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Breast cancer incidence has increased in the last two decades and, simultaneously, survival has improved due to earlier detection and improved treatment options. Despite this improvement, locoregional recurrences and distant metastases occur in up to 10 and 30% of women diagnosed with early breast cancer, respectively. Around 70% of breast cancers are hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), and associated with a persistent risk of relapse up to 20 years after diagnosis/initial treatment. We conducted a narrative review by combining PubMed searches with our clinical experience to describe patient characteristics, biomarkers, and genomic profiling tools available to clinicians for the identification of patients with HR+, HER2- early breast cancer at high risk of recurrence and to provide recommendations to classify patients into recurrence risk categories. National and international treatment guidelines are also summarised. Accurate assessment of the risk of recurrence in these patients is crucial as the predicted risk guides treatment decisions; imprecise estimations can result in over- or undertreatment, with either scenario having negative consequences for patients. Multiple prognostic tools and factors are recommended for early breast cancer, and no single test provides accurate prognosis in isolation. Since no single test can provide accurate prognosis in isolation, a combination of tools should be used. Risk thresholds are important to guide optimised and balanced therapeutic decisions in HR+, HER2- early breast cancer. However, prognostic assessment should be performed on a case-by-case basis, making patient-specific prognostic approaches essential to avoid over- or undertreatment.
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INTRODUCTION: Integration of patient preferences into shared decision making improves disease-related outcomes, but such data from patients with advanced breast cancer (aBC) are limited. The objective of this study was to demonstrate the relative importance of overall survival (OS) and progression-free survival (PFS) in relation to quality of life (QoL) and therapy-associated side effects from the perspective of patients with aBC. METHODS: Postmenopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative aBC receiving first- or second-line treatment were recruited throughout Germany. Patient-relevant attributes for aBC therapy assessment were collected using a stepwise multimodal approach. A conjoint matrix was developed, resulting in 2 attributes for therapy goals (OS and PFS), 4 for QoL, and 6 for side effects. An online quantitative survey was then performed using adaptive choice-based conjoint (ACBC) methodology. RESULTS: The quantitative survey included 104 patients: 67 (64.4%) receiving first-line treatment and 37 (35.6%) receiving second-line treatment. The QoL attribute "physical agility and mobility" received the highest utility score (19.4 of 100%), reflecting the greatest importance to patients, followed by treatment goals (OS [15.2%] and PFS [14.4%]). Therapy-related side effects were less important, with nausea/vomiting being the most important (9.3%), followed by infection (6.4%) and hair loss (5.0%). The McFadden pseudo R2 (0.805), the root likelihood (0.864), and the χ2 test (2,809.041; p < 0.0001) indicated a very good fit of the statistical model. CONCLUSION: Using ACBC analysis, it appears that QoL, OS, and PFS are most important to postmenopausal patients with aBC in relation to cancer treatment. Side effects seem to be less important if OS or PFS are prolonged and the QoL is maintained. Thus, QoL, OS, and PFS should be considered equally when making treatment decisions in aBC.
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BACKGROUND: MONARCH 3, a phase III trial (NCT02246621) of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), previously demonstrated significantly improved progression-free survival in patients receiving abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI). This study evaluated patient-reported outcomes, including global health-related quality of life (HRQoL), functioning, and symptoms. METHODS: Patients were randomly assigned 2:1 to receive abemaciclib (150 mg twice daily; n = 328) or placebo (n = 165), plus 1 mg anastrozole or 2.5 mg letrozole daily. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Breast Cancer-Specific Quality of Life Questionnaire HRQoL instruments were administered at baseline, every two cycles during cycles 2 through 19 (each cycle being 28 days), every three cycles thereafter, and once at a short-term posttherapy follow-up visit (approximately 30 days after discontinuation). Longitudinal mixed regression and Cox proportional hazards models evaluated postbaseline change and time to sustained deterioration (TTSD), respectively. RESULTS: Baseline scores were similar between treatment arms. Although select scores statistically favored the placebo arm, global HRQoL, most symptoms, and functioning scales did not meet the threshold for clinically meaningful differences between treatment arms. Only diarrhea favored the placebo arm with statistically and clinically meaningful differences. There were no TTSD differences between treatment arms for global HRQoL, most symptoms (except diarrhea), or functioning. CONCLUSION: Over a 2-year period, there were no clinically meaningful differences in global HRQoL, functioning, and most symptoms for patients receiving abemaciclib plus NSAI compared with NSAI alone. Only diarrhea favored the placebo arm, consistent with prior safety data, which has been shown to be manageable and reversible. Combined with clinical efficacy, results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2- ABC. IMPLICATIONS FOR PRACTICE: The addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) was not associated with a clinically meaningful detriment in patient-reported global health-related quality of life, functioning, and most symptoms in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Prior studies have also demonstrated clinical efficacy of abemaciclib plus NSAI compared with NSAI alone, including improved progression-free survival and objective response rate. These results also complement previously reported toxicity data, as measured by investigator-assessed adverse events. Taken together, these results support treatment with abemaciclib plus NSAI for postmenopausal women with HR+, HER2- ABC.
