RESUMEN
Aim & methods: Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). RESULTS: Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In KRAS-wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively. In KRAS-mutated patients TTP was 7.4 and 1.9 months in Arms 1 and 2, respectively (p = 0.023). Arm 2 KRAS-WT patients, left-sided primaries, had an overall survival of 16.0 versus 12.1 months in right-sided primaries. CONCLUSION: Adding erlotinib to capecitabine increased TTP by 3.2 months in KRAS-WT patients. This study suggests that erlotinib harms patients with KRAS-mutated advanced CRC while it may provide benefit to those with KRAS-WT CRC. Further study of EGFR-tyrosine kinase inhibitors in patients with left-sided KRAS-WT CRC is warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Capecitabina/administración & dosificación , Neoplasias Colorrectales/mortalidad , Terapia Combinada , Clorhidrato de Erlotinib/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas p21(ras)/genética , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non-clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized. METHODS: Data on 2215 patients (1963 with clear-cell RCC [ccRCC] and 252 with nccRCC) treated with first-line VEGF- and mTOR-targeted therapies were collected from the IMDC. Time to treatment failure (TTF) and overall survival (OS) were compared in groups with favorable, intermediate, and poor prognoses according to IMDC prognostic criteria RESULTS: The median OS of the entire cohort was 20.9 months. nccRCC patients were younger (P < .0001) and more often presented with low hemoglobin (P = .014) and elevated neutrophils (P = .0001), but otherwise had clinicopathological features similar to those of ccRCC patients. OS (12.8 vs 22.3 months; P < .0001) and TTF (4.2 vs 7.8 months; P < .0001) were worse in nccRCC patients compared with ccRCC patients. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95% CI, 1.19-1.67; P < .0001) and 1.54 (95% CI, 1.33-1.79; P < .0001), respectively. The IMDC prognostic model reliably discriminated 3 risk groups to predict OS and TTF in nccRCC; the median OS of the favorable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 months, respectively (P < .0001), and the median TTF was 9.6, 4.9, and 2.1 months, respectively (P < .0001). CONCLUSIONS: Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared with patients with ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Canadá/epidemiología , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Humanos , Japón/epidemiología , Masculino , Pronóstico , República de Corea/epidemiología , Singapur/epidemiología , Análisis de Supervivencia , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. METHODS: Eligible patients who had no prior systemic therapy received cediranib 45 mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD) ≥ 4 months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. RESULTS: Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44-83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38 %) partial responses (95 % CI: 23-55 %); 18 stable disease (SD) for a clinical benefit rate of 33/39 = 85 % (95 % CI: 69-94 %) and 6 progressive disease. Median PFS was 8.9 months (95 % CI: 5.1-12.9); and median OS was 28.6 months (95 % CI: 18.2-37.3 months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. CONCLUSIONS: Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30 mg daily appears warranted.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Progresión de la Enfermedad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renales/patología , Medios de Contraste , Demografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
The purpose of this phase I trial was to establish the maximum tolerated dose and define the dose-limiting toxicities of a combination of temsirolimus and metformin. Patients with advanced solid tumours who had exhausted standard treatment options were eligible. Treatment included weekly intravenous temsirolimus and daily oral metformin. Eleven patients were enrolled. Dose-limiting toxicities were observed in all patients at the initial dose level of 25 mg weekly of temsirolimus and metformin 500 mg po BID. At dose level -1, 2 of 8 patients experienced dose-limiting toxicities. Toxicities included grade 4 pneumonitis, persistent grade 3 fatigue, and thrombocytopenia requiring dose delays. The maximum tolerated dose (level -1) was 20 mg temsirolimus weekly and 500 mg po daily of metformin. One patient with head and neck cancer experienced a partial response. Five patients had stable disease including a patient with melanoma who had stable disease for 22 months.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Metformina/administración & dosificación , Persona de Mediana Edad , Neoplasias/enzimología , Neoplasias/patología , Ontario , Proyectos Piloto , Inhibidores de Proteínas Quinasas/administración & dosificación , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. METHODS: We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079. FINDINGS: 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia. INTERPRETATION: Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. FUNDING: Sanofi-Aventis.
