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1.
BMJ Open ; 13(6): e069973, 2023 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-37286324

RESUMO

INTRODUCTION: Circadian clocks regulate cellular proliferation and drug effects. Tolerability and/or efficacy of anticancer therapies have been improved by their administration according to circadian rhythms, while being predicted by circadian robustness. The combination of leucovorin, fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) is a standard treatment for pancreatic ductal adenocarcinoma (PDAC), that generates grades 3-4 adverse events in the majority of patients and an estimated 15%-30% emergency admission rate. The MultiDom study evaluates whether mFOLFIRINOX safety can be improved using a novel circadian-based telemonitoring-telecare platform in patients at home. The detection of early warning signals of clinical toxicities could guide their early management, possibly preventing emergency hospital admissions. METHODS AND ANALYSIS: This multicentre, interventional, prospective, longitudinal, single-arm study hypothesises that the mFOLFIRINOX-related emergency admission rate will be 5% (95% CI 1.7% to 13.7%), among 67 patients with advanced PDAC. Study participation is 7 weeks for each patient, including a reference week before chemotherapy onset and 6 weeks afterwards. Accelerometry and body temperature are measured q1-min using a continuously worn telecommunicating chest surface sensor, daily body weight is self-measured with a telecommunicating balance and 23 electronic patient-reported outcomes (e-PROs) are self-rated using a tablet. Hidden Markov model, spectral analyses and other algorithms automatically compute physical activity, sleep, temperature, body weight change, e-PRO severity and 12 circadian sleep/activity parameters, including the dichotomy index I

Assuntos
Neoplasias Pancreáticas , Humanos , Estudos Prospectivos , Neoplasias Pancreáticas/tratamento farmacológico , Ritmo Circadiano , Medidas de Resultados Relatados pelo Paciente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Multicêntricos como Assunto , Neoplasias Pancreáticas
2.
Cancers (Basel) ; 14(4)2022 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-35205644

RESUMO

HYPOTHESIS: Prior experimental and human studies have demonstrated the circadian organization of immune cells' proliferation, trafficking, and antigen recognition and destruction. Nivolumab targets T(CD8) cells, the functions, and trafficking of which are regulated by circadian clocks, hence suggesting possible daily changes in nivolumab's efficacy. Worse progression-free survival (PFS), and overall survival (OS) were reported for malignant melanoma patients receiving more than 20% of their immune checkpoint inhibitor infusions after 16:30 as compared to earlier in the day. METHODS: Consecutive metastatic non-small-cell cancer (NSCLC) patients received nivolumab (240 mg iv q 2 weeks) at a daily time that was 'randomly' allocated for each course on a logistical basis by the day-hospital coordinators. The median time of all nivolumab administrations was computed for each patient. The study population was split into two timing groups based upon the median value of the median treatment times of all patients. CTCAE-toxicity rates, iRECIST-tumor responses, PFS and OS were computed according to nivolumab timing. PFS and OS curves were compared and hazard ratios (HR) were computed for all major categories of characteristics. Multivariable and sensitivity analyses were also performed. RESULTS: The study accrued 95 stage-IV NSCLC patients (PS 0-1, 96%), aged 41-83 years. The majority of nivolumab administrations occurred between 9:27 and 12:54 for 48 patients ('morning' group) and between 12:55 and 17:14 for the other 47 ('afternoon' group). Median PFS (95% CL) was 11.3 months (5.5-17.1) for the 'morning' group and 3.1 months (1.5-4.6) for the 'afternoon' one (p < 0.001). Median OS was 34.2 months (15.1-53.3) and 9.6 months (4.9-14.4) for the 'morning' group and the 'afternoon' one, respectively (p < 0.001). Multivariable analyses identified 'morning' timing as a significant predictor of longer PFS and OS, with respective HR values of 0.26 (0.11-0.58) and 0.17 (0.08-0.37). The timing effect was consistent across all patient subgroups tested. CONCLUSIONS: Nivolumab was nearly four times as effective following 'morning' as compared to 'afternoon' dosing in this cohort of NSCLC patients. Prospective timing-studies are needed to minimize the risk of resistance and to maximize the benefits from immune checkpoint inhibitors.

