management of patients with clinically defined ‘locally advanced rectal cancer’ often involves fluoropyrimidine-based preoperative chemoradiotherapy (CRT) followed by total mesorectal excision. The focus remains primarily on reducing local recurrence, and improving survival, with organ preservation an increasing target. The best neoadjuvant CRT is the most effective regimen, balanced against the tolerability and late functional consequences, which should be selected for the individual according to their individual risk of local and distant recurrence. Hence, what makes the best neoadjuvant treatment depends on the activity and toxicity of the particular schedule, the aims of treatment, the individual disease characteristics and the individual patient pharmacogenomics. Current research efforts focus on enhancing the efficacy of CRT by integrating additional cytotoxics and biologically targeted agents.
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Affiliation(s)
- Rob Glynne Jones
- Consultant Radiation Oncologist, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex, HA6 2RN, UK
| | - David Tan
- Radiation Oncologist, FRCR, Consultant Radiation Oncologist, National Cancer Centre, Singapore
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Hernando-Requejo O, López M, Cubillo A, Rodriguez A, Ciervide R, Valero J, Sánchez E, Garcia-Aranda M, Rodriguez J, Potdevin G, Rubio C. Complete pathological responses in locally advanced rectal cancer after preoperative IMRT and integrated-boost chemoradiation. Strahlenther Onkol 2014; 190:515-20. [PMID: 24715243 DOI: 10.1007/s00066-014-0650-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 02/25/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND PURPOSE To analyze the efficacy and safety of a new preoperative intensity-modulated radiotherapy (IMRT) and integrated-boost chemoradiation scheme. PATIENTS AND METHODS In all, 74 patients were treated with IMRT and concurrent standard dose capecitabine. The dose of the planning target volume (PTV) encompassing the tumor, mesorectum, and pelvic lymph nodes was 46 Gy in 23 fractions; the boost PTV, at a dose of 57.5 Gy in 23 fractions, included the macroscopic primary tumor and pathological lymph nodes. The patients underwent surgery 6-8 weeks after chemoradiation. RESULTS The complete treatment data of 72 patients were analyzed. Tumor downstaging was achieved in 55 patients (76.38 %) and node downstaging in 34 (47.2 %). In 22 patients (30.6 %), there was complete pathological response (ypCR). The circumferential resection margin was free of tumor in 70 patients (97.2 %). The 3-year estimated overall survival and disease-free survival rates were 95.4 and 85.9 % respectively, and no local relapse was found; however, ten patients (13.8 %) developed distant metastases. High pathologic tumor (pT) downstaging was shown as a favorable prognostic factor for disease-free survival. No grade 4 acute radiotherapy-related toxicity was found. CONCLUSIONS The IMRT and integrated-boost chemoradiation scheme offered higher rates of ypCR and pT downstaging, without a significant increase in toxicity. The circumferential margins were free of tumors in the majority of patients. Primary tumor regression was associated with better disease-free survival.
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12
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Kim D. More Treatment is not Necessarily Better - Limited Options for Chemotherapeutic Radiosensitization. COLORECTAL CANCER 2014. [DOI: 10.1002/9781118337929.ch12] [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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13
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Carrato A, Gallego-Plazas J, Guillén-Ponce C. Capecitabine plus oxaliplatin for the treatment of colorectal cancer. Expert Rev Anticancer Ther 2014; 8:161-74. [DOI: 10.1586/14737140.8.2.161] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Lu JY, Xiao Y, Qiu HZ, Wu B, Lin GL, Xu L, Zhang GN, Hu K. Clinical outcome of neoadjuvant chemoradiation therapy with oxaliplatin and capecitabine or 5-fluorouracil for locally advanced rectal cancer. J Surg Oncol 2013; 108:213-9. [PMID: 23913795 DOI: 10.1002/jso.23394] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Accepted: 07/12/2013] [Indexed: 02/06/2023]
Affiliation(s)
- Jun-Yang Lu
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Yi Xiao
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Hui-Zhong Qiu
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Bin Wu
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Guo-Le Lin
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Lai Xu
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Guan-Nan Zhang
- Department of Surgery; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
| | - Ke Hu
- Department of Radiation; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences; Beijing China
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Díaz Beveridge R, Aparicio J, Tormo A, Estevan R, Artes J, Giménez A, Segura Á, Roldán S, Palasí R, Ramos D. Long-term results with oral fluoropyrimidines and oxaliplatin-based preoperative chemoradiotherapy in patients with resectable rectal cancer. A single-institution experience. Clin Transl Oncol 2013; 14:471-80. [PMID: 22634537 DOI: 10.1007/s12094-012-0826-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Neoadjuvant 5-FU-based chemoradiotherapy in resectable rectal cancer (RC) is a standard of treatment. The use of oral fluoropyrimidines and new agents such as oxaliplatin may improve efficacy and tolerance. MATERIAL AND METHODS Between 1999 and 2009, 126 RC patients with T3-T4 and/or N+ disease were given three successive protocols: UFT (32), UFT-oxaliplatin (75) and capecitabine-oxaliplatin (19), alongside 45 Gy of radiotherapy; with surgery 4-6 weeks after. Adjuvant treatment was given in all patients. The primary objective was pathologic complete response (pCR). RESULTS Preoperative therapy was well tolerated, with no toxic deaths and a 15% grade 3-4 toxicity rate. Eighty-five percent of patients received the full chemotherapy dose, 56% had an abdominoperineal resection, 6% reinterventions and 57% received the full adjuvant chemotherapy planned. The pCR rate was 13%. The downstaging rate was 80%; 8% had progression of disease. The relapse rate was 20%, with local relapse in 6%. By 5 years of followup, 92% of relapses had occurred. Median follow-up was 73 months, 5- and 10-year disease-free survival rates were 75% and 50%, and 5- and 10-year overall survival rates were 79% and 66% respectively. There was no benefit from the use of oxaliplatin regarding survival or pCR rates. Older patients had worse long-term outcomes. CONCLUSIONS Neoadjuvant chemoradiotherapy with oral fluoropyrimidines and oxaliplatin is feasible and well tolerated. The risk of early progression is low. However, there was no added benefit with the use of oxaliplatin. There were no relapses in patients with pCR. The role of adjuvant chemotherapy is unclear.
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Affiliation(s)
- Robert Díaz Beveridge
- Medical Oncology Department, University Hospital La Fe, C/ Bulevar Sur, s/n, ES-46026 Valencia, Spain.
