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Paty PB, Garcia-Aguilar J. Colorectal cancer. J Surg Oncol 2022; 126:881-887. [PMID: 36087081 DOI: 10.1002/jso.27079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 11/12/2022]
Abstract
Although surgery is the established standard and mainstay for treatment of colorectal cancer, advances in technology and clinical trials over the past 50 years have dramatically expanded and improved the detection, staging, treatment, and understanding of this disease. This review highlights contributions by surgeons, oncologists, gastroenterologists, engineers, and scientists to increase postsurgical recurrence-free survival, reduce the time and toxicity of treatment, and improve the quality of life for patients over the past half-century.
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Affiliation(s)
- Philip B Paty
- Colorectal Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Julio Garcia-Aguilar
- Colorectal Surgery Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
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Chakrabarti S, Peterson CY, Sriram D, Mahipal A. Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions. World J Gastrointest Oncol 2020; 12:808-832. [PMID: 32879661 PMCID: PMC7443846 DOI: 10.4251/wjgo.v12.i8.808] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/16/2020] [Accepted: 08/01/2020] [Indexed: 02/05/2023] Open
Abstract
Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.
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Affiliation(s)
- Sakti Chakrabarti
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Carrie Y Peterson
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Deepika Sriram
- Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
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Barzi A, Hershman DL, Till C, Barlow WE, Ramsey S, Lenz HJ, Hochster HS, Unger JM. Osteoporosis in colorectal cancer survivors: analysis of the linkage between SWOG trial enrollees and Medicare claims. Arch Osteoporos 2019; 14:83. [PMID: 31352608 PMCID: PMC6852789 DOI: 10.1007/s11657-019-0629-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 07/02/2019] [Indexed: 02/03/2023]
Abstract
UNLABELLED To explore the rates of osteoporosis (diagnosis and screening) and fractures in colorectal cancer survivors (CRCS), records of clinical trial enrollees was linked to Medicare. Female/male risk of fracture in CRCS is 74% higher than general population. Less than 30% of male and female CRCS receive osteoporosis screening. Osteoporosis is a significant morbidity in CRCS. INTRODUCTION In the USA, the population of colorectal cancer survivors (CRCS) is on the rise. Calcium and vitamin D are the common thread between colorectal cancer and osteoporosis. We set to explore the patterns and prevalence of osteoporosis (OP) and osteoporotic fractures (OF) in CRCS who received fluorouracil-based therapy on SWOG trials. METHODS Data for CRCS from three SWOG phase III treatment trials between 1994 and 2000 (N = 3775) were linked to Medicare claims (N = 1233). OP was identified using ICD9 and HCPCS codes; OF was defined using a more restricted set of codes. We compared patterns of OP, OF, and screening for OP by gender in CRCS. Given the gender disparities in the rates of OP and OF, we used data from the National Health Interview Survey (NHIS) and the National Hospital Discharge Survey (NHDS) to assess the ratio of OF in females and males in general population. RESULTS Forty-seven percent of females and 15% of men CRCS had OP claims. Female CRCS were more likely than males to have OP (HR = 4.76 [3.77-6.01], p < 0.0001) and OF (HR = 2.64 [2.04-3.42], p < 0.0001). In the general population, the female to male ratio of OF was 1.67 as opposed to 2.90 in CRCS, indicating a significantly larger gender disparity of OF in CRCS (p < 0.001). Only 7% of men and 27% of women CRCS had OP screening. CONCLUSION Despite a low rate of OP screening, the gender disparity of OF in CRCS is more pronounced than the general population. These findings provide an impetus for studying OP and OF in CRCS.
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Affiliation(s)
| | | | | | | | - Scott Ramsey
- Fred Hutchinson Cancer Research Center, Seattle, WA
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Prognostic significance of systemic inflammatory response in stage II colorectal cancer. J Surg Res 2017; 208:158-165. [DOI: 10.1016/j.jss.2016.08.100] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 08/17/2016] [Accepted: 08/31/2016] [Indexed: 01/21/2023]
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Validity of Adjuvant! Online in older patients with stage III colon cancer based on 2967 patients from the ACCENT database. J Geriatr Oncol 2016; 7:422-429. [PMID: 27468630 DOI: 10.1016/j.jgo.2016.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/13/2016] [Accepted: 07/07/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND Adjuvant! Online is a tool used for clinical decision making in patients with early stage colon cancer. As details of the tool's construction are not published, the ability of Adjuvant! Online to accurately predict outcomes for older patients (age 70+) with node positive colon cancer receiving adjuvant chemotherapy is unclear. METHODS Individual data from older patients with stage III colon cancer who enrolled into multiple trials within the ACCENT database were entered into the Adjuvant! Online program to obtain predicted probabilities of 5-year overall survival (OS) and recurrence-free survival (RFS). Median predictions were compared with known rates. As co-morbidities were not known for ACCENT patients, but required for calculator entry, patients were assumed to have either "minor" or "average for age" co-morbidities. RESULTS 2967 older patients from 10 randomized studies were included. When "minor" co-morbidities were assumed, the median predicted 5-year OS rate of 64% nearly matched the actual rate of 65%; when "average for age" co-morbidities were assumed, the median prediction dropped to 58%, outside the CI for the actual rate. On the other hand, assuming "minor" co-morbidities gave a median 5-year RFS prediction of 62%, outside the 95% CI for the actual rate of 58%, while assuming "average for age" co-morbidities yielded a better median prediction of 57%. CONCLUSION Adjuvant! Online is reasonably accurate overall for predicting outcomes in older trial patients with stage III colon cancer, though accuracy may differ between 5-year RFS and 5-year OS predictions when a fixed degree of co-morbidities is assumed.
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Dong YY, Xiang C, Lu JX, Su YX, Pan YF, Cai R, Zhang RJ, He ZK, Liu ML, Huang H, Bai X, Tang HY, Shi YH, Wang Y, Jiang W. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma : A matched-pair multicenter analysis of outcomes. Strahlenther Onkol 2016; 192:394-402. [PMID: 27215563 DOI: 10.1007/s00066-016-0970-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 03/23/2016] [Indexed: 11/25/2022]
Abstract
PURPOSE The benefit of adjuvant chemotherapy (AC) in locoregionally advanced nasopharyngeal carcinoma (NPC) is controversial. This study compared concurrent chemoradiotherapy plus AC (CCRT/AC) with CCRT. METHODS Pair-matched analysis based on eight clinicopathological features of 244 patients treated with platinum-based CCRT/AC or CCRT alone was performed. Survival outcomes were assessed using the Kaplan-Meier method and log-rank test. Toxicities and response rates were compared using Fisher's exact test. RESULTS Four-year overall survival, progression-free survival, distant failure-free survival, and locoregional failure-free survival were 72 %, 61 %, 71 %, and 81 %, respectively, for the CCRT arm, compared to 74 % (hazard ratio, HR 0.89; 95 % confidence interval, CI 0.64-1.23; P = 0.474), 62 % (HR 0.91, 95 % CI 0.68-1.20, P = 0.489), 73 % (HR 0.84, 95 % CI 0.59-1.18, P = 0.316), and 84 % (HR 0.84, 95 % CI 0.52-1.24, P = 0.323), respectively, for the CCRT/AC arm. Cox multivariate regression analysis demonstrated AC was not an independent prognostic factor. Overall, there was a higher incidence of grade 3-4 toxicities in the CCRT/AC arm. The most common grade 3-4 adverse events in the CCRT/AC arm were vomiting (27 %), nausea (43 %), leukopenia/neutropenia (23 %), thrombocytopenia (8.8 %), and anemia (6.2 %). CONCLUSION Addition of AC to CCRT increased toxicities but did not improve survival in locoregionally advanced NPC.
