Print version ISSN 2237-9363
J. Coloproctol. (Rio J.) vol.32 no.2 Rio de Janeiro Apr./June 2012
Michelle Fraga EisenhardtI; Fabrine HuweI; Marcelo Luis DottoII; Cátia SeveroIII; Juliana Jornada FontellaIII; Andreia Rosane De Moura ValimIV; Helen Tais Da RosaV; Cézane Priscila ReuterVI; Lia Gonçalves PossueloIV
IAcademician, School of Pharmacy, Universidade de Santa Cruz do Sul (UNISC) - Santa Cruz do Sul (RS), Brazil
IIOncologist, Centro de Oncologia Integrado, Hospital Ana Nery - Santa Cruz do Sul (RS), Brazil
IIINurse, Centro de Oncologia Integrado, Hospital Ana Nery - Santa Cruz do Sul (RS), Brazil
IVPost-Graduation Program of Health Promotion, Universidade de Santa Cruz do Sul (UNISC) - Santa Cruz do Sul (RS), Brazil
VAcademician, Course of Biological Sciences, UNISC - Santa Cruz do Sul (RS), Brazil
VIPharmacist, attending postgraduate program (master's degree) in Health Promotion, UNISC - Santa Cruz do Sul (RS), Brazil
Colorectal cancer has a high incidence in Brazil, with the South and Southeast regions presenting the largest number of cases.
OBJECTIVE: Identify the epidemiological characteristics and the regimens used as first-line treatment of patients with colorectal cancer treated at a cancer center in Santa Cruz do Sul (RS, Brazil) from 2006 to 2011.
METHODS: The records of 130 patients were retrospectively evaluated. Clinical and epidemiological characteristics, such as age, gender, ethnic group, stage of disease, primary site of disease and first-line treatment, were evaluated. The association of significance was evaluated using the chi-square and Fischer exact tests. The confidence interval used was 95% (p<0.05).
RESULTS: The mean age of patients with colorectal cancer in this study was 60.8 years, with higher incidence of the disease in men. At diagnosis, 40% of the patients had advanced disease stage IV. The regimen of 5-fluorouracil/folic acid (68.5%) was used as first-line treatment.
CONCLUSION: This study showed high prevalence of colorectal cancer in patients of advanced age with the diagnosis made in the later stage of the disease. This fact demonstrates the importance of prevention campaigns that encourage periodic examinations in patients over 50 years of age.
Keywords: colorectal neoplasms; incidence; drug toxicity; 5-fluorouracil/folic acid.
No Brasil, o câncer colorretal apresenta uma elevada incidência, sendo as Regiões Sul e Sudeste as com maior número de casos.
OBJETIVO: Identificar as características epidemiológicas e os esquemas terapêuticos utilizados como primo-tratamento dos pacientes portadores de câncer colorretal atendidos em um centro especializado em oncologia em Santa Cruz do Sul (RS) no período de 2006 a 2011.
MÉTODO: Foram avaliados retrospectivamente 130 prontuários de pacientes portadores de câncer colorretal. Características clínicas e epidemiológicas como idade, sexo, cor da pele, estádio da doença, sítio primário da doença e primo-tratamento foram avaliadas. A associação de significância foi avaliada pelos testes do qui-quadrado e exato de Fischer. O intervalo de confiança utilizado foi de 95% (p<0,05).
RESULTADOS: A idade média dos pacientes encontrada neste estudo foi de 60,8 anos com incidência maior da doença entre os homens. No momento do diagnóstico, 40% dos pacientes estavam com a doença no estádio IV. Como primo-tratamento o esquema terapêutico mais utilizado foi o 5-fluoracil/ácido folínico (68,5%).
CONCLUSÃO: Este estudo ratificou a alta prevalência do câncer colorretal em pacientes com idade mais avançada, com o diagnóstico realizado na fase mais avançada da doença. Esse fato evidencia a importância da realização de campanhas de prevenção que estimulem a realização de exames periódicos nos pacientes com idade acima de 50 anos.