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Wolff HA, Conradi LC, Beissbarth T, Leha A, Hohenberger W, Merkel S, Fietkau R, Raab HR, Tschmelitsch J, Hess CF, Becker H, Wittekind C, Sauer R, Rödel C, Liersch T. Gender affects acute organ toxicity during radiochemotherapy for rectal cancer: long-term results of the German CAO/ARO/AIO-94 phase III trial. Radiother Oncol 2013; 108:48-54. [PMID: 23768685 DOI: 10.1016/j.radonc.2013.05.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 04/26/2013] [Accepted: 05/02/2013] [Indexed: 01/27/2023]
Abstract
INTRODUCTION The CAO/ARO/AIO-94 phase-III-trial demonstrated a significant improvement of preoperative chemoradiotherapy (CRT) versus postoperative CRT on local control for UICC stage II/III rectal cancer patients, but no effect on long-term survival. In this add-on evaluation, we investigated the association of gender and age with acute toxicity and outcome. PATIENTS AND METHODS According to actual treatment analyses, 654 of 799 patients had received pre- (n=406) or postoperative CRT (n=248); in 145 patients postoperative CRT was not applied. Gender, age and clinicopathological parameters were correlated with CRT-associated acute toxicity and survival. RESULTS The 10-year survival was higher in women than in men, with 72.4% versus 65.6% for time to recurrence (p=0.088) and 62.7% versus 58.4% for overall-survival (OS) (p=0.066), as expected. For patients receiving CRT, women showed higher hematologic (p<0.001) and acute organ toxicity (p<0.001) in the entire cohort as well as in subgroup analyses according to pre- (p=0.016) and postoperative CRT (p<0.001). Lowest OS was seen in patients without acute toxicity (p=0.0271). Multivariate analyses for OS showed that acute organ toxicity (p=0.034) was beneficial while age (p<0.001) was associated with worse OS. DISCUSSION Female gender is significantly associated with CRT-induced acute toxicity in rectal cancer. Acute toxicity during CRT may be associated with improved long-term outcome.
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Musio D, De Felice F, Bulzonetti N, Guarnaccia R, Caiazzo R, Bangrazi C, Raffetto N, Tombolini V. Neoadjuvant-intensified treatment for rectal cancer: Time to change? World J Gastroenterol 2013; 19:3052-3061. [PMID: 23716984 PMCID: PMC3662944 DOI: 10.3748/wjg.v19.i20.3052] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 01/10/2013] [Accepted: 03/09/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether neoadjuvant-intensified radiochemotherapy improved overall and disease-free survival in patients with locally advanced rectal cancer.
METHODS: Between January 2007 and December 2011, 80 patients with histologically confirmed rectal adenocarcinoma were enrolled. Tumors were clinically classified as either T3 or T4 and by the N stage based on the presence or absence of positive regional lymph nodes. Patients received intensified combined modality treatment, consisting of neoadjuvant radiation therapy (50.4-54.0 Gy) and infusional chemotherapy (oxaliplatin 50 mg/m2) on the first day of each week, plus five daily continuous infusions of fluorouracil (200 mg/m2 per die) from the first day of radiation therapy until radiotherapy completion. Patients received five or six cycles of oxaliplatin based on performance status, clinical lymph node involvement, and potential risk of a non-sphincter-conserving surgical procedure. Surgery was planned 7 to 9 wk after the end of radiochemotherapy treatment; adjuvant chemotherapy treatment was left to the oncologist’s discretion and was recommended in patients with positive lymph nodes. After treatment, all patients were monitored every three months for the first year and every six months for the subsequent years.
RESULTS: Of the 80 patients enrolled, 75 patients completed the programmed neoadjuvant radiochemotherapy treatment. All patients received the radiotherapy prescribed total dose; five patients suspended chemotherapy indefinitely because of chemotherapy-related toxicity. At least five cycles of oxaliplatin were administered to 73 patients. Treatment was well tolerated with high compliance and a good level of toxicity. Most of the acute toxic effects observed were classified as grades 1-2. Proctitis grade 2 was the most common symptom (63.75%) and the earliest manifestation of acute toxicity. Acute toxicity grades 3-4 was reported in 30% of patients and grade 3 or 4 diarrhoea reported in just three patients (3.75%). Seventy-seven patients underwent surgery; low anterior resection was performed in 52 patients, Miles’ surgery in 11 patients and total mesorectal excision in nine patients. Fifty patients showed tumor downsizing ≥ 50% pathological downstaging in 88.00% of tumors. Out of 75 patients surviving surgery, 67 patients (89.33%) had some form of downstaging after preoperative treatment. A pathological complete response was achieved in 23.75% of patients and a nearly pathologic complete response (stage ypT1ypN0) in six patients. An involvement of the radial margin was never present. During surgery, intra-abdominal metastases were found in only one patient (1.25%). Initially, 45 patients required an abdominoperineal resection due to a tumor distal margin ≤ 5 cm from the anal verge. Of these patients, only seven of them underwent Miles’ surgery and sphincter preservation was guaranteed in 84.50% of patients in this subgroup. Fourteen patients received postoperative chemotherapy. In the full analysis of enrolled cohort, eight of the 80 patients died, with seven deaths related to rectal cancer and one to unrelated causes. Local recurrences were observed in seven patients (8.75%) and distant metastases in 17 cases (21.25%). The five-year rate of overall survival rate was 90.91%. Using a median follow-up time of 28.5 mo, the cumulative incidence of local recurrences was 8.75%, and the overall survival and disease-free survival rates were 90.00% and 70.00%, respectively.
CONCLUSION: The results of this study suggest oxaliplatin chemotherapy has a beneficial effect on overall survival, likely due to an increase in local tumor control.
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Ricardi U, Racca P, Franco P, Munoz F, Fanchini L, Rondi N, Dongiovanni V, Gabriele P, Cassoni P, Ciuffreda L, Morino M, Filippi AR, Aglietta M, Bertetto O. Prospective phase II trial of neoadjuvant chemo-radiotherapy with Oxaliplatin and Capecitabine in locally advanced rectal cancer (XELOXART). Med Oncol 2013; 30:581. [PMID: 23606239 DOI: 10.1007/s12032-013-0581-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 04/11/2013] [Indexed: 01/25/2023]
Abstract
Neo-adjuvant chemo-radiotherapy (CT-RT) has been shown to decrease local recurrence rate in locally advanced rectal cancer. This multicenter phase II trial was conducted to evaluate the feasibility, safety and effectiveness of a combination of pre-operative radiotherapy and concurrent Capecitabine plus Oxaliplatin (XELOXART Trial). From October 2008 to May 2011, fifty consecutive patients affected with T3/T4 and/or N+ rectal cancer were enrolled. Treatment protocol consisted of 50.4 Gy in 28 fractions, Oxaliplatin 60 mg/m(2) once a week for 6 weeks and oral Capecitabine 825 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35. Surgery was planned 6-8 weeks after. Main endpoints were pathological complete response rate (pCR) and the type of surgery performed compared to the planned one at diagnosis. 50 patients were included; pCR (ypT0N0M0) was achieved in 6 patients (12 %). Tumour downstaging was observed in 27 patients (54 %), and nodal downstaging in 32 patients (64 %). A total of 32 patients had lower rectal cancer, with 24 candidate for abdominal-perineal resection. At the end of CT-RT, a total of 12/24 (50 %) underwent conservative surgery. Grade 3 toxicity (fatigue and diarrhoea) occurred in 4 % of patients; grade 4 sensory neuropathy occurred in 2 % of patients. Perioperative complications of any grade occurred in 10 % of patients. Pre-operative CT-RT with Capecitabine-Oxaliplatin was well tolerated and resulted in an encouraging sphincter preservation and tumour downstaging rate. No improvements in terms of pathological complete response rate were shown.
