Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study.

PURPOSE: GEMPAX was an open-label, randomized phase III clinical trial designed to assess the efficacy and tolerability of gemcitabine plus paclitaxel versus gemcitabine alone as second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received 5-fluorouracil, oxaliplatin, and irinotecan. METHODS: Patients with histologically or cytologically confirmed mPDAC were randomly assigned (2:1) to receive GEMPAX (paclitaxel 80 mg/m2 + gemcitabine 1,000 mg/m2; IV; once at day (D) 1, D8, and D15/arm A) or gemcitabine (arm B) alone once at D1, D8, and D15 every 28 days until progression, toxicity, or patient's decision. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), quality of life, and safety. RESULTS: Overall, 211 patients (median age, 64 [30-86] years; 62% male) were included. After a median study follow-up for alive patients of 13.4 versus 13.8 months in arm A versus arm B, the median OS (95% CI) was 6.4 (5.2 to 7.4) versus 5.9 months (4.6 to 6.9; hazard ratio [HR], 0.87 [0.63 to 1.20]; P = 0.4095), the median PFS was 3.1 (2.2 to 4.3) versus 2.0 months (1.9 to 2.3; HR, 0.64 [0.47 to 0.89]; P = 0.0067), and the ORR was 17.1% (11.3 to 24.4) versus 4.2% (0.9 to 11.9; P = 0.008) in arm A versus arm B, respectively. Overall, 16.7% of patients in arm A and 2.9% in arm B discontinued their treatment because of adverse events (AEs). One grade 5 AE associated with both gemcitabine and paclitaxel was reported in arm A (acute respiratory distress), and 58.0% versus 27.1% of patients experienced grade ≥3 treatment-related AEs in arm A versus arm B, among which 15.2% versus 4.3% had anemia, 15.9% versus 15.7% had neutropenia, 19.6% versus 4.3% had thrombocytopenia, 10.1% versus 2.9% had asthenia and 12.3% versus 0.0% had neuropathy. CONCLUSION: While GEMPAX did not meet the primary end point of OS versus gemcitabine alone in patients with mPDAC in the second-line setting, both PFS and ORR were significantly improved.

Management and outcomes of brain metastases from pancreatic adenocarcinoma: a pooled analysis and literature review.

Background: Brain metastases (BM) are rare in pancreatic ductal adenocarcinoma (PDAC) and little data exists concerning these patients and their outcomes. Aim: We aimed to analyze the management, practices, and outcomes of patients presenting BM from PDAC both in our institution and in all cases reported in the literature. Methods: We conducted a retrospective, monocentric analysis using a data mining tool (ConSoRe) to identify all patients diagnosed with PDAC and BM in our comprehensive cancer center (Paoli-Calmettes Institute), from July 1997 to June 2022 (cohort 1). Simultaneously, we reviewed and pooled the case reports and case series of patients with PDAC and BM in the literature (cohort 2). The clinical characteristics of patients in each cohort were described and survival analyses were performed using the Kaplan-Meier method. Results: In cohort 1, 19 patients (0.3%) with PDAC and BM were identified with a median age of 69 years (range: 39-81). Most patients had metastatic disease (74%), including 21% with BM, at diagnosis. Lung metastases were present in 58% of patients. 68% of patients had neurological symptoms and 68% were treated by focal treatment (surgery: 21%, radiotherapy: 42%, Gamma Knife radiosurgery: 5%). In cohort 2, among the 61 PDAC patients with BM described in the literature, 59% had metastatic disease, including 13% with BM at diagnosis. Lung metastases were present in 36% of patient and BM treatments included: surgery (36%), radiotherapy (36%), radiosurgery (3%), or no local treatment (25%). After the pancreatic cancer diagnosis, the median time to develop BM was 7.8 months (range: 0.0-73.9) in cohort 1 and 17.0 months (range: 0.0-64.0) in cohort 2. Median overall survival (OS) in patients of cohort 1 and cohort 2 was 2.9 months (95% CI [1.7,4.0]) and 12.5 months (95% CI [7.5,17.5]), respectively. Conclusion: BM are very uncommon in PDAC and seem to occur more often in younger patients with lung metastases and more indolent disease. BM are associated with poor prognosis and neurosurgery offers the best outcomes and should be considered when feasible.

Advance Approval of Outpatient Chemotherapy via Phone Call Optimizes Healthcare Delivery without Compromising Patient Satisfaction with Care.