Palavras-chave: neoplasias colorretais; incidência; toxicidade de drogas; 5-fluoracil/ácido folínico.
Colorectal cancer (CRC) is one of the most common types of cancer worldwide, with predominance in more industrialized and economically richer countries. In Brazil, CRC has a high incidence, with the South and Southeast regions presenting the largest number of cases1,2. CRC is a disease that predominates in individuals over 50 years of age, only 10% of people with CRC are under 50 years old, with 2% to 10.6% of the diagnoses made in patients under 40 years old and only 2.4% of the diagnoses made in patients under 30 years old3,4.
CRC is a disease that can be treated and frequently healed; with the treatment usually involving surgery, radiotherapy and chemotherapy. Surgery is the main type of treatment, which, alone or combined with chemotherapy, can offer long survival and, consequently, healing, since diagnosed in its early stage5. The treatment selection is basically dependent on the tumor size, location and extension, and the patient's general health, and the different forms of treatment can be used individually or combined6. Adjuvant chemotherapy is habitually used in the treatment of high-risk stage III and stage II CRC to reduce recurrences after the initial treatment with surgery, eliminating residual tumor cells and increasing the number of patients that obtain long-term disease-free survival and increased overall survival (OS)7.
The chemotherapeutic treatment for CRC has become increasingly complex in the last years8. The combination of 5-fluorouracil and folic acid (5-FU/LV) became the standard treatment for CRC many years ago, and remains as the standard treatment for stage II CRC and one of the options for stage III CRC9-11. However, stage III e IV CRC may be treated with different therapeutic regimens that incorporate new agents, such as irinotecan and oxaliplatin12,13. Examples of these combinations include: irinotecan, 5-FU (continuous bolus infusion) and folic acid (FOLFIRI) and oxaliplatin, 5-FU (continuous bolus infusion) and folic acid (FOLFOX)13. These therapeutic regimens present different toxicity profiles, but both are considered first-line therapeutic options for the treatment of advanced CRC14-16.
Before the introduction of these regimens, the combination of irinotecan, 5-FU (bolus) and folic acid (IFL) was largely accepted as the first-line treatment for the metastatic colorectal cancer (mCRC), producing better results than those obtained with 5-FU/LV17.
When selecting the therapeutic regimen, an effective, well-tolerated and convenient therapy is desirable18. Goldberg et al.19 demonstrated that FOLFOX presents significantly lower rates of nauseas, vomiting, diarrhea, febrile neutropenia and dehydration when compared to IFL. And, when compared to FOLFIRI, the occurrence of diarrhea and febrile neutropenia is also higher in patients treated with IFL20. The regimen of 5-FU/LV is associated with adverse drug reactions (ADRs), such as diarrhea, leukopenia, neutropenia, mucositis and vomiting, but at significantly lower rates than IFL21.
The fact that innumerous pharmacological agents are not effective in the treatment of advanced CRC or present high toxicity raises an important question about what really constitutes the standard treatment for this disease and about how the active agents for such disease should be combined22,23.
Thus, the purpose of this study was to identify the epidemiological characteristics of patients with CRC treated at a cancer center in Santa Cruz do Sul (RS) and the main therapeutic regimens used as the first-line treatment and their ADRs.
Study design and data collection
A retrospective descriptive study was conducted, which analyzed patients with CRC treated at the Centro de Oncologia Integrado (COI) at the Hospital Ana Nery, in the city of Santa Cruz do Sul, 155 km from the State capital, Porto Alegre, in the central region of the State of Rio Grande do Sul. Hospital Ana Nery is a hospital of medium complexity, with a cancer center that is a reference to Vale do Rio Pardo and Centro-Serra, a region of 458,238 inhabitants.
Selection of patients and data collection
The medical records of patients over 18 years of age diagnosed with CRC confirmed by biopsy between March 2006 to April 2011 were evaluated. The patients' data were collected between October 2010 and December 2011.