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Affiliation(s)
- Umberto Ricardi
- Department of Oncology, Radiation Oncology, University of Torino, via Genova 3, 10126 Turin, Italy
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Fernández-Martos C, Nogué M, Cejas P, Moreno-García V, Machancoses AH, Feliu J. The role of capecitabine in locally advanced rectal cancer treatment: an update. Drugs 2012; 72:1057-73. [PMID: 22621694 DOI: 10.2165/11633870-000000000-00000] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m(2) twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. Oxaliplatin and irinotecan are therefore good candidates. However, two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and, by contrast, increased toxicity. Capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial. New strategies with induction chemotherapy with or without chemoradiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further development of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropyrimidine-based regimen remains investigational.
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Salazar R, Navarro M, Losa F, Alonso V, Gallén M, Rivera F, Benavides M, Escudero P, González E, Massutí B, Gómez A, Majem M, Aranda E. Phase II study of preoperative radiotherapy and concomitant weekly intravenous oxaliplatin combined with oral capecitabine for stages II–III rectal cancer. Clin Transl Oncol 2012; 14:592-8. [DOI: 10.1007/s12094-012-0846-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 11/02/2011] [Indexed: 01/03/2023]
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Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer. Int J Surg Oncol 2012; 2012:406568. [PMID: 22830003 PMCID: PMC3399366 DOI: 10.1155/2012/406568] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Accepted: 05/15/2012] [Indexed: 12/29/2022] Open
Abstract
Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose-rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.
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Schirmer MA, Mergler CPN, Rave-Fränk M, Herrmann MK, Hennies S, Gaedcke J, Conradi LC, Jo P, Beissbarth T, Hess CF, Becker H, Ghadimi M, Brockmöller J, Christiansen H, Wolff HA. Acute Toxicity of Radiochemotherapy in Rectal Cancer Patients: A Risk Particularly for Carriers of the TGFB1 Pro25 variant. Int J Radiat Oncol Biol Phys 2012; 83:149-57. [DOI: 10.1016/j.ijrobp.2011.05.063] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 05/19/2011] [Accepted: 05/26/2011] [Indexed: 01/10/2023]
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Winkler J, Zipp L, Knoblich J, Zimmermann F. Simultaneous neoadjuvant radiochemotherapy with capecitabine and oxaliplatin for locally advanced rectal cancer. Treatment outcome outside clinical trials. Strahlenther Onkol 2012; 188:377-82. [PMID: 22402868 DOI: 10.1007/s00066-012-0073-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Accepted: 01/11/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Phase II trials of neoadjuvant treatment in UICC-TNM stage II and III rectal cancer with capecitabine and oxaliplatin demonstrated favourable rates on tumour regression with acceptable toxicity. PATIENTS AND METHODS Retrospective evaluation of 34 patients treated from 2005-2008 outside clinical trials (CTR) with neoadjuvant irradiation (45-50.4 Gy) and simultaneous capecitabine 825 mg/m(2) b.i.d. on days 1-14 and 22-35 and oxaliplatin 50 mg/m(2) on days 1, 8, 22 and 29 (CAPOX). Twenty-six (77%) patients received one or two courses of capecitabine 1,000 mg/m(2) b.i.d. on days 1-14 and oxaliplatin 130 mg/m(2) on day 1 (XELOX) prior to simultaneous chemoradiotherapy. RESULTS UICC-TNM stage regression was observed in 60% (n = 20). Dworak's regression grades 3 and 4 were achieved in 18.2% (n = 6) and 15.1% (n = 5) of the patients. Sphincter-preserving surgery was performed in 53% (n = 8) of patients with a tumour of the lower rectum. Within the mean observation of 24 months, none of the patients relapsed locally, 1 patient had progressive disease and 5 patients (15%) relapsed distantly. Toxicity of grade 3 and 4 was mainly diarrhoea 18% (n = 6) and perianal pain 9% (n = 3). Nevertheless, severe cardiac events (n = 2), severe electrolyte disturbances (n = 2), and syncopes (n = 2) were observed as well. CONCLUSION Treatment efficacy and common toxicity are similar to the reports of phase I/II trials. However, several severe adverse events were observed in our cohort study. The predisposing factors for these events have yet to be studied and may have implications for the selection of patients outside CTR.
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Affiliation(s)
- J Winkler
- Department of Radiation Oncology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland
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Gasent Blesa JM, Garde Noguera J, Laforga Canales JB, Giner Bosch V, Alberola A, Soler Tortosa M, Peris Godoy M, Sanchez JL, Provencio Pulla M, Alberola Candel V. Phase II Trial of Concomitant Neoadjuvant Chemotherapy with Oxaliplatin and Capecitabine and Intensity-Modulated Radiotherapy (IMRT) in Rectal Cancer. J Gastrointest Cancer 2012; 43:553-61. [DOI: 10.1007/s12029-012-9364-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Czito BG, Willett CG. Potential Novel Drugs to Combine with Radiation in Rectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2012. [DOI: 10.1007/s11888-012-0120-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Hill EJ, Nicolay NH, Middleton MR, Sharma RA. Oxaliplatin as a radiosensitiser for upper and lower gastrointestinal tract malignancies: what have we learned from a decade of translational research? Crit Rev Oncol Hematol 2012; 83:353-87. [PMID: 22309673 DOI: 10.1016/j.critrevonc.2011.12.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Revised: 12/14/2011] [Accepted: 12/28/2011] [Indexed: 01/08/2023] Open
Abstract
Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies should be designed, the pre-clinical evidence for the use of oxaliplatin chemotherapy as a radiosensitising agent is appraised. Particular focus is placed on oxaliplatin's biological mechanisms of action, including cell cycle effects, the formation of DNA adducts and interstrand cross-links and the role of DNA repair proteins. At a clinical level, there is currently no evidence to suggest that oxaliplatin provides an additional benefit to concurrent chemo-radiation regimes that utilise fluoropyrimidines; we evaluate the reasons for this observation, the limitations of clinical trial design and the opportunities that currently exist to design clinical trials which are underpinned by an understanding of the basic biology.
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Affiliation(s)
- Esme J Hill
- Gray Institute of Radiation Oncology and Biology, Oncology Department, Old Road Campus Research Building, Oxford OX3 7DQ, UK
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Minsky BD. Progress in the Treatment of Locally Advanced Clinically Resectable Rectal Cancer. Clin Colorectal Cancer 2011; 10:227-37. [DOI: 10.1016/j.clcc.2011.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2011] [Accepted: 06/21/2011] [Indexed: 12/11/2022]
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Wolff HA, Wagner DM, Conradi LC, Hennies S, Ghadimi M, Hess CF, Christiansen H. Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: a planning study with clinical implications. Radiother Oncol 2011; 102:30-7. [PMID: 22112780 DOI: 10.1016/j.radonc.2011.10.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2011] [Revised: 09/20/2011] [Accepted: 10/17/2011] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND PURPOSE Ongoing clinical trials aim to improve local control and overall survival rates by intensification of therapy regimen for patients with locally advanced rectal cancer. It is well known that whenever treatment is intensified, risk of therapy-related toxicity rises. An irradiation with protons could possibly present an approach to solve this dilemma by lowering the exposure to the organs-at-risk (OAR) without compromising tumor response. MATERIAL AND METHODS Twenty five consecutive patients were treated from 04/2009 to 5/2010. For all patients, four different treatment plans including protons, RapidArc, IMRT and 3D-conformal-technique were retrospectively calculated and analyzed according to dosimetric aspects. RESULTS Detailed DVH-analyses revealed that protons clearly reduced the dose to the OAR and entire normal tissue when compared to other techniques. Furthermore, the conformity index was significantly better and target volumes were covered consistent with the ICRU guidelines. CONCLUSIONS Planning results suggest that treatment with protons can improve the therapeutic tolerance for the irradiation of rectal cancer, particularly for patients scheduled for an irradiation with an intensified chemotherapy regimen and identified to be at high risk for acute therapy-related toxicity. However, clinical experiences and long-term observation are needed to assess tumor response and related toxicity rates.