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Inibidores da Aromatase , Neoplasias da Mama , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Benzimidazóis , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Qualidade de Vida , Receptor ErbB-2/uso terapêutico , Receptores de EstrogênioRESUMO
BACKGROUND: In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms. MATERIALS AND METHODS: Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30 days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm. RESULTS: On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n = 446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n = 223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10). CONCLUSION: HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC. IMPLICATIONS FOR PRACTICE: In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.
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Neoplasias da Mama , Qualidade de Vida , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis , Neoplasias da Mama/tratamento farmacológico , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Receptores de EstrogênioRESUMO
The objectives of this single-center, open-label, phase II study were to evaluate (a) the feasibility and safety of neoadjuvant administration of pemetrexed with oral folic acid and vitamin B12 (FA/B12) in newly diagnosed patients with resectable rectal cancer and (b) intracellular and systemic vitamin metabolism. Patients were treated with three cycles of pemetrexed (500 mg/m, every 3 weeks) and FA/B12 before surgery. The reduced folates tetrahydrofolate, 5-methyltetrahydrofolate, and 5,10-methylenetetrahydrofolate were evaluated from biopsies in tumor tissue and in adjacent mucosa. Serum levels of homocysteine, cystathionine, and methylmalonic acid were also measured. All 37 patients received three cycles of pemetrexed; 89.2% completed their planned dosage within a 9-week feasibility time frame. Neither dose reductions nor study drug-related serious adverse events were reported. Reduced folate levels were significantly higher in tumor tissue compared with adjacent mucosa at baseline. After FA/B12 administration, tissue levels of reduced folates increased significantly and remained high during treatment in both tumor and mucosa until surgery. Serum levels of cystathionine increased significantly compared with baseline after FA/B12 administration, but then decreased, fluctuating cyclically during pemetrexed therapy. Homocysteine and methylmalonic acid levels decreased significantly after FA/B12 administration, and remained below baseline levels during the study. These results indicate that administration of three neoadjuvant cycles of single-agent pemetrexed, every 3 weeks, with FA/B12 in patients with resectable rectal cancer is feasible and tolerable. Tissue and serum vitamin metabolism results demonstrate the influence of pemetrexed and FA/B12 on vitamin metabolism and warrant further study.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Ácido Fólico/metabolismo , Pemetrexede/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Vitamina B 12/sangue , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistationina/sangue , Estudos de Viabilidade , Feminino , Ácido Fólico/administração & dosagem , Homocisteína/sangue , Humanos , Mucosa Intestinal/metabolismo , Masculino , Ácido Metilmalônico/sangue , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Retais/metabolismo , Reto/metabolismo , Vitamina B 12/administração & dosagemRESUMO
BACKGROUND: This study's primary objective was evaluation of the progression-free survival rate at 6 months (PFS-6) in patients with newly diagnosed glioblastoma without O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation postsurgically treated with enzastaurin before and concomitantly with radiation therapy, followed by enzastaurin maintenance therapy. PFS-6 of at least 55% was set to be relevant compared with the data of the EORTC 26981/22981 NCIC CE.3 trial. METHODS: Adult patients with a life expectancy of at least 12 weeks who were newly diagnosed with a histologically proven supratentorial glioblastoma without MGMT promoter hypermethylation were eligible. Patients were treated with enzastaurin prior to, concomitantly with, and after standard partial brain radiotherapy. Here we report on a multicenter, open-label, uncontrolled phase II study of patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation treated with enzastaurin and radiation therapy within 4 study periods. RESULTS: PFS-6 was 53.6% (95% confidence interval [CI]: 39.8-65.6). The median overall survival was 15.0 months (95% CI: 11.9-17.9) for all patients, 3.9 months (95% CI: 0.8-9.0) for patients with biopsy, 15.4 months (95% CI: 10.1-17.9) for patients with partial resection, and 18.9 months (95% CI: 13.9-28.5) for patients with complete resection. The safety profile in this study was as expected from previous trials, and the therapy was well tolerated. CONCLUSIONS: PFS-6 missed the primary planned outcome of 55%. The secondary exploratory analysis according to resection status of the different subgroups of patients with biopsies, partial resection, and complete resection demonstrates the strong prognostic influence of resection on overall survival.