During the analysis of medical records, clinical and epidemiological data were evaluated and transcribed to a previously elaborated data form. The epidemiological data included age, gender, occupation, marital status and ethnic group. The clinical data included disease stage, primary site of the disease, metastases at the diagnosis, lymph node invasion, chemotherapeutic regimen adopted as the first-line treatment, ADRs and therapeutic response.
This study was approved by the Research Ethics Committee of the Universidade de Santa Cruz do Sul (UNISC), under protocol number 2.523/10.
Clinical and epidemiological data were stored and analyzed in a database created with the software Statistical Package for the Social Science (SPSS, Chicago, IL), version 18.0. The association of significance was evaluated using the chi-square and Fischer exact tests. The confidence interval used was 95% (p<0.05). Descriptive statistics were calculated and univariate comparisons were performed.
Characteristics of patients
The medical records of 130 patients were analyzed; 53 (40.8%) of them were of patients from the city of Santa Cruz do Sul. This number refers to the total patients treated at COI in the studied period; 125 (96.2%) of them were treated under the government's Unified Health System (SUS). Table 1 shows the epidemiological characteristics of patients. The mean age of patients at the diagnosis was 60.8 years (±12.6), with 6 (4.6%) patients under 40 years of age. In terms of gender, 71 (54.6%) were male patients, but the difference between male and female patients was not statistically significant (p=0,29). Regarding the tumor site, 85 (65.4%) patients had colon cancer and 45 (34.6%) had rectal cancer.
Regarding the TNM staging system, at the diagnosis, 52 (40%) patients presented stage IV CRC, 32 (24.6%) stage III CRC and 42 (32.3%) stage II CRC and, regarding the lymphatic invasion, 67 (51.5%) patients did not present metastasis in regional lymph nodes. In this group of patients, the most frequent metastatic site at the diagnosis was the liver (23.8%).
Regarding the chemotherapeutic treatments, the most frequent first-line treatment was 5-FU/LV (68.5%). The second most frequent treatment was IFL, used by 13 (10%) patients, followed by FLOX (5-FU bolus infusion, LV and oxaliplatin), used by 9 (6.9%) patients. Table 2 correlates the most frequent therapeutic regimen with the patients' clinical characteristics.
The regimen of 5-FU/LV was used in the treatment of 40 (95.2%) patients with stage II CRC and 27 (84.4%) patients with stage III CRC. Sixty-nine patients (71.9%) that used this regimen had moderately differentiated tumors. The level of carcinoembryonic antigen (CEA) above 5 ng/mL before starting the treatment was observed in 50 (83.3%) patients.
The purpose of the 5-FU/LV treatment was to act as an adjuvant therapy for 77 (89.5%) patients, while the other therapeutic regimens were used in only 9 (10.5%) patients with the same purpose (p<0.001).
The patients who, according to the analyzed medical records, reported any ADR during the chemotherapeutic treatment totaled 64 (49.2%). Forty-six (71.9%) of these received the 5-FU/LV treatment. Reported ADRs included diarrhea (62.3%), mucositis (50.8%), leukopenia (7.5%), thrombopcytopenia (11.7%), nauseas (11.3%), neutropenia (10.5%) and vomiting (7.5%).
Regarding the treatment response rate, the disease remained stable in 30 (23.1%) patients, 26 (86.7%) of them were treated with 5-FU/LV. Complete remission occurred in only 7 (5.4%) patients and partial remission in 26 (20%) patients, 14 (53.8%) of them were treated with 5-FU/LV. The analysis of medical records identified 53 (40.8%) deaths, 30 (56.6%) of them were treated with 5-FU/LV as the first-line treatment.
CRC is usually affects men more often, regardless of their age24-27. In this study, the disease frequency in male patients was 54.6%, in agreement with the world tendency4. In the United States and the European Union, the disease is diagnosed in patients over 70 years old26. In this study, the mean age at the diagnosis was 60 years old, in agreement with other studies described in the literature27,28. In addition, the risk of cancer increases with the age - 50% of the cases affect individuals over 60 years old1.
