OBJECTIVE:The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma ...(PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients.
BACKGROUND:Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging.
METHODS:Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected.
RESULTS:Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR49%, LA51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9 >100 U/mL and >8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index >1, preoperative CA 19-9 >100 U/mL and tumor size (>3.0 cm on CT or >2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS29.1 vs 13.7, P < 0.001; OS37.7 vs 25.1 months from diagnosis, P = 0.01).
CONCLUSION:BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.
ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict ...treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer.
A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response.
A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR,
< 0.0001) and clinical benefit CB: PR and stable disease (SD),
< 0.0001. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (
< 0.0001). Four-week change in tumor markers also predicted response (
= 0.0026) and CB (
= 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (
= 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00;
< 0.0001).
Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.
On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to ...evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy.
Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon.
Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX.
After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.
During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient
. Previous case reports and small case ...series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance
. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require ...tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.
A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.
Of 103 patients, 84 stage I (9.5%), II (23.8%), III (47.6%), IV (19%) had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (
= 39) or completion of adjuvant therapy (
= 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred positive predictive value (PPV), 100%; HR, 11.28 (
< 0.0001). Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence HR, 1.84 (
= 0.18); PPV = 53.9%.
Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
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The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression‐free survival, and safety/toxicity of neoadjuvant FOLFIRINOX ...(5‐fluorouracil 5‐FU, oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty‐two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression‐free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty‐two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.
This retrospective institutional experience from the Massachusetts General Hospital Cancer Center reports the overall response rate, R0 resection rate, progression‐free survival, and safety/toxicity of neoadjuvant FOLFIRINOX and chemoradiation in patients with locally advanced pancreatic cancer. FOLFIRINOX demonstrated substantial activity in patients with LAPC, although recurrences after resection and toxicities raise important questions about how to best treat these patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).
In this single-arm, phase II, ...multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC.
Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC.
High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.
Patients who undergo an R0 resection of their pancreatic ductal adenocarcinoma (PDAC) have an improved survival compared with patients who undergo an R1 resection. It is unclear whether an R1 ...resection confers a survival benefit over locally advanced (LA) unresectable tumors. Our aim was to compare the survival of patients undergoing an R1 resection with those having LA tumors and to explore the prognostic significance of a 1-mm surgical margin.
Clinicopathologic data from a pancreatic cancer database between January 1993 and July 2008 were reviewed. Locally advanced tumors had no evidence of metastatic disease at exploration.
A total of 1705 patients were evaluated for PDAC in the Department of Surgery. Of the 1084 (64%) patients who were surgically explored, 530 (49%) were considered unresectable (286 locally unresectable, 244 with distant metastasis). One hundred fifty-seven (28%) of the resected PDACs had an R1 resection. Patients undergoing an R1 resection had a slightly longer survival compared with those who had locally advanced unresectable cancers (14 vs 11 months; P < 0.001). Patients with R0 resections had a favorable survival compared with those with R1 resections (23 vs 14 months; P < 0.001), but survival after resections with 1-mm margin or less (R0-close) were similar to R1 resections: both groups had a significantly shorter median survival than patients with a margin of greater than 1 mm (R0-wide) (16 vs 14 vs 35 months, respectively; P < 0.001).
Patients undergoing an R1 resection still have an improved survival compared with patients with locally advanced unresectable pancreatic adenocarcinoma. R0 resections have an improved survival compared with R1 resections, but this survival benefit is lost when the tumor is within 1 mm of the resection margin.
Ablative radiation therapy is increasingly being used for hepatocellular carcinoma (HCC) resulting in excellent local control rates; however, patients without evidence of disease progression often ...die from liver failure. The clinical benefit of proton- over photon-based radiation therapy is unclear. We therefore sought to compare clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC.
This is a single-institution retrospective study of patients treated during 2008 to 2017 with nonmetastatic, unresectable HCC not previously treated with liver-directed radiation therapy and who did not receive further liver-directed radiation therapy within 12 months after completion of index treatment. The primary outcome, overall survival (OS), was assessed using Cox regression. Secondary endpoints included incidence of non-classic radiation-induced liver disease (defined as increase in baseline Child-Pugh score by ≥2 points at 3 months posttreatment), assessed using logistic regression, and locoregional recurrence, assessed using Fine-Gray regression for competing risks. All outcomes were measured from radiation start date.
The median follow-up was 14 months. Of 133 patients with median age 68 years and 75% male, 49 (37%) were treated with proton radiation therapy. Proton radiation therapy was associated with improved OS (adjusted hazard ratio, 0.47; P = .008; 95% confidence interval CI, 0.27-0.82). The median OS for proton and photon patients was 31 and 14 months, respectively, and the 24-month OS for proton and photon patients was 59.1% and 28.6%, respectively. Proton radiation therapy was also associated with a decreased risk of non-classic radiation-induced liver disease (odds ratio, 0.26; P = .03; 95% CI, 0.08-0.86). Development of nonclassic RILD at 3 months was associated with worse OS (adjusted hazard ratio, 3.83; P < .001; 95% CI, 2.12-6.92). There was no difference in locoregional recurrence, including local failure, between protons and photons.
Proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. Our findings support prospective investigations comparing proton versus photon ablative radiation therapy for HCC.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
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