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Affiliation(s)
- Yi-Yuan Dong
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
- Department of Otorhinolaryngology, Guilin Medical University Affiliated Hospital, 15 Lequn Road, 541001, Guilin, PR China
| | - Chun Xiang
- Department of Otorhinolaryngology, Nan Xishan Hospital, 46 Chongxin Road, 541001, Guilin, PR China
| | - Jian-Xun Lu
- Department of Oncology, Affiliated Hospital of Youjiang Medical University for Nationalities, 18 Zhongshan Second Road, 533000, Baise, PR China
| | - Yi-Xin Su
- Department of Radiation Oncology, Lingshan People's Hospital, 1 Zhongxiu Road, 535400, Lingshan, PR China
| | - Yu-Fei Pan
- Department of Radiation Oncology, Nan Xishan Hospital, 46 Chongxin Road, 541001, Guilin, PR China
| | - Rui Cai
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Rong-Jun Zhang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Zhuo-Kai He
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Mei-Lian Liu
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Hui Huang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Xue Bai
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Hua-Ying Tang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Yun-Hua Shi
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Yan Wang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China
| | - Wei Jiang
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, 15 Lequn Road, 541001, Guilin, PR China.
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Jeong IS, Yoo JH, Seo SH, An MS, Kim KH, Bae KB, Choi CS, Hwang JW, Kim JH, Kang MS, Oh MK, Hong KH. Association Between Time (Initiation and Length) and Oncological Outcomes for the Patients with Colon Cancer Treated with Adjuvant Chemotherapy. Indian J Surg 2016; 77:1252-7. [PMID: 27011547 DOI: 10.1007/s12262-015-1270-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 04/06/2015] [Indexed: 11/24/2022] Open
Abstract
Adjuvant chemotherapy is benefit for high-risk stage II and stage III colon cancer after curative resection. But, the optimal time between surgical and initiation of adjuvant chemotherapy remains unclear. Moreover, no study of efficacy with different lengths of adjuvant chemotherapy has appeared. This study was aimed to identify association between time (initiation and length) and oncological outcomes of adjuvant chemotherapy on the stages II and III colon cancer patients. A total of 406 high-risk stages II and III colon cancer patients were retrospectively enrolled in prospectively collected data. They were categorized into three groups representing chemotherapy initiation time: less than 4 weeks (group 1), 4 to 6 weeks (group 2), and more than 6 weeks (group 3). They were categorized into two groups representing chemotherapy length time : less than 200 days (group 1a) and more than 200 days (group 2a). The 5-year disease-free survival (DFS) rates were 74.97 % in group 1, 76.94 % in group 2, and 63.97 % in group 3 (p > 0.05). The 5-year DFS rates were 75.49 % in the group that received adjuvant chemotherapy within 6 weeks and 63.97 % in the group that received adjuvant chemotherapy >6 weeks (p = 0.0539). The 5-year DFS rates were 77.21 % in group 1a and 81.82 % in group 2a (p > 0.05). Adjuvant chemotherapy should be safely offered within 6 weeks after surgical excision in patients with colon cancer after considering the patient's general physical condition and hematological factors, even if the chemotherapy length is prolonged.
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Affiliation(s)
- In Seob Jeong
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Jong Han Yoo
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Sang Hyuk Seo
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Min Sung An
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Kwang Hee Kim
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Ki Beom Bae
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Chang Soo Choi
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
| | - Jin Won Hwang
- Department of Internal Medicine, Inje University College of Medicine, Busan Paik Hospital, Busan, Korea
| | - Ji Hyun Kim
- Department of Internal Medicine, Inje University College of Medicine, Busan Paik Hospital, Busan, Korea
| | - Mi Seon Kang
- Department of Pathology, Inje University College of Medicine, Busan Paik Hospital, Busan, Korea
| | - Min Kyung Oh
- Department of Clinical Trial Center in Pharmacology, Inje University College of Medicine, Busan Paik Hospital, Busan, Korea
| | - Kwan Hee Hong
- Department of Surgery, Inje University College of Medicine, Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan, 614-735 Korea
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Genetic variants within obesity-related genes are associated with tumor recurrence in patients with stages II/III colon cancer. Pharmacogenet Genomics 2015; 25:30-7. [PMID: 25379721 DOI: 10.1097/fpc.0000000000000101] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Obesity is an established risk factor for colorectal cancer (CRC) incidence and it is also linked to CRC recurrence and survival. Polymorphisms located in obesity-related genes are associated with an increased risk of developing several cancer types including CRC. We evaluated whether single-nucleotide polymorphisms in obesity-related genes may predict tumor recurrence in colon cancer patients. MATERIALS AND METHODS Genotypes were obtained from germline DNA from 207 patients with stage II or III colon cancer at the Norris Comprehensive Cancer Center. Nine polymorphisms in eight obesity-related genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA, and DSCR1) were evaluated. The primary endpoint of the study was the 3-year recurrence rate. Positive associations were also tested in an independent Japanese cohort of 350 stage III CRC patients. RESULTS In univariate analysis, for PPARrs1801282, patients with a CC genotype had significantly lower recurrence probability (29 ± 4% SE) compared with patients with a CG genotype (48 ± 8% SE) [hazard ratio (HR): 1.77; 95% confidence interval (CI), 1.01-3.10; P = 0.040]. For DSCR1rs6517239, patients with an AA genotype had higher recurrence probability than patients carrying at least one allele G (37 ± 4% SE vs. 15 ± 6% SE) (HR: 0.51; 95% CI, 0.27-0.94; P = 0.027). This association was stronger in the patients bearing a left-sided tumor (HR: 0.34; 95% CI, 0.13-0.88; P = 0.018). In the Japanese cohort, no associations were found. CONCLUSION This hypothesis-generating study suggests a potential influence of polymorphisms within obesity-related genes in the recurrence probability of colon cancer. These interesting results should be evaluated further.
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Upadhyay S, Dahal S, Bhatt VR, Khanal N, Silberstein PT. Chemotherapy use in stage III colon cancer: a National Cancer Database analysis. Ther Adv Med Oncol 2015; 7:244-51. [PMID: 26327922 DOI: 10.1177/1758834015587867] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although adjuvant chemotherapy in stage III colon cancer improves overall survival, prior studies have shown that it is underused. We analyzed different factors that may influence its use. METHODS This is a retrospective study of stage III colon cancer patients (n = 207,718) diagnosed between 2000 and 2011 in the National Cancer Data Base (NCDB). The NCDB contains ~70% of new cancer diagnosis from >1500 American College of Surgeons accredited cancer programs in the United States and Puerto Rico. The chi-squared test was used to determine any difference in characteristics of patients who did or did not receive chemotherapy. RESULTS A total of 35% of all stage III colon cancer patients, and 38% of stage III cases undergoing surgery, did not receive adjuvant chemotherapy. The use of chemotherapy had increased in recent years (64% in 2007-2011 versus 59% in 2000-2002; p < 0.0001). Its use was lower in whites (61%), females (60%), patients ⩾60 years (55%), patients with one or more comorbidities (55%), nonacademic centers (62%), those with medicare insurance (52%), lower education (61%) and income levels (59%, all p < 0.0001). The nonwhite and uninsured were more likely to be <60 years old. CONCLUSION More than one-third did not receive adjuvant chemotherapy, although its use has increased in more recent years. Age was one of the most important determinants of chemotherapy use, which may explain higher rates in nonwhite and uninsured. In addition to patient characteristics, race, gender and socioeconomic factors influence chemotherapy use. These findings have important implications for healthcare reform.
