Background
Stereotactic body radiation therapy (SBRT) is a promising option for patients with pancreatic cancer (PCA); however, limited data support its efficacy. This study reviews our institutional ...experience of SBRT in the treatment of locally advanced (LAPC) and borderline resectable (BRPC) PCA.
Methods
Charts of all PCA patients receiving SBRT at our institution from 2010 to 2014 were reviewed. Most patients received pre-SBRT chemotherapy. Primary endpoints included overall survival (OS) and local progression-free survival (LPFS). Patients received a total dose of 25–33 Gy in five fractions.
Results
A total of 88 patients were included in the analysis, 74 with LAPC and 14 with BRPC. The median age at diagnosis was 67.2 years, and median follow-up from date of diagnosis for LAPC and BRPC patients was 14.5 and 10.3 months, respectively. Median OS from date of diagnosis was 18.4 months (LAPC, 18.4 mo; BRPC, 14.4 mo) and median PFS was 9.8 months (95 % CI 8.0–12.3). Acute toxicity was minimal with only three patients (3.4 %) experiencing acute grade ≥3 toxicity. Late grade ≥2 gastrointestinal toxicity was seen in five patients (5.7 %). Of the 19 patients (21.6 %) who underwent surgery, 79 % were LAPC patients and 84 % had margin-negative resections.
Conclusions
Chemotherapy followed by SBRT in patients with LAPC and BRPC resulted in minimal acute and late toxicity. A large proportion of patients underwent surgical resection despite limited radiographic response to therapy. Further refinements in the integration of chemotherapy, SBRT, and surgery might offer additional advancements toward optimizing patient outcomes.
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete ...αSMA+ myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4+Foxp3+ Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.
•Depletion of myofibroblasts in mouse pancreas cancer led to invasive tumors•Decreases in fibrosis and myofibroblasts led to enhanced EMT and cancer stem cells•Fewer myofibroblasts in tumors are associated with poor survival in mice and patients•Immunotherapy combined with loss of myofibroblasts prolongs survival
In contrast to current thinking, Özdemir et al. show that low myofibroblast proportions in human pancreatic ductal adenocarcinoma (PDAC) are associated with reduced patient survival, and ablation of myofibroblasts in the mouse pancreas promotes PDAC aggressiveness but does not improve the therapeutic effect of gemcitabine.
Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including ...endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158.
Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety.
As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up; N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events).
Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer.
Abstract Background Pivotal clinical trials supported survival benefits of liposomal irinotecan (nal‐IRI) plus fluorouracil/leucovorin in patients with pancreatic ductal adenocarcinoma (PDAC) who ...previously received gemcitabine‐based therapy. There are concerns about the benefits of nal‐IRI in patients who received FOLFIRINOX (combined fluorouracil, leucovorin, IRI, and oxaliplatin) because of potential cross‐resistance to IRI. The objective of this meta‐analysis was to characterize the impact of the previous receipt of IRI on the outcomes of nal‐IRI regimens in patients with advanced PDAC. Methods Real‐world studies evaluating the outcomes of nal‐IRI in patients who had prior IRI exposure published up to April 2023 were searched using electronic databases. The meta‐analysis was conducted using a random effects model to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results Eight studies ( n = 1368 patients) were included. The pooled median progression‐free survival (PFS) was 2.02 months (95% CI, 1.43–2.57 months), and the median overall survival (OS) was 4.26 months (95% CI, 3.03–5.39 months). Patients with prior IRI exposure had PFS (HR, 1.17; 95% CI, 0.94–1.47; p = .17) and OS (HR, 1.16; 95% CI, 0.95–1.42; p = .16) comparable to patients without prior IRI exposure. Likewise, patients who had progressive disease on conventional IRI had PFS (HR, 1.50; 95% CI, 0.73–3.08; p = .24) and OS (HR, 1.70; 95% CI, 0.68–4.27; p = .26) with nal‐IRI comparable to patients who had no progressive disease. Conclusions Prior IRI exposure does not affect the survival outcomes of nal‐IRI regimens in patients who have advanced PDAC. The selection of later lines of chemotherapy regimens should be based on the differential safety profile, patient status, the cost of treatment, and health‐related quality of life.
In this meta‐analysis of real‐world evidence, the authors evaluated the outcomes of liposomal irinotecan in patients with advanced pancreatic ductal adenocarcinoma who had prior irinotecan exposure by using electronic databases. The results indicate that prior irinotecan exposure does not significantly affect the survival outcomes of patients who receive regimens containing liposomal irinotecan.
The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma ...and Hh signalling.
Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib).
Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval CI: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment.
Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population.
ClinicalTrials.gov Identifier: NCT01088815.
Background
Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, ...whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells.
Methods
We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates.
Results
Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval CI, 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients.
Conclusions
GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.
Mismatch repair proficient colorectal cancer has been refractory to single‐agent programmed cell death protein 1 inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. In this single‐arm study, we find that GVAX/Cy plus pembrolizumab results in biochemical responses but not radiographic responses.
Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). ...Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX).
Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS).
The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA.
It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.
In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite ...instability−high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K).
Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score.
At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean 95% CI change, 3.07 0.19–5.94), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 6.36–15.35). Patients with CR/PR showed improvements in physical (5.58 1.91–9.25), role (9.88 3.80–15.97), emotional (5.62 1.56–9.68), and social (8.33 2.70–13.97) functioning, and stable cognitive functioning (1.74 −1.45 to 4.94).
Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours.
•Patients with previously treated MSI-H/dMMR cancer received pembrolizumab treatment.•Treatment was associated with improved QLQ-C30 GHS/QoL from baseline to week 9.•Improvements were greatest among patients with a complete or partial response.•Pembrolizumab improved or preserved QoL in previously treated MSI-H/dMMR cancer.
Abstract Background Pancreatic ductal adenocarcinoma (PDA) is comprised of a prominent desmoplastic stromal compartment and only 10–40% of the tumour consists of PDA cells. However, how stromal ...components should be assessed and how the characteristics of the stromal compartment determine clinical outcomes in PDA patients remain unknown. Method A cohort of 66 consecutive patients who underwent pancreaticoduodenectomy and were primarily followed at Johns Hopkins Hospital between 1998 and 2004, and treated with adjuvant therapy, were included in a retrospective analysis. Resected PDA blocks with good tissue preservation were available for all patients. A new, computer-aided, quantitative method was developed to assess the density and activity of stroma in PDAs and the associations of these characteristics with clinical outcomes. Results High stromal density in resected PDA was found to be significantly associated with longer disease-free adjusted hazard ratio (aHR) 0.39; P = 0.001 and overall (aHR 0.44; P = 0.004) survival after adjusting for the use of pancreatic cancer vaccine therapy, as well as gender and resection margin positivity. Stromal activity, representing activated pancreatic stellate cells in PDAs, was not significantly associated with the prognosis of resected PDAs. Conclusions These results illustrate the complexity of the role of stroma in PDAs. Further exploration of the prognostic ability of the characteristics of stroma is warranted.
Background
Patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body ...radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT).
Methods
Patients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes.
Results
Of 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%;
p
< 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months;
p
= 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%;
p
< 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%;
p
< 0.001), negative nodes (59% vs 42%;
p
< 0.001), and pathologic complete response (7% vs 0%;
p
= 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (
p
< 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (
p
= 0.81).
Conclusions
Despite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.
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