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Docetaxel , Esquema de Medicación , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Neutropenia/inducido químicamente , Dimensión del Dolor , Prednisona/administración & dosificación , Prednisona/efectos adversos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/mortalidad , Taxoides/administración & dosificación , Taxoides/efectos adversos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
The treatment for colorectal cancer is largely surgical followed by adjuvant chemotherapy in high-risk cases. In patients with stage II cancer, there is no clear benefit for chemotherapy, and the current tools for assessment of risk are inadequate. A recent study identified that colorectal cancer with a gene signature similar to undifferentiated colonic stem cells was associated with a worse outcome. It was later shown that loss of CDX2 detected by immunohistochemistry (IHC) alone resulted in a worse prognosis and that this could be used to predict patients who would benefit from chemotherapy. Having observed that CDX2 expression can be patchy, we elected to validate these prior results for clinical practice using whole-slide IHC. The pathology of all cases was reviewed, and 3 blocks were selected for CDX2 IHC. We also expanded the panel beyond CDX2 to assess whether other markers in the gene signature including CDX1, Muc2, GPX2, and villin could better predict outcome. Among 210 cases, CDX2 expression was diffusely lost in 11% and focally lost in 23% of cases. There was no difference in survival based on CDX2 expression, but Muc2 loss was associated with reduced survival (hazard ratio, 3.32; 95% confidence interval, 1.20 to 9.20). No significant differences in outcome were identified based on CDX1, GPX2, or villin expression. In keeping with this, assessment of The Cancer Genome Atlas gene expression data demonstrated that decreased Muc2 expression was associated with reduced overall survival. Our results with whole-slide IHC are different from the previous studies and caution against the use of CDX2 in isolation as a prognostic marker in clinical practice. We have identified that loss of Muc2 is associated with reduced survival. This supports the use of the colonic differentiation gene expression signature to identify high-risk patients but cautions against the use of any one IHC-based marker in isolation.
Asunto(s)
Adenocarcinoma/mortalidad , Biomarcadores de Tumor/metabolismo , Factor de Transcripción CDX2/metabolismo , Neoplasias del Colon/mortalidad , Mucina 2/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
Non-traumatic osteonecrosis of bone is recognized as a potential complication in solid-tumour cancer patients receiving treatment with cytotoxic chemotherapy. This review summarizes recent reports of osteonecrosis associated with chemotherapy in cancer patients, and describes the possible underlying pathophysiology and options available for its diagnosis, prevention and treatment. Fifty-four reported cases of non-traumatic osteonecrosis in adult patients with solid tumours receiving chemotherapy were identified by searching for reports in the medical literature. Osteonecrosis was observed most commonly in men receiving chemotherapy for testicular cancer. Osteonecrosis was also seen in patients receiving chemotherapy for breast, ovarian, small-cell lung cancer and osteosarcoma. Most patients had received corticosteroids, had femoral head involvement and had delayed onset of osteonecrosis. It appears that patients at higher risk for osteonecrosis with chemotherapy are identifiable. As the long-term survival of patients with solid tumours receiving chemotherapy increases, the prevalence of treatment-related osteonecrosis may also increase. Patients should be informed that osteonecrosis is a potential complication of cancer treatment. Measures to reduce risk should be taken, and patients should be monitored for early symptoms. Routine screening for chemotherapy-associated osteonecrosis is not recommended; however, a high index of clinical suspicion in patients at risk may allow for early intervention and preservation of the joints.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias/complicaciones , Osteonecrosis/inducido químicamente , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Osteonecrosis/diagnóstico , Osteonecrosis/diagnóstico por imagen , Osteonecrosis/patología , Osteonecrosis/fisiopatología , Osteonecrosis/cirugía , RadiografíaRESUMEN
BACKGROUND: Cytoreductive nephrectomy is thought to improve survival in metastatic renal cell carcinoma (mRCC). As many patients are ineligible for major surgery, we hypothesized that SABR could be a safe alternative. METHODS: In this dose-escalation trial, inoperable mRCC patients underwent SABR targeting the entire affected kidney. Toxicity (CTCAE v3.0), quality of life (QoL), renal function, and tumour response (RECIST v1.0) were assessed. RESULTS: Twelve patients of mostly intermediate (67%) or poor (25%) International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class, median KPS of 70%, and median tumour size of 8.7 cm (range: 4.8-13.8) were enrolled in successive dose cohorts of 25 (n = 3), 30 (n = 6), and 35 Gy (n = 3) in 5 fractions. SABR was well tolerated with 3 grade 3 events: fatigue (2) and bone pain (1). QoL decreased for physical well-being (p = 0.016), but remained unchanged in other domains. SABR achieved a median tumour size reduction of - 17.3% (range: + 5.3 to - 54.4) at 5.3 months. All patients progressed systemically and median OS was 6.7 months. Crude median follow-up was 5.8 months. CONCLUSIONS: In non-operable mRCC patients, renal-ablative SABR to 35 Gy in 5 fractions yielded acceptable toxicity, renal function preservation, and stable QoL. SABR merits further prospective investigation as an alternative to cytoreductive nephrectomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02264548. Registered July 22 2014 - Retrospectively registered: https://clinicaltrials.gov/ct2/show/NCT02264548.