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Neoplasias Encefálicas/terapia , Quimiorradioterapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/terapia , Indóis/uso terapêutico , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico , Feminino , Seguimentos , Glioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m(2) for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Indóis/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Dacarbazina/administração & dosagem , Dacarbazina/farmacocinética , Dacarbazina/uso terapêutico , Feminino , Glioblastoma/radioterapia , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Temozolomida , Adulto JovemRESUMO
BACKGROUND: Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS: Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia. CONCLUSIONS: Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Humanos , Indóis/administração & dosagem , Leucovorina/administração & dosagem , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Placebos , RetratamentoRESUMO
BACKGROUND: Second-line treatment of advanced non-small-cell lung cancer (NSCLC) improves overall survival. There is a lack of data regarding the impact on patients' overall health condition. This prospective, non-interventional study evaluated performance status (PS) and health-related quality of life (HR-QoL) during second-line pemetrexed treatment in routine clinical practice. METHODS: Stage III/IV NSCLC patients who initiated second-line pemetrexed (standard vitamin and dexamethasone supplementation) were observed for a maximum of 9 treatment cycles. The primary objective was to evaluate the proportion of patients achieving improvement of Karnofsky Index (KI) of ≥ 10% (absolute) or maintaining KI ≥ 80% after the second treatment cycle ("KI benefit response"). HR-QoL was self-rated using the EuroQoL-5D questionnaire (EQ-5D). Factors potentially associated with KI benefit response were evaluated using logistic regression models. RESULTS: Of 521 eligible patients (73.5% Stage IV, median age 66.3 yrs, 36.1% ≥ 70 yrs, 62.0% with KI ≥ 80%), 471 (90.4%) completed at least 2 treatment cycles. 58.0% (95%CI 53.6%;62.2%) achieved KI benefit response after the second cycle. Patients with baseline KI ≥ 80%, no Grade 3/4 toxicities during the first 2 cycles, or combination regimen as prior first-line therapy were more likely to achieve a KI benefit response. EQ-5D scores improved over time. Grade 3/4 toxicities were reported in 23.8% of patients (mainly fatigue/asthenia 15.9%, neutropenia 8.7%). CONCLUSIONS: In this large prospective, non-interventional study of second-line pemetrexed treatment in patients with advanced NSCLC, including 36% elderly patients ( ≥ 70 years), physician-rated PS and self-rated HR-QoL were maintained or improved in the majority of patients. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT00540241) on October 4, 2007.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/psicologia , Feminino , Guanina/uso terapêutico , Humanos , Avaliação de Estado de Karnofsky , Modelos Logísticos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/psicologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pemetrexede , Estudos ProspectivosRESUMO
BACKGROUND: Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. OBJECTIVE: To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1-3). DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), > or = pT2 disease, or intraoperative complications, patients were discontinued. INTERVENTION: We used a single, postoperative 30-40-min instillation of GEM (2000 mg/100 ml of saline) or PBO (100 ml of saline) followed by continuous bladder irrigation for > or = 20 h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (BCG) instillations were allowed. MEASUREMENTS: Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, alpha = 0.050). RESULTS AND LIMITATIONS: Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1-3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1-G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8-84.3]; PBO: 75.3% [66.3-82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64-1.39], log-rank test, p=0.777). CONCLUSIONS: In this study of NMIBC, the immediate single instillation of GEM 2000 mg/100 ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.
