Adjuvant imatinib in high-risk resected gastrointestinal stromal tumors: Merely delaying the inevitable?

INTRODUCTION: Patients with high-risk resected gastrointestinal stromal tumors (GIST) receiving adjuvant imatinib have improved recurrence-free survival (RFS), however whether a complete cytocidal effect exists is unknown. We investigated this using a normalized recurrence timeline measured from end of oncologic treatment (EOOT), defined as the later of resection or end of adjuvant therapy. METHODS: We reviewed patients with resected high-risk GIST at our cancer center from 2003 to 2018. RFS (measured from resection and EOOT), overall survival (OS), and time to imatinib resistance (TTIR) were analyzed using Kaplan-Meier analysis and multivariable Cox proportional hazards modeling. The performance of the Memorial Sloan Kettering (MSK) GIST nomogram was assessed. RESULTS: We identified 86 patients with high-risk GIST with a median 106 months of postsurgical follow-up. One-third (n = 29; 34%) did not receive adjuvant imatinib, while 57 (66%) did for a median of 3 years. The MSK nomogram-predicted 5-year RFS for patients receiving adjuvant imatinib was similar to those who did not (29% vs. 31%, p = 0.64). When RFS was measured from EOOT, the MSK-predicted RFS was independently associated with EOOT RFS (hazard ratio 0.22, p = 0.02), while adjuvant imatinib receipt and duration were not. Neither receipt nor duration of adjuvant imatinib were associated with TTIR or OS (all p > 0.05). CONCLUSIONS: Treatment with adjuvant imatinib delays, but does not clearly impact ultimate recurrence, TTIR, or OS, suggesting many patients with high-risk GIST may receive adjuvant imatinib unnecessarily. Additional studies are needed to establish the benefit of adjuvant therapy versus initiating therapy at first radiographic recurrence.

Ten-Year Survivorship in Patients with Metastatic Gastrointestinal Stromal Tumors.

INTRODUCTION: Patients developing metastatic gastrointestinal stromal tumors (mGIST) have heterogenous disease biology and oncologic outcomes; prognostic factors are incompletely characterized. We sought to evaluate predictors of 10-year metastatic survivorship in the era of tyrosine kinase inhibitor (TKI) therapy. METHODS: We reviewed patients with mGIST treated at our Comprehensive Cancer Center from 2003 to 2019, including only patients with either mortality or 10 years of follow-up. Ten-year survivorship was evaluated with logistic regression. RESULTS: We identified 109 patients with a median age of 57 years at mGIST diagnosis. Synchronous disease was present in 57% (n = 62) of patients; liver (n = 48, 44%), peritoneum (n = 40, 37%), and liver + peritoneum (n = 18, 17%) were the most common sites. Forty-six (42%) patients were 10-year mGIST survivors. Following mGIST diagnosis, radiographic progression occurred within 2 years in 53% (n = 58) of patients, 2-5 years in 16% (n = 17), and 5-10 years in 16% (n = 17), with median survival of 32, 76, and 173 months, respectively. Seventeen (16%) patients had not progressed by 10 years. Fifty-two (47%) patients underwent metastasectomy, which was associated with improved progression-free survival (hazard ratio 0.63, p = 0.04). In patients experiencing progression, factors independently associated with 10-year survivorship were age (odds ratio [OR] 0.96, p = 0.03) and time to progression (OR 1.71/year, p < 0.001). CONCLUSIONS: Ten-year survivorship is achievable in mGIST in the era of TKIs and is associated with younger age and longer time to first progression, while metastasectomy is associated with longer time to first progression. The role of metastasectomy in the management of patients with disease progression receiving TKI therapy merits further study.

Hepatic arterial infusion pump chemotherapy combined with systemic therapy for patients with advanced colorectal liver metastases: Outcomes in a newly established program.

