Near Complete Pathologic Response to PD-1 Inhibitor and Radiotherapy in a Patient with Locally Advanced Pancreatic Ductal Adenocarcinoma.
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SUBMITTER: McCarthy PM
PROVIDER: S-EPMC8179799 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is considered a non-immunogenic tumor, and immune checkpoint inhibitor monotherapy lacks efficacy in this disease. Radiotherapy (RT) can stimulate the immune system. Here, we show that treatment of KPC and Pan02 murine PDAC cells with RT and gemcitabine upregulated PD-L1 expression in a JAK/Stat1-dependent manner. In vitro, PD-L1 inhibition did not alter radio- and chemosensitivity. In vivo, addition of anti-PD-L1 to high (12, 5 × 3, 20 Gy) but not low (6, 5 × 2 Gy) RT doses significantly improved tumor response in KPC and Pan02 allografts. Radiosensitization after PD-L1 blockade was associated with reduced CD11b+Gr1+ myeloid cell infiltration and enhanced CD45+CD8+ T-cell infiltration with concomitant upregulation of T-cell activation markers including CD69, CD44, and FasL, and increased CD8:Treg ratio. Depletion of CD8+ T cells abrogated radiosensitization by anti-PD-L1. Blockade of PD-L1 further augmented the effect of high RT doses (12 Gy) in preventing development of liver metastases. Exploring multiple mathematical models reveals a mechanism able to explain the observed synergy between RT and anti-PD-L1 therapy. Our findings provide a rationale for testing the use of immune checkpoint inhibitors with RT in PDAC.
| S-EPMC5286375 | biostudies-literature
Project description:The prognostic role of serum LDH, CA19-9, CRP and ALB in PDAC patients are controversial. In contrast to single factor, there is much less information about the prognostic value of the combination of the four factors in locally advanced and metastatic PDAC patients. It's essential to set up a survival model with the combination of tumor metabolism, tumor biomarker, systemic inflammation and nutritional status to eliminate the prognostic inaccuracy in single biomarker. 94 advanced PDAC patients who received palliative chemotherapy from 2009 to 2017 were recruited for this study. The predictive value of pretreatment serum LDH, CA19-9, CRP and ALB levels for OS were evaluated, and the same as combination of the four factors. It was confirmed that serum LDH, CA19-9, CRP and ALB levels were independent prognostic factors for OS by multivariate analyses. The results of Kaplan-Meier analyses revealed that serum LDH, CA19-9, CRP, ALB levels as well as the combination of the four factors were correlated with OS. It's concluded that the combination of the pretreatment serum LDH, CA19-9, CRP and ALB levels is a prognostic factor for advanced PDAC patients.
| S-EPMC5907678 | biostudies-literature
Project description:BackgroundRecent advances in chemotherapy and chemoradiotherapy have enabled conversion surgery (CS) to be performed for selected patients with initially unresectable locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Many studies indicate CS might extend the survival of patients with initially unresectable LA PDAC. However, several clinical questions concerning CS remain, such as the optimal preoperative treatment. Carbon-ion radiotherapy (CIRT) is a unique radiotherapy that offers higher biological effectiveness than conventional radiotherapy. Here, we report a long-term survival case with initially unresectable LA PDAC who underwent CS after chemotherapy followed by CIRT.Case presentationThe patient was a 72-year-old Japanese woman with unresectable LA pancreatic head cancer with tumor contact to the superior mesenteric artery (SMA). She underwent four courses of chemotherapy (gemcitabine plus nanoparticle albumin-bound paclitaxel). However, the lesion did not shrink and tumor contact with the SMA did not improve after chemotherapy. Because the probability of achieving curative resection was judged to be low, she underwent radical dose CIRT, and chemotherapy was continued. She complained of vomiting 2 months after CIRT. Although imaging studies showed no tumor growth or metastasis, a duodenal obstruction which was speculated to be an adverse effect of CIRT was observed. She could not eat solid food and a trans-nasal feeding tube was inserted. Therapeutic intervention was required to enable enteral nutrition. We proposed several treatment options. She chose resection with the expectation of an anti-tumor effect of chemotherapy and CIRT rather than course observation with tube feeding or bypass surgery. Therefore, subtotal-stomach-preserving pancreatoduodenectomy with portal vein resection was performed as CS. Pathological examination of the resected specimen revealed an R0 resection with a histological response of Evans grade IIA. Postoperatively, she recovered uneventfully. Adjuvant chemotherapy with tegafur/gimeracil/oteracil (S1) was administrated. At the time of this report, 5 years have passed since the initial consultation and she has experienced no tumor recurrence.ConclusionsThe present case suggests that multidisciplinary treatment consisting of a combination of recent chemotherapy and CIRT may be beneficial for unresectable LA PDAC. However, further studies are required to assess the true efficacy of this treatment strategy.