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Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Desoxicitidina/análogos & derivados , Cuidados Pós-Operatórios , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Idoso , Carcinoma de Células de Transição/cirurgia , Terapia Combinada , Desoxicitidina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Neoplasias da Bexiga Urinária/cirurgia , GencitabinaRESUMO
The epigenetic inactivation of genes plays an important role in lung cancer. We have investigated the methylation status of the promoter region of seven genes (APC1A, DAPK, FHIT, p14(ARF), p16(INK4a), RARbeta, RASSF1A) in serum DNA of NSCLC patients. The objective of our study was to reveal the influence of such alterations on overall survival. Blood samples were drawn pretherapeutically. Genomic DNA was purified from serum, treated with sodium bisulfite and hypermethylation was detected by a nested methylation-specific PCR in a group of 92 patients with histologically confirmed stage IIIB and IV NSCLC. All patients received gemcitabine first-line alone or in combination with other drugs. The vast majority (n=87) showed at least one epigenetic alteration. The methylation frequencies of individual genes varied between 25.9 and 47.3%. The hypermethylation status of none of the genes had a significant influence on median overall survival of the total population. In contrast, patients with a methylated RASSF1A gene who showed a partial response survived significantly longer (33.6+/-10.4 month) compared to those with a wild-type allele (12.9+/-4.7 month, P=0.0045). This effect became even more pronounced in combination with p14(ARF) (P=0.0004). This difference was not seen in patients with stable or progressive disease. A multivariate analysis confirmed that RASSF1A methylation was an independent prognostic factor. Our results show that the hypermethylation frequency of single genes and the accumulation of epigenetic alterations in individual samples of NSCLC patients may vary considerably. Molecular parameters such as hypermethylation of RASSF1A or p14(ARF) may be useful prognostic markers in subpopulations.
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Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Proteínas Supressoras de Tumor/sangue , Adulto , Idoso , Distribuição de Qui-Quadrado , Metilação de DNA , Primers do DNA , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , GencitabinaRESUMO
The therapeutic benefit and side-effect profile of gemcitabine in adults with relapsed solid tumors is well known. So far, few data are available about its significance in pediatric relapsed solid tumors. To determine the efficacy and tolerability of gemcitabine in children, the drug was administered by intravenous short-term infusion over 30 min at a dose of 1200 mg/m2 weekly for 3 weeks as one cycle in children with relapsed solid tumor of embryonic or mesenchymal origin. From May 2003 to September 2004, 14 male and six female patients (2-23, median 15.8 years) were recruited for this prospective open-label phase II study (two-step Simon design). The patients suffered from rhabdomyosarcoma (n=8), Ewing's sarcoma (n=4), osteosarcoma (n=2), neuroblastoma (n=3), hepatoblastoma (n=2) and nephroblastoma (n=1). Median duration of therapy was 27.5 days (7-99), corresponding to 4.0 (2-11) infusions of gemcitabine. Two patients (neuroblastoma and Ewing) had stable disease documented for 69 and 70 days, whereas no objective responses were observed. In 34/94 administered infusions; doses had to be reduced or omitted for grade 3-4 hematotoxicity. Minimal activity was observed in this cohort of children with a wide spectrum of mesenchymal and embryonic tumors. Given the relatively low dose of gemcitabine administered, this study does not exclude the possibility of activity at higher doses. Secondly, the tolerability of gemcitabine in children was consistent with that expected in adults. For further studies in this population, we recommend the use of gemcitabine in combination with other agents.