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Affiliation(s)
- Hendrik Andreas Wolff
- Department of Radiotherapy and Radiooncology, University Medical Center, Göttingen, Germany.
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Arbea L, Martínez-Monge R, Díaz-González JA, Moreno M, Rodríguez J, Hernández JL, Sola JJ, Ramos LI, Subtil JC, Nuñez J, Chopitea A, Cambeiro M, Gaztañaga M, García-Foncillas J, Aristu J. Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial. Int J Radiat Oncol Biol Phys 2011; 83:587-93. [PMID: 22079731 DOI: 10.1016/j.ijrobp.2011.06.2008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 06/07/2011] [Accepted: 06/29/2011] [Indexed: 02/07/2023]
Abstract
PURPOSE To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.
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Affiliation(s)
- Leire Arbea
- Department of Oncology, Clínica Universidad de Navarra, Pamplona, Navarra, Spain.
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30
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Engels B, Tournel K, Everaert H, Hoorens A, Sermeus A, Christian N, Storme G, Verellen D, De Ridder M. Phase II study of preoperative helical tomotherapy with a simultaneous integrated boost for rectal cancer. Int J Radiat Oncol Biol Phys 2011; 83:142-8. [PMID: 22014952 DOI: 10.1016/j.ijrobp.2011.05.068] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2011] [Revised: 05/20/2011] [Accepted: 05/26/2011] [Indexed: 12/27/2022]
Abstract
PURPOSE The addition of concomitant chemotherapy to preoperative radiotherapy is considered the standard of care for patients with cT3-4 rectal cancer. The combined treatment modality increases the complete response rate and local control (LC), but has no impact on survival or the incidence of distant metastases. In addition, it is associated with considerable toxicity. As an alternative strategy, we explored prospectively, preoperative helical tomotherapy with a simultaneous integrated boost (SIB). METHODS AND MATERIALS A total of 108 patients were treated with intensity-modulated and image-guided radiotherapy using the Tomotherapy Hi-Art II system. A dose of 46 Gy, in daily fractions of 2 Gy, was delivered to the mesorectum and draining lymph nodes, without concomitant chemotherapy. Patients with an anticipated circumferential resection margin (CRM) of less than 2 mm, based on magnetic resonance imaging, received a SIB to the tumor up to a total dose of 55.2 Gy. Acute and late side effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS A total of 102 patients presented with cT3-4 tumors; 57 patients entered the boost group and 51 the no-boost group. One patient in the no-boost group developed a radio-hypersensitivity reaction, resulting in a complete tumor remission, a Grade 3 acute and Grade 5 late enteritis. No other Grade ≥3 acute toxicities occurred. With a median follow-up of 32 months, Grade ≥3 late gastrointestinal and urinary toxicity were observed in 6% and 4% of the patients, respectively. The actuarial 2-year LC, progression-free survival and overall survival were 98%, 79%, and 93%. CONCLUSIONS Preoperative helical tomotherapy displays a favorable acute toxicity profile in patients with cT3-4 rectal cancer. A SIB can be safely administered in patients with a narrow CRM and resulted in a promising LC.
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Affiliation(s)
- Benedikt Engels
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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Abstract
In the past two decades, substantial progress has been made in the adjuvant management of colorectal cancer. Chemotherapy has improved overall survival in patients with node-positive (N+) disease. In contrast with colon cancer, which has a low incidence of local recurrence, patients with rectal cancer have a higher incidence requiring the addition of pelvic radiation therapy (chemoradiation). Patients with rectal cancer have a number of unique management considerations: for example, the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? This review will address these and other controversies specific to patients with rectal cancer.
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Affiliation(s)
- Bruce D Minsky
- Department of Radiation and Cellular Oncology, University of Chicago Medical Center, Chicago, IL 60637, USA.
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McRee AJ, Cowherd S, Wang AZ, Goldberg RM. Chemoradiation therapy in the management of gastrointestinal malignancies. Future Oncol 2011; 7:409-26. [PMID: 21417904 DOI: 10.2217/fon.11.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Concurrent administration of chemotherapy and radiotherapy has been increasingly used in cancer treatment, leading to improvements in survival as well as quality of life. Currently, it is a feasible preference, often regarded as the standard therapeutic option, for many locally confined solid tumors, including anal, bladder, cervical, esophageal, gastric, head and neck, lung, pancreatic and rectal cancers. In patients with these tumors, combined modality therapy improves local tumor control and survival while, in some instances, obviating the need for surgical removal of the organ of origin. The scientific rationale for the use of chemoradiation derives from the preclinical and clinical observations of synergistic interactions between radiotherapy and chemotherapy. When chemotherapy and radiotherapy are administered together, the chemotherapeutic agents can sensitize the cancer cells to the effects of ionizing radiation, leading to increased tumor-killing effects within the radiotherapy field. This, in turn, can improve local control of the primary tumor and, in some cancers, render surgical resection unnecessary. In other cases, patients with tumors that were initially considered unresectable are able to undergo curative interventions after completing chemoradiation. The chemotherapy component can address any potential micrometastatic disease that, without therapy, leads to an increased risk of distant recurrence. A large body of evidence exists that supports the use of chemoradiotherapy in gastrointestinal cancers. In fact, one of the first tumor types in which the superior efficacy of chemoradiation was described was anal cancer. Since then, chemoradiotherapy has been explored in other gastrointestinal malignancies with superior outcomes when compared with either radiation or chemotherapy alone. This article aims to recapitulate the clinical evidence supporting the use of chemoradiotherapy in a variety of gastrointestinal tumor types.