BACKGROUND AND OBJECTIVES: Colorectal liver metastasis (CRLM) is a leading cause of morbidity and mortality in patients with colorectal cancer. Hepatic arterial infusion (HAI) chemotherapy has been demonstrated to improve survival in patients with resected CRLM and to facilitate conversion of technically unresectable disease. METHODS: Between 2016 and 2018, n = 22 HAI pumps were placed for CRLM. All patients received systemic chemotherapy concurrently with HAI floxuridine/dexamethasone. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. RESULTS: HAI pumps were placed in seven patients with completely resected CRLM and 15 patients with unresectable disease. Twenty-one patients received HAI floxuridine with a median of 5 total HAI cycles (interquartile range: 4-7). Biliary sclerosis was the most common HAI-related complication (n = 5, 24%). Of the 13 patients treated to convert unresectable CRLM, 3 (23%) underwent hepatic resection with curative intent after a median of 7 HAI cycles (range: 4-10). For all HAI patients, the mean OS was 26.7 months from CRLM diagnosis, while the median PFS and hepatic PFS from pump placement were 9 and 13 months, respectively. CONCLUSION: Concomitant HAI and systemic therapy can be utilized at multidisciplinary programs for patients with advanced CRLM, both in the adjuvant setting and to facilitate conversion of unresectable disease.

Surgical timing after preoperative chemotherapy is associated with oncologic outcomes in resectable colorectal liver metastases.

INTRODUCTION: Preoperative chemotherapy (POC) is often employed for patients with resectable colorectal liver metastasis (CRLM). The time to resection (TTR) following the end of chemotherapy may impact oncologic outcomes; this phenomenon has not been studied in CRLM. METHODS: We queried our institutional cancer database for patients with resected CRLM after POC from 2003 to 2019. TTR was calculated from date of last cytotoxic chemotherapy. Kaplan-Meier analysis and multivariable Cox proportional hazards modeling were used to analyze recurrence-free survival (RFS) and overall survival (OS). RESULTS: We identified n = 187 patients. One hundred twenty-four (66%) patients had a TTR of <2 months, while 63 (33%) had a TTR of ≥2 months. Median follow-up was 36 months. On Kaplan-Meier analysis, patients with TTR ≥ 2 months had shorter RFS (median 11 vs. 17 months, p = 0.002) and OS (median 44 vs. 62 months, p < 0.001). On multivariable analysis, TTR ≥ 2 months was independently associated with worse RFS (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.06-2.22, p = 0.02) and OS (HR = 1.75, 95% CI = 1.11-2.77, p = 0.01). CONCLUSION: TTR ≥ 2 months following POC is independently associated with worse oncologic outcomes in patients with resectable CRLM. We therefore recommend consideration for hepatic resection of CRLM within this window whenever feasible.

The patient's perspective: a qualitative study of individual experience with decision-making, treatment, and recovery for resectable pancreatic cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma cancer (PDAC) remains a challenging diagnosis. The likelihood of long-term survival is limited even for patients who undergo maximal medical therapy with systemic chemotherapy and surgical resection. Within this intensive process, there remains limited understanding of patients' pretreatment expectations of PDAC treatment experience and their decision-making process. METHODS: PDAC patients who underwent chemotherapy and surgical resection were retrospectively identified. Semi-structured phone interviews were completed regarding patient experience with therapy. Qualitative descriptive analysis was performed, and categories, subcategories, and themes were determined. RESULTS: Fifteen patients were interviewed regarding their experience with PDAC treatment. An overall personal disease trajectory experience was identified with two phases. The first phase encompassed the patients' treatment. In this phase, patients expressed a choice, non-choice regarding therapy decisions, viewing therapy as the only option. Misconceptions about the roles of therapies and expected experience of treatment were observed. The second phase focused on life after therapy. Patients reported persistent physical changes secondary to therapy. An overall realistic understanding of the patient's limited prognosis was observed, with patients expressing appreciation of the life time gained as a benefit of treatment. CONCLUSIONS: There remains critical areas for improvement in communication and care of patients with PDAC. Physicians should continue to ensure that patient's goals and wishes are respected when making treatment decisions and confirm that patients understand the roles and limitations of prescribed therapies. Additionally, patients continue to have significant physical changes post treatment which should be assessed for and managed as appropriate to maintain quality of life.