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Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Antimetabólitos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Estudos Prospectivos , Tamanho da Amostra , GencitabinaRESUMO
Hypermethylation occurs frequently in neoplastic cells and affects tumorigenesis. Malignant mesothelioma is an aggressive cancer developing in the thoracic cavity and patients have a rather bad prognosis. Our goal was to determine epigenetic alterations of a series of genes and to analyse the potential correlation of such changes with overall survival. We have analysed the methylation status of the promoter region of nine genes in serum DNA of mesothelioma patients by a nested methylation-specific PCR. Modest methylation frequencies were detected for APC1A (14.3%), RASSF1A (19.5%) and DAPK (20.0%) while hypermethylation of E-cadherin (71.4%) and FHIT (78.0%) occurred at a high incidence. Intermediate values were seen for p16(INK4a) (28.2%), APC1B (32.5%), p14(ARF) (44.2%) and RARbeta (55.8%). The methylation status of none of the single genes significantly influenced prognosis. In contrast, combining RARbeta with either DAPK or RASSF1A showed a significantly shorter overall survival of those patients who had both genes methylated compared to those with only one or no epigenetic alteration (P=0.025 and 0.040, respectively). Similarly, the combination of all three genes revealed a worse prognosis for patients with double or triple methylations compared to the group which had only one or no gene methylated (P=0.028). Our results support the idea that the prognostic value of a combination of epigenetic alterations is superior to the impact of an individual gene alone on overall survival.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Metilação de DNA , Mesotelioma/genética , Neoplasias Pleurais/genética , Receptores do Ácido Retinoico/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , Proteínas Quinases Associadas com Morte Celular , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Mesotelioma/patologia , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Regiões Promotoras Genéticas , Taxa de SobrevidaRESUMO
PURPOSE: This is the first preclinical report evaluating a trimodal therapy consisting of irradiation, chemotherapy, and antiangiogenesis in the context of a multimodal anticancer strategy. The combination of the folate antimetabolite pemetrexed, SU5416, a receptor tyrosine kinase inhibitor of VEGFR2, and irradiation was investigated in human endothelial cells and tumor cell lines. METHODS AND MATERIALS: Primary isolated human umbilical vein endothelial cells (HUVEC), human dermal microvascular endothelial cells (HDMEC), and human glioblastoma (U87) and prostate cancer cells (PC3) were exposed to pemetrexed (2 h) alone and in combination with SU5416 (2 h). When combined with irradiation up to 8 Gy, fixed concentrations of pemetrexed (1.06 muM) and SU5416 (1.0 muM) were used. Proliferation and clonogenic assays were conducted with endothelial and tumor cells. The migration/invasion ability of endothelial cells and the ability to produce tubular structures were tested in Matrigel and tube formation assays. Apoptosis was measured by sub-G1 DNA and caspase-3 flow cytometry. To investigate underlying cell signaling, immunocytochemistry was used to detect Akt survival signaling involvement. RESULTS: Triple combination using only a low-toxicity drug exposure of pemetrexed and SU5416 results in greater response than each treatment alone or than each combination of two modalities in all tested endothelial and tumor cell models. Triple combination substantially inhibits proliferation, migration/invasion, tube formation, and clonogenic survival. Triple combination also induced the highest rate of apoptosis in HDMEC and HUVEC as indicated by sub-1 G1 and caspase-3 assessment. Interestingly, triple combination therapy also reduces proliferation and clonogenic survival significantly in U87 and PC3 tumor cell lines. SU5416 potently inhibited Akt phosphorylation which could be induced by radiation and radiochemotherapy in human endothelial cells. CONCLUSIONS: Our findings demonstrate the high antiendothelial/antitumoral efficacy of the concurrent administration of irradiation, chemotherapy, and angiogenesis inhibition in vitro. A potential explanation for the favorable combination would be that VEGF signaling inhibition downregulates Akt survival signaling upon activation by radiation and/or chemotherapy. The data also suggest that endothelial cell apoptosis may have an important role in the benefits of the presented therapy.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Terapia Combinada/métodos , Glutamatos/uso terapêutico , Guanina/análogos & derivados , Guanina/uso terapêutico , Indóis/uso terapêutico , Neoplasias/terapia , Pirróis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Neovascularização Patológica/prevenção & controle , Pemetrexede , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaio Tumoral de Célula-Tronco/métodosRESUMO