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Affiliation(s)
- Autumn J McRee
- Department of Hematology/Oncology, University of North Carolina School of Medicine, NC, USA
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A phase II study of neoadjuvant chemoradiotherapy with oxaliplatin and capecitabine for rectal cancer. Cancer Lett 2011; 310:134-9. [PMID: 21782322 DOI: 10.1016/j.canlet.2011.06.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Revised: 06/15/2011] [Accepted: 06/16/2011] [Indexed: 12/11/2022]
Abstract
PURPOSE This study evaluated the efficacy and safety of neoadjuvant chemoradiotherapy with the XELOX regimen in rectal cancer patients. PATIENTS AND METHODS Twenty-five patients with histopathologically confirmed and locally advanced rectal cancer (T3/T4 or N+) were enrolled in the study. Radiotherapy of 5000 cGy was delivered in 25 fractions of 200 cGy five times per week for a total of 5 weeks. During the first, second, fourth and fifth weeks of radiotherapy, the patients also received the following chemotherapy: 50 mg/m2 oxaliplatin on day one and 850 mg/m2 capecitabine bid for 5 days. Surgery was scheduled 5-6 weeks after the completion of the preoperative chemoradiotherapy. Four weeks after the surgery, four more cycles of chemotherapy were administered every 3 weeks. The postoperative chemotherapy consisted of 130 mg/m2 oxaliplatin on day 1 and 1000 mg/m2 capecitabine bid from day 1 to day 14. The end points were the downstage rate, R0 resection rate, and sphincter preservation rate. RESULTS Twenty-five patients received the neoadjuvant chemoradiotherapy. The overall regression rate was 85%, with a Grade 3/4 regression rate of 30% and a pathological complete response rate of 12%. Among the 17 patients with lower rectal cancer, thirteen (76%) were originally indicated for abdominal-perineal resection (APR). However, after the neoadjuvant chemoradiotherapy, the anus could be preserved in nine patients (53%). The most frequent toxicities of the chemoradiotherapy were diarrhea (64%) and hematological toxicity (60%), followed by nausea and vomiting (48%), urinary tract irritation (28%), and anal pain (24%). Grade 3 or 4 adverse events were relatively infrequent and presented as diarrhea (12%), myelosuppression (8%), and elevated transaminase (4%). Six cases also experienced long-term anal exudates after surgery. CONCLUSIONS Neoadjuvant chemoradiotherapy using the XELOX regimen in rectal cancer patients obviously reduced the TNM staging and improved the pathological complete response rate. The therapy was well-tolerated and had mild adverse events and no serious perioperational complications.
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Beyond 5-Fluorouracil: The Emerging Role of Newer Chemotherapeutics and Targeted Agents with Radiation Therapy. Semin Radiat Oncol 2011; 21:203-11. [DOI: 10.1016/j.semradonc.2011.02.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Wolff HA, Conradi LC, Schirmer M, Beissbarth T, Sprenger T, Rave-Fränk M, Hennies S, Hess CF, Becker H, Christiansen H, Liersch T. Gender-specific acute organ toxicity during intensified preoperative radiochemotherapy for rectal cancer. Oncologist 2011; 16:621-31. [PMID: 21558132 DOI: 10.1634/theoncologist.2010-0414] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil-based (5-FU-based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity. All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5-FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade ≥3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone. Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5-FU+oxaliplatin. A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity. These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity.
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Affiliation(s)
- Hendrik A Wolff
- Department of Radiotherapy and Radiooncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
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He Q, Li J, Yin W, Song Z, Zhang Z, Yi T, Tang J, Wu D, Lu Y, Wang Z, Liu D, Zhang X, Hu Z, Gao J. Low-dose paclitaxel enhances the anti-tumor efficacy of GM-CSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer. Cancer Immunol Immunother 2011; 60:715-30. [PMID: 21331814 PMCID: PMC11028932 DOI: 10.1007/s00262-011-0988-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Accepted: 01/11/2011] [Indexed: 12/30/2022]
Abstract
Chemotherapy combined with a tumor vaccine is an attractive approach in cancer therapy. This study was designed to investigate the optimal schedule and mechanisms of action of a novel GM-CSF (granulocyte-macrophage colony-stimulating factor) surface-modified tumor-cell vaccine in combination with paclitaxel in the treatment of mouse RM-1 prostate cancer. First, the anti-tumor efficiencies of various dosage of paclitaxel (4, 20, 40 mg/kg) in combination with the vaccine in different administration sequences were examined in the mouse RM-1 prostate cancer model. Then, the in vivo and in vitro effects of various dosage of paclitaxel on RM-1 cells, T cells, and DCs (dendritic cells) were evaluated. The results showed that: (a) the GM-CSF-surface-modified tumor-cell vaccine was more potent at inducing the uptake of tumor antigens by DCs than irradiated tumor cells plus free GM-CSF; (b) 4 mg/kg paclitaxel combined with the GM-CSF-surface-modified tumor-cell vaccine was the most effective at enhancing tumor regression in RM-1 prostate cancer mice when the vaccine was administrated 2 days after paclitaxel; and (c) administration of 4 mg/kg paclitaxel followed by the vaccine induced the highest degree of CD8(+) T-cell infiltration in tumor tissue, suggesting that the induction of tumor-specific immune response had occurred. These findings suggested that the GM-CSF-surface-modified tumor-cell vaccine may have potential clinical benefit for patients with prostate cancer when it is combined with paclitaxel. Furthermore, the effect of immunochemotherapy depends on careful selection of paclitaxel dosage and the sequence of paclitaxel/vaccine administration.
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Affiliation(s)
- Qiushan He
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
- Department of Oncology, Affiliated Xiangfan Hospital, Tongji Medical College, Huazhong Scientific and Technical University, Xiangfan, China
| | - Jinlong Li
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, China
| | - Weihua Yin
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, China
| | - Zhichun Song
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Zhen Zhang
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, China
| | - Tienan Yi
- Department of Oncology, Affiliated Xiangfan Hospital, Tongji Medical College, Huazhong Scientific and Technical University, Xiangfan, China
| | - Jia Tang
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Demin Wu
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Yue Lu
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Zhen Wang
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Dan Liu
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Xiaoren Zhang
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
| | - Zhiming Hu
- Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, China
- 1838 Guangzhou da dao bei, Guangzhou, 510515 China
| | - Jimin Gao
- Zhejiang Provincial Key Lab for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical College, University Park, 325035 Wenzhou, China
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Hirsch BR, Zafar SY. Capecitabine in the management of colorectal cancer. Cancer Manag Res 2011; 3:79-89. [PMID: 21629830 PMCID: PMC3097797 DOI: 10.2147/cmr.s11250] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Indexed: 12/27/2022] Open
Abstract
5-Fluorouracil has been a mainstay in the treatment of colorectal cancer for nearly five decades; however, the use of oral formulations of the medication has been gaining increasing traction since capecitabine was approved for use in adjuvant settings by the US Food and Drug Administration in 2005. The use of capecitabine has since spread to a number of off-label indications, including the treatment of advanced or metastatic colorectal cancer and the neoadjuvant treatment of rectal cancer. In light of increasing utilization, it is critical that clinicians have a firm understanding of the literature supporting capecitabine across various settings as well as the attributes of the drug, such as its dosing recommendations, side-effect profile, and use in the elderly. The purpose of this review is to synthesize the literature in a fashion that can be used to help guide decisions. In a setting of increasing focus on cost, the pharmacoeconomic literature is also briefly reviewed.