| S-EPMC10782725 | biostudies-literature
Project description:ImportanceChemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat basis are poorly understood.ObjectiveTo investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy.Design, setting, and participantsThis prospective study took place in a national referral center for pancreatic diseases in Italy. Consecutive patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma were enrolled at the time of diagnosis (January 2013 through December 2015) and followed up to June 2018.ExposuresThe chemotherapy regimen, assigned based on multidisciplinary evaluation, was delivered either at a hub center or at spoke centers. By convention, primary chemotherapy was considered completed after 6 months. After restaging, surgical candidates were selected based on radiologic and biochemical response. All surgeries were carried out at the hub center.Main outcomes and measuresRates of receipt and completion of chemotherapy, rates of conversion to surgery, and disease-specific survival.ResultsOf 680 patients, 267 (39.3%) had borderline resectable and 413 (60.7%) had locally advanced pancreatic ductal adenocarcinoma. Overall, 66 patients (9.7%) were lost to follow-up. The rate of chemotherapy receipt was 92.9% (n = 570). The chemotherapeutic regimens most commonly used included FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) (260 [45.6%]) and gemcitabine plus nanoparticle albumin-bound-paclitaxel (123 [21.6%]). Nineteen patients (3.3%) receiving chemotherapy died within 6 months, mainly for disease progression. The treatment completion rate was 71.6% (408 of 570). The overall rate of resection was 15.1% (93 of 614) (borderline resectable, 60 of 249 [24.1%]; locally advanced, 33 of 365 [9%]; resection:exploration ratio, 63.3%). Independent predictors of resection were age, borderline resectable disease, chemotherapy completion, radiologic response, and biochemical response. The median survival for the whole cohort was 12.8 (95% CI, 11.7-13.9) months. Factors independently associated with survival were completion of chemotherapy, receipt of complementary radiation therapy, and resection. In patients who underwent resection, the median survival was 35.4 (95% CI, 27.0-43.7) months for initially borderline resectable and 41.8 (95% CI, 27.5-56.1) months for initially locally advanced disease. No pretreatment and posttreatment factors were associated with survival after pancreatectomy.Conclusions and relevanceThis pragmatic observational cohort study with an intention-to-treat design provides real-world evidence of outcomes associated with the most current primary chemotherapy regimens used for borderline resectable and locally advanced pancreatic ductal adenocarcinoma.
| S-EPMC6659151 | biostudies-literature
Project description:Globally, the death rate of pancreatic ductal adenocarcinoma (PDAC) has doubled over 30 years and is likely to further increase, making PDAC a leading cause of cancer-related death in the coming years. PDAC is typically diagnosed at an advanced stage, and modified FOLFIRINOX or nab-paclitaxel and gemcitabine are the mainstay of systemic therapy. For elderly patients with good performance status, low-dose treatment can preserve quality of life without compromising cancer control or survival. Maintenance therapy should be considered in PDAC patients achieving disease control with systemic therapy. In particular, olaparib has demonstrated a progression-free survival benefit of 3.6 months in a subgroup of PDAC patients with germline BRCA1/2 mutations (ca. 10% of all PDAC). Pancreatic enzyme replacement therapy is often omitted in the treatment of patients with PDAC, with possibly deleterious consequences. Small intestinal bacterial overgrowth is highly prevalent in patients with PDAC and should be considered in the diagnostic algorithm of PDAC patients with bloating and diarrhea. Rivaroxaban has been associated with a reduced risk of thrombosis without an increase in major bleeding events, and its use should be considered in every patient with advanced PDAC undergoing systemic therapy.
| S-EPMC7409054 | biostudies-literature
Project description:ObjectiveTo evaluate whether pCR exclusively defines major pathologic response to treatment with improved survival.Summary background datapCR after trimodality therapy for EAC is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint.MethodsWe analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adeno-carcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage TR in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis.ResultsAmong 788 patients, median follow-up was 37.5 months (range, 0.4210.6); median OS was 48.3 months (95% CI, 42.2-58.8). Absence of residual nodal disease was independently associated with improved survival ( P < 0.001). Survival curves for 90% to 99% TR and 100% TR were similar, and a change in probability of improved OS was observed at 90% TR. On multivariable analysis, combining 90% to 99% and 100% TR was independently associated with improved OS, compared with 50% to 89% and <50% TR.ConclusionsypN0 status is the strongest indicator of major pathologic response to trimodality therapy, in addition to >90% TR in the primary tumor bed. These findings may allow the definition of major pathologic response to be expanded, from pCR to > 90% TR and ypN0. This has meaningful implications for future clinical trials and correlative studies.