3.
Support Care Cancer ; 29(11): 6167-6170, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33963910

RESUMO

BACKGROUND AND AIM: The evaluation of patient-reported outcomes (PRO) in cancer has proven relevant positive clinical impact on patients' communication with healthcare professionals, decision-making for management, well-being, and overall survival. However, the optimal frequency of PRO assessment has yet to be defined. Based on the assumption that more frequent sampling would enhance accuracy, we aimed at identifying the optimal sampling frequency that does not miss clinically relevant insight. METHODS: We used pilot data from 31 advanced cancer patients who completed once daily the 19-item MD Anderson Symptom Inventory at home. The resulting dataset allowed us to compare different PRO assessment frequencies to daily sampling, i.e., alternate days (q2d), every third day (q3d), or once a week (q1w). We evaluated the sampling frequencies for two main outcomes: average symptom intensity and identification of severe symptoms. RESULTS: The majority of the differences between corresponding averages of daily data and those for q2d, q3d, and q1w datasets were close to 0, yet the extremes exceeded 5. Clinically meaningful differences, i.e., > 1, were observed in 0.76% of patient items for q2d, in 2.72% for q3d, and in 11.93% for q1w. Moreover, median values of missed instances of a severe symptom (i.e., > 6) were 14.6% for q2d, 27.8% for q3d, and 55.6% for q1w. CONCLUSIONS: Our analysis suggests that in patients receiving chemotherapy for advanced cancer, increasing the density of PRO collection enhances the accuracy of PRO assessment to a clinically meaningful extent. This is valid for both computations of averages symptom burden and for the recognition of episodes of severe symptom intensity.


Assuntos
Neoplasias , Telemedicina , Humanos , Neoplasias/epidemiologia , Neoplasias/terapia , Avaliação de Resultados da Assistência ao Paciente , Medidas de Resultados Relatados pelo Paciente
4.
Int J Cancer ; 148(10): 2512-2521, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33270911

RESUMO

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian-based administration (chronoIFLO5) as either first- or second-line treatment, within the time-finding EORTC 05011 trial. Five-day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil-leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first- and second-line settings. Primary endpoints included Grade 3-4 toxicity rates, best objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). One-hundred forty-nine and 44 patients were treated in first-line and second-line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty-six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2-70.4] and resulted in median PFS and OS of 8.7 months [7.5-9.9] and 19.9 months [15.4-24.5]. Corresponding figures in second line were 37.5% [22.5-52.5], 6.7 months [4.8-8.9] and 16.3 months [11.8-20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33015528

RESUMO

PURPOSE: Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with RAS wild-type (RAS-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with RAS mutation (RAS-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was RAS-wt. MATERIALS AND METHODS: The occurrence of Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (BRAF), and PI3KCA mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed RAS-mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with RAS-wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with RAS-mt ctDNA were treated with the oncologist's choice of therapy. RESULTS: Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified RAS-mt in seven patients (44%) and RAS-wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with RAS-wt ctDNA and 17.9% for those with RAS-mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively. CONCLUSION: Patients with RAS-mt mCRC whose plasma biopsies contained RAS-wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.

8.
Cancer Med ; 9(12): 4148-4159, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32319740

RESUMO

The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population. 130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed-time chronomodulated Fluorouracil-Leucovorin-Oxaliplatin for 4 days, q3 weeks. The sex-specific circadian characteristics of grade (G) 3-4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test. Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3-4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P < .05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P = .023; neutropenia, P = .015; fatigue, P = .062; anorexia, P = .032). Irinotecan timing was most critical for females, with grades 3-4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Europa (Continente)/epidemiologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/administração & dosagem , Prognóstico , Caracteres Sexuais , Taxa de Sobrevida
9.
Sleep ; 42(10)2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31323086

RESUMO

Subjective sleep assessment in cancer patients poorly correlates with actigraphy parameters that usually encompass multiple nights. We aimed to determine the objective actigraphy measures that best correlated with subjective sleep ratings on a night-by-night basis in cancer patients. Thirty-one cancer patients daily self-rated sleep disturbances using the single dedicated item of the MD Anderson Symptom Inventory (0-10 scale) with 18 other items, and continuously wore a wrist actigraph for 30 days. Objective sleep parameters were computed from the actigraphy nighttime series, and correlated with subjective sleep disturbances reported on the following day, using repeated measures correlations. Multilevel Poisson regression analysis was performed to identify the objective and subjective parameters that affected subjective sleep rating. Poor subjective sleep score was correlated with poor sleep efficiency (rrm = -0.13, p = 0.002) and large number of wake episodes (rrm = 0.12, p = 0.005) on the rated night. Multilevel analysis demonstrated that the expected sleep disturbance score was affected by the joint contribution of the wake episodes (exp(ß) = 1.01, 95% confidence interval = 1.00 to 1.02, p = 0.016), fatigue (exp(ß) = 1.35, 95% confidence interval = 1.15 to 1.55, p < 0.001) and drowsiness (exp(ß) = 1.70, 95% confidence interval = 1.19 to 2.62, p = 0.018), self-rated the following evening, and sleep disturbance experienced one night before (exp(ß) = 1.77, 95% confidence interval = 1.41 to 2.22, p < 0.001). The night-by-night approach within a multidimensional home tele-monitoring framework mainly identified the objective number of wake episodes computed from actigraphy records as the main determinant of the severity of sleep complaint in cancer patients on chemotherapy. This quantitative information remotely obtained in real time from cancer patients provides a novel framework for streamlining and evaluating interventions toward sleep improvement in cancer patients.


