Rofecoxib In Patients Research Articles

Aspirin Therapy for Colorectal Cancer With PIK3CA Mutation: Simply Complex!

Prospective observational studies and randomized clinical trials have demonstrated that regular use of aspirin and selective cyclooxygense-2 (COX-2) inhibitors reduces the risk of developing colorectal cancer (CRC) and adenoma. More recently, large observational studies have suggested that regular aspirin use may also be associated with improved survival among patients with established CRC. The mechanisms by which aspirin influences CRC risk and possibly survival are poorly understood. COX-2 (or prostaglandinendoperoxide synthase 2 [PTGS2]) promotes inflammation and cell proliferation, and most adenomas and CRCs overexpress this enzyme. Previous studies have reported that aspirin may preferentially reduce the risk of COX-2–expressing CRC and also preferentially improve the survival of patients with CRC with COX-2–expressing tumors. Nonetheless, in laboratory models, aspirin seems to decrease proliferation and increase apoptosis in CRC cell lines without detectable COX activity. Ongoing studies have sought to define the molecular basis for the effect of aspirin on CRC risk and progression. In a large observational study of patients with CRC, Liao et al found that aspirin conferred improved survival in patients with PIK3CA-mutated CRC, but not among those with PIK3CA–wild-type tumors. In the report accompanying our article in Journal of Clinical Oncology, Domingo et al similarly observe a preferential benefit for aspirin in PIK3CA-mutated CRC in a large randomized trial of rofecoxib in patients with stage II/III CRC (VICTOR [Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime] trial), potentially moving us closer to clinical use of PIK3CA mutation as a predictive biomarker for aspirin use in patients with CRC. Here, we review some of the relevant complex relationships between aspirin, phosphatidylinositol 3-kinase (PI3K) signaling, and other cellular interactions.

Metronomic Cyclophosphamide and Vinblastine in Refractory Lymphoma

Full Abstract Introduction A recent phase I report drew attention to the effectiveness of metronomic (daily low-dose oral) CPA and I.V. vinblastine in refractory Hodgkin disease. 1 We used this combination in a patient with Hodgkin lymphoma and extensive prior treatment. The regimen was adapted to include rituximab for another patient who was unfit for R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab) therapy due to prior myocardial infarction. Case 1 A 56-year-old patient had first-line chemotherapy for Hodgkin lymphoma stage IVB in 2004, treated with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine). A year later a recurrence was treated with stem cell transplantation. He presented in February 2008 with extensive bone metastases, for which 45 Gy radiotherapy was given, also with curative intent. In April 2008 we started with metronomic chemotherapy (cyclophosphamide 50 mg + methylprednisolone 32 mg per day orally, vinblastine 3 mg/m 2 intravenously [I.V.] 1 × per week) for retroperitoneal lymph node recurrence. This treatment was well tolerated. After 9 months of treatment, there were no lymph nodes detectable on computed tomography scan. Complete remission now lasts > 3 months. Case 2 An 81-year-old farmer had a myocardial infarction 40 years ago. He presented with cutaneous involvement and axillary lymph node. Biopsy showed a cutaneous involvement by B-cell diffuse large-cell lymphoma. International Prognostic Index score was low. Ejection fraction was 42%. The same chemotherapy was applied (cyclophosphamide 50 mg/d and methylprednisolone 32 mg per day, vinblastine I.V. days 1, 8, 15), but on day 22 of the 28-day cycle, we applied rituximab 375 mg/m 2 . The patient had a complete remission after 4 months of treatment. Conclusion These data confirm the effectiveness of this well-tolerated regimen in refractory lymphoma as well as in a lymphoma patient unfit for anthracyclines. Reference Young S, Whissell M, Noble JC. Phase II clinical results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors. Clin Cancer Res 2006; 12; 3092-9.

An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ϵ4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.

A systematic review on the effectiveness of willow bark for musculoskeletal pain

Since ancient times preparations from Salix species have been used to alleviate pain. The aim of this study was to update the evidence of the effectiveness of willow bark products in the treatment of musculoskeletal pain. OVID(MEDLINE), PUBMED, Silverplatter, and CENTRAL and manual searches were used to identify clinical trials investigating Salix preparations. Authors SC and JEV extracted the data independently and discussed disagreements. Seven manuscripts were identified, reporting four trials with confirmatory and four with exploratory study designs. Three manuscripts presented the same trial data: repetitious reports were excluded. One confirmatory and two exploratory studies indicate a dose-dependent analgesic effect not inferior to rofecoxib in patients with low back pain. In one exploratory and one confirmatory study conflicting results were achieved in participants with osteoarthritis. No significant effect was seen in a confirmatory study in patients with rheumatoid arthritis, but this study was grossly underpowered. All studies investigated ethanolic extracts with daily doses up to 240 mg salicin over periods of up to six weeks. Minor adverse events occurred during treatment. The review provides moderate evidence of effectiveness for the use of ethanolic willow bark extract in low back pain. Further studies are required to find out if treatment of osteoarthritis and rheumatoid arthritis requires extract with higher doses than 240 mg salicin per day.

