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BACKGROUND: Trifluridine/tipiracil (FTD/TPI) showed clinical benefit, including improved survival and manageable safety in previously treated patients with metastatic colorectal (mCRC) or gastric/gastroesophageal junction (mGC/GEJC) cancer in the phase III RECOURSE and TAGS trials, respectively. A pooled analysis was conducted to further characterize FTD/TPI safety, including management of haematologic toxicities and use in patients with renal or hepatic impairment. PATIENTS AND METHODS: Adults with ≥2 prior regimens for advanced mGC/GEJC or mCRC were randomized (2 : 1) to FTD/TPI [35 mg/m2 twice daily days 1-5 and 8-12 (28-day cycle); same dosage in both trials] or placebo plus best supportive care. Adverse events (AEs) were summarized in the safety population (patients who received ≥1 dose) and analysed by renal/hepatic function. RESULTS: TAGS and RECOURSE included 335 and 533 FTD/TPI-treated and 168 and 265 placebo-treated patients, respectively. Overall safety of FTD/TPI was similar in TAGS and RECOURSE. Haematologic (neutropenia, anaemia) and gastrointestinal (nausea, diarrhoea) AEs were most commonly observed. Laboratory-assessed grade 3-4 neutropenia occurred in 37% (TAGS)/38% (RECOURSE) of FTD/TPI-treated patients (median onset: 29 days/55 days), and 96% (TAGS)/97% (RECOURSE) of cases resolved regardless of renal/hepatic function. Supportive medications for neutropenia were received by 17% (TAGS) and 9% (RECOURSE); febrile neutropenia was reported in 2% and 4%, respectively. Overall grade ≥3 AEs were more frequent in patients with moderate renal impairment [81% (TAGS); 85% (RECOURSE)] versus normal renal function (74%; 67%); anaemia and neutropenia were more common in patients with renal impairment. FTD/TPI safety (including haematologic AEs) was consistent across patients with normal and mildly impaired hepatic function. CONCLUSIONS: These results support FTD/TPI as a well-tolerated treatment in patients with mGC/GEJC or mCRC, with a consistent safety profile. Safety was largely similar in patients with normal or mildly impaired renal/hepatic function; however, patients with renal impairment should be monitored for haematologic toxicities.
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Neoplasias del Colon , Neoplasias Colorrectales , Demencia Frontotemporal , Neutropenia , Neoplasias Gástricas , Adulto , Humanos , Trifluridina/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Demencia Frontotemporal/inducido químicamente , Uracilo/efectos adversos , Timina/efectos adversos , Pirrolidinas/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Unión Esofagogástrica/patología , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológicoRESUMEN
BACKGROUND: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. PATIENTS AND METHODS: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. RESULTS: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. CONCLUSIONS: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.
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Neoplasias Colorrectales , Neoplasias Gástricas , Humanos , Pirrolidinas , Neoplasias Gástricas/tratamiento farmacológico , Timina , Trifluridina/uso terapéutico , UraciloAsunto(s)
Receptores ErbB , Neoplasias Esofágicas , Cetuximab , Quimioradioterapia , Humanos , Terapia NeoadyuvanteRESUMEN
BACKGROUND AND SCOPE: The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe. METHODOLOGY: Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine. RESULTS: Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible. CONCLUSION: GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.
