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BACKGROUND AND OBJECTIVES: Surgical site infections (SSIs) after cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) are a major cause of potentially avoidable morbidity. We explored the association of negative pressure wound therapy (NPWT) with SSI in patients undergoing CRS/HIPEC. METHODS: Retrospective analysis of consecutive patients undergoing CRS/HIPEC for non-gynecologic cancers. Exposure was the receipt of NPWT versus traditional skin closure. Primary outcome was SSI within 90 days of surgery. We performed multivariable logistic regression (before and after entropy balancing) to evaluate the association of exposure with outcomes. RESULTS: A total of 251 patients were included, of which 43 (17%) received NPWT and 26 (10.4%) developed SSIs. Baseline demographics and clinicopathologic characteristics were similar between the two groups with some exceptions: Patients who received NPWT had a higher Peritoneal Carcinomatosis Index (median 19 vs. 11, p = 0.002) and operative time (10 vs. 8.2 h, p = 0.003) but were less likely to undergo HIPEC (84% vs. 95%, p < 0.05). After entropy balancing, on multivariable logistic regression, NPWT was not associated with 90-day SSI (odds ratio = 0.90; 95% confidence interval = 0.21-3.80; p = 0.89). CONCLUSION: NPWT was not associated with a reduction in SSIs. These findings prompt a reevaluation of the routine use of NPWT in CRS/HIPEC.
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Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases. Methods: NCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings. Results: Four patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%. Conclusion: PIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.
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BACKGROUND: There is variation in the probability of nodal metastases from low-grade appendiceal adenocarcinomas, and the role of right colectomy is unclear. We aimed to define the prevalence and utility of lymphovascular invasion in predicting the risk of nodal metastases to help stratify patients who may benefit from right hemicolectomy. METHODS: Patients with nonmetastatic low-grade appendiceal adenocarcinomas were identified from the National Cancer Database (2010-2017). The primary outcome was probability of nodal metastases. Logistic regression was used to identify independent predictors of nodal metastases. A 4-tier risk model-the COH Composite Score-was calculated by assigning 1 point each for a high-risk feature (lymphovascular invasion, T3/T4 T stage, or nonmucinous histology). Survival analysis was performed using the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify independent predictors of survival. RESULTS: A total of 1,303 patients with nonmetastatic low-grade appendiceal adenocarcinomas (64.2% mucinous) were identified. Of the 1,133 patients with known lymphovascular invasion status, 78 (6.9%) were lymphovascular invasion positive. In multivariate analysis, lymphovascular invasion was independently associated with nodal metastases (odds ratio, 8.68; P < .001). Overall accuracy of lymphovascular invasion in predicting nodal metastases was 86%. The COH Composite Score stratified patients in 4 categories with increasing risk of nodal metastases and incrementally worse survival. For patients with the COH Composite Score of 0 (12%), the nodal metastasis rate was 3.1%, and a right hemicolectomy in this group did not improve survival. CONCLUSION: The presence of lymphovascular invasion is strongly predictive of nodal metastases. Lymphovascular invasion as part of the COH Composite Score may help guide the extent of surgery in low-grade appendiceal adenocarcinomas.
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Adenocarcinoma , Neoplasias do Apêndice , Colectomia , Metástase Linfática , Invasividade Neoplásica , Humanos , Colectomia/métodos , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/cirurgia , Neoplasias do Apêndice/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Adenocarcinoma/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Invasividade Neoplásica/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Gradação de Tumores , Medição de Risco , Linfonodos/patologia , Linfonodos/cirurgiaRESUMO
Peritoneal metastases from gastrointestinal malignancies present difficult management decisions, with options consisting primarily of systemic chemotherapy or major surgery with or without hyperthermic intraperitoneal chemotherapy. Current research is investigating expanding therapeutic modalities, and the aim of this review is to provide an overview of the existing and emerging therapies for the peritoneal metastases from gastrointestinal cancers, primarily through the recent literature (2015 and newer). These include the current data with systemic therapy and cytoreduction with hyperthermic intraperitoneal or pressurized intraperitoneal aerosol chemotherapy, as well as novel promising modalities under investigation, including dominating oncolytic viral therapy and adoptive cellular, biologic, and bacteria therapy, or nanotechnology. The novel diverse strategies, although preliminary and preclinical in murine models, individually and collectively contribute to the treatment of peritoneal metastases, offering hope for improved outcomes and quality of life. We foresee that these evolving treatment approaches will facilitate the transfer of knowledge and data among studies and advance discovery of new drugs and optimized treatments for patients with peritoneal metastases.
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BACKGROUND AND METHODS: We characterized colorectal liver metastasis recurrence and survival patterns after surgical resection and intraoperative ablation ± hepatic arterial infusion pump (HAIP) placement. We estimated patterns of recurrence and survival in patients undergoing contemporary multimodal treatments. Between 2017 and 2021, patient, tumor characteristics, and recurrence data were collected. Primary outcomes included recurrence patterns and survival data based on operative intervention. RESULTS: There were 184 patients who underwent hepatectomy and intraoperative ablation. Sixty patients (32.6%) underwent HAIP placement. A total of 513 metastases were ablated, median total of 2 ablations per patient. Median time to recurrence was 31 [22-40] months. Recurrence patterns included tumor at ablative margin on first scheduled postoperative imaging (8, 4.3%), local tumor recurrence at ablative site (69, 37.5%), and non-ablated liver tumor recurrence (38, 20.6%). In patients who underwent HAIP placement, the rate of liver recurrence was reduced (45% vs 70.9%, p = 0.0001). Median overall survival was 64 [41-58] months and prolonged survival was associated with HAIP treatment (85 [66-109] vs 60 [51-70] months. CONCLUSIONS AND DISCUSSION: Hepatic recurrence is common and combination of intraoperative ablation and HAIP treatments were associated with prolonged survival. These data may reflect patient selection however, future work will clarify preoperative tumor and patient characteristics that may better predict recurrence expectations.
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Neoplasias Colorretais , Hepatectomia , Artéria Hepática , Infusões Intra-Arteriais , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/cirurgia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Masculino , Feminino , Recidiva Local de Neoplasia/patologia , Pessoa de Meia-Idade , Idoso , Hepatectomia/métodos , Terapia Combinada , Taxa de Sobrevida , Estudos Retrospectivos , Seguimentos , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.
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Antineoplásicos , Hipertermia Induzida , Neoplasias Ovarianas , Humanos , Feminino , Cisplatino/uso terapêutico , Quimioterapia Intraperitoneal Hipertérmica , Antineoplásicos/uso terapêutico , Estudos Prospectivos , Hipertermia Induzida/efeitos adversos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia CombinadaRESUMO
INTRODUCTION: In patients with disseminated appendiceal cancer (dAC) who underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), characterizing and predicting those who will develop early recurrence could provide a framework for personalizing follow-up. This study aims to: (1) characterize patients with dAC that are at risk for recurrence within 2 y following of CRS ± HIPEC (early recurrence; ER), (2) utilize automated machine learning (AutoML) to predict at-risk patients, and (3) identifying factors that are influential for prediction. METHODS: A 12-institution cohort of patients with dAC treated with CRS ± HIPEC between 2000 and 2017 was used to train predictive models using H2O.ai's AutoML. Patients with early recurrence (ER) were compared to those who did not have recurrence or presented with recurrence after 2 y (control; C). However, 75% of the data was used for training and 25% for validation, and models were 5-fold cross-validated. RESULTS: A total of 949 patients were included, with 337 ER patients (35.5%). Patients with ER had higher markers of inflammation, worse disease burden with poor response, and received greater intraoperative fluids/blood products. The highest performing AutoML model was a Stacked Ensemble (area under the curve = 0.78, area under the curve precision recall = 0.66, positive predictive value = 85%, and negative predictive value = 63%). Prediction was influenced by blood markers, operative course, and factors associated with worse disease burden. CONCLUSIONS: In this multi-institutional cohort of dAC patients that underwent CRS ± HIPEC, AutoML performed well in predicting patients with ER. Variables suggestive of poor tumor biology were the most influential for prediction. Our work provides a framework for identifying patients with ER that might benefit from shorter interval surveillance early after surgery.