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Affiliation(s)
- Bradford R Hirsch
- Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA
| | - S Yousuf Zafar
- Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA
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Preoperative intensified radiochemotherapy for rectal cancer: experience of a single institution. Int J Colorectal Dis 2011; 26:153-64. [PMID: 21107849 DOI: 10.1007/s00384-010-1064-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/04/2010] [Indexed: 02/04/2023]
Abstract
PURPOSE The aim of our study was to evaluate the feasibility and the effectiveness of an intensified neoadjuvant protocol with the addition of weekly oxaliplatin in the preoperative strategy of rectal cancer treatment. PATIENTS AND METHODS Patients with locally advanced rectal cancer received continous infusion 5-Fluorouracil (5-FU) 200 mg/m(2)/day in combination with weekly oxaliplatin at a dose of 50 mg/m(2). Doses of radiotherapy were 45 Gy to the whole pelvis plus 5.4-9 Gy to the tumour mass. The primary end-points of the study were evaluation of toxicity, compliance with radiotherapy and chemotherapy, downstaging, pathological complete response (pCR) and the rate of sphincter preservation for distal cancers. Secondary end-points were relapse-free and overall survival. RESULTS From November 2006 to June 2009, 51 patients were enrolled into the study. Compliance with chemotherapy was 80%. The incidence of G3 diarrhoea and proctitis were 17.6% and 21.5%, respectively. Surgery was performed in 48 patients with 100% R0 resection. 76.4% of low-lying tumours underwent conservative treatment. Seventy-nine percent of patients were downstaged: T and N downstaging were observed in 71% and 75% of patients, respectively. A pCR was obtained in 11 (22.9%) patients. CONCLUSIONS Intensification of neoadjuvant treatment for rectal cancer with the addition of weekly oxaliplatin is feasible, with remarkable rates of downstaging and pathological complete response. Data on sphincter preservation for distal cancers were excellent. Phase III trials with a longer follow-up will establish whether this good outcome in terms of surrogate end-points will translate into better rates of disease-free and overall survival.
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Minsky BD. Chemoradiation for rectal cancer: rationale, approaches, and controversies. Surg Oncol Clin N Am 2011; 19:803-18. [PMID: 20883955 DOI: 10.1016/j.soc.2010.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The standard adjuvant treatment of cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These controversies include the role of short course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery following chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation, as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.
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Affiliation(s)
- Bruce D Minsky
- Department of Radiation and Cellular Oncology, University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
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40
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Ofner D, Devries AF, Schaberl-Moser R, Greil R, Rabl H, Tschmelitsch J, Zitt M, Kapp KS, Fastner G, Keil F, Eisterer W, Jäger R, Offner F, Gnant M, Thaler J. Preoperative oxaliplatin, capecitabine, and external beam radiotherapy in patients with newly diagnosed, primary operable, cT₃NxM0, low rectal cancer: a phase II study. Strahlenther Onkol 2011; 187:100-7. [PMID: 21267531 DOI: 10.1007/s00066-010-2182-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 11/11/2010] [Indexed: 01/08/2023]
Abstract
PURPOSE In patients with locally advanced rectal cancer (LARC), preoperative chemoradiation is known to improve local control, and down-staging of the tumor serves as a surrogate for survival. Intensification of the systemic therapy may lead to higher downstaging rates and, thus, enhance survival. This phase II study investigated the efficacy and safety of preoperative capecitabine and oxaliplatin in combination with radiotherapy. PATIENTS AND METHODS Patients with LARC of the mid and lower rectum, T₃NxM0 staged by MRI received radiotherapy (total dose 45 Gy) in combination with oral capecitabine (825 mg/m² twice a day on radiotherapy days; weeks 1-4) and oxaliplatin 50 mg/m² intravenously (days 1, 8, 15, and 22). Efficacy was evaluated as rate of tumor down-categorization at the T level. RESULTS A total of 59 patients were enrolled (19 women, 40 men; median age of 61 years) and all were evaluable for efficacy and toxicity. Down-categorization at the T level was observed in 53% with pathological complete response in 6 patients (10%). Actual total radiotherapy, oxaliplatin and capecitabine doses received were 97%, 90%, and 93% of the protocol-specified preplanned doses, respectively. Grade 3/4 toxicity was observed in 15 patients (25%). The most frequent was diarrhea (12%). CONCLUSIONS Preoperative chemoradiation with capecitabine and oxaliplatin is feasible in patients with MRI-proven cT₃ LARC. The only clinically relevant toxicity was diarrhea. Overall, efficacy of the multimodality treatment was good, but not markedly exceeding that of 5-FU- or capecitabine-based chemoradiation approaches.
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Affiliation(s)
- Dietmar Ofner
- Department of Surgery, Paracelsus Private Medical University, Salzburg, Austria.
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Kao PS, Chang SC, Wang LW, Lee RC, Liang WY, Lin TC, Chen WS, Jiang JK, Yang SH, Wang HS, Lin JK. The impact of preoperative chemoradiotherapy on advanced low rectal cancer. J Surg Oncol 2011; 102:771-7. [PMID: 20872811 DOI: 10.1002/jso.21711] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Preoperative chemoradiotherapy (CCRT) followed by radical resection is an option for advanced low rectal cancer. This study was aimed to clarify the impact of CCRT on patients' outcome. PATIENTS AND METHODS One hundred thirty-six patients with rectal cancer (<10 cm from anal verge) were enrolled prospectively between July 2000 and December 2004. The preoperative clinical stage was T3, T4, or node-positive disease. Sixty-nine and 67 patients underwent surgery with and without preoperative CCRT, respectively. The regimen of pre-op CCRT was a radiation dosage of 45 Gy in 20 fractions and oral tegafur-uracil (UFUR) and leucovorin. RESULTS There was no statistical difference in the preserved anorectal function between two groups after 5 years of follow-up (62.3% vs. 47.8%; P = 0.125). The 5-year overall survival and disease-free survival (DFS) percentage were 88.4% and 76.8% for patients with preoperative CCRT, and 65.7% and 58.2% for patients without CCRT, respectively. Patients with preoperative CCRT had a higher overall survival rate and DFS (P = 0.001 and 0.015). CONCLUSIONS In patients with advanced low rectal cancer, preoperative CCRT followed by radical surgery significantly improved overall survival and DFS compared with surgery alone. The effect of sphincter preservation with preoperative CCRT is questionable.
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Affiliation(s)
- Ping-Sheng Kao
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan
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Silvestris N, Maiello E, De Vita F, Cinieri S, Santini D, Russo A, Tommasi S, Azzariti A, Numico G, Pisconti S, Petriella D, Lorusso V, Millaku A, Colucci G. Update on capecitabine alone and in combination regimens in colorectal cancer patients. Cancer Treat Rev 2010; 36 Suppl 3:S46-55. [DOI: 10.1016/s0305-7372(10)70020-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Abstract
The standard adjuvant treatment for cT3 and/or N+ rectal cancer is preoperative chemoradiation. However, there are many controversies regarding this approach. These include the role of short course radiation, whether postoperative adjuvant chemotherapy necessary for all patients and whether the type of surgery after chemoradiation should be based on the response rate. More accurate imaging techniques and/or molecular markers may help identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve the results of radiation as well as modify the need for pelvic radiation? These questions and others remain active areas of clinical investigation.
