Active recruitment
After the evaluation by the oncologist of the multidisciplinary team, patients surgically treated for IEN receive a Hospital Discharge Report including an appointment to discuss the trial and, when possible, the alternative options. Unaffected subjects carrying a mutation of BRCA1 or with high probability of BRCA1/2 mutation on the basis of the geneticist evaluation are contacted by the staff of the Division of Cancer Prevention and Genetics for a first phone interview and the check of all inclusion criteria. The trial design is explained and willingness to participate is asked. Candidates accepting to participate or interested in the study are invited for a clinic visit at the European Institute of Oncology (EIO) or the Department of Oncology & Haematology of the University of Modena and Reggio Emilia for informed consent and baseline visit.
Treatment groups
Patients who signed an informed consent and who met the eligibility criteria are randomly assigned to one of three groups for 12 months of treatment, as follows.
Group 1: nimesulide 100 mg/day, administered per os and on full stomach. A single oral dose of 100 mg of nimesulide suppresses COX-2 activity by 90% in both in vitro and ex vivo assays and, at a much lesser extent, COX-1 activity with a 20-fold selectivity for the former isoenzyme [
23]. This dose is half the standard dose to obtain a faster effect on pain control and inflammation, but it may represent an active and safer dose for testing the chemopreventive efficacy of nimesulide. Moreover, this dose is able to reach a plasma concentration of 2–4 μg/ml [
23], which is more than 10 times the IC
50 necessary for the inhibition of COX-2 activity in blood assays, whereas it is five times lower than the IC
50 for COX-1 inhibition [
24]. Therefore, 100 mg/day appears a reasonable dose for chemopreventive purposes implying prolonged administration.
On May 15, 2007 the Irish Medicines Board (IMB) decided to suspend nimesulide from the Irish market and refer it to the EU Committee for Human Medicinal Products (CHMP) for a review of its benefit/risk profile. The decision was due to the reporting of six cases of potentially related liver failures to the IMB by the National Liver Transplant Unit, St Vincent Hospital. These cases occurred in the period from 1999 to 2006. On September 21, 2007 the EMA released a press release on their review on the liver-related safety of nimesulide. The EMA concluded that the benefits of these medicines outweigh their risks, but that there was a need to limit the duration of use to ensure the risk of patients developing liver problems is kept to a minimum. Therefore the EMA has limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, released officially on October 10, 2007 which recommended the maintenance of the study according to the present design, we are now performing an even more careful monitoring of the study participants and we are carrying out a systematic check of the possible side effects, both in those who are receiving treatment and in those who have finished. We have modified the Inform consent and we have informed all the participants accordingly.
Group 2: simvastatin 20 mg/day. The most important adverse events associated with statins are asymptomatic increases in liver transaminases, and myopathy. Myopathy and its serious complication, rhabdomyolysis, are potential side effects of therapy with the available statins, but occur very rarely. The molecular and biochemical mechanisms of myopathy and rhabdomyolysis caused by statins are yet to be fully elucidated [
25]. However, a compilation of all randomized statin trials revealed that among 83,858 patients randomly assigned to receive either statin treatment or placebo, there were only 49 cases of myositis and 7 cases of rhabdomyolysis in the statin groups, compared with 44 cases of myositis and 5 cases of rhabdomyolysis in the placebo groups [
26].
Group 3: placebo. An identical appearing tablet containing placebo is taken daily by participants assigned to the placebo group.
Toxicity is evaluated at each visit using the NCI toxicity criteria (CTCAE version 3.0, published 12/12/03). Any use of systemic drugs is clearly documented (time, doses, routes, and indications) and strictly followed by the physician. All medications (prescription and over-the counter), vitamin and mineral supplements, and/or herbs taken by the participant are documented on the concomitant medication CRF and included: start and stop date, dose and route of administration, and indication for use. Medications taken for a procedure (e.g., biopsy) are included. Patients are discouraged from taking unspecified medications.