| S-EPMC8126574 | biostudies-literature
Project description:ObjectivesPatients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX.MethodsAn institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated.ResultsThere were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4).ConclusionNearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.
| S-EPMC8933849 | biostudies-literature
Project description:Objective:We want to explore the safety and technical feasibility of MRI-guided stereotactic radiotherapy for locally advanced pancreatic cancer.Methods:A custom-made abdominal corset was manufactured to reduce breathing induced tumour motion. Delineation of the tumour and organs at risk (OARs) was performed on CT and multiparametric MRI. Tumour motion was quantified with cine MRI. After treatment planning, the static dose distribution was convolved with the cine MRI-based motion trajectory to simulate the delivered dose to the tumour and OARs. Stereotactic body radiation therapy (SBRT) was carried out up to a dose of 24 G in three fractions in 1 week.Results:From July 2013 to January 2016, 20 patients were included. Tumours and OARs were clearly visible with contrast-enhanced CT and MRI. After simulation of the delivered dose taking the motion into account, an adequate target coverage was achieved with acceptable dose in the OARs. No Grade3 or higher treatment related toxicity was observed.Conclusion:MRI-guided SBRT for pancreatic cancer is technical feasible and safe, with no treatment related grade ≥3 toxicity. New strategies are applied, including an individual corset to reduce breathing motion, MRI-based delineation and simulation of motion-integrated dose distributions.Advances in knowledge:This article is the first to describe an MRI-integrated workflow in SBRT for locally advanced pancreatic cancer. In addition, it demonstrated that SBRT with an abdominal corset to reduce tumour motion is feasible and safe.Trial registration:This trial was registered at www.clinicaltrials.gov (NCT01898741) on July 9, 2013.
| S-EPMC6475956 | biostudies-literature
Project description:At diagnosis, about 15% of patients with pancreatic cancer present with a resectable tumour, 50% have a metastatic tumour, and 35% a locally advanced tumour, non-metastatic but unresectable due to vascular invasion, or borderline resectable. Despite the technical progress made in the field of radiation therapy and the improvement of the efficacy of chemotherapy, the prognosis of these patients remains very poor. Recently, the role of radiation therapy in the management of pancreatic cancer has been much debated. This review aims to evaluate the role of radiation therapy for patients with locally advanced tumours.
| S-EPMC9327749 | biostudies-literature
Project description:IntroductionThe optimal dose and treatment modality of neoadjuvant radiotherapy applied for treating borderline resectable and locally advanced pancreatic ductal adenocarcinoma (PDAC) have been debated topics in oncology. The objective of the present network meta-analysis (NMA) is to study and compare the efficacy and safety of neoadjuvant radiotherapy comprehensively using different doses in patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC).Methods and analysisFour electronic databases, including PubMed, EMBASE, Cochrane library and Web of science, will be searched thoroughly to identify relevant studies published from 2006 to October 2020. Electronic searching by titles using neoadjuvant treatments for PDAC will be performed in the annual meetings of European Society of Medical Oncology and American Society of Clinical Oncology (2018-2020).Clinicaltrialsgov will also be searched for grey literature. Two reviewers will perform search strategies and extract data independently. R0 resection rate and local control rate are defined as primary outcomes. Secondary outcomes include overall survival, disease-free survival and acute and late grade 3 and grade 4 toxicities. For randomised control trials, the risk of bias will be assessed using the Cochrane Risk of Bias Tool, while the risk of bias for non-randomised, observational studies will be evaluated using the Risk Of Bias In Non-randomised Studies-of Interventions. The quality of evidence will be evaluated using the version of Cochrane tool and Grades of Recommendation, Assessment, Development and Evaluation. Subgroup analysis and sensitivity analysis will be conducted in the present NMA.Ethics and disseminationThis study will synthesise the evidence regarding dose schedule of neoadjuvant radiotherapy in patients with BRPC and LAPC. We hope the findings from this NMA will help clinicians and patients select the optimal modality and dose schedule of neoadjuvant radiotherapy with respect to patient-reported outcomes. As no primary data collection will be undertaken, no ethics approval is required. The results will be disseminated through peer-reviewed journal.Prospero registration numberCRD42020222408.
| S-EPMC9280870 | biostudies-literature