ABSTRACT
BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Pancreatic Neoplasms , Humans , Irinotecan/therapeutic use , Oxaliplatin/therapeutic use , Leucovorin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/surgery , Fluorouracil/therapeutic use , Neoadjuvant Therapy/methods , Chemotherapy, Adjuvant , Adjuvants, Immunologic/therapeutic use , Randomized Controlled Trials as Topic , Multicenter Studies as Topic , Pancreatic NeoplasmsABSTRACT
BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.
Subject(s)
Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/therapy , Health Plan Implementation , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Quality of Life , Adolescent , Adult , Aged , Aged, 80 and over , Biliary Tract Surgical Procedures , Carcinoma, Pancreatic Ductal/epidemiology , Child , Child, Preschool , Cluster Analysis , Drainage , Enzyme Replacement Therapy , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Multicenter Studies as Topic , Neoadjuvant Therapy , Netherlands/epidemiology , Palliative Care , Pancreatic Neoplasms/epidemiology , Pancreaticoduodenectomy , Patient Compliance , Randomized Controlled Trials as Topic , Stents , Treatment Outcome , Young AdultABSTRACT
This review examines transdermal drug delivery systems (TDS) and focuses on the specific side effects they can have on the skin and how these may be avoided. After a general overview of the structure of skin and its functions, an outline is given of how TDS are composed and how they operate. Upon basic treatment of relevant skin irritation and sensitization phenomena, techniques are described for monitoring them. Subsequently, various specific skin reactions are dealt with; these can be evoked by TDS on both short- and long-term application. Suggestions are then put forward for improving the skin compliance of TDS. For example, it is proposed that hydrogel patches may prove to be a useful alternative for current systems in that they are suitable for long-term applications, having minimal side effects because they are less occlusive.
Subject(s)
Administration, Cutaneous , Skin/metabolism , Animals , Humans , Skin Physiological PhenomenaABSTRACT
We have studied the skin irritation produced by the prolonged application of transdermal therapeutic systems. The systems were applied to the skin of the back of male volunteers for 120 hours, and sweat accumulation and bacterial growth were studied. In some cases hydrogel discs were attached to the systems. The results showed that sweat accumulation contributed more to the skin irritation than the bacterial overgrowth. The incorporation of hydrogels in the transdermal delivery system may help to reduce skin irritation by absorbing water.
Subject(s)
Delayed-Action Preparations/adverse effects , Erythema/etiology , Administration, Topical , Bacteria/growth & development , Erythema/microbiology , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate , Male , Polyethylene Glycols , Skin/microbiology , SweatABSTRACT
Thirty-five ophthalmological patients with symptoms of contact allergy due to external eye medication were examined with patch tests in the dermatological outpatient department. Attention is paid to sensitization due to antibiotics, in particular Neomycin.
Subject(s)
Anti-Bacterial Agents/adverse effects , Drug Hypersensitivity/diagnosis , Administration, Topical , Anti-Bacterial Agents/administration & dosage , Humans , Neomycin/administration & dosage , Neomycin/adverse effects , Ointments/adverse effects , Ophthalmic Solutions/adverse effects , Patch TestsABSTRACT
Regular observation of 16 patients with chronic skin diseases, treated twice daily with applications of Tibicorten for 2 to 14 weeks, showed that this treatment did not give rise to development of local side-effects. Even protracted local application of Tibicorten is tolerated excellently.
