Silvia Zanon

Central nervous system gliomas

Evidence-based practical guidelines on diagnosis, prognosis, and treatment on the most frequent adult brain tumours are delineated. In Europe, 27,000 new cases of malignant glial tumours and 1000 new cases of malignant ependymal tumours are diagnosed every year. The most common glial tumours are glioblastoma multiforme and anaplastic glioma, comprising more than 50% and 10%, respectively, of the total gliomas. Prognosis of gliomas is generally poor. Environmental and genetic factors have been correlated with an increased risk of developing brain tumours. Surgical resection represents the first treatment option for all histotypes. Role and timing of radiotherapy and chemotherapy as well as treatment for recurrent/progressive disease should be based on age, performance status, histopathological diagnosis, molecular markers, and previous therapy. Impaired neurocognitive and neuropsychological function is common in long-term survivors, regardless of the histology and grade of the tumour and should be taken into account in treatment planning.

Phase 1B trial of Nab-paclitaxel plus gemcitabine, capecitabine, and cisplatin (PAXG regimen) in patients with unresectable or borderline resectable pancreatic adenocarcinoma.

Background:Nab-paclitaxel–gemcitabine combination significantly improved overall survival over gemcitabine in metastatic pancreatic adenocarcinoma. A phase 1b trial was performed (ClinicalTrials.gov number, NCT01730222) to determine the recommended phase 2 dose (RP2D) of nab-paclitaxel in combination with cisplatin, capecitabine, and gemcitabine at fixed dose (800, 30, and 1250 mg m−2 every 2 weeks, respectively; PAXG regimen).Methods:Nab-paclitaxel doses were escalated from 100 (level one) to 125 (level two) and 150 mg m−2 (level three) every 2 weeks in cohorts of 3–6 patients with pathologically confirmed unresectable or borderline resectable pancreatic adenocarcinoma.Results:Between Dec 2012 and Apr 2014, 24 patients were enroled (3 at level one, 5 at level two, 16 at level three) and received 117 cycles of PAXG. No dose-limiting toxicity occurred and level three was the RP2D. At this dose, nab-paclitaxel dose-intensity was 91%. Worse per patient grade 3/4 toxicity were neutropenia 25/31%; fatigue 19%; anaemia and hand-foot syndrome 12%, nausea 6%, and febrile neutropenia 6%. A partial response (PR) was observed in 16 (67%) and stable disease (SD) in 8 patients (33%). Among 21 patients with a baseline positive positron emission tomography (PET) scan, a complete metabolic response was observed in 9 (43%), PR in 10 (48%), SD in 2. CA19-9 decreased by ⩾49% in all the 19 patients with elevated basal value. Six patients were resected after chemotherapy. Progression-free survival at 6 months (PFS-6) was 96%.Conclusions:The RP2D of nab-paclitaxel in the PAXG regimen was 150 mg m−2 every 2 weeks. The preliminary results are promising and warrant further exploration.

Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2–3 trial

BACKGROUND Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. METHODS We did this randomised, open-label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m2 on days 1, 8, 15 every 4 weeks for six cycles (arm A), surgery followed by six cycles of adjuvant PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 every 4 weeks and capecitabine 1250 mg/m2 on days 1-28; arm B), or three cycles of PEXG before and three cycles after surgery (arm C). Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary endpoint was the proportion of patients who were event-free at 1 year. The primary endpoint was analysed in the per-protocol population. Safety analysis was done for all patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, number NCT01150630. FINDINGS Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. INTERPRETATION Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. FUNDING PERLAVITA ONLUS and MyEverest ONLUS.

Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.

BACKGROUND Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. METHODS This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 and oral capecitabine 1250 mg/m2 on days 1-28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. FINDINGS Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. INTERPRETATION Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. FUNDING Celgene.

Biomarker-Driven and Molecularly Targeted Therapies for Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with few effective treatment options. Our knowledge of molecular alterations in PDAC has significantly grown and helped identify new therapeutic targets. The success of immune checkpoint inhibition in mismatch repair deficient tumors, PARP inhibitors for tumors with DNA repair defects, and targeting hyaluronan with PEGPH20 in patients with high expressing (hyaluronan-high) tumors are examples of promising biomarker-driven therapies. We review the major biological mechanisms in PDAC and discuss current and future directions for molecularly targeted therapies in this disease.

The personalized medicine for pancreatic ductal adenocarcinoma patients: The oncologist perspective

Over the past 15 years, therapeutic strategies have evolved toward a personalized approach, leading to significant clinical benefit in many tumors. Early diagnosis, progress in surgical and radiotherapy techniques and the availability of more effective chemotherapy agents, targeted therapies, and better management strategies leaded to longer survival in cancer patients, reducing mortality of at least 1%/year since the early 2000s.[1,2] Unfortunately, this was not the case for pancreatic cancer, which is still the malignant tumor with the highest mortality rate and remains one of the most challenging oncological issues. Furthermore, over the last decades, its incidence has progressively increased compared to the other tumors, and the estimated incidence curves show a further increase in the near future. Moreover, since no remarkable therapeutic improvements have been reported since the early 2000s, also its mortality rate has alarmingly grown.[3]