Regarding the ethnic origin, most patients with CRC are known to have a Caucasian origin, also in agreement with this study, as 98.5% of the patients were white12,29.
Colon was the primary tumor site in 65.4% of the analyzed patients, confirming what has been demonstrated by other investigators12,27. On the other hand, the rectum is more frequently indicated in other studies as the primary tumor site18,30.
Today, the CRC staging at the diagnosis is considered an important factor of prognosis, as it is directly related to OS. Once the disease staging is known, it is possible to define the best therapy. Through the TNM system, proposed by the Union for International Cancer Control (UICC), the analysis observed that 40% of the patients had stage IV CRC at the diagnosis. This is the most severe stage, which may indicate delayed diagnosis in most patients, who, for this reason, presented more advanced neoplasms, making prognosis more difficult28. Unlike this study, other authors show stages II and III as the most frequent at the diagnosis31. In this study, the site most frequently affected by metastasis was the liver, which is in agreement with the studies conducted by Roits et al.27 and Adachi et al.4.
The cellular differentiation degree is the most frequent histological variable in association with the TNM staging system, attributing a more careful prognosis to little differentiated adenocarcinomas32. In this study, only 3.1% of the tumors were well differentiated, which agrees with findings reported in previous studies28,30.
Evidences show that the presence of metastatic lymph node invasion at the diagnosis is related to factors of worse prognosis, such as advanced disease and presence of distant metastasis33. Such identification is extremely important for the prognosis, but the macroscopic access to lymph nodes is not viable, as a considerable part of lymph node metastasis (more than 30%) have maximum diameter of 3 mm34. In this study, most patients (51.5%) did not present lymph node metastasis at the diagnosis, just as demonstrated by other authors33,34.
Only 23 (20.4%) patients presented levels of CEA above 5ng/mL at the diagnosis. These values confirm the idea that this antigen does not have a diagnostic value, it is beneficial only for prognosis and treatment monitoring28-30.
Regarding the occurrence of ADRs during the chemotherapeutic treatment, 64 (49.2%) patients mainly had diarrhea, mucositis and leukopenia, but some medical records (37.7%) did not have information about ADR occurrences, making the analysis and calculation of ADR frequency in oncological patients more difficult.
In terms of first-line chemotherapeutic treatment, the 5-FU/LV regimen is indicated by two meta-analyses as the treatment of option to patients with stage II CRC10,11. In this study, 95.2% of the patients in this stage received 5-FU/LV as adjuvant therapy.
In this study, 27 (84.4%) stage III patients received 5-FU/LV, which is considered by some authors a generally well-tolerated adjuvant regimen and effective for the treatment of CRC35,36. The study conducted by Twelves et al. demonstrated that oral capecitabine is a highly effective alternative to 5-FU/LV for the treatment of stage III CRC, with disease-free survival equivalent to that of 5-FU/LV with less ADRs18. On the other hand, the study conducted by Van Cutsem et al. shows capecitabine as an alternative to mCRC treatment37, where it was used as the first-line treatment by 7 (5.4%) patients, all with stage IV CRC.
Other therapeutic options to treat stage II and III CRC were considered by Twelves et al., Thierry et al. and Cassidy et al. better than 5-FU/LV, as they significantly increase the overall survival of patients, such as XELOX, FOLFOX and FLOX9,18,38. In this study, these therapeutic options were used in 5 (15.6%) patients, and the regimens were FLOX and FOLFOX.
The therapeutic regimen used as the first-line treatment of 21 (40.4%) stage IV patients was 5-FU/LV. The other stage IV patients (59.6%) received other therapeutic regimens, including the IFL, used by 13 (10%) patients. For the treatment of the disease at a more advanced stage, FOLFOX and FOLFIRI, in the presence or absence of monoclonal antibodies - bevacizumab (an anti-VEGF antibody) or cetuximab (an anti-EGFR antibody) - are considered first-line treatment for mCRC, as both regimens offer similar OS and disease-free survival, with different toxicity profiles14,15. However, XELOX, FOLFOXIRI, 5-FU/LV and capecitabine are also considered alternatives to first-line treatment for mCRC37-40.