Patient satisfaction is linked to the amount of time spent with the physician. At the same time, long waiting times in hospitals are a major source of patient dissatisfaction. The aim of this study was to determine whether advance approval of outpatient chemotherapy (CT) via phone call can optimize healthcare delivery without compromising patient satisfaction with care. Between 2013 and 2016, 343 patients with breast/gynecological cancer scheduled to undergo CT on day 8 and/or day 15 of the CT cycle were enrolled in a before-after study conducted in a French comprehensive cancer center. In the control group, 168 patients received a face-to-face consultation with an oncologist on the day of CT for approval of the upcoming CT session. In the intervention group, 175 patients received a phone call from a healthcare provider the day before CT, where assessment of toxicity from the previous CT session was recorded and submitted to an oncologist for approval of the upcoming CT session. At the end of the 6th CT cycle, patient satisfaction was evaluated using EORTC IN-PATSAT32. A total of 233 questionnaires were analyzed (response rate: 77.7%). Satisfaction with care was similar between the two groups. No differences in perceived health status were observed, but self-reported time in hospital was lower in the intervention group than in the control group (p = 0.007). Advance approval of outpatient CT via phone call is feasible and particularly relevant in the current context of immunotherapy development.

Outcomes of patients with initially locally advanced pancreatic adenocarcinoma who did not benefit from resection: a prospective cohort study.

BACKGROUND: The current study aimed to evaluate the outcomes of patients with unresectable non-metastatic locally advanced pancreatic adenocarcinoma (LAPA) who did not benefit from resection considering the treatment strategy in the clinical settings. METHODS: Between 2010 and 2017, a total of 234 patients underwent induction chemotherapy for LAPA that could not be treated with surgery. After oncologic restaging, continuous chemotherapy or chemoradiation (CRT) was decided for patients without metastatic disease. The Kaplan-Meier method was used to determine overall survival (OS), and the Wilcoxon test to compare survival curves. Multivariate analysis was performed using the stepwise logistic regression method. RESULTS: FOLFIRINOX was the most common induction regimen (168 patients, 72%), with a median of 6 chemotherapy cycles and resulted in higher OS, compared to gemcitabine (19 vs. 16 months, hazard ratio (HR) = 1.2, 95% confidence interval: 0.86-1.6, P = .03). However, no difference was observed after adjusting for age (≤75 years) and performance status score (0-1). At restaging, 187 patients (80%) had non-metastatic disease: CRT was administered to 126 patients (67%) while chemotherapy was continued in 61 (33%). Patients who received CRT had characteristics comparable to those who continued with chemotherapy, with similar OS. They also had longer progression-free survival (median 13.3 vs. 9.6 months, HR = 1.38, 95% confidence interval: 1-1.9, P < .01) and limited short-term treatment-related toxicity. CONCLUSIONS: The median survival of patients who could not undergo surgery was 19 months. Hence, CRT should not be eliminated as a treatment option and may be useful as a part of optimised sequential chemotherapy for both local and metastatic disease.

Palliative endoscopic drainage of malignant stenosis of biliary confluence: Efficiency of multiple drainage approach to drain a maximum of liver segments.

Background and aim: More than 50% of the liver should be drained in case of unresectable hilar liver stenosis; however, it remains unclear if the use of several types of drainage (endoscopic retrograde cholangiography and pancreatography, percutaneous-biliary drainage, endoscopic ultrasound biliary drainage (EUS-BD)), allowing better drainage, has an impact on survival. The aim of our study was to evaluate the percentage of liver drained and its correlation on survival whatever the drainage technique used. Patients and methods: This study was a retrospective analysis of a prospective registry of patients with malignant drainage stenosis of the hilum. The quality of drainage was evaluated based on the percentage of liver segments drained, which was calculated by dividing the number of liver segments drained by the total number of liver segments. Drainage could be achieved via an endoscopic, EUS-guided or percutaneous route not associated with the procedure. Results: Sixty patients (38 men) were included from January 2015 to July 2016. The mean patient age was 69.84 years. Stenosis was classified as type II for 17 (29%) patients, type III for 20 (34%) patients, and type IV for 22 (37%) patients. Histology revealed cholangiocarcinoma for 26 (43%) patients, metastatic disease from colorectal cancer for 15 (25%) patients and another cancer for 19 (32%) patients. The median survival time was five (2.3-12.3) months.The percentage of liver segments drained had a significant prognostic impact on overall survival regardless of the technique used to drain the liver. The percentage of liver segments drained was dichotomized based on a threshold value of 80%, resulting in two groups (<80% and ≥80%). Univariate analysis of overall survival revealed that the patients with <80% of liver segments drained had significantly worse prognoses (hazard ratio (HR) = 3.25 (1.66-6.36), p < 0.001) than the patients with ≥80% of liver segments drained. This effect was confirmed in multivariate analysis (HR = 2.46 (1.16-5.23), p = 0.02).The other factor that affected survival was invasion of <50% of the liver by the tumor.A receiver operating characteristic curve was used to establish a correlation between patients receiving chemotherapy and the percentage of liver drained (area under the curve = 0.77 (0.65-0.88)). Conclusion: The survival of patients with malignant stenosis of the biliary confluence is highly correlated with the percentage of liver segments drained, regardless of the technique used.

