RESUMO
BACKGROUND: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). MATERIALS AND METHODS: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. RESULTS: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. CONCLUSION: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. IMPLICATIONS FOR PRACTICE: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.
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Neoplasias da Mama , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Sistema Nervoso Central , Feminino , Humanos , Quinolinas , Receptor ErbB-2/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Despite meticulous preoperative diagnostics, aborted hyperthermic intraperitoneal chemotherapy (AHIPEC) is a common, unsuccessful outcome of curative cytoreductive surgery (CRS)/HIPEC. OBJECTIVE: The aim of this study was to evaluate the association between AHIPEC and preoperative risk factors of patients with mucinous appendiceal cancer (AC). METHODS: A single-institute, case-control study was conducted using a prospective database. Potentially resectable patients with peritoneal carcinomatosis of mucinous AC origin with AHIPEC between October 1994 and February 2019 were identified. Preoperative risk factors were reviewed. Analysis was conducted by tumor grade: low-grade, high-grade, and signet ring cell carcinoma (high-S). All available tumor-type-matched successful CRS/HIPEC controls were obtained from the same database. Univariable and multivariable analyses were performed. RESULTS: Overall, 21, 44, and 15 AHIPEC cases and 153, 133, and 53 tumor-matched controls were identified for low-grade, high-grade, and high-S populations, respectively. Multivariable analysis revealed preoperative cancer antigen (CA) 19-9 > 1 upper limit of normal (ULN) [odds ratio (OR) 6.32; p = 0.014], CA125 > 2 ULN (OR 7.02; p = 0.039), C-reactive protein (CRP) > 2.5 mg/L (OR 13.7; p = 0.001), and previous HIPEC (OR 7.5; p = 0.031) were significantly associated with AHIPEC in the low-grade population. Preoperative CRP > 2.5 mg/L (OR 7.77; p < 0.0001) and previous HIPEC (OR 4.69; p = 0.004) were associated with AHIPEC in a multivariable model for high-grade AC. No single factor showed a significant association with AHIPEC in high-S patients. CONCLUSION: Risk factors vary for AHIPEC among low-grade, high-grade, and high-S AC histology. Elevated preoperative CA19-9, CA125, CRP, and previous HIPEC should be considered in the selection process for CRS/HIPEC in low-grade AC, as well as elevated CRP and previous HIPEC in high-grade AC, to avoid unnecessary surgery.
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Neoplasias do Apêndice , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneais , Antineoplásicos/administração & dosagem , Neoplasias do Apêndice/tratamento farmacológico , Neoplasias do Apêndice/cirurgia , Neoplasias do Apêndice/terapia , Estudos de Casos e Controles , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Neoplasias Peritoneais/terapia , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: MD Anderson Cancer Center developed a computed tomography (CT)-based preoperative assessment tool simplified preoperative assessment for appendix tumor (SPAAT) for predicting incomplete cytoreduction (IC) in low-grade mucinous adenocarcinoma (LGMA) of the appendix, based on preoperative CT scans. This study independently evaluates the tool's performance. METHODS: Seventy-six preoperative CT scans of LGMA patients were evaluated by two surgeons unfamiliar with the patients' medical history. Scores were assigned based on SPAAT criteria, with a SPAAT ≥3 predictive of IC. Binary regression analyses and area under the receiver operating characteristic (AUROC) curve analyses were performed. Patients with splenic resection were excluded due to the structure of the SPAAT assessment tool. RESULTS: Seventy-six LGMA patients underwent attempted cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Of 68 patients, 58 had complete cytoreduction and 10 had IC; 8 patients were ineligible due to prior splenectomy. The mean SPAAT score was 0.8, with six patients having SPAAT scores ≥3. SPAAT scores ≥3 were predictive of IC, with a hazard ratio (HR) of 19 (95% confidence interval 2.8-124.1) (p = 0.002). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were 40, 97, 50, and 90%, respectively. A SPAAT score ≥3 was not associated with worse survival prognosis. Median follow-up was 2.4 years and AUROC curve was 71%. SPAAT components with respective HR and p-values were foreshortening of the bowel mesentery (29.5; p = 0.004), and scalloping of the pancreas (9; p = 0.008), spleen (4.3; p = 0.04), portal vein (3.1; p = 0.4), and liver (2.1; p = 0.3). CONCLUSION: A SPAAT score ≥3 predicted IC based on a binary regression model. The clinical value of this score is controversial due to low sensitivity and PPV.
