Approximately 7% of pancreatic cancers occur in patients with a germline mutation in
BRCA1
or
BRCA2
, an alteration that compromises DNA repair. In a randomized trial in patients with metastatic ...pancreatic cancer that had responded to platinum-based chemotherapy, progression-free survival was nearly twice as long with olaparib than with placebo (7.4 months vs. 3.8 months).
In this report, the addition of nab-paclitaxel to standard gemcitabine increased the response rate, progression-free survival, and overall survival among patients with metastatic pancreatic ...adenocarcinoma.
Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States.
1
,
2
Since 1997, gemcitabine therapy has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer.
3
Among patients with metastatic disease, the 5-year survival rate is only 2%,
1
and 1-year survival rates of 17 to 23% have been reported with gemcitabine.
3
–
5
Numerous phase 2 studies involving patients with advanced pancreatic cancer have shown promising results; however, most subsequent large phase 3 studies have not shown significantly improved survival,
6
–
16
with the exception of a study involving patients who . . .
Pancreatic adenocarcinoma is a rare tumor with a very poor outcome. Even with surgery, 5-year overall survival is less than 10%, due to the propensity of the disease for local and systemic ...recurrence. Adjuvant chemoradiotherapy and systemic chemotherapy were assessed in prospective trials in order to improve disease control and patients' prognosis. However, due to the difficulty of performing prospective trials in a rare disease; to the progress in surgical and radiotherapic techniques; and to the availability of novel anti-cancer agents, the existing information on the best possible management of patients with resectable disease is limited and becomes rapidly obsolete. Accordingly and also due to some contradictory findings from randomized trials, the topic of optimal adjuvant therapy for this disease encompasses several areas of controversy. The present review reports the main opinions on the role of adjuvant chemoradiotherapy, adjuvant chemotherapy, best single agent, and combination chemotherapy. Data from randomized trials are presented and critically analyzed to identify the available evidence supporting the different therapeutic choices and the main methodological drawbacks hampering the proper interpretation of results. Single agent chemotherapy yields a clinically significant, albeit modest, improvement in overall survival and may represent a standard option. The role of combination chemotherapy warrants further investigation and the impact of adjuvant chemoradiation both on local control and on the final outcome is uncertain. The need for more active and effective systemic treatments, for a better knowledge of the disease biology, for new therapeutic agents and predictors of pattern of recurrence is evident.
The investigator-assessed response rate was 14 (58%) of 24 (four each in B1, C1, and C2, and two in B2), median progression-free survival was 11·7 months (12·5 months for B1, 10·4 months for B2, 10·8 ...months for C1, and 12·4 months for C2), and median overall survival was 20·1 months (12·7 months for B1, 20·1 months for B2, 15·9 months for C1, and not evaluable for C2).1 The nab-paclitaxel plus gemcitabine combination, which constitutes the chemotherapy backbone of the O’Hara and colleagues trial, has yielded variable outcome figures across differently selected populations. ...the history of pancreatic ductal adenocarcinoma clinical research is paved with countless disappointing and resource-wasting failures of trials based on promising, hope-raising, preclinical or early clinical development findings that have been misinterpreted. ...the authors are extremely careful in interpreting the outcome data and acknowledge that this is beyond the scope of phase 1 trials.
The aim of this study is to provide a comprehensive characterization of stemness in pancreatic ductal adenocarcinoma (PDAC) cell lines. Seventeen cell lines were evaluated for the expression of ...cancer stem cell (CSC) markers. The two putative pancreatic CSC phenotypes were expressed heterogeneously ranging from 0 to 99.35% (median 3.46) for ESA+CD24+CD44+ and 0 to 1.94% (median 0.13) for CXCR4+CD133+. Cell lines were classified according to ESA+CD24+CD44+ expression as: Low-Stemness (LS; <5%, n = 9, median 0.31%); Medium-Stemness (MS; 6−20%, n = 4, median 12.4%); and High-Stemness (HS; >20%, n = 4, median 95.8%) cell lines. Higher degree of stemness was associated with in vivo tumorigenicity but not with in vitro growth kinetics, clonogenicity, and chemo-resistance. A wide characterization (chemokine receptors, factors involved in pancreatic organogenesis, markers of epithelial−mesenchymal transition, and secretome) revealed that the degree of stemness was associated with KRT19 and NKX2.2 mRNA expression, with CD49a and CA19.9/Tie2 protein expression, and with the secretion of VEGF, IL-7, IL-12p70, IL-6, CCL3, IL-10, and CXCL9. The expression of stem cell markers was also evaluated on primary tumor cells from 55 PDAC patients who underwent pancreatectomy with radical intent, revealing that CXCR4+/CD133+ and CD24+ cells, but not ESA+CD24+CD44+, are independent predictors of mortality.
Summary Background Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these ...treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. Methods We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0–1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days one cycle for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer’s EORTC QLQ-C30 version 3 and the EORTC Brain Cancer Module QLQ-BN20) and global cognitive functioning (assessed using the Mini-Mental State Examination MMSE). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov , number NCT00182819. Findings Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months’ follow-up (mean between group difference averaged over all timepoints 0·06, 95% CI −4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. Interpretation The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. Funding Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and ...prognostic/predictive factors in patients with mPAC.
Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors.
Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19-9 (CA 19-9) levels.
Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma (PDAC) receiving primary chemotherapy is an unmet need. The role of time to CA19-9 nadir ...and of nadir magnitude was explored in this study.
Patients and methods
The databases of our institution’s prospective trials were queried to speculate on the time to maximum chemotherapy response. Patients with pathologically proven, metastatic (
N
= 356) or non-metastatic non-resected (
N
= 163) PDAC and elevated baseline (> 34 UI/mL) CA19-9 were analyzed. Survival curves were estimated using the Kaplan–Meier method and compared by means of the log-rank test for analyses including at least 45 patients. Multivariable Cox proportional hazards model was used to estimate clinical features for their association with OS. All probability values were from two-sided tests.
Results
Time to CA19-9 nadir was ≥ 4 months in 184 of 346 (53%) metastatic and 121 of 163 (74%) non-metastatic patients (
p
= 0.002). The likelihood of a later nadir was higher with taxane-based chemotherapy as compared to taxane-free combinations (73% versus 56%;
p
= 0.02). Both metastatic and non-metastatic patients had significantly longer survival when nadir occurred later. Patients with a larger CA19-9 nadir magnitude had significantly longer survival. Metastatic patients with CA19-9 reduced by < 50%, 50–89%, or > 89% and had a median survival of 7.4, 9.8, and 14.7 months, respectively (
p
≤ 0.001 for all comparisons). The corresponding figures for non-metastatic patients were 10.6; 17.0; and 18.7 months, respectively (
p
≤ 0.02 for < 50% versus 50–89% or > 89%;
p
= 0.14 for 50–89% versus > 89%). Multivariable analyses showed that time to CA19-9 nadir but not CA19-9 nadir magnitude was independently predictive of survival.
Conclusion
The present study suggests that a 4–6 months program might be a more suitable candidate for prospective assessment in comparison to shorter pre-defined period in patients who are candidates to surgery after primary chemotherapy.
Background New therapies are needed for pancreatic cancer. Objective To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor ...growth measured with CT scan and to find the overall survival. Design A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. Setting San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. Patients A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. Intervention Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. Main Outcome Measurements Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. Results The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass ( P = .07). Limitations Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. Conclusion EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.
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