METRO1: A Phase I Study of Metronomic Chemotherapy in Adults with Advanced Refractory Solid Tumors.

BACKGROUND: The present monocentric and prospective phase 1 study evaluated the safety of a metronomic chemotherapy in refractory tumors. PATIENTS AND METHODS: Patients with advanced solid cancer refractory to standard therapy received a combination of low-dose vinorelbine, cyclophosphamide and interferon-alpha. A dose escalation model with 3 levels was planned. The primary end-point was safety and tolerability, secondary end-points were treatment continuation rate at 4 months, progression-free survival (PFS), overall survival (OS), radiological assessment (MRI) of anti-angiogenic effect. RESULTS: Thirty patients were enrolled. No dose-limiting toxicity was observed. All but two adverse events were toxicities of grade 1-2. Treatment continuation rate at 4 months was 6.67% (2 out of 30 patients). Median PFS and OS were 1.6 and 6.1 months. Exploratory MRI analyses related to anti-angiogenic effect did not show any relevant modification. CONCLUSION: This combination of metronomic chemotherapy is well-tolerated and deserves to be deeply explored in refractory solid tumors.

Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib.

BACKGROUND: Breast cancer stem cells (BCSCs) have been recognized as playing a major role in various aspects of breast cancer biology. To identify specific biomarkers of BCSCs, we have performed comparative proteomics of BCSC-enriched and mature cancer cell populations from the human breast cancer cell line (BCL), BrCA-MZ-01. METHODS: ALDEFLUOR assay was used to sort BCSC-enriched (ALDH+) and mature cancer (ALDH-) cell populations. Total proteins were extracted from both fractions and subjected to 2-Dimensional Difference In-Gel Electrophoresis (2-D DIGE). Differentially-expressed spots were excised and proteins were gel-extracted, digested and identified using MALDI-TOF MS. RESULTS: 2-D DIGE identified poly(ADP-ribose) polymerase 1 (PARP1) as overexpressed in ALDH+ cells from BrCA-MZ-01. This observation was confirmed by western blot and extended to four additional human BCLs. ALDH+ cells from BRCA1-mutated HCC1937, which had the highest level of PARP1 overexpression, displayed resistance to olaparib, a specific PARP1 inhibitor. CONCLUSION: An unbiased proteomic approach identified PARP1 as upregulated in ALDH+, BCSC-enriched cells from various human BCLs, which may contribute to clinical resistance to PARP inhibitors.

[Exemestane-everolimus in HER2-negative, hormonal receptor-positive, post-menopausal metastatic breast cancer with resistance to non-steroidal aromatase inhibitor: a new option]. / Exémestane-évérolimus dans les cancers du sein métastatiques de la femme ménopausée, HER2-négatifs, exprimant les récepteurs hormonaux et résistants aux inhibiteurs de l'aromatase non stéroïdiens: une nouvelle option thérapeutique.

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is commonly deregulated in breast cancer and has been involved in resistance to endocrine therapy. In the BOLERO-2 study, the addition of everolimus, a selective inhibitor of mTOR protein, to exemestane was associated with a significant improvement in progression-free survival, compared to exemestane plus placebo, in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and resistant to non-steroidal aromatase inhibitor therapy. However, adverse events and treatment stops were more often observed with the combination therapy, suggesting the need for a careful benefit/risk evaluation before initiating this new combination. This review aims at synthesizing the biological basis of the everolimus-exemestane association, presenting the main validated and ongoing therapeutic trials, interests and limits, as well as the multiple potential therapeutic perspectives.

Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review.

BACKGROUND: Chordomas are very rare low-grade malignant bone tumors that arise from the embryonic rests of the notochord. They are characterized by slow growth and long history with frequent local relapses, and sometimes metastases. While chemotherapy is not efficient, imatinib has shown antitumor activity. CASE PRESENTATION: We report on a 76-year-old patient with EGFR-overexpressing advanced chordoma that progressed on imatinib and subsequently responded to erlotinib during 12 months. CONCLUSIONS: We report the fourth case of advanced chordoma treated with an EGFR inhibitor. We also review the literature concerning the rationale and potential of EGFR targeting in chordoma.