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Adenocarcinoma Mucinoso/diagnóstico por imagem , Neoplasias do Apêndice/diagnóstico por imagem , Quimioterapia do Câncer por Perfusão Regional , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Neoplasias Peritoneais/diagnóstico por imagem , Adenocarcinoma Mucinoso/secundário , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
PURPOSE: We evaluated the 7th edition of the American Joint Committee on Cancer (AJCC) staging classification in terms of overall survival (OS) in patients with PMP treated with cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A total of 208 PMP patients treated with CRS/HIPEC were identified from a prospective database. Patients with peritoneal mucinous carcinomatosis (PMCA) were retrospectively staged at time of diagnosis according to AJCC staging classification. Patients with disseminated peritoneal adenomucinosis (DPAM) were evaluated in a separate group. RESULTS: Median follow-up was 5.2 years. Of 208 patients, 124 had PMCA and 84 patients had DPAM. According to the AJCC staging classification 47 lymph node (LN) negative patients with well-differentiated PMCA, were classified as a stage IVA. 77 patients with either moderately or poorly differentiated PMCA irrespective of LN status, or well-differentiated PMCA with positive LN were classified as stage IVB. 84 patients with DPAM, constituted a separate group. OS of stage IVA and IVB patients was 100, 90, 67, and 91, 50, and 27 for 1, 3, and 5 years, respectively (p < 0.001). OS of DPAM patients was 96, 90, and 88 % for 1, 3, and 5 years, respectively (p = 0.025 comparing to IVA). PFS was estimated for IVA and IVB PMCA patients who were considered disease free after CRS/HIPEC and was 78, 52, and 43 % in the IVA patients and 65 %, 15 %, and 0 in the IVB group at 1, 3, and 5 years, respectively (p = 0.004). The adjusted HR for AJCC stages (IVA/IVB) was 3.7 (95 % confidence interval 2.0-6.7) (p < 0.001). CONCLUSIONS: The 7th edition of the AJCC staging classification is a simple, reproducible, and valid classification for staging patients with PMCA undergoing CRS/HIPEC.
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Adenocarcinoma Mucinoso/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice/patologia , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Neoplasias Peritoneais/secundário , Adenocarcinoma Mucinoso/classificação , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/classificação , Neoplasias do Apêndice/terapia , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/classificação , Neoplasias Peritoneais/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
INTRODUCTION: Port-site metastases (PSMs) have been reported after laparoscopy in patients with peritoneal carcinomatosis (PC). We hypothesize that PSM is an independent negative predicting factor of survival in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: A retrospective review of a prospective database was conducted to search patients who underwent laparoscopy prior to CRS/HIPEC. Most of the tumors were of appendiceal origin. All previous laparoscopy port sites were excised regardless of macroscopic tumor involvement. Patients were divided into two groups: patients with PSM [PSM (+)] and patients without PSM [PSM (-)]. Overall survival (OS) was estimated by Kaplan-Meier curves and the log-rank test. Cox regression [hazard ratios (HRs) and 95 % confidence intervals (CIs)] was used to test for independent effects of the PSM (+) and the associated clinicopathological variables. RESULTS: Sixty-five patients had laparoscopy before CRS/HIPEC. One hundred and forty-four port-sites were resected; 41 (29 %) ports were positive for malignancy in a total of 22 (34 %) patients. Mean OS at 1, 3, and 5 years was 88, 66, and 63 %, respectively. Survival in patients with PSM was 73, 35, and 23 %, respectively, compared with 95, 82, and 82 %, respectively, in patients without PSM (p ≤ 0.001). Positive lymph nodes (LNs) were detected in 13/22 patients with PSM and 11/43 patients without PSM. Independent effects on survival shows an HR of 3.136, 95 % CI 1.150-8.549 (p = 0.026) for LN metastases, and an HR of 3.462, 95 % CI 1.198-10.006 (p = 0.022) in patients with positive PSM. CONCLUSION: PSMs are common in patients with PC undergoing CRS/HIPEC and are independently associated with a worse prognosis. Resection of previous laparoscopy port sites is advocated in patients with PC to ensure complete cytoreduction.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inoculação de Neoplasia , Neoplasias/patologia , Neoplasias Peritoneais/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/mortalidade , Feminino , Seguimentos , Humanos , Hipertermia Induzida/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/mortalidade , Neoplasias/terapia , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: CRS/HIPEC has evolved as a therapeutic option for selected patients with peritoneal surface malignancies. To achieve complete cytoreduction (CC), some patients require extensive abdominal-wall resection (AWR) and subsequent complex reconstructions, which may be associated with wound complications (WC) and delay of postoperative cancer therapy. METHODS: Review of a prospective database of 350 patients revealed 213 patients with peritoneal carcinomatosis who underwent AWR due to suspected or proven wound/port site metastases during CRS/HIPEC. Tumor origin included: appendix, colon, ovarian, peritoneal mesothelioma, primary peritoneal, and others. WC were related to peritoneal carcinomatosis index (PCI), CC score, length of surgery, type of AWR and closure, blood transfusion, and albumin levels using binary logistic regression (odds ratios (OR) and 95 % CIs) analysis. RESULTS: PCI ≥ 20 was found in 151 (71 %), CC was achieved in 178 (84 %). Mean length of surgery was 613 min. Postoperative WC were detected in 49 of 213 (23 %) patients, 13 (6 %) had Grade III (according to Clavien-Dindo's classification) WC, and led to delay of postoperative chemotherapy. WC occurred in 21 of 64 (32.8 %) patients with excision of port sites (odds ratio [OR] = 2.11, confidence interval [CI] = 1.09-4.10, p = 0.026). Primary fascial closure was performed in 191 of 213 (89.7 %) patients, 40 (21 %) of whom had WC. Mesh-assisted abdominal wall reconstruction was required in 22 of 213 (10.3 %) patients, of whom 9 (40.9 %) had WC (OR = 2.61, CI = 1.04-6.55, p = 0.035). CONCLUSIONS: Port-site excision and mesh-assisted abdominal wall reconstruction were associated with higher incidence of postoperative WC following CRS/HIPEC. The implications of these preliminary findings may need to be considered during surgical planning for these patients.
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Parede Abdominal/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Hipertermia Induzida/efeitos adversos , Morbidade , Procedimentos de Cirurgia Plástica , Complicações Pós-Operatórias , Infecção dos Ferimentos/etiologia , Parede Abdominal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/complicações , Neoplasias/patologia , Neoplasias/terapia , Neoplasias Peritoneais/complicações , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has survival benefit in the treatment of selected patients with peritoneal carcinomatosis (PC) from appendiceal cancer (AC). We evaluated factors affecting the survival of patients with PC from AC after CRS/HIPEC. METHODS: A retrospective analysis of 387 CRS/HIPEC procedures performed between February 1998 and February 2013 identified 202 patients with PC from AC. Tumor histopathology, complete cytoreduction (CC 0-1), Peritoneal Cancer Index (PCI), and lymph node (LN) status were related to overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. RESULTS: Overall, 129 women (64 %) and 73 men (36 %), mean age 54 years (range 25-81), with a mean follow-up of 36 months were included in the study. Seventy-seven low-grade tumors (disseminated peritoneal adenomucinosis [DPAM]; 38 %) and 125 high-grade tumors (peritoneal mucinous carcinomatosis [PMCA]; 62 %) were identified. Five- and 10-year OS was 56 % and 47 %, respectively, with PFS of 44 % at 5 and 10 years. Five-year OS in DPAM patients was 83 %, with a 5-year OS significant difference related to CC 0-1 versus CC 2-3 (incomplete cytoreduction) [p = 0.021]. Five-year OS in PMCA patients was 41 %, with a 5-year OS significant difference related to CC 0-1 versus CC 2-3 (p < 0.001), PCI <20 versus PCI ≥20 (p = 0.002), and (-)LN versus (+)LN (p < 0.001). Grade III/IV complications were 16 %. No perioperative mortality was reported. CONCLUSION: Positive LN, PMCA histopathology, and PCI ≥20 are negative prognostic factors, while CC 0-1 is a positive survival predictor in PC from AC treated with CRS/HIPEC. However, in patients with PMCA and PCI ≥20 in whom CC 0-1 was a potential outcome should not be denied CRS/HIPEC.
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Adenocarcinoma Mucinoso/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice/mortalidade , Procedimentos Cirúrgicos de Citorredução , Hipertermia Induzida , Recidiva Local de Neoplasia/mortalidade , Neoplasias Peritoneais/mortalidade , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/terapia , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intraperitoneais , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Diffuse malignant peritoneal mesothelioma (DMPM) is an uncommon malignancy, which can be difficult to treat. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have evolved as the treatment of choice when complete cytoreduction is to be achieved. This study reports the outcomes of CRS/HIPEC for peritoneal mesothelioma performed in a center for peritoneal surface malignancy. A retrospective analysis of a prospective database of 389 CRS/HIPEC procedures identified 23 patients who underwent CRS/HIPEC for DMPM from 1999 to 2014. Gender, age at diagnosis, age at surgery, previous surgeries, follow-up time, peritoneal cancer index (PCI) score, completeness of cytoreduction (CC), pathology, and overall survival (OS) were analyzed. The univariate analysis was used to determine the prognostic value of age, gender, neoadjuvant chemotherapy, histopathology of the tumor, PCI, CC, and lymph node status on survival. Mean follow-up time from surgery was 31 months (range = 0.5-124). The median PCI score was 28, and 77 per cent had PCI ≥20. CC 0-1 was achieved in 65 per cent of cases. One- and 5-year actuarial OS rates from diagnosis were 86 per cent and 60 per cent, respectively. One- and 5-year actuarial OS from HIPEC was 70 per cent and 64 per cent, respectively. The univariate analysis showed that the CC was the only significant prognostic factor. Patients with DMPM may achieve long-term survival when treated with CRS/HIPEC. The CC is the most significant prognostic factor for long-term survival.