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Affiliation(s)
- Smrity Upadhyay
- Department of Internal Medicine, Creighton University, 601 North 30th Street Suite 5850, Omaha, NE 68131, USA
| | - Sumit Dahal
- Department of Medicine, Interfaith Medical Center, Brooklyn, NY, USA
| | - Vijaya Raj Bhatt
- Department of Internal Medicine, Division of Hematology-Oncology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Nabin Khanal
- Department of Internal Medicine, Creighton University Medical Center, Omaha, NE, USA
| | - Peter T Silberstein
- Department of Internal Medicine, Creighton University Medical Center, Omaha, NE, USA
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Schmoll HJ, Twelves C, Sun W, O'Connell MJ, Cartwright T, McKenna E, Saif M, Lee S, Yothers G, Haller D. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol 2014; 15:1481-1492. [PMID: 25456367 DOI: 10.1016/s1470-2045(14)70486-3] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer. Adjuvant capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin has not been directly compared; therefore, we aimed to analyse the efficacy and safety of these treatments using individual patient data pooled from four randomised controlled trials. We also assessed post-relapse survival, which has been postulated to be worse in patients receiving adjuvant oxaliplatin. METHODS Patients with resected stage III colon cancer who were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from four randomised controlled trials (NSABP C-08, XELOXA, X-ACT, and AVANT; 8734 patients in total) were pooled and analysed. The treatment regimens included in our analyses were: XELOX (oxaliplatin and capecitabine); leucovorin and fluorouracil; capecitabine; FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin); and modified FOLFOX-6 (mFOLFOX-6). Disease-free survival was the primary endpoint for all trials that supplied patients for this analysis. Here, we compared disease-free, relapse-free, and overall survival between the patient groups who received capecitabine with or without oxaliplatin and those who received leucovorin and fluorouracil with or without oxaliplatin. Post-relapse survival was compared between the combined XELOX and FOLFOX groups, and the leucovorin and fluorouracil groups. Post-relapse survival was also compared between the capecitabine with or without oxaliplatin and leucovorin and fluorouracil with or without oxaliplatin groups. FINDINGS Disease-free survival did not differ significantly between patients who received leucovorin and fluorouracil versus those who received capecitabine in adjusted analyses (hazard ratio [HR] 1·02 [0·93-1·11; p=0·72]) or in unadjusted analyses (HR 1·01 [95% CI 0·92-1·10; p=0·86]). Relapse-free survival was similar (adjusted HR 1·02 [0·93-1·12; p=0·72] and unadjusted HR 1·01 [95% CI 0·92-1·11; p=0·86]), as was overall survival (adjusted HR 1·04 [95% CI 0·93-1·15; p=0·50] and unadjusted HR 1·02 [0·92-1·14]; p=0·65). For overall survival, a significant interaction between oxaliplatin and fluoropyrimidine was recorded in the multiple Cox regression analysis (p=0·014). Post-relapse survival was similar in adjusted (p=0·23) and unadjusted analyses (p=0·33) for the comparison of XELOX or FOLFOX versus leucovorin and fluorouracil, and was also similar for capecitabine-based regimens versus leucovorin and fluorouracil-based regimens (unadjusted p=0·26). INTERPRETATION Combination therapy with oxaliplatin provided consistently improved outcomes without adversely affecting post-relapse survival in the adjuvant treatment of stage III colon cancer, irrespective of whether the fluoropyrimidine backbone was capecitabine or leucovorin and fluorouracil. These data add to the existing evidence that oxaliplatin plus capecitabine or leucovorin and fluorouracil is the standard of care for the adjuvant treatment of stage III colon cancer, and offers physicians flexibility to treat patients according to the patients' overall physical performance and preference. FUNDING Genentech Inc.
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Affiliation(s)
| | - Chris Twelves
- Leeds Institute of Cancer and Pathology and St James's University Hospital, Leeds, UK
| | - Weijing Sun
- University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Michael J O'Connell
- National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA
| | | | | | - Muhammad Saif
- Tufts University School of Medicine, Boston, MA, USA
| | - Steve Lee
- Genentech Inc, South San Francisco, CA, USA
| | - Greg Yothers
- NSABP Biostatistical Center and University of Pittsburgh Graduate School of Public Health Department of Biostatistics, Pittsburgh, PA, USA
| | - Daniel Haller
- Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA
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Liu KC, Yo YT, Huang RL, Wang YC, Liao YP, Huang TS, Chao TK, Lin CK, Weng SJ, Ma KH, Chang CC, Yu MH, Lai HC. Ovarian cancer stem-like cells show induced translineage-differentiation capacity and are suppressed by alkaline phosphatase inhibitor. Oncotarget 2014; 4:2366-82. [PMID: 24280306 PMCID: PMC3926833 DOI: 10.18632/oncotarget.1424] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Spheroid formation is one property of stem cells—such as embryo-derived or neural stem cells—that has been used for the enrichment of cancer stem-like cells (CSLCs). However, it is unclear whether CSLC-derived spheroids are heterogeneous or whether they share common embryonic stemness properties. Understanding these features might lead to novel therapeutic approaches. Ovarian carcinoma is a deadly disease of women. We identified two types of spheroids (SR1 and SR2) from ovarian cancer cell lines and patients' specimens according to their morphology. Both types expressed stemness markers and could self-renew and initiate tumors when a low number of cells were used. Only SR1 could differentiate into multiple-lineage cell types under specific induction conditions. SR1 spheroids could differentiate to SR2 spheroids through epithelial–mesenchymal transition. Alkaline phosphatase (ALP) was highly expressed in SR1 spheroids, decreased in SR2 spheroids, and was absent in differentiated progenies in accordance with the loss of stemness properties. We verified that ALP can be a marker for ovarian CSLCs, and patients with greater ALP expression is related to advanced clinical stages and have a higher risk of recurrence and lower survival rate. The ALP inhibitor, levamisole, disrupted the self-renewal of ovarian CSLCs in vitro and tumor growth in vivo. In summary, this research provides a plastic ovarian cancer stem cell model and a new understanding of the cross-link between stem cells and cancers. This results show that ovarian CSLCs can be suppressed by levamisole. Our findings demonstrated that some ovarian CSLCs may restore ALP activity, and this suggests that inhibition of ALP activity may present a new opportunity for treatment of ovarian cancer.
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Affiliation(s)
- Kuei-Chun Liu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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Xu F, Rimm AA, Fu P, Krishnamurthi SS, Cooper GS. The impact of delayed chemotherapy on its completion and survival outcomes in stage II colon cancer patients. PLoS One 2014; 9:e107993. [PMID: 25238395 PMCID: PMC4169603 DOI: 10.1371/journal.pone.0107993] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Accepted: 08/14/2014] [Indexed: 11/18/2022] Open
Abstract
Background Delayed chemotherapy is associated with inferior survival in stage III colon and stage II/III rectal cancer patients, but similar studies have not been performed in stage II colon cancer patients. We investigate the association between delayed and incomplete chemotherapy, and the association of delayed chemotherapy with survival in stage II colon cancer patients. Patients and Methods Patients (age ≥66) diagnosed as stage II colon cancer and received chemotherapy from 1992 to 2005 were identified from the linked SEER–Medicare database. The association between delayed and incomplete chemotherapy was assessed using unconditional and conditional logistic regressions. Survival outcomes were assessed using stratified Cox regression based on propensity score matched samples. Results 4,209 stage II colon cancer patients were included, of whom 73.0% had chemotherapy initiated timely (≤2 months after surgery), 14.7% had chemotherapy initiated with moderate delay (2–3 months), and 12.3% had delayed chemotherapy (≥3 months). Delayed chemotherapy was associated with not completing chemotherapy (adjusted odds ratio (OR): 1.33 (95% confidence interval: 1.11, 1.59) for moderately delayed group, adjusted OR: 2.60 (2.09, 3.24) for delayed group). Delayed chemotherapy was associated with worse survival outcomes (hazard ratio (HR): 1.75 (1.29, 2.37) for overall survival; HR: 4.23 (2.19, 8.20) for cancer-specific survival). Conclusion Although the benefit of chemotherapy is unclear in stage II colon cancer patients, delay in initiation of chemotherapy is associated with an incomplete chemotherapy course and poorer survival, especially cancer-specific survival. Causal inference in the association between delayed initiation of chemotherapy and inferior survival requires further investigation.
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Affiliation(s)
- Fang Xu
- Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Department of Gastroenterology, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America
- * E-mail:
| | - Alfred A. Rimm
- Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Pingfu Fu
- Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Smitha S. Krishnamurthi
- Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Gregory S. Cooper
- Department of Gastroenterology, University Hospitals Case Medical Center, Cleveland, Ohio, United States of America
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, United States of America
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Accuracy of Predefined Hypotheses in Colon Cancer Adjuvant Phase III Trials: Observations and Recommendations. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0229-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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14
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Borda F, Borda A, Jiménez J, Zozaya JM, Prieto C, Gómez M, Urman J, Ibáñez B. Valor predictivo de la hipoalbuminemia pre-tratamiento sobre el pronóstico del cáncer colorrectal resecado. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:289-95. [DOI: 10.1016/j.gastrohep.2013.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/16/2013] [Accepted: 12/19/2013] [Indexed: 12/11/2022]
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15
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Staal S, Daily K, Allegra C. Controversies in Adjuvant Chemotherapy. COLORECTAL CANCER 2014. [DOI: 10.1002/9781118337929.ch10] [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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16
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Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial. Br J Cancer 2014; 110:1438-45. [PMID: 24548866 PMCID: PMC3960626 DOI: 10.1038/bjc.2014.74] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Revised: 12/04/2013] [Accepted: 12/17/2013] [Indexed: 01/17/2023] Open
Abstract
Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer. Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial. Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6–4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction. Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings.
