RESUMO
BACKGROUND: Reproductive-aged women are, according to American and European guidelines, recommended to avoid pregnancy for 12-24 months after bariatric surgery. Oral contraceptives may have suboptimal efficacy after malabsorptive bariatric procedures. AIM: The aim of this study was to assess contraceptive use pre- and postoperatively in women who underwent bariatric surgery in two obesity clinics in The Netherlands. Also, the recall of contraceptive and pregnancy counseling was investigated. METHODS: A validated questionnaire was performed among women aged 18-45 years who underwent bariatric surgery from October 2017 through August 2018. RESULTS: In total, 230 women were eligible for final analysis. Postoperatively, 60% used safe contraception, 16.1% unsafe contraception, and 23.9% no contraception. In this study, 43.7% of women using a potential unsafe contraceptive method preoperatively switched to a safe method of contraception postoperatively (p < 0.0001). Only 62.6% of women confirmed to have received contraceptive counseling, mainly preoperatively. The odds ratio for receiving contraceptive counseling and using safe contraceptive methods compared with not receiving contraceptive counseling was 2.20 (95% CI, 1.27-3.79; p = 0.005). Eighty-three percent confirmed that they have received counseling regarding delaying a pregnancy, and 52.6% were familiar with the recommendation to avoid a pregnancy for 24 months postoperatively. CONCLUSIONS: In our study, 60% of women are using safe contraception postoperatively. Contraceptive counseling is suboptimal as 62.6% recall receiving counseling. Those who confirmed receiving counseling were more likely to use safe contraception after bariatric surgery. More counseling and monitoring in the postoperative and in the outpatient setting is recommended.
Assuntos
Cirurgia Bariátrica , Comportamento Contraceptivo , Aconselhamento , Adolescente , Adulto , Anticoncepcionais Femininos/uso terapêutico , Dispositivos Anticoncepcionais/estatística & dados numéricos , Anticoncepcionais Orais Hormonais/efeitos adversos , Contraindicações de Medicamentos , Feminino , Humanos , Pessoa de Meia-Idade , Período Pós-Operatório , Esterilização Tubária/estatística & dados numéricos , Inquéritos e Questionários , Adulto JovemRESUMO
Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Panitumumabe , Proteínas Proto-Oncogênicas p21(ras) , Sinvastatina/administração & dosagemRESUMO
Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with cetuximab. Treatment data were obtained from patients who were treated with capecitabine, oxaliplatin bevacizumab ± cetuximab in the phase III CAIRO2 study. A total of 529 patients were included in this study, of whom 78 patients were on statin therapy. In patients with a KRAS wild type tumor (n = 321) the median PFS was 10.3 vs. 11.4 months for non-users compared to statin users and in patients with a KRAS mutant tumor (n = 208) this was 7.6 vs. 6.2 months, respectively. The hazard ratio (HR) for PFS for statin users was 1.12 (95% confidence interval 0.78-1.61) and was not influenced by treatment arm, KRAS mutation status or the KRAS*statin interaction. Statin use adjusted for covariates was not associated with increased PFS (HR = 1.01, 95% confidence interval 0.71-1.54). In patients with a KRAS wild type tumor the median OS for non-users compared to statin users was 22.4 vs. 19.8 months and in the KRAS mutant tumor group the OS was 18.1 vs. 14.5 months. OS was significantly shorter in statin users versus non-users (HR = 1.54; 95% confidence interval 1.06-2.22). However, statin use, adjusted for covariates was not associated with increased OS (HR = 1.41, 95% confidence interval 0.95-2.10). In conclusion, the use of statins at time of diagnosis was not associated with an improved PFS in KRAS mutant mCRC patients treated with chemotherapy and bevacizumab plus cetuximab.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Resultado do TratamentoRESUMO
BACKGROUND: Currently, only Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status is used as a decisional marker for epidermal growth factor receptor (EGFR) inhibitor therapy in colorectal cancer (CRC) patients. Concordance of KRAS status between primary tumors and metastases has always been considered to be close to perfect; however, cases of discordance have been reported. The actual rate of concordance of KRAS status remains unclear, as is the same for v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatidylinositol 3-kinase CA subunit (PIK3CA), and loss of phosphatase and tensin homologue deleted on chromosome ten (PTEN). Therefore, it is unknown whether it is necessary to perform mutational analysis on metastases instead of on (or in addition to) primary tumors. DESIGN: A systematic literature search was conducted to collect all studies testing concordance of KRAS in CRC, and also of BRAF, PIK3CA, and loss of PTEN. RESULTS: Twenty-one studies have reported concordance of KRAS, with an overall concordance rate of 93% (range, 76%-100%). Overall concordance rates of studies testing concordance of BRAF status and loss of PTEN were 98% and 68%, respectively. Three studies reported concordance of PIK3CA status (range, 89%-94%). CONCLUSION: Though discordance of KRAS status does occur, it is uncommon. When considering the downsides of testing metastatic tissue in all patients along with the low incidence of discordance, we conclude that that testing the primary tumor (or whatever tissue available) is sufficient for clinical decision making on EGFR inhibitor therapy.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Animais , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/metabolismoRESUMO
KRAS has an important role in colorectal carcinogenesis and mutant KRAS leads to a permanently activated k-ras protein. To exert its biological activity, k-ras requires post-translational modification by prenylation. K-ras modulation has become a promising concept for new therapies, mostly by interference with the mevalonate pathway and subsequently by the prenylation of k-ras. Clinical data of agents interfering with the mevalonate pathway and the prenylation of ras are summarized and suggest that these agents might be effective when administered in combination with anticancer drugs that target k-ras. Here, we discuss the novel concept that modulation of k-ras might potentiate EGFR therapy by altering the KRAS phenotype.