Regarding the utilization of IFL regimen, studies have demonstrated that FOLFIRI, FOLFOX and 5-FU/LV are related to less ADRs, such as neutropenia and gastrointestinal effects, when compared to IFL18-20. However, the adoption of chemotherapeutic regimens that use 5-FU in continuous infusion, such as FOLFIRI and FOLFOX, require the implantation of a long-term catheter (Port-A-Cath). As a result, typical complications of this type of device occur, especially thrombosis of superior vena cava and infection, both very serious and with risk of death. However, as demonstrated in this study, IFL is used as the first-line treatment for mCRC.
As described above, there are many treatment options for CRC, but the selection of the best treatment to each patient is made by the oncologist based on international regulations, such as the National Comprehensive Cancer Guideline. However, this selection is many times limited, as most patients are treated under SUS, which has specific protocols. But, regardless of the therapeutic regimens available, the treatment option should be always selected on an individual basis, considering the best to each patient, based on his/her clinical characteristics. In addition, it should be noted that, in stage IV CRC, as the treatment is usually palliative, it is not always interesting to use the whole therapeutic arsenal in the first intervention. Not using a drug in the first-line treatment may represent the possibility of using it in the future, as the second- or third-line treatment, depending on the response rate expected to alleviate the symptoms caused by the disease.
The epidemiological characteristics showed higher frequency of CRC in male patients, over 60 years of age. This study demonstrated that the most frequent primary tumor site is the colon, and that patients are diagnosed with CRC at a more advanced clinical stage of the disease, which leads to lower possibility of healing and more indefinite prognosis.
Regarding the first-line treatment, the most frequent therapeutic regimen was 5-FU/LV. The treatment selection is based on international protocols, according to the patient's clinical characteristics and the availability of the therapeutic regimen at the hospital. Most patients (49.2%) reported, at one point of the treatment, any type of ADR, regardless of the therapeutic regimen. And the most frequent ADRs were diarrhea, mucositis and leukopenia.
This study demonstrates the importance of prevention campaigns that encourage periodic examinations to prevent the disease development through the identification of CRC precursor lesions.
We would like to thank the nursing team, physicians and other staff members of the Oncology Center at the Hospital Ana Nery for their technical support and help in the collection of data used in this article.
1. Habr-Gama A. Câncer colorretal - A importância de sua prevenção. Arq Gastroenterol 2005;42(1):2-3. [ Links ]
2. Instituto Nacional de Câncer (INCA). Estimativa 2010: incidência de câncer no Brasil. Rio de Janeiro: INCA; 2009. [ Links ]
3. Born LJ, Imperiale TF, Kahi CJ, Stuart JS, Qi R, Glowinski EA et al. Risk factors for advanced sporadic colorectal neoplasia in persons younger than age 50. Cancer Detect Prev 2008;32(1):33-8. [ Links ]
4. Adachi CT, Nadal LRM, Nunes MAA, Ishiy CAA, Bobotis VC, Andreotti AP et al. Evolução do Carcinoma Colorretal, Comparando Doentes com Idades Acima e Abaixo de 40 Anos, Quanto à Diferenciação Tumoral e ao Estádio do Tumor. Rev bras Coloproct 2009;29(3):351-7. [ Links ]
5. Jin L, Inoue N, Sato N, Matsumoto S, Kanno K, Hashimoto Y, et al. Comparison between surgical outcomes of colorectal cancer in younger and elderly patients. World J Gastroenterol 2011;17(12):1642-8. [ Links ]