PURPOSE: The novel folate antimetabolite Alimta (pemetrexed disodium, LY231514) exhibits antitumor activity in a broad array of human malignancies and was recently found to enhance radiation-induced cell killing in vitro. In the present study, a possible cell cycle phase-specific radiosensitization by pemetrexed was assessed. METHODS AND MATERIALS: Widr human colon carcinoma cells were synchronized by serum withdrawal/stimulation that yielded about 80% cells with G1 DNA content 6 h after replating and more than 60% S-phase cells after 22 h, as assessed by flow cytometry. The respective cultures were irradiated with doses up to 12 Gy in combination with a subtoxic pemetrexed exposure (1.06 microM for 2 h: about 80% survival), or after mock treatment. Survival curves were generated by the clonogenic assay; apoptosis was measured by sub-G1 DNA flow cytometry. RESULTS: The combination treatment of the G1 cells and of the more radioresistant S-phase cell preparations yielded survival rates that were lower than expected for independent cell killing. Radiosensitization, calculated as the ratio of the mean inactivation doses without or with drug exposure (enhancement ratio), was not significantly different for the two cell preparations (enhancement ratio of 2.1 and 2.3, respectively) and was similar to the previously reported value for log-phase cells. Pemetrexed exposure was unable to stimulate an apoptotic response of these cells to radiation. CONCLUSIONS: Radiosensitization by pemetrexed is not cell cycle phase-specific, and the relative radioresistance of S-phase cells is retained. Apoptosis seems to have no influence on radiosensitization in this cell line.
Assuntos
Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Neoplasias do Colo/metabolismo , Glutamatos/farmacologia , Guanina/análogos & derivados , Guanina/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Pemetrexede , Radiossensibilizantes/farmacologia , Células Tumorais CultivadasRESUMO
BACKGROUND: Concomitant radiotherapy and chemotherapy with gemcitabine appears to be a promising tool for the treatment of pancreatic cancer since gemcitabine -- applied as single or combination therapy -- proved to have better efficacy in pancreatic cancer than 5-FU containing schemes and furthermore offers radiosensitizing potential. In the present paper our pilot data of concomitant and sequential chemoradiation with gemcitabine and cisplatin are presented. PATIENTS AND METHODS: A total of 57 patients (f/m 23/34) with pancreatic cancer was treated, of whom 33 patients had irresectable tumors, 19 patients following resection (R1 and/or pN+) and five patients with local recurrent disease. Radiotherapy was delivered in 25 fractions up to a total dose of 45.0 Gy specified according to ICRU reference point (50 patients, 1.8 Gy/fraction) respectively 50.0 Gy to gross tumor volume (seven patients; 45.0 Gy in locoregional lymphatic pathways; 2.0/1.8 Gy/fraction). Concomitant with radiotherapy cisplatin (30 mg/m(2)) and gemcitabine (300 mg/m(2)) were applied on days 1, 8, 22 and 29. After simultaneous chemoradiation two sequential cycles gemcitabine and cisplatin (1000 mg/m(2) and 50 mg/m(2) d 1, 15) were applied. RESULTS: With a median follow-up of 8.2 months the median survival time was 14.8 months (irresectable patients: 10.3 months, postoperative patients, 15.1 months). Within 33 irresectable patients 19 and four partial and complete remissions, respectively, were observed. In 14 patients a secondary resection was possible. Using leveled antiemetics with ondansetron and dexamethasone no gastrointestinal toxicities grade III or IV were observed. Hematologic toxicities were the most grave side effects (leukocytopenia III/IV in 29/five patients and thrombocytopenia III/IV in 21/eight patients), however with minor clinical relevancy (one neutropenic infection, one thrombopenic epistaxis). CONCLUSION: The presented treatment scheme using concomitant and sequential gemcitabine and cisplatin with radiation is feasible with justifiable side effects. To evaluate the promising remission and survival rates, randomized trials of neoadjuvant and primary chemoradiation are started.