Rofecoxib in Patients with Mild Cognitive Impairment: Further Analyses of Data from a Randomized, Double-Blind, Trial

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Combination Therapy With Gefitinib and Rofecoxib in Patients With Platinum-Pretreated Relapsed Non–Small-Cell Lung Cancer

In non-small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45). Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33). Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea. Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs.

Cyclooxygenase-2 Inhibitors: A Painful Lesson

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.

Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors

Preclinical studies indicate that conventional chemotherapeutic agents given continuously at low doses (metronomic chemotherapy) may provide an improved therapeutic index. Cyclophosphamide and vinblastine have been best studied in experimental models, where tumor growth inhibition is achieved, at least in part, through antiangiogenic mechanisms. Fifty patients with advanced solid tumors were enrolled in this phase II trial, 43 of whom had received at least one prior chemotherapy regimen. Patients were required to have Eastern Cooperative Oncology Group performance status of < or = 2, a life expectancy of >3 months, and at least one measurable lesion. All patients received oral cyclophosphamide (50 mg) and rofecoxib (25 mg) daily in addition to weekly injections of vinblastine (3 mg/m2). Half of the patients also received minocycline (100 mg) orally twice daily with the intent of further inhibiting tumor angiogenesis. The primary end point of the study was clinical benefit, defined as the percentage of patients experiencing an objective response or exhibiting stable disease for at least 6 months. For the 47 eligible patients, there were two (4%) complete responses and four (9%) partial responses, for an overall objective response rate of 13%. An additional eight patients achieved disease stabilization (stable disease > or = 6 months) (17%). The primary end point of clinical benefit was therefore 30%, (95% confidence interval, 16-44%). The median progression-free survival for all patients was 103 days and 289 days for patients experiencing clinical benefit. The incidence of patients experiencing grade 3/4 toxicities were as follows: neutropenia (10/2), anemia (2/0), and thrombocytopenia (1/0). No patients developed grade 3 or 4 nausea, vomiting, mucositis, or alopecia. This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population and indicate that this approach merits further investigation in specific disease site studies.

Can rofecoxib delay a diagnosis of Alzheimer's disease in patients with mild cognitive impairment?

Original article Thal LJ et al. (2005) A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 30: 1204–1215 PubMed Clinical studies have failed to show convincing effects of nonsteroidal anti-inflammatory drugs (NSAIDs)—including the selective cyclo-oxygenase 2 (COX2) inhibitor rofecoxib—on the progression of Alzheimer's disease (AD).

Preoperative Oral Rofecoxib and Postoperative Pain in Patients after Laparoscopic Cholecystectomy: A Prospective, Randomized, Double-Blinded, Placebo-Controlled Trial

Cyclooxygenase-2 (COX-2) inhibitors are a class of drugs that may avoid some of the side effects of narcotics and nonsteroidal anti-inflammatory drugs (NSAIDs). We performed a randomized, double-blinded, placebo-controlled trial giving a single oral dose of the COX-2 inhibitor rofecoxib 25 mg or placebo preoperatively to determine the impact upon postoperative pain, complications, narcotic use, and hospital stay after laparoscopic cholecystectomy. Investigators and patients were blinded. Pain was measured on a 10-point visual analogue scale. Eighty patients were randomized: 40 to the rofecoxib group and 40 to the placebo group. The amount of pain between the two groups postoperatively was equivalent. Pain was recorded at 1 hour, 4.03 +/- 1.93 in the rofecoxib group versus 4.38 +/- 1.34 in the placebo group (P = 0.36); at 6 hours, 3.00 +/- 1.12 in the rofecoxib group versus 2.78 +/- 0.78 in the placebo group (P = 0.42); and at 24 hours, 1.64 +/- 0.67 in the rofecoxib group versus 2.68 +/- 1.90 in the placebo group (P = 0.17). The amount of pain medication received and lengths of hospital stay was not significantly different between the two groups. Our data demonstrate no significant benefit of preoperative oral rofecoxib in patients undergoing laparoscopic cholecystectomy.