6. Brasil. Ministério da Saúde. Secretaria de Assistência à Saúde. Instituto Nacional de Câncer. Falando sobre câncer do intestino/Instituto Nacional de Câncer, Sociedade Brasileira de Coloproctologia, Colégio Brasileiro de Cirurgiões, Associação Brasileira de Colite Ulcerativa e Doença de Crohn, Colégio Brasileiro de Cirurgia Digestiva, Sociedade Brasileira de Endoscopia Digestiva, Sociedade Brasileira de Cancerologia, Sociedade Brasileira de Oncologia Clínica. Rio de Janeiro: INCA, 2003. [ Links ]
7. Cattell E, Tebbutt NC, Midgley R, Cunningham D, Kerr D, Systemic treatment of colorectal cancer. Euro J Cancer 2002;38(7):1000-15. [ Links ]
8. Board RE, Valle JW. Metastatic colorectal cancer: current systemic treatment options. Drugs 2007;67:1851-67. [ Links ]
9. Thierry A, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved Overall Survival With Oxaliplatin, Fluorouracil, and Leucovorin As Adjuvant Treatment in Stage II or III Colon Cancer in the MOSAIC Trial. J Clin Oncol 2009:27(19):3109-16. [ Links ]
10. Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L. Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group. J Clin Oncol 2004;22(16):3395-407. [ Links ]
11. Quasar. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007;370(9604):2020-9. [ Links ]
12. Obeidat NA, Pradel FG, Zuckerman IH, Delisle S, Mullins D. Outcomes of Irinotecan-Based Chemotherapy Regimens in Elderly Medicare Patients With Metastatic Colorectal Cancer. Am J Geriatr Pharmacother 2009;7(6):343-54. [ Links ]
13. Palomaki GE, Bradley LA, Douglas MP, Kolor K, Dotson D. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal câncer treated with irinotecan? An evidence-based review. Genet Med 2009;11(1):21-34. [ Links ]
14. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised Trial. Lancet 2000;355(9209):1041-7. [ Links ]
15. Hess GP, Wang PF, Quach D, Barber B, Zhao Z. Systemic Therapy for Metastatic Colorectal Cancer: Patterns of Chemotherapy and Biologic Therapy Use in US Medical Oncology Practice. J Oncol Pract 2010;6(6):301-7. [ Links ]
16. Ishida H, Fujita KI, Akiyama Y, Sunakawa Y, Yamashita K, Mizuno K, et al. Regimen selection for first-line FOLFIRI and FOLFOX based on UGT1A1 genotype and physical background is feasible in Japanese patients with advanced colorectal cancer. Jpn J Clin Oncol 2011;18(5):1-7. [ Links ]
17. Ishii Y, Hasegawa H, Endo T, Okabayashi K, Ochiai H, Moritani K, et al. Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer. Eur J Surg Oncol 2010;36(11):1061-5. [ Links ]
18. Twelves C, Wong A, Nowacki MP, Abt M, Burris H, Carrato A, et al. Capecitabine as Adjuvant Treatment for Stage III Colon Cancer. N Engl J Med 2005;352(26):2696-704. [ Links ]
19. Goldberg RM, Sargent DJ, Morton FJ, Fuchs CS, Ramanathan RK, Williamson SK, et al. Randomized Controlled Trial of Fluorouracil Plus Leucovorin, Irinotecan, and Oxaliplatin Combinations in Patients With Previously Untreated Metastatic Colorectal Cancer. J Clin Oncol 2004;22(1):23-30. [ Links ]
20. Tam VC, Rask S, Koru-Sengul T, Dhesy-Thind S. Generalizability of toxicity data from oncology clinical trials to clinical practice: toxicity of irinotecan-based regimens in patients with metastatic colorectal cancer. Curr Oncol 2009;16(6):13-20. [ Links ]
21. Van Cutsem e, Labianca r, Bodoky g, Barone c, Aranda e, Nordlinger b, et al. Randomized Phase III Trial Comparing Biweekly Infusional Fluorouracil/Leucovorin Alone or With Irinotecan in the Adjuvant Treatment of Stage III Colon Cancer: PETACC-3. J Clin Oncol 2009;279(19):3118-25. [ Links ]
22. Tebbutt NC, Cattell E, Midgley R, Cunningham D, Kerr D. Systemic treatment of colorectal cancer. Eur J Cancer 2002;38(7):1000-15. [ Links ]