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BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves survival in select patients with peritoneal metastases (PM), but the impact of social determinants of health on CRS/HIPEC outcomes remains unclear. PATIENTS AND METHODS: A retrospective review was conducted of a multi-institutional database of patients with PM who underwent CRS/HIPEC in the USA between 2000 and 2017. The area deprivation index (ADI) was linked to the patient's residential address. Patients were categorized as living in low (1-49) or high (50-100) ADI residences, with increasing scores indicating higher socioeconomic disadvantage. The primary outcome was overall survival (OS). Secondary outcomes included perioperative complications, hospital/intensive care unit (ICU) length of stay (LOS), and disease-free survival (DFS). RESULTS: Among 1675 patients 1061 (63.3%) resided in low ADI areas and 614 (36.7%) high ADI areas. Appendiceal tumors (n = 1102, 65.8%) and colon cancer (n = 322, 19.2%) were the most common histologies. On multivariate analysis, high ADI was not associated with increased perioperative complications, hospital/ICU LOS, or DFS. High ADI was associated with worse OS (median not reached versus 49 months; 5 year OS 61.0% versus 28.2%, P < 0.0001). On multivariate Cox-regression analysis, high ADI (HR, 2.26; 95% CI 1.13-4.50; P < 0.001), cancer recurrence (HR, 2.26; 95% CI 1.61-3.20; P < 0.0001), increases in peritoneal carcinomatosis index (HR, 1.03; 95% CI 1.01-1.05; P < 0.001), and incomplete cytoreduction (HR, 4.48; 95% CI 3.01-6.53; P < 0.0001) were associated with worse OS. CONCLUSIONS: Even after controlling for cancer-specific variables, adverse outcomes persisted in association with neighborhood-level socioeconomic disadvantage. The individual and structural-level factors leading to these cancer disparities warrant further investigation to improve outcomes for all patients with peritoneal malignancies.
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Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Humanos , Neoplasias Peritoneais/secundário , Quimioterapia Intraperitoneal Hipertérmica , Procedimentos Cirúrgicos de Citorredução , Disparidades Socioeconômicas em Saúde , Hipertermia Induzida/efeitos adversos , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Neoplasias Colorretais/patologiaAssuntos
Antineoplásicos , Neoplasias do Apêndice , Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Estados Unidos , Oxaliplatina/uso terapêutico , Neoplasias do Apêndice/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , AerossóisRESUMO
BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.
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Neoplasias do Apêndice , Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Oxaliplatina , Neoplasias do Apêndice/tratamento farmacológico , Neoplasias Peritoneais/secundário , Estudos Prospectivos , Aerossóis , Fluoruracila/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND: The AJCC 8th edition stratifies stage IV disseminated appendiceal cancer (dAC) patients based on grade and pathology. This study was designed to externally validate the staging system and to identify predictors of long-term survival. METHODS: A 12-institution cohort of dAC patients treated with CRS ± HIPEC was retrospectively analyzed. Overall survival (OS) and recurrence-free survival (RFS) were analyzed by using Kaplan-Meier and log-rank tests. Univariate and multivariate cox-regression was performed to assess factors associated with OS and RFS. RESULTS: Among 1009 patients, 708 had stage IVA and 301 had stage IVB disease. Median OS (120.4 mo vs. 47.2 mo) and RFS (79.3 mo vs. 19.8 mo) was significantly higher in stage IVA compared with IVB patients (p < 0.0001). RFS was greater among IVA-M1a (acellular mucin only) than IV M1b/G1 (well-differentiated cellular dissemination) patients (NR vs. 64 mo, p = 0.0004). Survival significantly differed between mucinous and nonmucinous tumors (OS 106.1 mo vs. 41.0 mo; RFS 46.7 mo vs. 21.2 mo, p < 0.05), and OS differed between well, moderate, and poorly differentiated (120.4 mo vs. 56.3 mo vs. 32.9 mo, p < 0.05). Both stage and grade were independent predictors of OS and RFS on multivariate analysis. Acellular mucin and mucinous histology were associated with better OS and RFS on univariate analysis only. CONCLUSIONS: AJCC 8th edition performed well in predicting outcomes in this large cohort of dAC patients treated with CRS ± HIPEC. Separation of stage IVA patients based on the presence of acellular mucin improved prognostication, which may inform treatment and long-term, follow-up strategies.