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Arbea L, Díaz-González JA, Subtil JC, Sola J, Hernandez-Lizoain JL, Martínez-Monge R, Moreno M, Aristu J. Patterns of response after preoperative intensity-modulated radiation therapy and capecitabine/oxaliplatin in rectal cancer: is there still a place for ecoendoscopic ultrasound? Int J Radiat Oncol Biol Phys 2010; 81:439-44. [PMID: 20800389 DOI: 10.1016/j.ijrobp.2010.05.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Revised: 05/07/2010] [Accepted: 05/12/2010] [Indexed: 01/13/2023]
Abstract
PURPOSE The main goals of preoperative chemoradiotherapy (CHRT) in rectal cancer are to achieve pathological response and to ensure tumor control with functional surgery when possible. Assessment of the concordance between clinical and pathological responses is necessary to make decisions regarding alternative conservative procedures. The present study evaluates the patterns of response after a preoperative CHRT regimen, and the value of endoscopic ultrasound (EUS) in assessing response. METHODS AND MATERIALS A total of 51 EUS-staged T3 to T4 and/or N0 to N+ rectal cancer patients received preoperative CHRT (intensity-modulated radiation therapy and capecitabine/oxaliplatin (XELOX) followed by radical resection. Clinical response was assesed by EUS. Rates of pathological tumor regression grade (TRG) and lymph node (LN) involvement were determined in the surgical specimen. Clinical and pathological responses were compared, and the accuracy of EUS in assessing response was calculated. RESULTS Twenty-four patients (45%) achieved a major pathological response (complete or >95% pathological response (TRG 3+/4)). Sensitivity, specificity, negative predictive value, and positive predictive value of EUS in predicting pathological T response after preoperative CHRT were 77.8%, 37.5%, 60%, and 58%, respectively. The EUS sensitivity, specificity, negative predictive value, and positive predictive value for nodal staging were 44%, 88%, 88%, and 44%, respectively. Furthermore, EUS after CHRT accurately predicted the absence of LN involvement in 7 of 7 patients (100%) with major pathological response of the primary tumor. CONCLUSION Preoperative IMRT with concomitant XELOX induces favorable rates of major pathological response. EUS has a limited ability to predict primary tumor response after preoperative CHRT, but it is useful for accurately determining LN status. EUS may have a potential value in identifying patients with a very low risk of LN involvement in association with a good pathological response as potential candidates for conservative local surgical protocols.
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Affiliation(s)
- Leire Arbea
- Department of Oncology, Radiation Oncology Division, Clinica Universidad de Navarra, Pamplona, Spain.
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Koukourakis GV, Zacharias G, Tsalafoutas J, Theodoridis D, Kouloulias V. Capecitabine for locally advanced and metastatic colorectal cancer: A review. World J Gastrointest Oncol 2010; 2:311-21. [PMID: 21160892 PMCID: PMC2999677 DOI: 10.4251/wjgo.v2.i8.311] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2010] [Revised: 07/30/2010] [Accepted: 08/06/2010] [Indexed: 02/05/2023] Open
Abstract
Capecitabine (Xeloda®) is an oral fluoropyrimidine which is produced as a pro-drug of fluorouracil, and shows improved tolerability and intratumor drug concentrations following its tumor-specific conversion to the active drug. We have searched the Pubmed and Cochrane databases from 1980 to 2009 with the purpose of reviewing all available information on Capecitabine, focusing on its clinical effectiveness against colorectal cancer. Special attention has been paid to trials that compared Capecitabine with standard folinic acid (leucovorin, LV)-modulated intravenous 5-fluorouracil (5-FU) bolus regimens in patients with metastatic colorectal cancer. Moreover the efficacy of Capecitabine on metastatic colorectal cancer, either alone or in various combinations with other active drugs such as Irinotecan and Oxaliplatin was also assessed. Finally, neoadjuvant therapy consisting of Capecitabine plus radiation therapy, for locally advanced rectal cancer was analysed. This combination of chemotherapy and radiotherapy has a special role in tumor down staging and in sphincter preservation for lower rectal tumors. Comparative trials have shown that Capecitabine is at least equivalent to the standard LV-5-FU combination in relation to progression-free and overall survival whilst showing a better tolerability profile with a much lower incidence of stomatitis. It is now known that Capecitabine can be combined with other active drugs such as Irinotecan and Oxaliplatin. The combination of Oxaliplatin with Capecitabine represents a new standard of care for metastatic colorectal cancer. Combinating the Capecitabine-Oxaliplatin regimen with promising new biological drugs such as Bevacizumab seems to give a realistic prospect of further improvement in time to progression of metastatic disease. Moreover, preoperative chemo-radiation using oral capecitabine is better tolerated than bolus 5-FU and is more effective in the promotion of both down-staging and sphincter preservation in patients with locally advanced rectal cancer. Finally, the outcomes of recently published trials suggest that capecitabine seems to be more cost effective than other standard treatments for the management of patients with colorectal cancer.
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Affiliation(s)
- Georgios V Koukourakis
- Georgios V Koukourakis, Department of Radiation Oncology, Anticancer Institute of Athens "Saint Savvas", Athens, Greece
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Gollins S. Radiation, chemotherapy and biological therapy in the curative treatment of locally advanced rectal cancer. Colorectal Dis 2010; 12 Suppl 2:2-24. [PMID: 20618363 DOI: 10.1111/j.1463-1318.2010.02320.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVE To review the published evidence relating to the use of radiotherapy (RT), chemotherapy and biological therapy as adjuncts to surgery in the curative treatment of rectal cancer. METHODS Searches were carried out of the MEDLINE and CANCERLIT databases together with conference abstracts from key meetings including the American Society of Clinical Oncology Annual Meeting and Gastrointestinal Cancers Symposium and the ECCO/ESMO Multidisciplinary Congress. RESULTS RT reduces local pelvic recurrence when used as an adjunct to surgery, even when this is performed optimally by total mesorectal excision (TME). RT is usually given as short-course preoperative radiotherapy (SCPRT) followed by immediate surgery which produces no or very little downstaging or long-course concurrent chemoradiation (CRT) followed by a 6-8 week gap prior to surgery which produces significant downstaging. The prognostic importance of achieving a clear histological circumferential resection margin is now well recognised and pathological assessment of the quality of surgery can predict long-term outcomes. Internationally there is considerable heterogeneity in the staging modalities and criteria used in deciding which approach might be used, in the reporting of histological results and in RT parameters (time/dose/fractionation/volume). Attempts to increase the potency of CRT have included the addition of concurrent chemotherapeutic and biological agents to the standard fluoropyrimidine although there is little randomised data and none with regard to long-term survival outcomes. Neither SCPRT nor downstaging CRT have been shown to reduce the rate of subsequent distant metastatic relapse which remains a significant clinical problem. The potential additional benefit of neoadjuvant or adjuvant chemotherapy in addition to SCPRT or long-course CRT remains ill-defined. Late morbidity can include bowel and sexual dysfunction, pelvic fractures and second malignancies with considerably more being known in relation to SCPRT than long-course CRT. CONCLUSIONS Improvements in imaging, pathology and surgical technique combined with multimodality treatment using RT and chemotherapy are leading to continuing improvements in the long term outcome for patients with rectal cancer although much remains to be learnt regarding the optimum strategy for use of these in different clinical contexts and their relationship to long-term morbidity.