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17
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de Gramont A, Chibaudel B, Bonnetain F, Dumont S, Larsen AK, André T. Clinical Reasons for Initiation of Adjuvant Phase III Trials on Colon Cancer. CURRENT COLORECTAL CANCER REPORTS 2013. [DOI: 10.1007/s11888-013-0176-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Redman MW, Goldman BH, LeBlanc M, Schott A, Baker LH. Modeling the relationship between progression-free survival and overall survival: the phase II/III trial. Clin Cancer Res 2013; 19:2646-56. [PMID: 23669424 PMCID: PMC4131693 DOI: 10.1158/1078-0432.ccr-12-2939] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach.
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Affiliation(s)
- Mary W Redman
- Southwest Oncology Group Fred Hutchinson Cancer Research Center; Seattle, Washington 98109, USA.
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Mazzeo MA, Linares JA, López MM, Bachmeier E, Wietz FM, Galván V, Valentinuzzi MC, Riveros JA, Finkelberg A. Analysis of saliva samples from oncological patients treated with 5-fluorouracil and leucovorin calcium by scanning electron microscopy with energy dispersive system. J Oral Pathol Med 2013; 42:788-92. [PMID: 23647127 DOI: 10.1111/jop.12078] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2013] [Indexed: 12/29/2022]
Abstract
This work presents a chemical and morphological analysis of samples of saliva taken from patients who were under treatment with intravenous chemotherapy with 5-fluorouracil and leucovorin calcium. Samples of saliva were extracted from fifteen patients during the three stages of the treatment: The initial stage (previous to the chemotherapy), the intermediate stage (during the chemotherapy), and the final stage (twenty-one days after finishing the treatment). An amount of 50 μl was collected in each visit. Chemical contrast images were taken by means of scanning electron microscopy, and X-ray characteristic spectra were obtained from all the studied samples by using an energy dispersive system from all the studied samples. Images that correspond to the intermediate stage showed important differences with respect to the initial and final stages. In addition, X-ray spectra provided information about the present elements in saliva and their relative abundance allowed us to determine variations in the chemical composition. The backscattered electron images and X-ray spectra from the intermediate stage showed clusters of crystals with fluorine content higher than those obtained in initial and final stages. This fact probably indicates the passage of metabolites of 5-fluorouracil and leucovorin calcium from the plasma to the oral cavity. This finding enhances the hypothesis proposed by other authors about the secondary effects of the drugs on the stomatognathic system such as oral mucositis, dysgeusia, and xerostomia with or without hyposalivation.
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Affiliation(s)
- Marcelo Adrián Mazzeo
- Cátedra de Fisiología, Facultad de Odontología, Universidad Nacional de Córdoba, Córdoba, Argentina
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Köhne CH, Bedenne L, Carrato A, Bouché O, Popov I, Gaspà L, Valladares M, Rougier P, Gog C, Reichardt P, Wils J, Pignatti F, Biertz F. A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study. Eur J Cancer 2013; 49:1868-75. [PMID: 23571150 DOI: 10.1016/j.ejca.2013.01.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Revised: 01/24/2013] [Accepted: 01/29/2013] [Indexed: 11/17/2022]
Abstract
PURPOSE To investigate whether infusional high-dose 5-flurouracil (HD-FU) provides a significant improvement in recurrence-free survival (RFS) and overall survival (OS) compared with a standard bolus 5-FU regimen (Mayo Clinic) in patients with curatively resectable stage III colon cancer. METHODS Patients (n=1601) were randomised to receive either the Mayo Clinic regimen or one of the three HD-FU regimens; LV5FU2, the Arbeitsgemeinschaft Internistische Onkologie (AIO) or the Grupo Espaňol para el Tratamiento Digestivos (TTD), the data from which were combined to provide the HD-FU arm for final analysis. RESULTS Patients were evenly balanced for age, TMN, tumor grade and vascular and lymphatic invasion. Median follow-up was approximately 42months, RFS (hazard ratio [HR]=0.997) and OS (HR=0.96) (primary end-point) were not statistically different between the two treatment arms. Infusional HD-FU was generally better tolerated than bolus 5-FU regimen. CONCLUSIONS Infusional HD-FU does not improve RFS and OS in curatively resected stage III colon cancer patients compared to the Mayo Clinic regimen, but is less toxic.
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Affiliation(s)
- Claus-Henning Köhne
- Department of Oncology and Hematology, Klinikum Oldenburg, European Medical School Oldenburg/Groningen, Carl von Ossietzky University, Oldenburg, Germany.
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Management of colon cancer: resource-stratified guidelines from the Asian Oncology Summit 2012. Lancet Oncol 2013; 13:e470-81. [PMID: 23117002 DOI: 10.1016/s1470-2045(12)70424-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Colon cancer is seen with increasing frequency in the Asia-Pacific region, and it is one of the most important causes of cancer mortality worldwide. This article reviews the available evidence for optimum management of colon cancer-in particular, with respect to screening and early detection of colon cancer, laparoscopic surgical treatment, adjuvant treatment of individuals with high-risk stage II and stage III cancer, palliative treatment of patients with metastatic disease, and management of resectable and potentially resectable metastases-and how these strategies can be applied in Asian countries with different levels of health-care resources and economic development, stratified by basic, limited, enhanced, and maximum resource levels.
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Abstract
A high-quality body of evidence supports the use of aspirin in reducing sporadic and hereditary adenomatous polyps, and numerous observational studies point to a reduction in colorectal cancer (CRC) risk. However, using aspirin as an adjuvant therapy in established CRC was until recently inconceivable. Now, evidence from both observational and clinical trials of aspirin for other indications suggests that aspirin initiation after (or before) the diagnosis of CRC improves CRC-specific mortality. These exciting findings need to be confirmed in prospective randomized trials that are underway. The recent failure of adjuvant irinotecan, bevacizumab, and cetuximab clinical trials compels us to reconsider our assumptions and paradigms for treating CRC. In this Review, we summarize clinical and preclinical evidence supporting aspirin use in established CRC and outline a framework for better understanding aspirin activity in the pathogenesis of CRC. We describe the data supporting adjuvant aspirin in resected CRC, including the issues of dose, duration and toxicity, and discuss potential biomarkers that may help better select patients for aspirin therapy.
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Cen P, Liu C, Du X. Comparison of toxicity profiles of fluorouracil versus oxaliplatin regimens in a large population-based cohort of elderly patients with colorectal cancer. Ann Oncol 2012; 23:1503-11. [DOI: 10.1093/annonc/mdr449] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
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Twelves C, Scheithauer W, McKendrick J, Seitz JF, Van Hazel G, Wong A, Díaz-Rubio E, Gilberg F, Cassidy J. Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy. Ann Oncol 2012; 23:1190-1197. [PMID: 21896539 DOI: 10.1093/annonc/mdr366] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer. PATIENTS AND METHODS Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS). RESULTS The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥ 70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand-foot syndrome may be associated with better outcomes in capecitabine recipients. CONCLUSION Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.