Hepatic metastases in gastrointestinal stromal tumors: oncologic outcomes with curative-intent hepatectomy, resection of treatment-resistant disease, and tyrosine kinase inhibitor therapy alone.

BACKGROUND: Hepatic resection for metastatic GIST (mGIST) is often performed with either curative-intent or for tyrosine kinase inhibitor (TKI)-resistant lesions. The efficacy of hepatectomy for treatment-resistant lesions (TRL) is uncertain. METHODS: We reviewed patients with liver-mGIST treated from 2003 to 2018. Oncologic outcomes including overall (OS), post-operative progression-free survival (PFS), and post-progression OS were evaluated using Kaplan-Meier and Cox proportional hazards modeling. RESULTS: We identified n = 91 patients; 31 (34%) underwent curative-intent hepatectomy, 60 (66%) were initially managed with TKI alone, and 17 (19%) had resection of a TRL. The median follow-up for resected patients was 102 months (range 5-209 months) with 23 (25%) managed with a major hepatectomy. Patients having curative-intent hepatectomy had 72% 10-year OS following diagnosis of liver-mGIST, compared with 58% (P = 0.50) for TRL resection and 41% (P = 0.01) for non-resected patients. Curative-intent hepatectomy (HR 0.39, P = 0.03) and age (HR 1.04, P = 0.004) were independently associated with 10-year OS, but not TRL resection. TRL resection was not associated with improved post-progression OS compared to second-line TKI therapy (HR 0.61, P = 0.21). CONCLUSIONS: Curative-intent hepatectomy is associated with improved OS in liver-mGIST. The oncologic benefit of resecting treatment-resistant liver-mGIST compared to second-line TKI therapy alone remains unclear in the era of multi-line TKI therapy.

Disease-free Interval Is Associated with Oncologic Outcomes in Patients with Recurrent Gastrointestinal Stromal Tumor.

BACKGROUND: Gastrointestinal stromal tumors (GIST) commonly recur following curative-intent resection. Patients with recurrent GIST display heterogeneous outcomes with limited prognostic tools. We investigated factors associated with post-recurrence survival (PRS) and progression-free survival (PFS). METHODS: We performed a review of our institutional cancer registry from 2003 to 2018 for patients with GIST. Clinicopathologic and outcome data were collected. The disease-free interval (DFI) was calculated from the end of curative-intent oncologic therapy until recurrence. Outcomes were evaluated using Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Overall, 254 patients underwent resection of primary, non-metastatic GIST, with 81 (32%) recurrences. The median age was 58 years and more than half of the patients with recurrence (n = 44; 54%) received adjuvant imatinib. Recurrence was most common in the liver (n = 34, 42%), peritoneum (n = 31, 38%), or liver plus peritoneum (n = 10, 12%). The median DFI was 14 months (interquartile range 2-26 months); 51 (63%) patients had a DFI ≤24 months and 30 (37%) had a DFI > 24 months. The median post-recurrence follow-up was 46 months. Compared with a DFI ≤24 months, patients with a DFI >24 months had increased 10-year PRS (77% vs. 41%, p < 0.05) and 10-year PFS (73% vs. 19%, p < 0.001). On multivariable analysis controlling for mutational and clinicopathologic features, a DFI >24 months was independently associated with increased PRS (hazard ratio [HR] 0.24, p < 0.01) and PFS (HR 0.18, p < 0.001). CONCLUSIONS: The DFI is independently associated with oncologic outcomes in recurrent GIST and may be useful in treatment planning. Recurrence after 24 months may signify indolent disease biology that may benefit from additional treatment, including metastasectomy.

Degree of biliary tract violation during treatment of gallbladder adenocarcinoma is independently associated with development of peritoneal carcinomatosis.

BACKGROUND: Gallbladder cancer (GBC) is often incidentally diagnosed after cholecystectomy. Intra-operative biliary tract violations (BTV) have been recently associated with development of peritoneal disease (PD). The degree of BTV may be associated with PD risk, but has not been previously investigated. METHODS: We reviewed patients with initially non-metastatic GBC treated at our institution from 2003 to 2018. Patients were grouped based on degree of BTV during their treatment: major (e.g., cholecystotomy with bile spillage, n = 27, 29%), minor (e.g., intra-operative cholangiogram, n = 18, 19%), and no violations (n = 48, 55%). Overall survival (OS) and peritoneal disease-free survival (PDFS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Ninety-three patients were identified; the median age was 64 years (range 31-87 years). Seventy-six (82%) were incidentally diagnosed. The median follow-up was 23 months; 20 (22%) patients developed PD. The 3-year PDFS for patients with major, minor, and no BTV was 52%, 83%, and 98%, respectively (major vs. none: p < 0.001; minor vs. none: p < 0.01). BTV was not associated with 5-year OS (HR 1.53, p = 0.16). CONCLUSION: Increasing degree of BTV is associated with higher risk of peritoneal carcinomatosis in patients with GBC and should be considered during preoperative risk stratification. Reporting biliary tract violations during cholecystectomy is encouraged.

Safety and feasibility of initiating a hepatic artery infusion pump chemotherapy program for unresectable colorectal liver metastases: A multicenter, retrospective cohort study.

INTRODUCTION: Hepatic artery infusion pump (HAIP) chemotherapy is a specialized therapy for patients with unresectable colorectal liver metastases (uCRLM). Its effectiveness was demonstrated from a high volume center, with uncertainty regarding the feasibility and safety at other centers. Therefore, we sought to assess the safety and feasibility of HAIP for the management of uCRLM at other centers. METHODS: We conducted a multicenter retrospective cohort study of patients with uCRLM treated with HAIP from January 2003 to December 2017 at six North American centers initiating the HAIP program. Outcomes included the safety and feasibility of HAIP chemotherapy. RESULTS: We identified 154 patients with HAIP insertion and the median age of 54 (48-61) years. The burden of disease was >10 intra-hepatic metastatic foci in 59 (38.3%) patients. Patients received at least one cycle of systemic chemotherapy before HAIP insertion. Major complications occurred in 7 (4.6%) patients during their hospitalization and 13 (8.4%) patients developed biliary sclerosis during follow-up. A total of 148 patients (96.1%) received at least one-dose of HAIP chemotherapy with a median of 5 (4-7) cycles. 78 patients (56.5%) had a complete or partial response and 12 (7.8%) received a curative liver resection. CONCLUSION: HAIP programs can be safely and effectively initiated in previously inexperienced centers with good response.

Results of COVID-minimal Surgical Pathway During Surge-phase of COVID-19 Pandemic.

OBJECTIVE: The outcomes of patients treated on the COVID-minimal pathway were evaluated during a period of surging COVID-19 hospital admissions, to determine the safety of continuing to perform urgent operations during the pandemic. SUMMARY OF BACKGROUND DATA: Crucial treatments were delayed for many patients during the COVID-19 pandemic, over concerns for hospital-acquired COVID-19 infections. To protect cancer patients whose survival depended on timely surgery, a "COVID-minimal pathway" was created. METHODS: Patients who underwent a surgical procedure on the pathway between April and May 2020 were evaluated. The "COVID-minimal surgical pathway" consisted of: (A) evolving best-practices in COVID-19 transmission-reduction, (B) screening patients and staff, (C) preoperative COVID-19 patient testing, (D) isolating pathway patients from COVID-19 patients. Patient status through 2 weeks from discharge was determined as a reflection of hospital-acquired COVID-19 infections. RESULTS: After implementation, pathway screening processes excluded 7 COVID-19-positive people from interacting with pathway (4 staff and 3 patients). Overall, 122 patients underwent 125 procedures on pathway, yielding 83 admissions (42 outpatient procedures). The median age was 64 (56-79) and 57% of patients were female. The most common surgical indications were cancer affecting the uterus, genitourinary tract, colon, lung or head and neck. The median length of admission was 3 days (1-6). Repeat COVID-19 testing performed on 27 patients (all negative), including 9 patients evaluated in an emergency room and 8 readmitted patients. In the postoperative period, no patient developed a COVID-19 infection. CONCLUSIONS: A COVID-minimal pathway comprised of physical space modifications and operational changes may allow urgent cancer treatment to safely continue during the COVID-19 pandemic, even during the surge-phase.