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Affiliation(s)
- S Gollins
- North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, Denbighshire, UK.
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Lin JZ, Zeng ZF, Wu XJ, Wan DS, Chen G, Li LR, Lu ZH, Ding PR, Pan ZZ. Phase II study of pre-operative radiotherapy with capecitabine and oxaliplatin for rectal cancer and carcinoembryonic antigen as a predictor of pathological tumour response. J Int Med Res 2010; 38:645-54. [PMID: 20515578 DOI: 10.1177/147323001003800227] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
This study investigated the efficacy and tolerability of pre-operative radiotherapy with concurrent capecitabine and oxaliplatin in patients with rectal cancer. Forty-seven patients with rectal adenocarcinoma (stages T3 - T4; node-positive) were enrolled and received radiotherapy (46 Gy in 23 fractions) in combination with capecitabine (1000 mg/m(2) twice daily on days 1 - 14 and 22 - 35) and oxaliplatin (130 mg/m(2) on days 1 and 22) (XELOX regimen). The main endpoints were safety and efficacy, as assessed by pathological complete response (pCR). All patients received pre-operative chemoradiotherapy (CRT) as planned. The most common severe toxicity was diarrhoea (12.8%); post-operative complications were rare (9.8%). The pCR rate was 20.9% in all patients and 34.8% in patients with normal pre-CRT serum carcinoembryonic antigen (CEA < or = 5 ng/ml) level, compared with 5.0% in the patients with elevated CEA (> 5 ng/ml). In conclusion, pre-operative radiotherapy with concurrent XELOX regimen in rectal cancer patients is feasible and effective. Serum CEA may be a suitable predictor of pCR.
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Affiliation(s)
- J Z Lin
- Department of Colorectal Surgery, Cancer Centre, Sun Yat-sen University, Guangzhou, China
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Hong YS, Kim DY, Lim SB, Choi HS, Jeong SY, Jeong JY, Sohn DK, Kim DH, Chang HJ, Park JG, Jung KH. Preoperative chemoradiation with irinotecan and capecitabine in patients with locally advanced resectable rectal cancer: long-term results of a Phase II study. Int J Radiat Oncol Biol Phys 2010; 79:1171-8. [PMID: 20605355 DOI: 10.1016/j.ijrobp.2009.12.073] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Revised: 12/16/2009] [Accepted: 12/16/2009] [Indexed: 01/24/2023]
Abstract
PURPOSE Preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer has shown benefit over postoperative CRT; however, a standard CRT regimen has yet to be defined. We performed a prospective concurrent CRT Phase II study with irinotecan and capecitabine in patients with locally advanced rectal cancer to investigate the efficacy and safety of this regimen. METHODS AND MATERIALS Patients with locally advanced, nonmetastatic, and mid-to-lower rectal cancer were enrolled. Radiotherapy was delivered in 1.8-Gy daily fractions for a total of 45 Gy in 25 fractions, followed by a coned-down boost of 5.4 Gy in 3 fractions. Concurrent chemotherapy consisted of 40 mg/m(2) of irinotecan per week for 5 consecutive weeks and 1,650 mg/m(2) of capecitabine per day for 5 days per week (weekdays only) from the first day of radiotherapy. Total mesorectal excision was performed within 6 ± 2 weeks. The pathologic responses and survival outcomes were included for the study endpoints. RESULTS In total, 48 patients were enrolled; 33 (68.7%) were men and 15 (31.3%) were women, and the median age was 59 years (range, 32-72 years). The pathologic complete response rate was 25.0% (11 of 44; 95% confidence interval, 12.2-37.8) and 8 patients (18.2% [8 of 44]) showed near-total tumor regression. The 5-year disease-free and overall survival rates were 75.0% and 93.6%, respectively. Grade 3 toxicities included leukopenia (3 [6.3%]), neutropenia (1 [2.1%]), infection (1 [2.1%]), alanine aminotransferase elevation (1 [2.1%]), and diarrhea (1 [2.1%]). There was no Grade 4 toxicity or treatment-related death. CONCLUSIONS Preoperative CRT with irinotecan and capecitabine with treatment-free weekends showed very mild toxicity profiles and promising results in terms of survival.
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Affiliation(s)
- Yong Sang Hong
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea
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Gunnlaugsson A, Anderson H, Lind P, Glimelius B, Johnsson A. Multicentre phase I–II trial of capecitabine and oxaliplatin in combination with radiotherapy for unresectable pancreatic and biliary tract cancer: The CORGI-U study. Radiother Oncol 2010; 95:292-7. [DOI: 10.1016/j.radonc.2010.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 03/10/2010] [Accepted: 04/05/2010] [Indexed: 11/30/2022]
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Oxaliplatin plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy for locally advanced rectal carcinoma: long-term outcome. Int J Radiat Oncol Biol Phys 2010; 79:670-6. [PMID: 20472346 DOI: 10.1016/j.ijrobp.2009.12.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2009] [Revised: 11/28/2009] [Accepted: 12/01/2009] [Indexed: 12/13/2022]
Abstract
PURPOSE To assess the safety and efficacy of oxaliplatin (OXA) plus dual inhibition of thymidilate synthase during preoperative pelvic radiotherapy (RT) in patients with poor prognosis for rectal carcinoma. METHODS AND MATERIALS Sixty-three patients with the following characteristics, a clinical (c) stage T4, cN1-2, or cT3N0 of ≤5 cm from the anal verge and/or with a circumferential resection margin (CRM) of ≤5 mm (by magnetic resonance imaging), received three biweekly courses of chemotherapy with OXA, 100 mg/m2; raltitrexed (RTX), 2.5 mg/m2 on day 1, and 5-fluorouracil (5-FU), 900 mg/m2 (31 patients) or 800 mg/m2 (32 patients); levo-folinic acid (LFA), 250 mg/m2 on day 2, during pelvic RT (45 Gy). Pathologic response was defined as complete pathological response (ypCR), major (tumor regression grade(TRG) 2 to 3, with ypCRM-ve and ypN-ve) or minor or no response (TRG4 to -5, or ypCRM+ve, or ypN+ve). Adjuvant 5-FU/LFA regimen was given in cases of cT4, ypN+ve, or ypCRM+ve. RESULTS Overall, neutropenia (40%) and diarrhea (13%) were the most common grade≥3 toxicities, and tolerability was better with a 5-FU dose reduction. No significant difference in pathologic response was seen according 5-FU dosage: overall, a ypCR was obtained in 24 (39%) patients, and a major response in 20 (32%) patients. The 5-year probability of freedom from recurrence was 80% (95% confidence interval, 68%-92%); it was 56% for the minor/no response group, while it was around 90% for both the ypCR and the major response group. CONCLUSIONS OXA, RTX, and 5-FU/LFA administered during pelvic RT produced promising early and long-term results in rectal carcinoma patients with poor prognosis. The postoperative treatment strategy applied in our study supports the risk-adapted approach in postoperative management.
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