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Affiliation(s)
- C Twelves
- University of Leeds and St James's Institute of Oncology Hospital, Leeds Cancer Research UK Centre, Leeds, UK.
| | - W Scheithauer
- Department of Internal Medicine I, Medical University Vienna, Vienna, Austria
| | - J McKendrick
- Department of Haematology and Medical Oncology, Box Hill Hospital, Melbourne, Australia
| | - J-F Seitz
- Digestive Oncology Unit, Hôpital La Timone, Université de la Méditerranée, Marseille, France
| | - G Van Hazel
- Perth Oncology, Mount Medical Centre, Perth, Australia
| | - A Wong
- Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, Canada
| | - E Díaz-Rubio
- Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain
| | - F Gilberg
- F. Hoffmann-La Roche Inc., Basel, Switzerland
| | - J Cassidy
- Department of Medical Oncology, University of Glasgow, Glasgow, UK
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Marin JJG, Sanchez de Medina F, Castaño B, Bujanda L, Romero MR, Martinez-Augustin O, Moral-Avila RD, Briz O. Chemoprevention, chemotherapy, and chemoresistance in colorectal cancer. Drug Metab Rev 2012; 44:148-72. [PMID: 22497631 DOI: 10.3109/03602532.2011.638303] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Impact of chemotherapy-related prognostic factors on long-term survival in patients with stage III colorectal cancer after curative resection. Int J Clin Oncol 2012; 18:242-53. [PMID: 22262452 DOI: 10.1007/s10147-011-0370-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Accepted: 12/17/2011] [Indexed: 12/27/2022]
Abstract
BACKGROUND This retrospective study evaluated the prognostic factors of chemotherapy in stage III colorectal cancer after curative resection. METHODS From 1996 to 2001, 1,054 patients with primary single colorectal cancer underwent curative resection. Seven hundred sixteen patients received various 5-fluorouracil (FU)-based adjuvant chemotherapy regimens, including oral and intravenous treatments. The chemotherapy-related parameters examined included therapeutic duration, frequency, route of administration, composition of combination therapies, and postoperative time interval from the operation to the start of chemotherapy. RESULTS The therapeutic duration and postoperative time interval of starting therapy were independent prognostic factors, in addition to clinicopathological factors. The 8-year cancer-specific/overall survival rates in patients who received chemotherapy for >4 months (63.0/58.6%) were significantly higher than the rates in patients who received no chemotherapy (56.7/37.7%, P < 0.01) and those who remained on chemotherapy for 1-4 months (49.4/41.9%, P < 0.05). The 8-year cancer-specific/overall survival rates in patients who waited 1-5 weeks after surgery to receive chemotherapy (62.9/58.5%) were significantly higher versus rates in those who did not receive chemotherapy (56.7/37.7%) and those who did not receive chemotherapy until >5 weeks after surgery (52.3/45.9%) (both P < 0.05). Survival rates did not differ between patients who did not undergo chemotherapy, those for whom chemotherapy lasted 1-4 months, and patients who did not receive chemotherapy until >5 weeks after surgery. CONCLUSIONS The appropriate duration of therapy and early chemotherapy after surgery were 2 of the most important factors in eradicating occult cancer and effecting long-term survival benefits in patients with stage III colorectal cancer.
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Ali R, Toh HC, Chia WK. The utility of Aspirin in Dukes C and High Risk Dukes B Colorectal cancer--the ASCOLT study: study protocol for a randomized controlled trial. Trials 2011; 12:261. [PMID: 22168568 PMCID: PMC3271983 DOI: 10.1186/1745-6215-12-261] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 12/14/2011] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND High quality evidence indicates that aspirin is effective in reducing colorectal polyps; and numerous epidemiological studies point towards an ability to prevent colorectal cancer. However the role of Aspirin as an adjuvant agent in patients with established cancers remains to be defined. Recently a nested case-control study within the Nurses Health cohort suggested that the initiation of Aspirin after the diagnosis of colon cancer reduced overall colorectal cancer specific mortality. Although this data is supportive of Aspirin's biological activity in this disease and possible role in adjuvant therapy, it needs to be confirmed in a randomized prospective trial. METHODS/DESIGN We hypothesize through this randomized, placebo-controlled adjuvant study, that Aspirin in patients with dukes C or high risk dukes B colorectal cancer (ASCOLT) can improve survival in this patient population over placebo control. The primary endpoint of this study is Disease Free Survival and the secondary Endpoint is 5 yr Overall Survival. This study will randomize eligible patients with Dukes C or high risk Dukes B colorectal cancer, after completion of surgery and standard adjuvant chemotherapy (+/- radiation therapy for rectal cancer patients) to 200 mg Aspirin or Placebo for 3 years. Stratification factors include study centre, rectal or colon cancer stage, and type of adjuvant chemotherapy (exposed/not exposed to oxaliplatin). After randomization, patient will be followed up with 3 monthly assessments whilst on study drug and for a total of 5 years. Patients with active peptic ulcer disease, bleeding diathesis or on treatment with aspirin or anti-platelet agents will be excluded from the study. DISCUSSION This study aims to evaluate Aspirin's role as an adjuvant treatment in colorectal cancer. If indeed found to be beneficial, because aspirin is cheap, accessible and easy to administer, it will positively impact the lives of many individuals in Asia and globally. TRIALS REGISTRATION Clinicaltrials.gov: NCT00565708.
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Affiliation(s)
- Raghib Ali
- INDOX Cancer Research Network,, Richard Doll building, University of Oxford, OX37LF, UK
| | - Han-Chong Toh
- Department of Medical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore 169610
| | - Whay-Kuang Chia
- Department of Medical Oncology, National Cancer Centre, 11 Hospital Drive, Singapore 169610
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Yothers G, Sargent DJ, Wolmark N, Goldberg RM, O'Connell MJ, Benedetti JK, Saltz LB, Dignam JJ, Blackstock AW. Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials. J Natl Cancer Inst 2011; 103:1498-506. [PMID: 21997132 DOI: 10.1093/jnci/djr310] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Among patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials. METHODS We assessed 14,611 patients (1218 black and 13,393 white) who received standardized adjuvant treatment in 12 randomized controlled clinical trials conducted in North America for resected stage II and stage III colon cancer between 1977 and 2002. Individual patient data on covariates and outcomes were extracted from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database. The endpoints examined in this meta-analysis were overall survival (time to death), recurrence-free survival (time to recurrence or death), and recurrence-free interval (time to recurrence). Cox models were stratified by study and controlled for sex, stage, age, and treatment to determine the effect of race. Kaplan-Meier estimates were adjusted for similar covariates to control for confounding. All statistical tests were two-sided. RESULTS Black patients were younger than whites (median age, 58 vs 61 years, respectively; P < .001) and more likely to be female (55% vs 45%, respectively; P < .001). Overall survival was worse in black patients than whites (hazard ratio [HR] of death = 1.22, 95% confidence interval [CI] = 1.11 to 1.34, P < .001). Five-year overall survival rates for blacks and whites were 68.2% and 72.8%, respectively. When subsets defined by sex, stage, and age were analyzed, overall survival was consistently worse in black patients. Recurrence-free survival was worse in black patients than whites (HR of recurrence or death = 1.14, 95% CI = 1.04 to 1.24, P = .0045). Three-year recurrence-free survival rates in blacks and whites were 68.4% and 72.1%, respectively. In contrast, recurrence-free interval was similar in black and white patients (HR of recurrence = 1.08, 95% CI = 0.97 to 1.19, P = .15). Three-year recurrence-free interval rates in blacks and whites were 71.3% and 74.2%, respectively. CONCLUSIONS Black patients with resected stage II and stage III colon cancer who were treated with the same therapy as white patients experienced worse overall and recurrence-free survival, but similar recurrence-free interval, compared with white patients. The differences in survival may be mostly because of factors unrelated to the patients' adjuvant colon cancer treatment.
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Affiliation(s)
- Greg Yothers
- National Surgical Adjuvant Breast and Bowel Project Biostatistical Center, One Sterling Plaza, 201 N Craig St, Pittsburgh, PA 15213, USA.