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Neoplasias do Apêndice , Hipertermia Induzida , Neoplasias Peritoneais , Humanos , Neoplasias do Apêndice/patologia , Procedimentos Cirúrgicos de Citorredução , Estudos Retrospectivos , Neoplasias Peritoneais/patologia , Mucinas/uso terapêutico , Taxa de Sobrevida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de NeoplasiasRESUMO
Treatment for endometrial cancer is rapidly evolving with the increased use and integration of somatic tumor RNA sequencing in clinical practice. There is a paucity of data regarding PARP inhibition in endometrial cancer given that mutations in homologous recombination genes are rare, and currently no FDA approval exists. A 50-year-old gravida 1 para 1 woman with a diagnosis of stage IVB poorly differentiated endometrioid endometrial adenocarcinoma presented to our comprehensive cancer center. Following surgical staging, she was placed on adjuvant chemotherapy with carboplatin/paclitaxel which was held multiple times due to poor performance status and complications. CT scan of the abdomen and pelvis following cycles 3 of adjuvant chemotherapy showed recurrent progressive disease. She received one cycle of liposomal doxorubicin but discontinued it due to severe cutaneous toxicity. Based on the BRIP1 mutation identified, the patient was placed on compassionate use of Olaparib in January 2020. Imaging during this surveillance period showed a significant decrease in hepatic, peritoneal, and extraperitoneal metastases, and eventually the patient had a clinical complete response in a year. The most recent CT A/P in December 2022 showed no sites of active recurrent or metastatic disease in the abdomen or pelvis. We present a unique case of a patient with recurrent stage IVB poorly differentiated endometrioid endometrial adenocarcinoma with multiple somatic gene mutations including BRIP1, who had a pathologic complete response following compassionate use of Olaparib for 3 years. To our knowledge, this is the first reported case of high grade endometrioid endometrial cancer that has shown a pathologic complete response to a PARP inhibitor.
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BACKGROUND: T4 colon cancers have been underrepresented in randomized trials comparing minimally invasive colectomy (MC) versus open colectomy (OC). Retrospective studies suggest improved survival with MC versus OC, but have not addressed the impact of tumor extent. METHODS: Using the National Cancer Database (NCDB), we analyzed patients undergoing colectomy for T4 colon adenocarcinoma from 2010 to 2014. Propensity score matching was performed between MC and OC patients. Tumor extent was defined by zones based on adjacent organ involvement. RESULTS: Of the 19 178 eligible patients, 6564 (34%) underwent MC. After matching, MC was associated with improved overall survival (hazard ratios: 0.71, 95% confidence interval: 0.67-0.76; median OS 59 vs. 42 months, p < 0.001). Compared to MC patients, those undergoing OC had: a higher margin positive rate (p = 0.009); lower median nodes examined (p < 0.001); a lower rate of adjuvant chemotherapy (p < 0.001); and a longer median time to chemotherapy (p < 0.001). Stratified survival analyses demonstrated that MC was associated with improved overall survival compared to OC in all zones except zone 3 and 4. CONCLUSIONS: Compared to OC, MC for T4 colon cancer is associated with improved oncologic outcomes when performed for zone 0-2 tumors. For, zone 3 and 4 tumors MC and OC have similar oncologic outcomes and patients should be cautiously selected.