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Adenocarcinoma/patología , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Unión Esofagogástrica/patología , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Congresos como Asunto , Quimioterapia , Endoscopía Gastrointestinal , Esofagostomía , Medicina Basada en la Evidencia , Gastrectomía , Humanos , Oncología Médica , Estadificación de Neoplasias , Apoyo Nutricional , Cuidados Paliativos , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Sociedades Médicas , España , Organización Mundial de la SaludRESUMEN
This study looks at toxicity and survival data when chemoradiation (CRT) is delivered using intensity-modulated radiation therapy (IMRT) after induction chemotherapy. Forty-one patients with esophageal adenocarcinoma treated with IMRT from March 2007 to May 2009 at Memorial Sloan-Kettering Cancer Center were analyzed. All patients received induction chemotherapy prior to CRT. Thirty-nine percent (n = 16) of patients underwent surgical resection less than 4 months after completing CRT. Patients were predominantly male (78%), with a median age of 68 years (range 32-85 years). The majority of acute treatment-related toxicity was hematologic or gastrointestinal, with 17% of patients having grade 3+ hematologic toxicity and 12% of patients having grade 3+ gastrointestinal toxicity. Only two patients developed grade 2-3 pneumonitis (5%) and 5 patients experienced post-operative pulmonary complications (29%). Eight patients (20%) required a treatment break. With a median follow up of 41 months for surviving patients, 2-year overall survival was 61%, and the cumulative incidences of local failure (LF) and distant metastases were 40% and 51%, respectively. This rate of LF was reduced to 13% in patients who underwent surgical resection. Surgery and younger age were significant predictors of decreased time to LF on univariate analysis. Induction chemotherapy followed by CRT using IMRT in the treatment of esophageal cancer is well tolerated and is not associated with an elevated risk of postoperative pulmonary complications. The use of IMRT may allow for integration of more intensified systemic therapy or radiation dose escalation for esophageal adenocarcinoma, ultimately improving outcomes for patients with this aggressive disease.
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Adenocarcinoma/secundario , Adenocarcinoma/terapia , Quimioradioterapia Adyuvante/efectos adversos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Recurrencia Local de Neoplasia , Radioterapia de Intensidad Modulada , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Quimioradioterapia Adyuvante/métodos , Esofagectomía/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Humanos , Quimioterapia de Inducción/efectos adversos , Irinotecán , Metástasis Linfática , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/administración & dosificación , Compuestos de Platino/administración & dosificación , Radioterapia de Intensidad Modulada/efectos adversos , Tasa de Supervivencia , Carga TumoralRESUMEN
Chemoradiotherapy for locally advanced esophageal squamous cell carcinoma is associated with high rates of pathological complete response. A pathological complete response is recognized to be an important predictor of improved survival, to the extent that observation rather than surgery is advocated by some in patients with presumed pathological complete response based on their clinical response. The goal of this study was to look at the ability of clinical variables to predict pathological complete response after chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. We reviewed retrospectively patients with locally advanced esophageal squamous cell carcinoma who underwent chemoradiotherapy followed by surgery and compared those with pathological complete response to patients with residual disease. Between January 1996 and December 2010, 116 patients met inclusion criteria. Fifty-six percent of patients had a pathological complete response and a median survival of 128.1 months versus 28.4 months in patients with residual disease. When compared with patients with residual disease, patients with a pathological complete response had a lower post-neoadjuvant positron emission tomography (PET) maximum standardized uptake value (SUVmax), a larger decrease in PET SUVmax, a less thick tumor on post-chemoradiotherapy computed tomography and a higher rate of normal appearing post-chemoradiotherapy endoscopy with benign biopsy of the tumor bed. However, none of these characteristics alone was able to correctly identify patients with a pathological complete response, and none has significant specificity. Although the rate of pathological complete response after chemoradiotherapy is high in patients with esophageal squamous cell carcinoma, the ability of identifying patients with pathological complete response is limited. A reduction of the PET SUVmax by >70%, a normal appearing endoscopic examination, and no residual disease on biopsy all were seen in >65% of the patients with a pathological complete response. Even if these findings were unable to confirm the absence of residual disease in the primary tumor, they can help guide expectant management in high-risk patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Técnicas de Apoyo para la Decisión , Neoplasias Esofágicas/terapia , Terapia Neoadyuvante , Anciano , Carcinoma de Células Escamosas/patología , Estudios de Cohortes , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago , Esofagectomía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Residual , Inducción de Remisión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.
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Adenocarcinoma/mortalidad , Neoplasias Esofágicas/mortalidad , Unión Esofagogástrica , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Gástricas/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/terapia , Anciano , Neoplasias Encefálicas/secundario , Terapia Combinada , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapiaRESUMEN
Pre- and peri-operative strategies are becoming standard for the management of localized gastro-esophageal cancer. For localized gastric/gastro-esophageal junction (GEJ) cancer there are conflicting data that a peri-operative approach with cisplatin-based chemotherapy improves survival, with the benefits seen in esophageal cancer likely less than a 5-10% incremental improvement. Further trends toward improvement in local control and survival, when combined chemotherapy and radiation therapy are given pre-operatively, are suggested by recent phase III trials. In fit patients, a significant survival benefit with pre-operative chemoradiation is seen in those patients who achieve a pathologic complete response. In esophageal/GEJ cancer, definitive chemoradiation is now considered in medically inoperable patients. In squamous cell carcinoma of the esophagus, surgery after primary chemoradiation is not clearly associated with an improved overall survival, however, local control may be better. In localized gastric/GEJ cancer, the integration of bevacizumab with pre-operative chemotherapy is being explored in large randomized studies, and with chemoradiotherapy in pilot trials. The addition of anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor-2 antibody treatment to pre-operative chemoradiation continues to be explored. Early results show the integration of targeted therapy is feasible. Metabolic imaging can predict early response to pre-operative chemotherapy and biomarkers may further predict response to pre-operative chemo-targeted therapy. A multimodality approach to localized gastro-esophageal cancer has resulted in better outcomes. For T3 or node-positive disease, surgery alone is no longer considered appropriate and neo-adjuvant therapy is recommended. The future of neo-adjuvant strategies in this disease will involve the individualization of therapy with the integration of molecular signatures, targeted therapy, metabolic imaging and predictive biomarkers.
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BACKGROUND: Esophageal small-cell carcinoma (SCC) is rare, highly malignant and the optimal treatment approach has not been defined. PATIENTS AND METHODS: We report the largest single-institution retrospective review of patients with esophageal and gastroesophageal (GE) junction SCC. RESULTS: Twenty-five patients were identified, with complete records available for 22. Eighty-two percent were male, 82% had pure SCC histology and 86% of tumors were in the lower esophagus or GE junction. On the basis of the Veterans' Administration Lung Study Group criteria, 14 patients (64%) presented with limited disease (LD). Median survival was 19.8 months (range, 1.5 months to 11.2+ years); for LD patients, 22.3 months (range, 6 months to 11.2+ years); for extensive disease (ED) patients, 8.5 months (range, 1.5 months to 2.2 years, P = 0.02). With a median follow-up of 38 months, six patients (27%) are alive, one with ED and five with LD. Two LD patients are alive and free of disease for >5 years. Four of the five LD patients who are long-term survivors received induction chemotherapy followed by chemoradiotherapy without surgery. CONCLUSIONS: Our data indicate that patients with LD esophageal SCC treated with induction chemotherapy followed by consolidative chemoradiation can achieve long-term survival. The contribution of surgery remains unclear.
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Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/terapia , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/terapia , Unión Esofagogástrica , Anciano , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/secundario , Terapia Combinada , Neoplasias Esofágicas/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
We present a single institution experience with 5-FU, mitomycin-C based chemoradiation for the primary treatment of elderly patients with oesophageal cancer. Twenty-five patients with a median age of 77 years (range 66-88) with a diagnosis of stage II-III squamous cell or adenocarcinoma of the oesophagus were treated at Memorial Sloan Kettering from 1996 to 2001 with two cycles of concurrent 5-FU, mitomycin-C and 50.4 Gy. Owing to age and comorbidity, these patients were not considered surgical candidates. The Charlson comorbidity score was used to evaluate patient comorbidity. Nine patients (36%) experienced grade 3-4 haematologic toxicity. Of the 23 patients evaluable for response, 17 patients (68%) had a negative post-treatment endoscopy and CT scan without evidence of progressive disease. Eleven patients (44%) are alive and 10 (40%) remain without evidence of recurrent or progressive oesophageal cancer at a median follow-up of 35 months. The median overall survival was 35 months and 2-year survival 64%. There was no significant difference in overall survival between Charlson score =2 and those with a score >/=2 (P=0.10). Similar survival was observed for patients with adenocarcinoma or squamous carcinoma. Primary chemoradiation with two cycles of 5-FU, mitomycin-C, and 50.4 Gy in elderly patients is an active regimen with moderate toxicity, despite the advanced age and heavy comorbidity burden of this cohort. Patients with local/regional oesophageal cancer with adequate functional status should not be excluded from potentially curative treatment based on age alone.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Adenocarcinoma/mortalidad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Terapia Combinada , Neoplasias Esofágicas/mortalidad , Fluorouracilo/administración & dosificación , Humanos , Mitomicina/administración & dosificación , Análisis de SupervivenciaRESUMEN
BACKGROUND: The purpose of the study was to evaluate the efficacy of weekly paclitaxel (Taxol) in advanced esophageal cancer. PATIENTS AND METHODS: One hundred and two patients with advanced esophageal cancer were treated with paclitaxel 80 mg/m2 weekly over a 1-h infusion. One cycle was defined as 4 weeks of therapy. Ninety-five patients were assessable for toxicity and 86 patients who completed at least two cycles of treatment were assessable for response. Sixty-six patients had adenocarcinoma (66%) and 65 patients (68%) had no prior chemotherapy. RESULTS: A median of three cycles was delivered (range 1-11). Partial responses (PRs) were seen in 11 patients [13%, 95% confidence interval (CI) 6% to 20%]. In patients without prior chemotherapy, PRs were seen in 10 patients (15%, 95% CI 6% to 24%), with comparable response in adenocarcinoma (8/50, 16%) and squamous carcinoma (2/15, 13%). Limited response was seen in patients with prior chemotherapy (1/21, 5%). The median duration of response was 172 days. The median survival was 274 days. Therapy was well tolerated with minimal hematologic or grade 3 or 4 toxicity. CONCLUSION: Weekly paclitaxel has limited activity in esophageal cancer. The median survival, modest activity, and tolerance of therapy indicate that weekly paclitaxel may be an option in patients unable to tolerate combination chemotherapy.
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Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Paclitaxel/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Artralgia/inducido químicamente , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Esquema de Medicación , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Paclitaxel/efectos adversos , Análisis de Supervivencia , Trombocitopenia/inducido químicamente , Factores de Tiempo , Resultado del TratamientoRESUMEN
Cancers of the esophagus, stomach, and pancreas account for 11% of American cancer deaths and have a high case fatality rate. For esophageal cancer, the superiority of chemoradiotherapy rather than radiotherapy alone as a nonsurgical management was reaffirmed by a large pattern-of-care study in the United States. The study of preoperative chemoradiotherapy followed by surgery continues, with the investigation of newer chemotherapeutic agents combined with radiotherapy in an attempt to improve the therapeutic index of therapy. Trials attempting to intensify chemoradiotherapy treatments have included the addition of postoperative chemotherapy, the addition of brachytherapy, and the escalation of radiotherapy dose above the standard dose of 50.4 Gy. Neither brachytherapy nor an increase in external beam radiotherapy dose has been proven to improve local tumor control or patient survival. Adjuvant chemotherapy alone may have an impact on patient survival in one preliminary report, despite the results of earlier trials that failed to show a benefit for adjuvant chemotherapy alone. In the adjuvant treatment of gastric cancer, a meta-analysis of adjuvant chemotherapy trials suggested a survival benefit for adjuvant chemotherapy compared with surgery alone; however, preliminary reports of two large adjuvant chemotherapy trials using cisplatin-based chemotherapy failed to improve survival compared with surgery alone. The large Intergroup Trial 116, comparing surgery alone to surgery followed by postoperative fluorouracil, leucovorin, and radiotherapy, indicated a significant survival benefit for postoperative chemoradiotherapy. Postoperative chemoradiotherapy is the new standard of care for high-risk resected gastric cancer. Ongoing and future trials will address the inclusion of newer chemotherapeutic agents, the use of preoperative chemotherapy and radiotherapy, and the use of intraperitoneal therapy. In the adjuvant treatment of pancreatic cancer, clinical trials continue to evaluate the role of fluorouracil and radiotherapy, the use of preoperative chemoradiotherapy, and the incorporation of new therapeutic agents.
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Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , HumanosRESUMEN
Irinotecan (CPT-11, Camptosar) a topoisomerase I inhibitor derived from the Chinese shrub Camptotheca acuminata, has broad activity in varied gastrointestinal malignancies, including pancreatic, biliary, esophageal, and stomach cancers. Using cisplatin (Platinol) plus irinotecan as a backbone for chemotherapy, a combination for which in vitro synergy and possible sequence dependency have been identified, several clinical trials are being conducted combining these two drugs with other chemotherapeutic agents and radiation. This article reviews a recently reported phase II study of cisplatin and irinotecan in esophageal cancer, and provides a preliminary report of two ongoing phase I studies of cisplatin/irinotecan/paclitaxel (Taxol); and cisplatin/irinotecan/fluorouracil (5-FU) in advanced gastrointestinal malignancies. Early results of an ongoing phase I study of cisplatin, irinotecan, and radiation in resectable and locally advanced unresectable esophageal cancer is also discussed. Preliminary data on all of these combinations suggest promising activity in upper gastrointestinal malignancies.
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Antineoplásicos/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Cisplatino/uso terapéutico , Quimioterapia Combinada , Humanos , IrinotecánRESUMEN
BACKGROUND: Aggressive treatment of peritoneal metastases from colon cancer by surgical cytoreduction and infusional intraperitoneal (IP) chemotherapy may benefit selected patients. We reviewed our institutional experience to assess patient selection, complications, and outcome. METHODS: Patients having surgical debulking and IP 5-fluoro-2'-deoxyuridine (FUDR) plus leucovorin (LV) for peritoneal metastases from 1987 to 1999 were evaluated retrospectively. RESULTS: There were 64 patients with a mean age of 50 years. Primary tumor sites were 47 in the colon and 17 in the appendix. Peritoneal metastases were synchronous in 48 patients and metachronous in 16 patients. Patients received IP FUDR (1000 mg/m2 daily for 3 days) and IP leucovorin (240 mg/m2) with a median cycle number of 4 (range, 1-28). The median number of complications was 1 (range, 0-5), with no treatment related mortality. Only six patients (9%) required termination of IP chemotherapy because of complications. The median follow-up was 17 months (range, 0-132 months). The median survival was 34 months (range, 2-132); 5-year survival was 28%. Lymph node status, tumor grade, and interval to peritoneal metastasis were not statistically significant prognostic factors for survival. Complete tumor resection was significant on multivariate analysis (P = .04), with a 5-year survival of 54% for complete (n = 19) and 16% for incomplete (n = 45) resection. CONCLUSIONS: Surgical debulking and IP FUDR for peritoneal metastases from colon cancer can be accomplished safely and has yielded an overall 5-year survival of 28%. Complete resection is associated with improved survival (54% at 5 years) and is the most important prognostic indicator.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Apéndice , Neoplasias del Colon , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/cirugía , Adenocarcinoma/secundario , Adolescente , Adulto , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Terapia Combinada , Femenino , Floxuridina/uso terapéutico , Formiltetrahidrofolatos/uso terapéutico , Humanos , Infusiones Parenterales/métodos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Neoplasias Peritoneales/secundario , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
PURPOSE: In a phase II trial of paclitaxel, cisplatin, and fluorouracil in metastatic esophageal cancer, we identified significant activity for the combination of agents, but there was severe associated toxicity. We therefore undertook a phase II trial of paclitaxel and cisplatin without fluorouracil. PATIENTS AND METHODS: Thirty-eight patients with carcinoma of the esophagus or gastroesophageal junction were treated. No patient who underwent prior chemotherapy was allowed to take part in the study. The majority (33 patients) had adenocarcinoma, and most (36 patients, 95%) had metastatic disease. Paclitaxel, 200 to 250 mg/m2, was given by 24-hour infusion on day 1, followed by cisplatin, 75 mg/m2, on day 2, with granulocyte colony stimulating factor support. Treatment was cycled every 21 days in the outpatient setting. The first 16 patients received paclitaxel at 250 mg/m2, but because of toxicity and treatment-related deaths, the dose was reduced to 200 mg/m2. RESULTS: Thirty-two patients were evaluable for response. Six patients were evaluated for toxicity after receiving only one cycle (due to toxicity or treatment-related death). Partial responses were seen in 14 patients (44%); responses occurred in 13/28 patients with adenocarcinoma (46%) and in one of four patients with squamous carcinoma (25%). Median duration of response was 3.9 months, and median survival was 6.9 months. Of twenty-five patients with dysphagia before therapy, eighteen patients (72%) had complete resolution of dysphagia, and two (8%) had partial resolution. Toxicity included grade 3/4 fatigue in 35% of patients and grade 4 neutropenia in 47% of patients. Nineteen patients (50%) required hospitalization for toxicity, and four patients (11%) died from therapy-related complications. CONCLUSION: The combination of paclitaxel and cisplatin has significant activity in esophageal adenocarcinoma. Because of hospitalization for toxicity and deaths resulting from treatment, the combination of paclitaxel and cisplatin used in this trial cannot be recommended. The optimal dose and schedule of paclitaxel/cisplatin combination therapy remain to be established.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma/tratamiento farmacológico , Cisplatino/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/toxicidad , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/toxicidad , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/administración & dosificación , Cisplatino/toxicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/toxicidad , Factores de TiempoRESUMEN
BACKGROUND: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker. METHODS: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. RESULTS: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016). CONCLUSION: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.
Asunto(s)
Adenocarcinoma/metabolismo , Poliposis Adenomatosa del Colon/genética , Biomarcadores de Tumor/sangre , Cromosomas Humanos Par 5/genética , ADN de Neoplasias/sangre , Neoplasias Esofágicas/metabolismo , Adenocarcinoma/genética , Esófago de Barrett/metabolismo , Biomarcadores de Tumor/aislamiento & purificación , Carcinoma de Células Escamosas/metabolismo , Distribución de Chi-Cuadrado , ADN de Neoplasias/aislamiento & purificación , Neoplasias Esofágicas/genética , Mucosa Gástrica/metabolismo , Humanos , Pérdida de Heterocigocidad , Metilación , Reacción en Cadena de la Polimerasa/métodos , Lesiones Precancerosas/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Análisis de SupervivenciaRESUMEN
Irinotecan (Camptosar) has shown activity in several solid tumor malignancies, including gastric and pancreatic cancer. In vitro studies suggest antitumor activity in esophageal cancer cell lines. Sequence-dependent synergy has been demonstrated in vitro between irinotecan and cisplatin. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) has demonstrated the safety and tolerability of cisplatin plus irinotecan. A phase II study of this combination in patients with previously untreated, advanced esophageal cancer, also at MSKCC, has demonstrated promising results. Current trials at MSKCC are attempting to combine this regimen with either paclitaxel (Taxol), fluorouracil (5-FU), or radiation therapy.
Asunto(s)
Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase II como Asunto , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificaciónRESUMEN
The incidence of esophageal cancer continues to increase due to a rapid increase in adenocarcinoma of the distal esophagus and gastroesophageal junction. At least 50% of patients present with metastatic cancer and most patients with localized disease will develop metastases despite potentially curative local therapy. Thus, the majority of esophageal cancer patients will become candidates for palliative chemotherapy. Traditionally, single agents effective in this disease have included cisplatin, 5-fluorouracil, and mitomycin. The combination of cisplatin and continuous-infusion 5-fluorouracil is the standard for both squamous cell carcinoma and adenocarcinoma, with a 25% to 35% response rate in metastatic disease. More recently, paclitaxel has shown favorable results as a single agent or in combination with cisplatin in both disease histologies. One-hour weekly paclitaxel, a promising schedule with little toxicity, is under active investigation. Weekly irinotecan and cisplatin is a highly effective new regimen in both adenocarcinoma and squamous cell carcinoma with relatively little toxicity. Vinorelbine has demonstrated response in squamous cell carcinoma and has less toxicity than its predecessor, vindesine. Use of newer agents in combination with concurrent radiotherapy in locally advanced disease is the subject of ongoing clinical trials.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Cuidados PaliativosRESUMEN
PURPOSE: To evaluate the response, toxicity, survival, and quality of life in patients with unresectable or metastatic esophageal cancer treated with weekly irinotecan and cisplatin. PATIENTS AND METHODS: Thirty-five patients with metastatic or unresectable esophageal adenocarcinoma (23 patients) or squamous cell carcinoma (12 patients) were treated. No prior chemotherapy was allowed. The majority of patients had metastatic and bidimensionally measurable disease (34 patients each [97%]). Patients were treated with cisplatin 30 mg/m(2) and irinotecan 65 mg/m(2), repeated weekly for 4 weeks, followed by a 2-week rest period. Treatment was recycled every 6 weeks. Degree of dysphagia relief was monitored, and quality of life was measured prospectively using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 and Functional Assessment of Cancer Therapy-General instruments. RESULTS: Thirty-five patients were assessable for response and toxicity. Major objective responses were observed in 20 patients (57%; 95% confidence interval, 41% to 73%), including two complete responses (6%). Similar response rates were observed for adenocarcinoma (12 of 23 patients; 52%) and squamous carcinoma (eight of 12 patients; 66%). The median duration of response was 4.2 months (range, 1 to 8.8+ months). Median actuarial survival was 14.6 months (range, 1 to 15.2+ months). In 20 patients with dysphagia assessable at baseline, 18 (90%) noted either improvement or resolution of dysphagia on chemotherapy. Global quality of life improved in responding patients, primarily because of improvements in pain, emotional state, and relationships with family and friends. Toxicity was relatively mild and included only three patients (9%) with grade 4 neutropenia and four (11%) with grade 3 diarrhea. There were no treatment-related deaths. CONCLUSION: The combination of weekly cisplatin plus irinotecan had significant activity in metastatic esophageal carcinoma and resulted in significant relief of dysphagia. The regimen was well tolerated, with acceptable myelosuppression and rare treatment-related diarrhea. Further evaluation of the combination of weekly irinotecan and cisplatin, including the addition of other agents to this regimen, is indicated.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Trastornos de Deglución/tratamiento farmacológico , Esquema de Medicación , Neoplasias Esofágicas/patología , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Calidad de Vida , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We defined the antitumor activity, toxicity, and tolerability of a combined chemoimmunotherapy approach in patients with advanced malignant mesothelioma using daily low-dose interferon alpha-2a and carboplatin given every 4 weeks. This was a phase II study of 15 patients with surgically unresectable or metastatic malignant mesothelioma. All patients had measurable or assessable disease. No prior chemotherapy or immunotherapy was allowable. Carboplatin was given at 150 mg/m2 daily on days 1-3 and interferon alpha-2a at 3 million units subcutaneously daily throughout the study. Treatment was recycled every 28 days. Therapy was continued until disease progression. Fifteen patients were assessable for toxicity and 14 for response. One partial response (7%, 95% CI, 0-20%), with a response duration of 40 weeks, was seen. Most patients had early progression of disease. Toxicity was tolerable, and grade III/IV toxicity was uncommon. The median time to progression was 14 weeks (range, 1-52 weeks). The median survival was 25 weeks (range, 8-66 weeks). The combination of low-dose interferon alpha-2a and carboplatin did not result in greater antitumor activity than that reported for single-agent carboplatin in advanced malignant mesothelioma. Although toxicity was mild, carboplatin and low-dose interferon, given at this dose and schedule, cannot be recommended for this patient group.