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Tsai WS, Hsieh PS, Yeh CY, Chiang JM, Tang R, Chen JS, Changchien CR, Wang JY. Long-term survival benefits of adjuvant chemotherapy by decreasing incidence of tumor recurrence without delaying relapse in stage III colorectal cancer. Int J Colorectal Dis 2011; 26:1329-38. [PMID: 21556841 DOI: 10.1007/s00384-011-1214-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUNDS AND AIMS To elucidate the survival benefits of adjuvant chemotherapy by decreasing incidence or by delaying time of tumor recurrence, we reported the long-term results of a nonrandomized prospective study comparing the adjuvant chemotherapy to no chemotherapy in stage III colorectal cancer. PATIENTS From 1991 to 1995, 463 patients with stage III colorectal cancer were divided to three groups which were no chemotherapy, weekly chemotherapy, and monthly chemotherapy (5-FU plus levamisole). RESULTS The recurrent incidence was significantly decreased in patients with chemotherapy (47.8% vs. 63.9% of no chemotherapy, P = 0.001), resulting into better survival. The 10-year cancer-specific and overall survival rates of patients with chemotherapy vs. no chemotherapy were 52.1% vs. 37.8% and 46.9% vs. 29.9%, respectively (P < 0.001). Weekly chemotherapy had better survival than monthly chemotherapy (P < 0.05). There was no significant difference in recurrent time or types between the patients with and without chemotherapy. The percentages of patients with recurrence happened within 3 years were 85.2% and 84.6% of those with and without chemotherapy, respectively. Patients with advanced stage of T4b invasion depth, N2, and central node invasion had no significant survival benefits by adjuvant chemotherapy. CONCLUSIONS Long-term survival benefits achieved by adjuvant chemotherapy is through decreasing recurrent incidence, not through postponing tumor recurrent time. That means adjuvant chemotherapy indeed cures some patients by eradicating occult tumor. In adjuvant setting, more powerful regimen for eradicating occult tumor is the keystone to improve long-term survival of stage III colorectal cancer.
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Affiliation(s)
- Wen-Sy Tsai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
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Hung HY, Chen JS, Yeh CY, Changchien CR, Tang R, Hsieh PS, Tasi WS, You JF, You YT, Fan CW, Wang JY, Chiang JM. Effect of preoperative neutrophil-lymphocyte ratio on the surgical outcomes of stage II colon cancer patients who do not receive adjuvant chemotherapy. Int J Colorectal Dis 2011; 26:1059-65. [PMID: 21479566 DOI: 10.1007/s00384-011-1192-x] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Selection of appropriate stage II colon cancer patients for adjuvant chemotherapy is critical for improving survival outcome. With the aim of identifying more high risk factors for stage II colon cancer, this study aimed to determine whether the neutrophil-lymphocyte ratio (NLR) is a predictor of surgical outcomes in patients with stage II colon cancer who do not receive adjuvant chemotherapy. MATERIALS AND METHODS We enrolled 1,040 stage II colon cancer patients who had undergone colectomy at a single institution between January 1995 and December 2005 and did not receive adjuvant chemotherapy. RESULTS Of these 1,040 patients, 785 (75.5%) patients had a normal NLR and 255 (24.5%) had an elevated NLR. Those with an elevated NLR included patients ≥65 years, T4b cancer, carcinoembryonic antigen ≥5 ng/mL, and tumor obstruction or perforation. Patients with an elevated NLR had a significantly worse overall survival (OS) and worse disease-free survival (DFS) than did patients with a normal NLR. Cox regression analysis revealed that elevated NLR was an independent predictor of OS (P=0.012) but not DFS (P=0.255). CONCLUSION An elevated NLR is an independent predictor of OS but not DFS in stage II colon cancer patients who did not receive adjuvant chemotherapy. Preoperative NLR measurement in stage II colon cancer patients may be a simple method for identifying patients with a poor prognosis who can be enrolled in further trials of adjuvant chemotherapy.
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Affiliation(s)
- Hsin-Yuan Hung
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Chang Gung University, 5, Fu-Hsing St., Kuei-Shan, Linko, Tao-Yuan, Taiwan
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Abstract
Colon cancer (CC) therapies have improved patient outcomes significantly over the last decades in both the adjuvant and metastatic settings. With the introduction of a number of novel agents, both traditional chemotherapies and biologically targeted agents, the need to identify subgroups that are likely and not likely to respond to a particular treatment regimen is paramount. This will allow patients who are likely to benefit to receive optimal care, while sparing those unlikely to benefit from unnecessary toxicity and cost. With the identification of several novel biomarkers and a variety of technologies to interrogate the genome, we already are able to rapidly study patient tumor or blood samples and normal tissues to generate a large dataset of aberrations within the cancer. How to digest this complex information to obtain accurate, reliable, and meaningful results that will allow us to provide truly personalized care for CC patients is just starting to be addressed. In this article, we briefly review the history of CC treatment, with an emphasis on current clinical standards that incorporate a "personalized medicine" approach. We then review strategies that will potentially improve our ability to individualize therapy in the future.
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Bastos DA, Ribeiro SC, de Freitas D, Hoff PM. Combination therapy in high-risk stage II or stage III colon cancer: current practice and future prospects. Ther Adv Med Oncol 2010; 2:261-72. [PMID: 21789139 PMCID: PMC3126021 DOI: 10.1177/1758834010367905] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Colon cancer represents the second leading cause of cancer-related deaths. For patients who have undergone curative surgery, adjuvant therapy can reduce the risk of recurrence and death from relapsed or metastatic disease. Postoperative chemotherapy with a 5-fluorouracil-based regimen combined with oxaliplatin is the current standard of care for stage III patients. However, there is still controversy in stage II disease about the real impact of adjuvant monotherapy or combined therapy on survival. Better identification of a subgroup of patients with a higher risk of recurrence can select patients who might benefit from adjuvant therapy. For the elderly population, there is a well-established role for postoperative therapy, although the most appropriate regimen remains to be defined. Targeted agents for combined adjuvant therapy in stage II and III colon cancer is a promising area, but to date, there is no evidence supporting its use in this setting. Results from large prospective trials with targeted therapy have been disappointing and new drugs and strategies are needed to define the role of these types of agents in the adjuvant scenario of colon cancer.
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Sinicrope FA, Foster NR, Sargent DJ, O'Connell MJ, Rankin C. Obesity is an independent prognostic variable in colon cancer survivors. Clin Cancer Res 2010; 16:1884-93. [PMID: 20215553 DOI: 10.1158/1078-0432.ccr-09-2636] [Citation(s) in RCA: 172] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) on the prognosis of colon cancer survivors and its relationship to gender remains unknown. EXPERIMENTAL DESIGN BMI (kg/m(2)) was categorized in patients with tumor-node-metastasis stage II and III colon carcinomas (n = 4,381) enrolled in seven randomized trials of 5-fluorouracil-based adjuvant chemotherapy. Cox proportional hazards models were used to determine the association of BMI with disease-free survival (DFS) and overall survival (OS). RESULTS Among colon cancer patients, 868 (20%) were obese (BMI, >or=30 kg/m(2)), of which 606 were class 1 (BMI, 30-34 kg/m(2)) and 262 were class 2,3 (BMI, >or=35 kg/m(2)). Obese versus normal-weight patients were more likely to be younger, have distal tumors, show intact DNA mismatch repair, and have more lymph node metastases (P < 0.017). In a multivariate analysis, BMI was significantly associated with both DFS (P = 0.030) and OS (P = 0.0017). Men with class 2,3 obesity showed reduced OS compared with normal-weight men [hazard ratio, 1.35; 95% confidence interval, 1.02-1.79; P = 0.039]. Women with class I obesity had reduced OS [hazard ratio, 1.24; 95% confidence interval, 1.01-1.53; P = 0.045] compared with normal-weight women. Overweight status was associated with improved OS in men (P = 0.006), and underweight women had significantly worse OS (P = 0.019). BMI was not predictive of therapeutic benefit. CONCLUSIONS Obesity is an independent prognostic variable in colon cancer survivors and shows gender-related differences. These data suggest that obesity-related biological factors can influence clinical outcome.