Prospective randomized, double-blinded, placebo-controlled trial of preoperative rofecoxib for pain relief in uterine curettage

To evaluate the analgesic efficacy of preoperative rofecoxib in patients who underwent uterine curettage. This double-blinded, randomized, placebo-controlled trial included 80 women who underwent uterine curettage. Forty women were randomly assigned to rofecoxib 50 mg and 40 women to the placebo. The main outcome measure was the intensity of pain measured by the visual analog scale and categorical pain scores during and after the procedure. Chi-squared, Fisher exact, Student t test, and Mann-Whitney U tests were used for statistical analysis. The intensity of pain was not found to be different between groups over the course of procedure (P>0.05). There were no serious adverse effects in this study. The preoperative administration of rofecoxib was not effective in reducing pain in uterine curettage.

A Randomized, Double-Blind, Study of Rofecoxib in Patients with Mild Cognitive Impairment

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

Short-term and long-term tolerability of rofecoxib in patients with prior reactions to nonsteroidal anti-inflammatory drugs

Rofecoxib is a selective cyclooxygenase 2 (COX-2) inhibitor and is well tolerated as an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. Until now, there has not been information in the literature about its long-term tolerability. To provide follow-up data on patients with a history of adverse cutaneous reactions to NSAIDs who underwent and tolerated a challenge test with rofecoxib. Study patients had historically experienced cutaneous adverse reactions to aspirin and NSAIDs and had undergone single-blind challenges with rofecoxib, 25 mg. A questionnaire was distributed to all participants. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. All patients were reexamined 1 to 3 years after testing. At reexamination, they were carefully and personally interviewed using the previously distributed questionnaire. Of the 182 patients who participated in the study, none reacted to rofecoxib during single-blind challenges. Fifty-one (28%) never received rofecoxib again, whereas 131 (72%) were exposed to rofecoxib, often on multiple occasions. Only 7 (5%) of the 131 patients reported cutaneous reactions to rofecoxib during the 3 years of follow-up. Rofecoxib appears to be a safe alternative drug among atopic individuals, antibiotic-hypersensitive individuals, and individuals who experienced adverse cutaneous reactions to more than 1 class of NSAIDs, but it is less safe among chronic urticaria patients. Further investigations that include a larger sample are required to confirm our results especially among chronic urticaria patients.

Safety of high-dose rofecoxib in patients with aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is characterized by progressive sinusitis, nasal polyposis, and asthma that begins and continues in the absence of exposure to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Cross-sensitivity to all NSAIDs that inhibit cyclooxygenase-1 (COX-1) occurs in these individuals. Reactions to aspirin and NSAIDs in patients with AERD are largely due to inhibition of COX-1. Despite accumulating data on the safety of COX-2 selective inhibitors in AERD, concern still remains that high doses of a COX-2 inhibitor may be sufficient to induce a cross-reaction. To determine whether high-dose rofecoxib cross-reacts in patients with AERD and asthma. Sixty asthmatic patients underwent blinded placebo-controlled oral challenges with 50 mg of rofecoxib. Aspirin sensitivity was subsequently confirmed in all patients with the use of single-blinded aspirin challenges. None of the 60 patients experienced any symptoms, changes in nasal examination results, or declines in lung function during rofecoxib challenge. All 60 patients experienced respiratory reactions to aspirin challenge, with a mean provoking dose of 57 mg. The exact 1-sided 95% confidence interval for the underlying probability of 50 mg of rofecoxib inducing respiratory cross-reactions in patients with AERD is 0 to 0.05, or 0% to 5%. These results confirm the lack of cross-reactivity of aspirin and the highly selective COX-2 inhibitors in AERD. We suggest that it is time for the labeling of highly selective COX-2 inhibitors to reflect these data and for the warning that patients with AERD in particular and asthmatic patients in general avoid selective COX-2 inhibitors to be removed.

Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme

Glioblastoma multiforme (GBM) represents the prototype of an angiogenic tumor. Recently, the continuous low-dose scheduling of chemotherapeutic drugs in combination with an inhibition of cyclooxygenase-2 (COX-2) has been suggested as a novel anti-angiogenic approach. The aim of this study was to evaluate the safety and activity of continuous low-dose temozolomide (TMZ) plus the COX-2 inhibitor rofecoxib in patients with newly diagnosed GBM. In vitro, endothelial cells were characterized by a tenfold higher sensitivity to TMZ than glioma cells. Consequently, a subgroup of patients with incompletely resected GBM (n=13) was divided into three groups aiming at a dose escalation to 1/10 of the daily MTD for TMZ: (A) TMZ 10 mg/m2 every third day and rofecoxib 25 mg/d; (B) TMZ 10 mg/m2/d and rofecoxib 25 mg/d; (C) TMZ 5 mg/m2 twice a day and rofecoxib 12.5 mg twice a day. COX-2, VEGF, VEGF Receptor-2, and CD34 were assessed immunohistochemically, in the clinical setting. The mean follow-up period was 15 months. We observed no severe toxicity attributable to the therapy. Quality of life was not impaired. For the whole study population, median time to progression and overall survival were 8 months and 16 months, respectively. Immunohistochemistry suggested that tumors with higher vessel densities were characterized by a significantly better control than those with lower vessel densities. Continuous low-dose TMZ plus rofecoxib is feasible, safe, and maintains good quality of life. This study is indicative of an anti-angiogenic efficacy of continuous low-dose TMZ plus rofecoxib in GBMs, especially in those tumors that are characterized by a high angiogenic activity.

A phase II clinical trial involving the use of low-dose daily oral cyclophosphamide, weekly vinblastine and rofecoxib in patients with advanced solid tumors

A phase II clinical trial involving the use of low-dose daily oral cyclophosphamide, weekly vinblastine and rofecoxib in patients with advanced solid tumors

A phase II clinical trial involving the use of low-dose daily oral cyclophosphamide, weekly vinblastine and rofecoxib in patients with advanced solid tumors

3137 Background: Preclinical studies indicate the conventional chemotherapeutic agents given continuously at low doses may provide an improved therapeutic index (RS Kerbel et al, Annals of Oncology 13:12–15, 2002). Cyclophosphamide and vinblastine have been best studied in experimental models where tumor growth retardation is achieved, at least in part, through antiangiogenic mechanisms. Methods: 50 with advanced solid tumors were enrolled (26 male and 24 female, median age 63 years - range 24 - 85). 43 patients had received at least one prior chemotherapy regimen. Patients were required to have ECOG performance status < 2, a life expectancy of > 3 months and at least one measurable lesion. All patients received cyclophosphamide 50 mg PO daily, weekly injections of vinblastine 3 mg/m2, and rofecoxib 25 mg PO daily. Results: Of the 45 evaluable patients, there were 2 complete responses (CR) (4%), 4 partial responses (PR) (9%) for an overall objective response rate of 13%. An additional 6 patients achieved disease stabilization (SD) ≥ 6 months (13%). The primary endpoint of clinical benefit (CR + PR + SD ≥ 6 months) was, therefore, 26%. The median progression-free survival for all patients was 105 days, and 240 days for patients experiencing clinical benefit. The incidence of grade 3/4 toxicities were as follows: neutropenia 12/2, anaemia 2/0, and thrombocytopenia 1/0. No patients developed grade 3 or 4 nausea, vomiting, mucositis or alopecia. Conclusions: This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population, and indicate that this regimen merits further investigation in specific disease site studies. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration This clinical research was supported only by the Northern Cancer Research Foundation - a non-profit, regional charitable organization. No personal income was included in this support.

Comparison of Lornoxicam and Rofecoxib in Patients with Activated Osteoarthritis (COLOR Study)