Asunto(s)
Carcinoma de Células Renales/radioterapia , Neoplasias Renales/radioterapia , Radiocirugia/métodos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefrectomía , Radiocirugia/efectos adversos , Dosificación Radioterapéutica , Resultado del TratamientoRESUMEN
AIM: To evaluate feasible doses of weekly everolimus and irinotecan given with cetuximab for previously treated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Adults with mCRC that progressed after 5-fluorouracil or capecitabine-plus-oxaliplatin were treated using a sequential dose escalation scheme. Dosing decisions were based on the probability of experiencing a dose-limiting toxicity (DLT) during the first two 21-day treatment cycles. RESULTS: Patients received everolimus 30 mg/week plus irinotecan 350 mg/m2 q3w (n=5; dose A1) or everolimus 30 mg/week plus irinotecan 250 mg/m2 q3w (n=14; dose B1). Among patients evaluable for the maximum tolerated dose, two out of four in A1 and one out of eight in B1 experienced four DLTs. The trial was terminated early based on changes in clinical practice and emerging data on everolimus dosing. CONCLUSION: The feasible doses of everolimus and irinotecan administered with cetuximab as second-line therapy in mCRC were 30 mg/week and 250 mg/m2, respectively.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorrectales/patología , Everolimus , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Proteínas ras/genéticaRESUMEN
Overexpression of insulin-like growth factor receptor type 1 (IGF-1R) may promote tumor development and progression in some cancer patients. Our objective was to assess tumor uptake of fluorodeoxyglucose by positron-emission tomography in patients with chemotherapy-refractory colorectal cancer treated with an anti-insulin-like growth factor receptor type 1 (anti-IGF-1R) monoclonal antibody, robatumumab. This was a randomized, open-label study with two periods (P1 and P2). Patients were randomized 3:1 into treatment arms R/R and C/R that received, respectively, one cycle of 0.3 mg/kg robatumumab or one or more cycles of second-line chemotherapy in P1, followed in either case by 10 mg/kg robatumumab biweekly in P2. The primary measure of fluorodeoxyglucose uptake was maximum standardized uptake value (SUV(max)). The primary endpoint was the proportion of patients in the R/R arm having a mean percent decrease from baseline in SUV(max) (DiSUV) greater than 20% 12-14 days postdose in P2. Secondary endpoints included Response Evaluation Criteria in Solid Tumors (RECIST)-defined tumor response and pharmacodynamic measures of target engagement. Among 41 patients who were evaluable for the primary endpoint, seven (17%, 95% CI 7%-32%) had DiSUV greater than 20%. Fifty robatumumab-treated patients were evaluable for RECIST-defined tumor response and six (12%) had stable disease lasting greater than or equal to 7 weeks in P2. Pharmacodynamic endpoints indicated target engagement after dosing with 10 mg/kg robatumumab, but not 0.3 mg/kg. The most frequently reported adverse events were fatigue/asthenia, nausea, anorexia, and gastrointestinal disturbances. In this study, few patients with chemotherapy-refractory colorectal cancer appeared to benefit from treatment with the IGF-1R antagonist robatumumab.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Neoplasias Colorrectales/patología , Fatiga/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor IGF Tipo 1/inmunología , Resultado del TratamientoRESUMEN
INTRODUCTION: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing. METHODS: In this study we evaluated mRCC patients who were initially treated on the first-line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies. RESULTS: Twenty-eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%-47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib. CONCLUSION: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second-line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease.