RESUMEN
BACKGROUND: Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. METHODS: Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. RESULTS: All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 µgPt h/mL, 49.3 ± 30.7 µg h/mL 5-FU (DL1), and 70.5 ± 35.5 µg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). CONCLUSIONS: The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia del Cáncer por Perfusión Regional , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/tratamiento farmacológico , Dosis Máxima Tolerada , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Antígeno Carcinoembrionario/sangre , Quimioterapia del Cáncer por Perfusión Regional/efectos adversos , Neoplasias Colorrectales/sangre , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacocinética , OxaliplatinoRESUMEN
Taken together, these reports provide very provocative and encouraging data that have prompted some to conclude that cytoreduction and HIPEC represents a "new standard of care" for patients with MPM [26]. Certainly, for selected patients who have good performance status (low operative risk) and in whom complete or near complete cytoreduction can be achieved, this form of therapy is associated with a very notable overall survival ranging from 67 to 92 months in 2 larger series. Patient selection remains the central criteria for successful outcome. Patients should be carefully evaluated for co-morbid illnesses that would make them an unacceptable operative risk. Subsequently, CT scan and possibly laparoscopy should be performed to assess resectability with the appreciation that patients with suboptimal resection do very poorly. Pre-operative assessment of disease resectability is difficult to ascertain but some useful information can be obtained from a careful review of the CT scan; some investigators have advocated routine laparoscopy. Technically, details of HIPEC vary from center to center to some degree with respect to type of chemotherapy, dose of chemotherapy, duration of HIPEC, degree of hyperthermia, and method of recirculating the chemotherapy using either the open or closed technique. The use of the HIPEC technique, however, is considered the optimal method of ensuring complete distribution of therapeutic agents to the peritoneal cavity. Hyperthermia is routinely used for its synergistic actions with chemotherapy and its direct tumoricidal activity in experimental models. However, the therapeutic contribution of HIPEC above the effects of successful cytoreduction cannot be determined with available data although palliation of ascites is observed with HIPEC even without cytoreduction. There are no data indicating that one intra-operative chemotherapy regimen is superior to any other. The centers that report use of prolonged induction or post-operative intraperitoneal chemotherapy do not appear to have superior outcomes to those centers that use a more simple treatment regimen. Finally, although the intensity of therapy is considerable, once recovered, the patients appear to enjoy a good HRQOL. Although not specific for patients with MPM, 2 reports have convincingly demonstrated that HRQOL is significantly improved after HIPEC.
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Quimioterapia del Cáncer por Perfusión Regional/métodos , Hipertermia Inducida , Infusiones Parenterales/métodos , Mesotelioma/terapia , Procedimientos Quirúrgicos Mínimamente Invasivos , Neoplasias Peritoneales/terapia , Terapia Combinada , Humanos , Mesotelioma/patología , Mesotelioma/cirugía , Neoplasias Peritoneales/patología , Neoplasias Peritoneales/cirugía , Resultado del TratamientoRESUMEN
We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperitoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected whenever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P < 0.001), and number of previous operations, which was greater in group II (P < 0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher's exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pancreaticoduodenectomía , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Análisis de Supervivencia , GemcitabinaRESUMEN
OBJECTIVES: To identify any risk factors for incidental parathyroidectomy and to define its association with symptomatic postoperative hypocalcemia. DESIGN: Retrospective study. SETTING: Tertiary referral cancer center. PATIENTS: Consecutive patients who underwent thyroid surgery between 1991 and 1999. Patients who underwent procedures for locally advanced thyroid cancer requiring laryngectomy, tracheal resection, or esophagectomy were excluded. INTERVENTIONS: All pathology reports were reviewed for the presence of any parathyroid tissue in the resected specimen. Slides were reviewed, and information regarding patient demographics, diagnosis, operative details, and postoperative complications was collected. MAIN OUTCOME MEASURE: Identification of parathyroid tissue in resected specimens and postoperative symptomatic hypocalcemia. RESULTS: A total of 141 thyroid procedures were performed: 69 total thyroidectomies (49%) and 72 total thyroid lobectomies (51%). The findings were benign in 68 cases (48%) and malignant in 73 cases (52%). In the entire series, incidental parathyroidectomy was found in 21 cases (15%). Parathyroid tissue was found in intrathyroidal (50%), extracapsular (31%), and central node compartment (19%) sites. The performance of a concomitant modified radical neck dissection was associated with an increased risk of unplanned parathyroidectomy (P =.05). There was no association of incidental parathyroidectomy with postoperative hypocalcemia (P =.99). Multivariate analysis identified total thyroidectomy as a risk factor for postoperative hypocalcemia (P =.008). In the entire study group, transient symptomatic hypocalcemia occurred in 9 patients (6%), and permanent hypocalcemia occurred in 1 patient who underwent a total thyroidectomy and concomitant neck dissection. CONCLUSIONS: Unintended parathyroidectomy, although not uncommon, is not associated with symptomatic postoperative hypocalcemia. Modified radical neck dissection may increase the risk of incidental parathyroidectomy. Most of the glands removed were intrathyroidal, so changes in surgical technique are unlikely to markedly reduce this risk.
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Hipocalcemia/etiología , Glándulas Paratiroides , Complicaciones Posoperatorias , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Adolescente , Adulto , Anciano , Humanos , Modelos Logísticos , Escisión del Ganglio Linfático , Persona de Mediana Edad , Glándulas Paratiroides/cirugía , Estudios RetrospectivosRESUMEN
We conducted a retrospective review of all patients who underwent surgical extirpation for stage III, stage IV, or recurrent carcinoma of the gallbladder. Between 1991 and 1999 ten patients underwent surgical resection for advanced gallbladder cancer. All patients received adjuvant therapy either pre- or postoperatively. Radiotherapy was used in all patients and chemotherapy in 90 per cent of patients. Two patients subsequently underwent resection for locally recurrent disease. An additional patient with stage II disease initially was also treated surgically for a local recurrence. Surgical management involved cholecystectomy and resection of various amounts of liver surrounding the gallbladder bed and regional lymphadenectomy. Contiguously involved structures were resected en bloc. Resection of recurrent disease included excision of all gross tumor. The median overall survival excluding the one 30-day mortality was 53.6 months (range 8-73 months). Four patients have survived 4 or more years, and currently four patients are alive and disease free at 73, 49, 33, and 8 months. Median disease-free interval after each resection of recurrent disease was 13.8 months (range 4-28 months). We conclude that trimodality therapy in selected patients with stage III, IV, or recurrent carcinoma of the gallbladder is possible and may result in prolonged survival.