Who Undergoes Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Appendiceal Cancer? An Analysis of the National Cancer Database.

BACKGROUND: We sought to identify patterns of care for patients with appendiceal cancer and identify clinical factors associated with patient selection for multimodality treatment, including cytoreductive surgery and perioperative intraperitoneal chemotherapy (CRS/PIC). MATERIALS AND METHODS: National Cancer Database (NCDB) data from 2004 to 2014 of all diagnoses of appendiceal cancers were examined. We examined treatment modalities, as well as demographic, tumor-specific, and survival data. A multivariate logistic regression analysis was performed to determine the patient cohort most likely to receive CRS/PIC. Kaplan-Meier was used to estimate survival for all treatment groups. Significance was evaluated at P ≤ 0.05. RESULTS: We analyzed data on 18,055 patients. Nine thousand nine hundred ninety-two (55.3%) were treated with surgery only, 5848 (32.4%) received surgery and systemic chemotherapy, 1393 (7.71%) received CRS/PIC, 520 (2.88%) received chemotherapy alone, and 302 (1.67%) received neither surgery nor chemotherapy. Significant predictors of receiving CRS/PIC included male sex (OR 1.33, 95% CI: 1.11-1.59), white race (OR 2.00, 95% CI 1.40-2.86), non-Hispanic ethnicity (OR 1.92, 95% CI 1.21-3.05), private insurance (OR 1.52, 95% CI 1.26-1.84), and well-differentiated tumors (OR 4.25, CI: 3.39-5.32) (P < 0.05). Treatment with CRS/PIC was associated with a higher 5-year survival for mucinous malignancies, when compared to surgery alone (65.6% versus 62.4%, P < 0.01). Treatment with CRS/PIC was also associated with higher 5-year survival for well-differentiated malignancies, when compared to all other treatment modalities (74.9% versus 65.4%, P < 0.01). CONCLUSIONS: Patients were more likely to undergo CRS/PIC if they were male, white, privately insured, and with well-differentiated tumors. CRS/PIC was associated with improved survival in patients with mucinous and low-grade tumors.

Epirubicin and Ifosfamide with Preoperative Radiation for High-Risk Soft Tissue Sarcomas.

BACKGROUND: The optimal treatment of high-risk soft tissue sarcomas (STS) of the extremities remains controversial. We report follow-up from a phase II study of dose-intense chemotherapy with preoperative hypofractionated radiation in this population supplemented with subsequent data from an extensive institutional experience using this regimen. METHODS: Patients with localized, intermediate- or high-grade STS of the extremity or body wall measuring > 5 cm were treated with epirubicin 30 mg/m2/day and ifosfamide 2.5 g/m2/day on days 1-4 every 21 days for 3 preoperative and 3 postoperative cycles. During cycle 2 of preoperative therapy, epirubicin was omitted, and a total of 28 Gy of radiation (8 fractions) was delivered. Twenty-five patients were treated on the phase II study (2002-2005). Fifty-one additional patients were identified from a retrospective chart review (2005-2014). RESULTS: The 5-year rates for overall survival, distant disease-free survival, and freedom from local regional failure were 70.4% (95% CI 59.2-83.7%), 55.9% (95% CI 44.5-70.2%), and 87.2% (95% CI 77.9-96.5%) respectively. Thirty-eight percent of tumors (29/76) demonstrated ≥ 90% pathologic response. Wound complications occurred in 32% (24/76) of patients. DISCUSSION: Treatment with preoperative radiation and pre- and post-operative epirubicin and ifosfamide was associated with favorable clinical outcomes. Survival and recurrence rates were comparable to those reported with other preoperative chemotherapy regimens in high-risk extremity sarcomas. Use of trimodality therapy should be considered for appropriate high-risk STS patients.

Preoperative optimization for major hepatic resection.

PURPOSE: Major hepatic resections are performed for primary hepatobiliary malignancies, metastatic disease, and benign lesions. Patients with chronic liver disease, including cirrhosis and steatosis, are at an elevated risk of malnutrition and impaired strength and exercise capacity, deficits which cause increased risk of postoperative complications and mortality. The aims of this report are to discuss the pathophysiology of changes in nutrition, exercise capacity, and muscle strength in patient populations likely to require major hepatectomy, and review recommendations for preoperative evaluation and optimization. METHODS: Nutritional and functional impairment in preoperative hepatectomy patients, especially those with underlying liver disease, have a complex and multifactorial physiologic basis that is not completely understood. RESULTS: Recognition of malnutrition and compromised strength and exercise tolerance preoperatively can be difficult, but is critical in providing the opportunity to intervene prior to major hepatic resection and potentially improve postoperative outcomes. There is promising data on a variety of nutritional strategies to ensure adequate intake of calories, proteins, vitamins, and minerals in patients with cirrhosis and reduce liver size and degree of fatty infiltration in patients with hepatic steatosis. Emerging evidence supports structured exercise programs to improve exercise tolerance and counteract muscle wasting. CONCLUSIONS: The importance of nutrition and functional status in patients indicated for major liver resection is apparent, and emerging evidence supports structured preoperative preparation programs involving nutritional intervention and exercise training. Further research is needed in this field to develop optimal protocols to evaluate and treat this heterogeneous cohort of patients.

Nomogram for Predicting Overall Survival and Salvage Abdominoperineal Resection for Patients with Anal Cancer.

BACKGROUND: Anal cancer treatment has evolved from abdominoperineal resection to chemoradiotherapy, which allows for sphincter preservation. OBJECTIVE: The aim of this study was to develop an accurate model and nomogram to predict overall survival and the probability of salvage abdominoperineal resection for anal cancer patients. DESIGN: This is a retrospective cohort study. SETTINGS: Data were gathered from National Cancer Database entries from 1998 to 2010. PATIENTS: Patients with de novo anal cancer were selected from the National Cancer Database in the years 1998 through 2010; 1778 patients were included, and their data were analyzed. MAIN OUTCOME MEASURES: Variables included time to death, censoring indicator, age, race, sex, tumor size, year of diagnosis, surgery status, nodal status, TNM stage, and chemoradiation therapy. A stratified Cox proportional hazards model for overall survival and a logistic regression model for salvage abdominoperineal resection were developed. Our final models were internally validated for discrimination and validation. RESULTS: Statistically significant variables in the salvage surgery model were tumor size and nodal status (p ≤ 0.001). For overall survival model, statistically significant variables (all with p ≤ 0.005), fitted across the strata of TNM clinical stage included age, sex, tumor size, nodal status, chemoradiotherapy treatment, and combination salvage surgery and chemoradiotherapy. Nomograms that predict events are based on our final models. LIMITATIONS: Limitations included clerical database errors and nonmeasured variables, such as HIV status. CONCLUSIONS: A nomogram can predict overall survival and salvage surgery for an individual with anal cancer. Such tools may be used as decision support aids to guide therapy and predict whether or not patients may need salvage surgery.

Chemoradiotherapy with a radiation boost for anal cancer decreases the risk for salvage abdominoperineal resection: analysis from the national cancer data base.

BACKGROUND: Chemoradiotherapy (CRT), the primary treatment for anal cancer, achieves complete tumor regression in most patients. Abdominoperineal resection (APR) is reserved for persistent or recurrent disease. An additional boost dose of radiation after CRT often is used to improve the response rate for advanced local disease (T3, 4, and N+). This study examines the need for salvage APR after radiation boost. METHODS: Patients with de novo anal cancer in the National Cancer Data Base from the years 2004-2010 were analyzed. Patients with missing data points or who did not receive standard CRT were excluded. Variables included age, gender, race, primary tumor size, clinical nodal status, TNM stage, radiation boost, and APR. A logistic regression model assessing the relationship between boost radiation and APR was developed. RESULTS: Of 1,025 patients meeting inclusion criteria, 450 patients received CRT without a radiation boost and 575 patients received CRT with a radiation boost. The two groups were similar in age, gender, race, tumor size, nodal status, and TNM stage (p values all >0.05). Significant multivariate predictors of salvage APR were tumor size, negative nodal status, and boost RT (all p < 0.05), whereas gender, age, race, and TNM stage were not significant (all p > 0.05). When controlling for age, tumor size, and nodal status, salvage APR is less likely to occur after boost RT (odds ratio 0.63; 95 % confidence interval 0.47, 0.85; p = 0.003). CONCLUSIONS: When controlling for age, tumor size, and nodal status, those who received boost radiation for anal cancer were less likely to require salvage APR.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Coagulopathy after a liver resection: is it over diagnosed and over treated?

BACKGROUND: Prothrombin time-international normalized ratio (PT-INR) is widely utilized to guide plasma therapy and initiation of thromboprophylaxis after a hepatectomy. Thrombelastography (TEG) monitors shear elasticity, which is sensitive to cellular and plasma components in blood, allowing for functional assessment of the life of the clot. The objective of this study was to prospectively compare PT-INR and TEG in liver resection patients. METHODS: Forty patients were enrolled before undergoing an elective hepatectomy. Patients underwent a liver resection utilizing a low central venous pressure (CVP) anaesthetic technique and intermittent Pringle manoeuver. PT-INR and TEG were drawn prior to incision, post-operatively, and post-operative days 1, 3 and 5. RESULTS: All post-operative PT-INR values increased significantly when compared with pre-operative PT-INR (P < 0.01). The time of onset to clot (R-value) decreased significantly at the post-operative time point (P = 0.04), consistent with a relative hypercoagulability. Subsequent R-values were not different compared with the pre-operative R-value. The strength of the clot (maximum amplitude, MA) was unchanged when comparing pre- and post-operative time points. DISCUSSION: In spite of an elevation in PT-INR, patients undergoing a liver resection demonstrated a brief hypercoagulable state, followed by normal coagulation function based on TEG. These data call into question the practice of utilizing PT-INR to guide plasma transfusion and timing of prophylactic anticoagulation after a liver resection.

Hepatopancreatobiliary malignancies: time to treatment matters.

Background: Initiation of oncologic care is often delayed, yet little is known about delays in hepatopancreatobiliary (HPB) cancers or their impact. This retrospective cohort study describes trends in time to treatment initiation (TTI), assesses the association between TTI and survival, and identifies predictors of TTI in HPB cancers. Methods: The National Cancer Database was queried for patients with cancers of the pancreas, liver, and bile ducts between 2004 and 2017. Kaplan-Meier survival analysis and Cox regression were used to investigate the association between TTI and overall survival for each cancer type and stage. Multivariable regression identified factors associated with longer TTI. Results: Of 318,931 patients with HPB cancers, median TTI was 31 days. Longer TTI was associated with increased mortality in patients with stages I-III extrahepatic bile duct (EHBD) cancer and stages I-II pancreatic adenocarcinoma. Patients treated within 3-30, 31-60, and 61-90 days had median survivals of 51.5, 34.9, and 25.4 months (log-rank P<0.001), respectively, for stage I EHBD cancer, and 18.8, 16.6, and 15.2 months for stage I pancreatic cancer, respectively (P<0.001). Factors associated with increased TTI included stage I disease (+13.7 days vs. stage IV, P<0.001), treatment with radiation only (ß=+13.9 days, P<0.001), Black race (+4.6 days, P<0.001) and Hispanic ethnicity (+4.3 days, P<0.001). Conclusions: Some HPB cancer patients with longer time to definitive care experienced higher mortality than patients treated expeditiously, particularly in non-metastatic EHBD cancer. Black and Hispanic patients are at risk for delayed treatment. Further research into these associations is needed.