Assuntos
Actigrafia/métodos , Serviços de Assistência Domiciliar , Neoplasias/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Transtornos do Sono-Vigília/fisiopatologia , Sono/fisiologia , Actigrafia/tendências , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Serviços de Assistência Domiciliar/tendências , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Projetos Piloto , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/epidemiologia , Vigília/fisiologia , Dispositivos Eletrônicos Vestíveis/tendências
10.
Cancer Med ; 7(9): 4396-4405, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30088335

RESUMO

BACKGROUND: Psychosocial symptoms often cluster together, are refractory to treatment, and impair health-related quality of life (HR-QoL) in cancer patients. The contribution of circadian rhythm alterations to systemic symptoms has been overlooked in cancer, despite a causal link shown under jet lag and shift work conditions. We investigated whether the circadian rest-activity rhythm provides a reliable and objective estimate of the most frequent patient-reported outcome measures (PROMs). METHODS: Two datasets were used, each involving concomitant 3-day time series of wrist actigraphy and HR-QoL questionnaires: EORTC QLQ-C30 was completed once by 237 patients with metastatic colorectal cancer; MD Anderson Symptom Inventory (MDASI) was completed daily by 31 patients with advanced cancer on continuous actigraphy monitoring, providing 1015 paired data points. Circadian function was assessed using the clinically validated dichotomy index I < O. Nonparametric tests compared PROMs and I < O. Effect sizes were computed. Sensitivity subgroup and temporal dynamics analyses were also performed. RESULTS: I < O values were significantly lower with increasing symptom severity and worsening HR-QoL domains. Fatigue and anorexia were worse in patients with circadian disruption. The differences were both statistically and clinically significant (P < 0.001; d ≥ 0.33). Physical and social functioning, and global quality/enjoyment of life were significantly better in patients with robust circadian rhythm (P < 0.001; d ≥ 0.26). Sensitivity analyses validated these findings. CONCLUSION: Objectively determined circadian disruption was consistently and robustly associated with clinically meaningfully severe fatigue, anorexia, and interference with physical and social functioning. This supports an important role of the circadian system in the determination of cancer patients' HR-QoL and symptoms that deserves therapeutic exploitation.


Assuntos
Ritmo Circadiano , Neoplasias/epidemiologia , Descanso , Actigrafia , Biomarcadores , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/fisiopatologia , Neoplasias/psicologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Inquéritos e Questionários
11.
J Med Internet Res ; 20(6): e204, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29704408