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Affiliation(s)
- Frank A Sinicrope
- Divisions of Oncology and Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
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Zemanova M, Petruzelka L, Pazdro A, Kralova D, Smejkal M, Pazdrova G, Honova H. Prospective non-randomized study of preoperative concurrent platinum plus 5-fluorouracil-based chemoradiotherapy with or without paclitaxel in esophageal cancer patients: long-term follow-up. Dis Esophagus 2010; 23:160-7. [PMID: 19515190 DOI: 10.1111/j.1442-2050.2009.00984.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Combined modality treatment for esophageal carcinoma seems to improve survival over surgery alone. Different combinations of cytotoxic drugs have been studied to improve antitumor efficacy and limit the toxicity of chemoradiotherapy (CRT) with inconsistent results. We present a prospective study of neoadjuvant CRT with or without paclitaxel in chemotherapy schedule. One hundred seven patients (93 males, 14 females), median age 59 years (range 44-76), with operable esophageal cancer were enrolled. They received the following neoadjuvant therapy: Carboplatin, area under curve (AUC) = 6, intravenously on days 1 and 22, 5-fluorouracil (5-FU), 200 mg/m(2)/day, continuous infusion on days 1 to 42, radiation therapy 45 grays/25fractions/5 weeks beginning on day 1. Forty-four patients (41%) were furthermore non-randomly assigned to paclitaxel 200 mg/m(2)/3 h intravenously on days 1 and 22. Nutritional support from the beginning of the treatment was offered to all patients. Surgery was done within 4-8 weeks after completion of CRT, if feasible. All patients were evaluated for grade 3 plus 4 toxicities: leukopenia (28%), neutropenia (30%), anemia (6%), thrombocytopenia (31%), febrile neutropenia (6%), esophagitis (24%), nausea and vomiting (7%), pneumotoxicity (8%). Seventy-eight patients (73%) had surgery and 63 of them were completely resected. Twenty-two patients (20%) achieved pathological complete remission, and additional 20 (19%) had node-negative and esophageal wall-positive residual disease. There were 10 surgery-related deaths, mostly due to pulmonary insufficiency. Twenty-nine patients were not resected, 15 for early progression, 14 for medical reasons or patient refusal. After a median follow-up of 52 months (range 27-80), median survival of 18.0 months and 1-, 2-, 3- and 5-year survival of 56.7, 37.5, 27.0 and 21% was observed in the whole group of 107 patients. Addition of paclitaxel to carboplatin and continual infusion of FU significantly increased hematologic and non-hematologic toxicity, but treatment results as overall survival or time to progression did not differ significantly in groups with and without paclitaxel. Patients achieving pathological complete remission or nodes negativity after neoadjuvant therapy had favorable survival prognosis, whereas long-term prognosis of node positive patients was poor. Distant metastases prevailed as a cause of the treatment failure. Factors significant for survival prognosis in multivariate analysis were postoperative node negativity, performance status, and grade of dysphagia. Addition of paclitaxel to carboplatin and continual FU significantly increased hematologic and non-hematologic toxicity without influencing efficacy of the treatment. This study confirmed improved prognosis of patients after achieving negativity of nodes. Distant metastases prevailed as cause of the treatment failure. Prospectively, it is important to look for a therapeutic combination with better systemic effect.
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Affiliation(s)
- M Zemanova
- Department of Oncology, I Medical Faculty of Charles University, 128 08 Prague, Czech Republic.
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Abstract
Colorectal cancer is the third most frequent malignant neoplasm in Western countries. After complete resection, 5-year overall survival varies according to the initial stage. Adjuvant chemotherapy (CT) is indicated in patients with colon cancer at high-risk stage II, stage III and after complete resection of metastases. 5-Fluorouracil (5FU), alone or modulated with levamisol or leucovorin (LV), oral fluoropyrimidines, raltitrexed, irinotecan and oxaliplatin have been studied as adjuvant therapy for colon cancer. Nowadays, oxaliplatin-based regimens, FOLFOX or FLOX, are considered as the standard adjuvant CT. If there are contraindications for oxaliplatin, the best alternatives are capecitabine or continuous infusion of 5FU/LV. The role of monoclonal antibodies, cetuximab and bevacizumab, combined with oxaliplatin/fluoropyrimidine-based CT is under investigation in clinical trials. This article reviews the state of the art and the future perspectives of adjuvant therapy in colon cancer. Prognostic and predictive factors are also commented on.
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Eynde MVD, Awada A, Hendlisz A. Is Tailored Adjuvant Treatment for Colon Cancer Possible? Clin Colorectal Cancer 2010; 9:15-21. [DOI: 10.3816/ccc.2010.n.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Fogli S, Caraglia M. Genotype-based therapeutic approach for colorectal cancer: state of the art and future perspectives. Expert Opin Pharmacother 2009; 10:1095-108. [DOI: 10.1517/14656560902889775] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Barone C, Landriscina M, Cassano A. Colorectal Cancer: Optimization of the Combination of 5-Fluorouracil and Irinotecan. COLORECTAL CANCER 2009. [DOI: 10.1007/978-1-4020-9545-0_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Daher IN, Yeh ETH. Vascular complications of selected cancer therapies. ACTA ACUST UNITED AC 2008; 5:797-805. [PMID: 18852710 DOI: 10.1038/ncpcardio1375] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2008] [Accepted: 09/08/2008] [Indexed: 11/09/2022]
Abstract
Over the past decade, therapies for several previously untreatable types of cancer have emerged or have improved; thus, more focus has been given to long-term complications of cancer therapy. The most commonly known cardiac toxicities of cancer therapy are cardiac dysfunction or congestive heart failure. Vascular complications--such as ischemia, myocardial infarction, venous or arterial thrombosis, and newly developed or worsened hypertension--are also relatively common following cancer treatment, particularly in patients with advanced-stage cancer. Experimental studies have suggested a number of potential mechanisms that might account for vascular complications of cancer therapies, which include dysfunction or damage of endothelial cells, increased platelet aggregation, and modulation of nitric oxide levels. This Review describes the vascular complications of treatment with 5-fluorouracil, bevacizumab, and several new tyrosine kinase inhibitors, with special emphasis on thrombotic complications and hypertension.
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Affiliation(s)
- Iyad N Daher
- Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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42
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43
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Hennig IM, Naik JD, Brown S, Szubert A, Anthoney DA, Jackson DP, Melcher AM, Crawford SM, Bradley C, Brown JMB, Seymour MT. Severe sequence-specific toxicity when capecitabine is given after Fluorouracil and leucovorin. J Clin Oncol 2008; 26:3411-7. [PMID: 18612156 DOI: 10.1200/jco.2007.15.9426] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients. PATIENTS AND METHODS Patients scheduled for adjuvant single-agent fluoropyrimidine therapy were randomly assigned to receive once-weekly FU/LV (425 mg/m(2) FU, 45 mg LV) for 6 weeks, followed by two 3-week cycles of capecitabine (1,250 mg/m(2) twice daily, days 1 through 14), or the same treatments but in reverse order. After 12 weeks, the patients were asked which treatment they preferred, and received the preferred treatment for an additional 12 weeks. The primary end point was patient preference. RESULTS After 40 of the planned 74 patients had been randomly assigned, real-time adverse event monitoring led to early trial closure because of excess sequence-specific toxicity. Eleven of 14 patients (79%) receiving capecitabine as their second treatment experienced grade >/= 3 toxicity. This compared with five of 18 patients (28%) receiving capecitabine as the first treatment, and no patients receiving FU/LV as the first treatment (zero of 16) or the second treatment (zero of 12). Similar imbalances were seen in the proportion of patients requiring interruption of treatment. CONCLUSION In chemotherapy-naïve patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.
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Affiliation(s)
- Ivo M Hennig
- Cancer Research UK Centre, St James's Institute of Oncology, St James's University Hospital, Leeds LS9 7TF, United Kingdom
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Chua YJ, Zalcberg JR. Progress and challenges in the adjuvant treatment of stage II and III colon cancers. Expert Rev Anticancer Ther 2008; 8:595-604. [PMID: 18402526 DOI: 10.1586/14737140.8.4.595] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Whereas the benefit of adjuvant 5-fluorouracil and leucovorin have been well established in resected stage III colon cancer, a significant benefit for patients with stage II disease has been more difficult to demonstrate. More recently, oxaliplatin-based chemotherapy with regimens such as oxaplatin plus 5-fluorouracil/leucovorin have been shown to improve disease-free and overall survival in these stage III patients. This review will discuss the development of adjuvant chemotherapy in colon cancer, focusing on recent progress and particular topical issues related to its use in this disease, such as the use of surrogate end points for overall survival in contemporary clinical trials.
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Affiliation(s)
- Yu Jo Chua
- The Canberra Hospital, Australian Capital Territory, Australia.