Impaired mobility and pain mean a loss of quality of life for patients with rheumatic diseases. Therefore the initial aim of therapy is rapid and efficient analgesia in order to achieve the best possible result for these patients. Lornoxicam is a strong analgesic and anti-inflammatory NSAID with balanced cyclo-oxygenase (COX)-1/COX-2 inhibition and excellent tolerability. In the course of the development of selective COX-2 inhibitors, it was maintained that COX-2 inhibitors decrease the risk of injury to the upper gastrointestinal (GI) tract with a similar efficacy to that of classic NSAIDs. However, a clinical trial comparing both substances has never been performed. In the present study we investigated the treatment of patients with osteoarthritis with lornoxicam in comparison with treatment with the selective COX-2 inhibitor rofecoxib. This multicentre clinical investigation focused on efficacy and tolerability. A total of 2520 patients (most of them with osteoarthritis) were treated over 25 days on average. Before and after treatment patients documented their individual scores for pain on movement, at rest and during the night, and their individual duration of morning stiffness as well as the consequent grade of restriction. At the end of the study all individuals involved judged the efficacy and safety of the therapy. All improvements in each efficacy parameter were clinically relevant in each treatment group and significantly superior (p < 0.001) in the lornoxicam group. Pain on movement (-45.3%), at rest (-42.0%) and at night (-42.5%) was reduced by rofecoxib, whereas improvements after treatment with lornoxicam exceeded those effects significantly (-55.8%, -55.8% and -59.9%, respectively). Shortening of the duration of morning stiffness was significantly (p < 0.001) more pronounced with lornoxicam (-66.6%) than with rofecoxib (-50.2%). Nearly three times as many patients discontinued rofecoxib treatment because of lack of efficacy compared with lornoxicam treatment (8.9% versus 3.4%). Physicians judged lornoxicam to be markedly superior to rofecoxib, since excellent efficacy was observed in 40.9% of all cases versus 20.1% with rofecoxib. Serious adverse events did not occur. Adverse events were reported in 5.4% of all lornoxicam patients compared with 12.0% of the rofecoxib recipients (p < 0.001). GI symptoms showed a slight trend of being less frequent following rofecoxib therapy. The results of this study confirmed the efficacy and safety of both drugs. Lornoxicam and rofecoxib are effective in the treatment of patients with activated osteoarthritis; the analgesic and anti-inflammatory effects of lornoxicam are significantly superior to those of rofecoxib without inferiority in tolerability.

Tolerability of Rofecoxib in Patients with Adverse Reactions to Nonsteroidal Anti-Inflammatory Drugs: A Study of 216 Patients and Literature Review

Background: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are frequent, particularly among patients with chronic urticaria or asthma. The identification of an alternative safe and reliable drug is a common problem in clinical practice. Objective: To assess the tolerability of rofecoxib, a new NSAID that selectively inhibits the inducible isoform of cyclooxygenase, in a large group of NSAID-sensitive patients. Methods: We studied 216 patients (164 females and 52 males) who had suffered adverse reactions to one or more NSAIDs; 98 subjects (45.4%) had experienced reactions to only one NSAID (single hypersensitivity) and 118 subjects (54.6%) had reacted to multiple NSAIDs (multiple hypersensitivity). Cutaneous reactions were reported by 79.6% of the subjects, respiratory symptoms by 10.7%, cutaneous and respiratory symptoms by 8.3%, anaphylaxis by 1.4%. All the subjects underwent a single-blind, placebo-controlled oral challenge with divided therapeutic doses of rofecoxib (6.25 mg +18.75 mg 1 h later = cumulative dose of 25 mg). Results: No reactions to the placebo were observed; only 1 subject (0.46%) experienced an urticarial reaction, after the second dose of rofecoxib. Conclusions: Considering previous studies and our own data, rofecoxib was well tolerated by all of the 174 patients with exclusively NSAID-related respiratory symptoms. Rofecoxib also had a very low rate (1.6%) of cross-reactivity in the 600 patients with exclusively cutaneous reactions to NSAIDs.

Experience of rofecoxib in patients with osteoarthritis previously treated with traditional non-steroidal anti-inflammatory drugs in Spain:results of phase 2 of theVICOXX study

SUMMARYObjectives: To compare patient and physician attitudes to osteoarthritis (OA) treatment with rofecoxib or traditional non-steroidal anti-inflammatory drugs (tNSAIDs).Methods: A 6-month prospective study involving 562 OA patients enrolled at 29 Spanish primary-care centres. Patients were continued on established tNSAID therapy for the first 3 months then switched to rofecoxib 12.5 or 25 mg/day.Results: Both patients and physicians were significantly more likely to be satisfied with rofecoxib treatment than with tNSAIDs (p < 0.001) and assessments of overall health status improved significantly during rofecoxib therapy (p < 0.001). Adherence to therapy was significantly better with rofecoxib than during tNSAID treatment (p < 0.001). Use of rofecoxib was associated with a significant reduction in the proportion of discontinuations attributed to lack of effectiveness (p < 0.001) or gastrointestinal (GI) adverse events (p < 0.001 compared with tNSAIDs). Rofecoxib was also associated with a >60% reduction in the proportion of patients experiencing a GI adverse event and a halving in the proportion of patients who received GI co-medications; concomitant analgesic use decreased by one-third during rofecoxib therapy.Conclusions: Use of rofecoxib was associated with marked improvements in several indices of treatment effectiveness and tolerability, and in patient and physician satisfaction and perception of general health status compared with tNSAIDs. Rofecoxib is a valuable additional medication for relieving the symptoms of OA and its use in place of tNSAIDs may lead to a reduction in the prescription of concomitant medications.