23. Poston GL. The use of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. Eur J Surg Oncol 2005;31(4):325-30. [ Links ]
24. Marcuell E, Altes A, Menoyo A, Rio E, Gomez-Pardo M, Baiget M. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 2004;91(4):678-82. [ Links ]
25. Capafons SR, Giner AP, Bioscay RG, Poblador RP. Quimioterapia neoadyuvante en la resección de metástasis hepáticas y pulmonares de cáncer colorrectal. Farmacia Hospitalaria. Arquivo in press. 2011. [ Links ]
26. Hall N. Colorectal cancer: features and investigation. Medicine 2011;39(5):250-3. [ Links ]
27. Rouits E, Charasson V, Petain A, Boisdron-Celle M, Delord, JP, Fonck M, et al. Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients. Br J Cancer 2008;99(8):1239-45. [ Links ]
28. Saad-Hossne R, Prado RG, Neto AB, Lopes OS, Nascimento SM, Santos CRV, et al. Estudo retrospectivo de pacientes portadores de câncer de colorretal atendidos na faculdade de medicina de Botucatu no período de 2000-2003. Rev bras Coloproct 2005;25(1);31-7. [ Links ]
29. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDPglucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004;22(8):1382-8. [ Links ]
30. Carneiro Neto JD, Barreto JBP, Freitas NS, Queiroz MA. Câncer colorretal: características clínicas e anatomopatológicas em pacientes com idade inferior a 40 anos. Rev bras Coloproct 2006;26(4):430-5. [ Links ]
31. Ychou M, Raoul JL, Douillard JY, Bourgade SG, Mineur BL, Viret F, et al. A phase III randomised trial of LV5FU2 1 irinotecan versus LV5FU2 alone in adjuvant high-risk colon câncer (FNCLCC Accord02/FFCD9802). Annals of Oncology 2009;20:674-680 [ Links ]
32. Lupinacci RM, Campos FGCM, Araújo SEA, Imperiale AR, Seid VE, et al. Análise comparativa das características clínicas, anátomo-patológicas e sobrevida entre pacientes com câncer colo-retal abaixo e acima de 40 anos de idade. Rev bras Coloproct 2003;23(3):155-62. [ Links ]
33. Pereira JrT, Torres RAB, Nogueira AMMF. Acometimento metastático linfonodal no câncer colorretal. Arq Gastroenterol 2006;43(2)89-93. [ Links ]
34. Cserni G. The influence of nodal size on the staging of colorectal carcinomas. J Clin Pathol 2002;55(5):386-90. [ Links ]
35. Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993;11(10):1879-87. [ Links ]
36. Efficacy of adjuvant fluorouracil and folinic acid in colon câncer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators. Lancet 1995;345(8955):939-44. [ Links ] Comments in: Lancet 1995;345(8955):938; [ Links ] Lancet 1995;345(8964):1582. [ Links ]
37. Van Cutsem E, Hoff PM, Harper P, Bukowski RM, Cunningham D, Dufour P, et al. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 2004;90(6):1190-7. [ Links ]
38. Cassidy J, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Randomized Phase III Study of Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid Plus Oxaliplatin As First-Line Therapy for Metastatic Colorectal Cancer. J Clin Oncol 2008;26(12):2006-12. [ Links ]
39. Souglakos J, Androulakis N, Syrigos K, Polyzos A, Ziras N, Athanasiadis A, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006;94(6):798-805. [ Links ]
40. Emmanuel Mitry E, Fields ALA, Bleiberg H, Labianca R, Portierg, Tu D, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol 2008;26(30):4906-11. [ Links ]
Lia Gonçalves Possuelo
Avenida Independência, 2293, bloco 35, sala 3504
CEP: 96815-900 - Santa Cruz do Sul (RS), Brazil
Submitted on: 02/09/2012
Approved on: 03/12/2012
Financing source: Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).
Conflict of interest: nothing to declare.
Study carried out at the Department of Biology and Pharmacy, Universidade de Santa Cruz do Sul (UNISC) Santa Cruz do Sul (RS), Brazil