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45
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Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology 2008; 134:1296-310. [PMID: 18471507 PMCID: PMC2528832 DOI: 10.1053/j.gastro.2008.02.098] [Citation(s) in RCA: 357] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Revised: 02/26/2008] [Accepted: 02/27/2008] [Indexed: 12/27/2022]
Abstract
Colorectal cancer is the fourth most common noncutaneous malignancy in the United States and the second most frequent cause of cancer-related death. Over the past 12 years, significant progress has been made in the systemic treatment of this malignant condition. Six new chemotherapeutic agents have been introduced, increasing median overall survival for patients with metastatic colorectal cancer from less than 9 months with no treatment to approximately 24 months. For patients with stage III (lymph node positive) colon cancer, an overall survival benefit for fluorouracil-based chemotherapy has been firmly established, and recent data have shown further efficacy for the inclusion of oxaliplatin in such adjuvant treatment programs. For patients with stage II colon cancer, the use of adjuvant chemotherapy remains controversial, but may be appropriate in a subset of individuals at higher risk for disease recurrence. Ongoing randomized clinical trials are evaluating how best to combine currently available therapies, while smaller studies are evaluating new agents, with the goal of continued progress in prolonging life among patients with metastatic colorectal cancer and increasing cure rates among those with resectable disease.
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Affiliation(s)
- Brian M Wolpin
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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Wind J, ten Kate FJW, Kiewiet JJS, Lagarde SM, Slors JFM, van Lanschot JJB, Bemelman WA. The prognostic significance of extracapsular lymph node involvement in node positive patients with colonic cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2008; 34:390-6. [PMID: 17614246 DOI: 10.1016/j.ejso.2007.05.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Accepted: 05/21/2007] [Indexed: 10/23/2022]
Abstract
AIMS In colonic cancer the prognostic significance of extracapsular lymph node involvement (LNI) is not established and is therefore the objective of this study. METHODS Between January 1994 and May 2005, all patients who underwent resection for primary colonic cancer with lymph node metastasis were reviewed. All resected lymph nodes were re-examined to assess extracapsular LNI. In uni- and multivariate analysis disease-free survival (DFS) was correlated with various clinicopathologic factors. RESULTS One hundred and eleven patients were included. In 58 patients extracapsular LNI was identified. Univariate analysis revealed that pN-stage (5-year DFS pN1 vs. pN2: 65% vs. 14%, p<0.001), extracapsular LNI (5-year DFS intracapsular LNI vs. extracapsular LNI: 69% vs. 41%, p=0.003), and lymph node ratio (5-year DFS <0.176 vs. > or =0.176: 67% vs. 42%, p=0.023) were significant prognostic indicators. Among these variables pN-stage (hazard ratio 3.5, 95% confidence interval [CI]: 1.72-7.42) and extracapsular LNI (hazard ratio 1.98, 95% CI: 1.00-3.91) were independent prognostic factors. Among patients without extracapsular LNI, those receiving adjuvant chemotherapy had a significantly better survival (p=0.010). In contrast, chemotherapy did not improve DFS in patients with extracapsular LNI. CONCLUSION Together with pN2 stage, extracapsular LNI reflects a particularly aggressive behaviour and has significant prognostic potential.
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Affiliation(s)
- J Wind
- Department of Surgery, Academic Medical Centre, P.O. Box 22660, 1100 DD Amsterdam, the Netherlands
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Law CC, Fu YT, Chau KK, Choy TS, So PF, Wong KH. Toxicity profile and efficacy of oral capecitabine as adjuvant chemotherapy for Chinese patients with Stage III colon cancer. Dis Colon Rectum 2007; 50:2180-7. [PMID: 17963003 DOI: 10.1007/s10350-007-9045-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The Xeloda in Adjuvant Cancer Therapy trial, conducted in a white population of patients, established capecitabine (Xeloda) as adjuvant chemotherapy for Stage III colon cancer. Given the ethnical difference in toxicity of adjuvant chemotherapy in colon cancer, this study was designed to evaluate the safety and efficacy of adjuvant capecitabine in Chinese patients with colon cancer. METHODS Chinese patients with curatively resected Stage III colon adenocarcinoma, who received adjuvant capecitabine, were entered into a prospective database. Oral capecitabine was given at 1,250 mg/m(2) twice daily, Days 1 to 14, every 21 days, for 8 cycles. Toxicities, laboratory abnormalities, and survival outcomes were evaluated. RESULTS Fifty-eight patients were entered into the database between August 2004 and October 2005. The median age was 63.9 years with a male-to-female ratio of 1.15:1. With a median follow-up duration of 20.9 months, 14 patients relapsed and 3 patients died. Disease-free and overall survival at two years was 69 and 97 percent, respectively. Grade 3 toxicities occurred as follows: stomatitis (1.7 percent), diarrhea (0 percent), hand-foot syndrome (41.4 percent), leucopenia (1.7 percent), neutropenia (3.4 percent), and hyperbilirubinemia (1.7 percent). No Grade 4 or 5 toxicity was noted. Compared with the Xeloda in the Adjuvant Cancer Therapy trial, a much higher incidence of serious hand-foot syndrome and a lower rate of severe diarrhea were found in this study. CONCLUSIONS A different toxicity profile of adjuvant capecitabine was noted in this study on Chinese patients with colon cancer compared with that reported in the Xeloda in Adjuvant Cancer Therapy trial, whereas the efficacy outcomes were comparable.
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Affiliation(s)
- Chi-Ching Law
- Department of Clinical Oncology, Queen Elizabeth Hospital, 11/F, Block R, 30 Gascoigne Road, Kowloon, Hong Kong, China.
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Ma WW, Hidalgo M. Exploiting novel molecular targets in gastrointestinal cancers. World J Gastroenterol 2007; 13:5845-56. [PMID: 17990350 PMCID: PMC4205431 DOI: 10.3748/wjg.v13.i44.5845] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2007] [Revised: 09/19/2007] [Accepted: 10/21/2007] [Indexed: 02/06/2023] Open
Abstract
Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor (EGFR) pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.
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Abstract
In patients with colon cancer who undergo resection for potential cure, 40% to 60% have advanced locoregional disease and are classified as either stage II or stage III. The role of adjuvant therapy in stage III colon cancer is well defined. The results from the MOSAIC trial (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) and the National Surgical Adjuvant Breast and Bowel Project C-07 trial confirm a definite disease-free survival (DFS) benefit with the addition of oxaliplatin to either infusional or bolus 5-fluorouracil/leucovorin (5-FU/LV). The Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial showed capecitabine to be of equivalent clinical benefit to bolus 5-FU/LV. However, adjuvant trials with irinotecan, including Cancer and Leukemia Group B (CALGB 89803), the Pan-European Trial in Adjuvant Colorectal Cancer 3 (PETACC-3), and the French ACCORD trial, have not shown a significant DFS advantage. In contrast, in patients with stage II disease, a small survival benefit of 1% to 5% exists with chemotherapy. Perhaps the analysis of molecular markers in combination with high-risk histopathologic features will help increase patient specificity and identify subsets of patients with stage II colon cancer who will derive a survival benefit with adjuvant therapy. The current Intergroup study stratifying stage II patients based on presence of microsatellite instability and loss of heterozygosity 18q allele will help us better understand the risk versus benefit observed.
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Affiliation(s)
- Olivia Aranha
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Division of Hematology/Oncology, 676 N. St. Clair, Suite 850, Chicago, IL 60611, USA
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André T, Quinaux E, Louvet C, Colin P, Gamelin E, Bouche O, Achille E, Piedbois P, Tubiana-Mathieu N, Boutan-Laroze A, Flesch M, Lledo G, Raoul Y, Debrix I, Buyse M, de Gramont A. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol 2007; 25:3732-8. [PMID: 17704423 DOI: 10.1200/jco.2007.12.2234] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
PURPOSE This randomized, 2 x 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer. PATIENTS AND METHODS LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m(2)) as a 2-hour infusion, followed by 400 mg/m(2) FU bolus and a 600-mg/m(2) FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m(2) FU 15-minute infusion. The primary end point was disease-free survival (DFS). RESULTS Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, >or= 2 years; log-rank test for trend P, .0497). CONCLUSION DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.
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Affiliation(s)
- Thierry André
- Public Hôpitaux de Paris and CancerEst, Hôpital Tenon, Paris, France.
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