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BACKGROUND: This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC). METHODS: Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 µg m-2) and docetaxel (75 mg m-2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan-Meier method. RESULTS: Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ⩾5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4-2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02-0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3-4 toxicities were febrile neutropenia and neutropenia. CONCLUSIONS: The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ⩾5 months in unselected patient population.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Biliar/tratamiento farmacológico , Endotelinas/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Taxoides/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/patología , Supervivencia sin Enfermedad , Docetaxel , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Endotelinas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Fragmentos de Péptidos/efectos adversos , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively. CONCLUSION: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.
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BACKGROUND: It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival. METHODS: Patients with stage II-III colon adenocarcinoma who received adjuvant chemotherapy at 2 centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse-free survival (RFS) were calculated from the day of surgery. Patients were dichotomized into early (time to adjuvant chemotherapy ≤ 60 days) and late treatment (time to adjuvant chemotherapy >60 days) groups. OS and RFS were compared using log-rank test and multivariate analysis by the Cox proportional hazards model. RESULTS: Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy >60 days after surgical resection. Thirty percent of the delays were system related (eg, late referrals, insurance authorizations). Time to adjuvant chemotherapy >60 days was associated with significantly worse OS in both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08-4.36). Although difference in RFS between the 2 groups favored time to adjuvant chemotherapy <60, this did not reach statistical significance. CONCLUSIONS: Adjuvant chemotherapy delay >60 days after surgical resection of colon cancer is associated with worse OS.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Quimioterapia Adyuvante , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de Riesgo , Factores de TiempoRESUMEN
PURPOSE: This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS: Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION: Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Antígeno CA-19-9/sangre , Camptotecina/análogos & derivados , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/administración & dosificación , Desoxicitidina/administración & dosificación , Progresión de la Enfermedad , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/mortalidad , Radiografía , Seguridad , Tasa de Supervivencia , Resultado del Tratamiento , GemcitabinaRESUMEN
The poor outcome of pancreatic cancer with conventional treatment options emphasizes the need for continued research. The benefits of gemcitabine in improving quality of life and survival have been established in patients with advanced pancreatic cancer. Randomized clinical trials studying the addition of a second drug to gemcitabine, either a classic cytotoxic (5-fluorouracil, cisplatin, irinotecan, pemetrexed, oxaliplatin, or exatecan) or targeted agents (ie, the farnesyl transferase inhibitor R115777 or the metalloproteinase inhibitor marimastat) have not resulted in improvement in survival compared with gemcitabine alone. Although limited activity of docetaxel in patients with pancreatic adenocarcinoma has been reported in single-agent studies, attractive efficacy results have been documented with docetaxel in combination with other chemotherapeutic agents for the management of advanced pancreatic cancer. Phase I and II trials of docetaxel in combination with gemcitabine, irinotecan, 5-fluorouracil, or thalidomide, as well as trials of docetaxel and radiotherapy, suggest that docetaxel combinations in pancreatic cancer should be further studied in randomized trials.
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Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Taxoides/uso terapéutico , Camptotecina/administración & dosificación , Capecitabina , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Ensayos Clínicos como Asunto , Desoxicitidina/administración & dosificación , Docetaxel , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Terapia Neoadyuvante , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Taxoides/administración & dosificación , Talidomida/administración & dosificación , GemcitabinaRESUMEN
Lung cancer is the leading cause of cancer-related death in males and females in the United States. Most patients have advanced disease at diagnosis. Chemotherapy is the treatment of choice for patients with good performance status. Progress in the management ofpatients with advanced disease has been slow, and platinum-based combinations result in a small survival benefit. The topoisomerase I inhibitors are active as single agents and in combination with platinums in non-small-cell lung cancer. Nonplatinum-based doublet combinations are beginning to be explored in an attempt to reduce toxicity and improve efficacy. Data available on some of the nonplatinum doublets that include topoisomerase I inhibitors suggest that these regimens provide efficacy equal to that achieved with platinum-based doublets. This article reviews the topoisomerase I-inhibitor nonplatinum combinations in the management of advanced non-small-cell lung cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Desoxicitidina/administración & dosificación , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , GemcitabinaRESUMEN
Perioperative chemotherapy plus surgery improves survival compared to surgery alone in GE junctional (GEJ) and gastric adenocarcinomas. The docetaxel/cisplatin/5-fluorouracil (DCF) combination is superior to CF in patients with metastatic gastric cancer. We retrospectively evaluated the safety and efficacy of preoperative DCF chemotherapy in patients with locally advanced gastric and GEJ cancer. Twenty-one gastric and 10 gastroesophageal junctional (GEJ) cancer patients received 2-3 cycles of preoperative docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, 5-FU 750 mg/m(2) (continuous infusion) on days 1-5 every 3 weeks. Clinical response was evaluated by comparing pre- and postchemotherapy CT scans. Overall survival (OS) and progression-free survival (PFS) were calculated from the initiation of chemotherapy. None of the patients achieved complete clinical remission while 11 (35%) patients achieved partial clinical remission. Ten patients with GEJ cancer (100%) and 13 with gastric cancer (62%) underwent curative surgery (P = 0.023). Seventeen (55%) patients experienced grade 3-4 chemotherapy-related adverse events. The most common adverse events were anemia, nausea/vomiting, diarrhea, and febrile neutropenia. At a median follow-up of 17.0 months, median OS and PFS were 26.1 months (95% CI: 22.7-29.5) and 18.8 months (95% CI: 9.9-27.7), respectively. The DCF regimen is active in patients with gastric and GEJ adenocarcinoma in the preoperative setting.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Clasificación del Tumor , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Taxoides/administración & dosificación , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
Small cell lung cancer (SCLC) is an aggressive type of lung cancer characterized by rapid growth and early metastasis. It is chemosensitive and radiosensitive, yet decades of research investigating multimodality treatments have failed to control or cure this disease in most patients. First-line treatment of limited-stage disease consists of chemotherapy (often etoposide/cisplatin or etoposide/carboplatin) combined with thoracic radiation therapy (TRT), followed by prophylactic cranial irradiation to decrease brain metastases as a site of disease progression for those who experience complete remission or a very good partial response to multimodality treatment. In a Japanese trial, the combination of irinotecan and cisplatin had initially shown promise in treating patients with extensive-stage SCLC, but a confirmatory trial in the United States did not find a difference in overall survival with irinotecan/cisplatin versus etoposide/cisplatin. Adding a third drug to the etoposide/cisplatin combination, as well as other triplet therapies, has mostly been ineffective in improving outcomes. Variables in chemotherapy administration, including maintenance therapy, alternating non-cross-resistance regimens, and dose intensification, have not been shown to increase survival at large. In terms of radiation therapy, early administration of TRT concurrent with chemotherapy, and hyperfractionation, have been beneficial in treatment of limited-stage disease. In patients who relapse, second-line therapy options consist of reinduction of previous chemotherapy or administration of a single agent. Targeted biological therapies for SCLC are now being investigated, and although a great deal of research remains to be done, these agents and their derivatives may provide the most hope for future treatment of SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Carcinoma de Células Pequeñas/cirugía , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Factores Inmunológicos/uso terapéutico , Neoplasias Pulmonares/cirugía , Metástasis de la Neoplasia , Pronóstico , SobrevidaRESUMEN
Pancreatic cancer remains the fourth leading cause of cancer deaths in males and females in the beginning of this new millennium. The 5-year survival for all stages remains less than 5%. The frequent diagnosis at late stages of the disease limits the role of surgery as a curative modality in pancreatic cancer. Despite recent advances, systemic treatment continues to have a limited role in the adjuvant setting, and chemotherapy is mostly palliative in advanced and metastatic pancreatic cancer patients. The differential diagnosis of pancreatic cancer and other gastrointestinal malignancies is, many times, challenging. Advances in the understanding of the disease biology may help in better diagnosis and treatment approaches. Clinical trials with molecular targeting agents are starting to emerge.
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Marcadores Genéticos , Cuidados Paliativos , Neoplasias Pancreáticas , Quimioterapia Adyuvante , Humanos , Estadificación de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/fisiopatología , Neoplasias Pancreáticas/terapia , Pronóstico , SobrevidaRESUMEN
BACKGROUND: Despite a greater risk of malignancy and a higher cancer mortality rate for patients age > 65 years, bias in accruing older patients to clinical trials persists. The results from two National Cancer Institute-approved cooperative group trials (Cancer and Leukemia Group B trial 8931 [CALGB 8931] and CALGB 9130) were analyzed retrospectively to determine the participation, tolerance of treatment, and outcome of patients age > 70 years. METHODS: Five hundred fifteen patients with locally advanced or metastatic nonsmall cell lung carcinoma participated in two separate, randomized, Phase III clinical trials conducted by CALGB. Retrospective evaluation of patients by four distinct age cohorts (< 50 years, 50-59 years, 60-69 years, and > 70 years) was carried out to determine differences in toxicity, response, and survival. RESULTS: No patients age > 80 were entered on either study, even though there was no age restriction in the study eligibility criteria. No significant differences were seen in response, survival, or continuation of treatment based on age cohort. Significantly increased leukocyte toxicity was seen in older cohorts without a concomitant increase in severe or worse infectious events. CONCLUSIONS: No patients age > 80 were entered on either trial despite their potential eligibility. Patients in the oldest cohort showed no negative impact of age on treatment tolerance, response to treatment, or survival. The aggregate clinical judgment of patients and physicians can identify septuagenarians who should not be denied active consideration for aggressive management of their advanced nonsmall cell lung carcinoma.