RESUMO

BACKGROUND: Experimental and epidemiologic studies have shown that circadian clocks' disruption can play an important role in the development of cancer and metabolic diseases. The cellular clocks outside the brain are effectively coordinated by the body temperature rhythm. We hypothesized that concurrent measurements of body temperature and rest-activity rhythms would assess circadian clocks coordination in individual patients, thus enabling the integration of biological rhythms into precision medicine. OBJECTIVE: The objective was to evaluate the circadian clocks' coordination in healthy subjects and patients through simultaneous measurements of rest-activity and body temperature rhythms. METHODS: Noninvasive real-time measurements of rest-activity and chest temperature rhythms were recorded during the subject's daily life, using a dedicated new mobile electronic health platform (PiCADo). It involved a chest sensor that jointly measured accelerations, 3D orientation, and skin surface temperature every 1-5 min and relayed them out to a mobile gateway via Bluetooth Low Energy. The gateway tele-transmitted all stored data to a server via General Packet Radio Service every 24 hours. The technical capabilities of PiCADo were validated in 55 healthy subjects and 12 cancer patients, whose rhythms were e-monitored during their daily routine for 3-30 days. Spectral analyses enabled to compute rhythm parameters values, with their 90% confidence limits, and their dynamics in each subject. RESULTS: All the individuals displayed a dominant circadian rhythm in activity with maxima occurring from 12:09 to 20:25. This was not the case for the dominant temperature period, which clustered around 24 hours for 51 out of 67 subjects (76%), and around 12 hours for 13 others (19%). Statistically significant sex- and age-related differences in circadian coordination were identified in the noncancerous subjects, based upon the range of variations in temperature rhythm amplitudes, maxima (acrophases), and phase relations with rest-activity. The circadian acrophase of chest temperature was located at night for the majority of people, but it occurred at daytime for 26% (14/55) of the noncancerous people and 33% (4/12) of the cancer patients, thus supporting important intersubject differences in circadian coordination. Sex, age, and cancer significantly impacted the circadian coordination of both rhythms, based on their phase relationships. CONCLUSIONS: Complementing rest-activity with chest temperature circadian e-monitoring revealed striking intersubject differences regarding human circadian clocks' coordination and timing during daily routine. To further delineate the clinical importance of such finding, the PiCADo platform is currently applied for both the assessment of health effects resulting from atypical work schedules and the identification of the key determinants of circadian disruption in cancer patients.


Assuntos
Atividades Cotidianas/psicologia , Ritmo Circadiano/fisiologia , Adulto , Idoso , Feminino , Humanos , Internet , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Projetos Piloto , Adulto Jovem
12.
JCO Clin Cancer Inform ; 2: 1-15, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30652550

RESUMO

PURPOSE: To assess the impact of chronomodulated irinotecan fluorouracil-leucovorin and oxaliplatin (chronoIFLO4) delivered at home on the daily life of patients with cancer in real time using a home-based e-Health multifunction and multiuser platform. This involved multidimensional telemonitoring of circadian rest-activity rhythm (CircAct), sleep, patient-reported outcome measures, and body weight changes (BWCs). PATIENTS AND METHODS: Patients received chronoIFLO4 fortnightly at home. Patients completed the 19-item MD Anderson Symptom Inventory on an interactive electronic screen, weighed themselves on a dedicated scale, and continuously wore a wrist accelerometer for CircAct and sleep monitoring. Daily data were securely teletransmitted to a specific server accessible by the hospital team. The clinically relevant CircAct parameter dichotomy index I < O and sleep efficiency (SE) were calculated. The dynamic patterns over time of patient-reported outcome measures, BWC, I < O, and SE informed the oncology team on tolerance in real time. RESULTS: The platform was installed in the home of 11 patients (48 to 72 years of age; 45% men; 27% with performance status = 0), who were instructed on its use on site. They received 26 cycles and provided 5,891 data points of 8,736 expected (67.4%). The most severe MD Anderson Symptom Inventory scores were: interference with work (mean: 5.1 of 10) or general activity (4.9), fatigue (4.9), distress (4.2), and appetite loss (3.6). Mean BWC was -0.9%, and mean SE remained > 82%. CircAct disruption (I < O ≤ 97.5%) was observed in four (15%) cycles before chronoIFLO4 start and in five (19%) cycles at day 14. CONCLUSION: The patient-centered multidimensional telemonitoring solution implemented here was well accepted by patients receiving multidrug chemotherapy at home. Moreover, it demonstrated that chronoIFLO4 was a safe therapeutic option. Such integrated technology allows the design of innovative management approaches, ultimately improving patients' experience with chemotherapy, wellbeing, and outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Peso Corporal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Sono/efeitos dos fármacos , Telemedicina/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Humanos , Irinotecano/administração & dosagem , Irinotecano/farmacologia , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacologia , Medidas de Resultados Relatados pelo Paciente , Assistência Centrada no Paciente , Projetos Piloto , Análise de Sobrevida , Interface Usuário-Computador
13.
Oncotarget ; 8(31): 50792-50803, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28881604

RESUMO

BACKGROUND: Limited data are available on the prevalence of oncogenic driver mutations in Caucasian populations, and especially in Europeans. AIM: To evaluate the targetable mutational spectra in unselected patients with lung adenocarcinoma in routine clinical practice from several French hospitals, using the same molecular platform. PATIENTS AND METHODS: Samples from 2,219 consecutive patients with histologically-proven advanced lung adenocarcinoma were centrally analysed at a referenced and certified diagnostic platform in order to test for activating and resistance mutations in EGFR, KRAS, BRAF, ERBB2 and PI3KCA. Demographic and clinical features were retrieved from the medical charts. Multivariate binary logistic regression was used to determine the independent predictive factors for the occurrence of specific mutations, in the whole study population or in selected subgroups. FINDINGS: The overall respective incidence of EGFR, KRAS, BRAF, ERBB2 and PI3KCA mutations was 10.5%, 0.9%, 25%, 1.5%, 2.1% and 1.4%, in our study sample including 87.4% white Caucasians, 10.8% Africans and 1.8% Asians; 60.6% men, 30.7% never smoker (median age: 68.3 years). Ethnicity was an independent predictor for EGFR, KRAS and ERBB2 gene abnormalities. In all cases, a significantly higher prevalence of targetable EGFR and ERBB2, and a lower prevalence of resistance KRAS mutations were observed in African women as compared to African men or Caucasians. CONCLUSIONS: In real life conditions of routine genetic testing, we have identified subsets of patients with specific targetable activating somatic mutations according to ethnicity, who could preferentially benefit from anti-EGFR and anti-ERBB2 targeted therapies.

14.
Br J Cancer ; 117(7): 965-973, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28817838

RESUMO

BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Arilamina N-Acetiltransferase/genética , Neoplasias Colorretais/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Vitamina K Epóxido Redutases/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Administração Intravenosa , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética , Cetuximab/administração & dosagem , Neoplasias Colorretais/patologia , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Diarreia/induzido quimicamente , Diarreia/genética , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Glucuronosiltransferase/genética , Hepatectomia , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Irinotecano , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/genética , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Farmacogenética , Polimorfismo de Nucleotídeo Único , Taxa de Sobrevida , Resultado do Tratamento
15.
Clin Pharmacokinet ; 56(2): 165-177, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27393140

RESUMO

The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined during the first course of chronomodulated triplet HAI in 11 patients and related to toxicities after one or three courses. Consistent trends were found between the area under the plasma concentration-time curve (AUC) values of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN38; a bioactive metabolite), total oxaliplatin and platinum ultrafiltrate (P-UF), on the one hand, and subsequent leukopenia severity, on the other hand. Moreover, the maximum plasma concentration (C max) and the AUC of P-UF significantly predicted grades of diarrhoea (p = 0.004 and 0.017, respectively) and anaemia (p = 0.001 and 0.008, respectively) after the first course. Systemic drug exposure helps explain both the adverse events and the low rate of extrahepatic progression-a usual drawback of HAI chemotherapy-thus supporting upfront testing of the regimen. Systems optimization of chronomodulated HAI delivery could further reduce adverse events.


Assuntos
Camptotecina/análogos & derivados , Cronofarmacoterapia , Fluoruracila/farmacocinética , Artéria Hepática/metabolismo , Neoplasias Hepáticas/sangue , Compostos Organoplatínicos/farmacocinética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Europa (Continente)/epidemiologia , Feminino , Fluoruracila/administração & dosagem , Artéria Hepática/efeitos dos fármacos , Humanos , Infusões Intra-Arteriais/métodos , Irinotecano , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina
16.
J Med Internet Res ; 18(11): e305, 2016 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-27888171

RESUMO

BACKGROUND: Telehealth solutions can improve the safety of ambulatory chemotherapy, contributing to the maintenance of patients at their home, hence improving their well-being, all the while reducing health care costs. There is, however, need for a practicable multilevel monitoring solution, encompassing relevant outputs involved in the pathophysiology of chemotherapy-induced toxicity. Domomedicine embraces the delivery of complex care and medical procedures at the patient's home based on modern technologies, and thus it offers an integrated approach for increasing the safety of cancer patients on chemotherapy. OBJECTIVE: The objective was to evaluate patient compliance and clinical relevance of a novel integrated multiparametric telemonitoring domomedicine platform in cancer patients receiving multidrug chemotherapy at home. METHODS: Self-measured body weight, self-rated symptoms using the 19-item MD Anderson Symptom Inventory (MDASI), and circadian rest-activity rhythm recording with a wrist accelerometer (actigraph) were transmitted daily by patients to a server via the Internet, using a dedicated platform installed at home. Daily body weight changes, individual MDASI scores, and relative percentage of activity in-bed versus out-of-bed (I

Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cronoterapia/métodos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Cooperação do Paciente , Inquéritos e Questionários , Telemedicina , Adulto Jovem
17.
Eur J Cancer ; 68: 163-172, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27768923

RESUMO

BACKGROUND: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV. METHODS: Irinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models. RESULTS: Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter ≤57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4-100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses. CONCLUSIONS: Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab/administração & dosagem , Neoplasias Colorretais/patologia , Fadiga/induzido quimicamente , Feminino , Fluoruracila/administração & dosagem , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Infusões Intravenosas , Irinotecano , Neoplasias Hepáticas/secundário , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
18.
Cancer Chemother Pharmacol ; 67(2): 339-48, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20401611

RESUMO

BACKGROUND: Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination. METHODS: All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy. RESULTS: Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy. CONCLUSIONS: The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Cronofarmacoterapia , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Fluoruracila/administração & dosagem , Amplificação de Genes/genética , Genes ras/genética , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/terapia , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Terapia de Salvação/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento
19.
Cancer Chemother Pharmacol ; 66(3): 605-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20361188

RESUMO

PURPOSE: Documentation of a wild-type (wt) KRAS gene in tumor has become mandatory for the prescription of anti-EGFR monoclonal antibodies in patients with colorectal cancer (CRC). Acquired KRAS mutations have seldom been reported in metastases from wt KRAS primary CRC. We report the first case of multiple KRAS mutations acquired during the metastatic phase of CRC, and retrospectively reviewed all patients with CRC, in whom KRAS was analyzed in at least two tumor samples from distinct lesions. METHODS: Genomic DNA purified from paraffin-embedded tissues was used after histological quantification of tumor tissue. The seven KRAS mutations located within codons 12 and 13 were screened using the allelic discrimination assay. RESULTS: A 35-year-old woman with CRC liver metastasis, resistant to all conventional cytotoxic agents, experienced for the first time significant tumor shrinkage while cetuximab was added, allowing hepatic resection. Further liver relapse occurred on cetuximab, but a new hepatic resection was attempted. No mutation in KRAS was detected in the primary colon tumor or in synchronous liver metastases. In contrast, in metachronous liver metastasis samples, two distinct mutations at codon 13 and 12 were detected. No acquired mutations were found in all the other 12 CRC cases with at least two serially performed KRAS analyses. CONCLUSIONS: Our findings suggest that late switch in KRAS mutational status could occur more frequently than currently recognized and account for acquired resistance to anti-EGFR therapies. Prospective studies are warranted to better estimate the incidence of change in KRAS mutational status and assess their clinical relevance.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos
20.
Cancer ; 115(21): 4990-9, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19637365

RESUMO

BACKGROUND: : Hepatic arterial infusion (HAI) chemotherapy delivers a high concentration of drugs both to liver metastases and to healthy liver with specific, limiting, hepatobiliary toxicities. Relevant detoxification and cellular proliferation pathways are controlled by the molecular circadian clock in normal liver but not in advanced tumors. In this article, the authors report their experience with chronomodulated HAI chemotherapy as rescue therapy in heavily pretreated patients who had metastatic colorectal cancer. METHODS: : Data from all consecutive patients with colorectal cancer liver metastases who received HAI with chronomodulated, multidrug chemotherapy regimens in the authors' center after failure on standard chemotherapy were reviewed for efficacy and safety. RESULTS: : Twenty-nine patients were treated, including 76% with liver metastasis only and 24% with liver and lung metastases. Seventy-five percent of patients had received > or =3 chemotherapy lines, including intravenous, chronomodulated chemotherapy in 59% of patients. Patients received a median of 4 HAI courses (range, 1-9 courses). The most frequent grade (according to National Cancer Institute of Canada Common Toxicity Criteria [version 3]) 3 and 4 nonhematologic toxicities were vomiting, diarrhea, abdominal pain, and fatigue. No severe hematologic or hepatic toxicities and no chemical cholangitis were reported. An objective tumor response was observed in 10 patients (34.5%), including 4 patients who subsequently underwent R0 or R1 hepatic resection. The median progression-free survival and overall survival were 4.5 months (95% confidence limits, 2.4-6.5 months) and 18 months (95% confidence limits, 5.8-30.2 months), respectively. CONCLUSIONS: : HAI chronomodulated chemotherapy had well tolerated activity in selected, heavily pretreated patients, and the authors believe it deserves to be assessed prospectively in clinical trials among patients who have less advanced disease. Cancer 2009. (c) 2009 American Cancer Society.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Colorretais/tratamento farmacológico , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ritmo Circadiano , Neoplasias Colorretais/patologia , Feminino , Artéria Hepática , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Retratamento , Estudos Retrospectivos
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