A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized wegener's granulomatosis

Guillevin, Loı̈c; Cordier, Jean-François; Lhote, F.; Cohen, Pascal; Jarrousse, B; Royer, Isabelle; Lesavre, Philippe; Jacquot, C.; Bindi, P.; Bielefeld, Philippe; Desson, J.F.; Detrée, F.; Dubois, A; Hachulla, É.; Hoën, Bruno; Jacomy, Dominique; Seigneuric, C; Lauque, D.; Stern, M.; Longy‐Boursier, M.

doi:10.1002/art.1780401213

Cited by 469 publications

(257 citation statements)

References 26 publications

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“…Furthermore, neither of these studies involved 4-OH-CPA measurements and the daily CPA doses used were rather high compared with the 50 mg/d commonly used in clinical trials that show antitumor activity of LDM CPA-based regimens (1, 3, 8 -14). Finally, our finding of maintained 4-OH-CPA levels and biological effects is in line with long-term beneficial effects of oral CPA protocols used for the treatment of immunologic disorders (38).…”

Section: Discussionsupporting

confidence: 82%

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Emmenegger

Shaked

Man

et al. 2007

Molecular Cancer Therapeutics

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Prolonged, frequently administered low-dose metronomic chemotherapy (LDM) is being explored (pre)clinically as a promising antiangiogenic antitumor strategy. Although appealing because of a favorable side effect profile and mostly oral dosing, LDM involves new challenges different from conventional maximum tolerated dose chemotherapy. These include possible altered pharmacokinetic characteristics due to long-term drug exposure potentially resulting in acquired resistance and increased risk of unfavorable drug interactions. We therefore compared the antitumor and antivascular effects of LDM cyclophosphamide (CPA) given to mice that had been pretreated with either LDM CPA or normal saline, obtained blood 4-hydroxy-CPA (activated CPA) concentrations using either gas chromatography/mass spectrometry or liquid chromatography/tandem mass spectrometry in mice treated with LDM CPA, and measured hepatic and intratumoral activity of enzymes involved in the biotransformation of CPA and many other drugs [i.e., cytochrome P450 3A4 (CYP3A4) and aldehyde dehydrogenase]. Exposure of mice to LDM CPA for z8 weeks did not compromise subsequent activity of LDM CPA therapy, and biologically active 4-hydroxy-CPA levels were maintained during long-term LDM CPA administration. Whereas the effects on CYP3A4 were complex, aldehyde dehydrogenase activity was not affected. In summary, our findings suggest that acquired resistance to LDM CPA is unlikely accounted for by altered CPA biotransformation. In the absence of reliable pharmacodynamic surrogate markers, pharmacokinetic parameters might become helpful to individualize/optimize LDM CPA therapy. LDM CPA-associated changes of CYP3A4 activity point to a potential risk of unfavorable drug interactions when compounds that are metabolized by CYP3A4 are coadministered with LDM CPA. [Mol Cancer Ther 2007;6(8):2280 -9]

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Section: Discussionsupporting

confidence: 82%

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Emmenegger

Shaked

Man

et al. 2007

Molecular Cancer Therapeutics

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“…According to a recently published retrospective analysis, it would appear that-for either disease-the addition of CY to CS benefits particularly patients presenting with factors of poor prognosis (4) and not for those without such signs (5). There is an ongoing controversy in the field of vasculitides whether CY should be administered orally (6,7) or intravenously (8,9). For PAN and MPA, prior studies suggested that an intermittent pulse-therapy may be as efficacious as oral CY at inducing remission (8,10) while generating fewer side effects (11).…”

Section: Introductionmentioning

confidence: 99%

Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: A prospective trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in sixty‐five patients

Guillevin¹,

Cohen²,

Mahr³

et al. 2003

Arthritis & Rheumatism

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234

111

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Objective. Because the optimal cyclophosphamide (CY) treatment duration for severe polyarteritis nodosa (PAN) without virus infection and microscopic polyangiitis (MPA) has not been established, we conducted a trial to compare the effectiveness of 6 versus 12 CY pulses given in combination with corticosteroids (CS). Methods. Sixty-five (18 PAN, 47 MPA) previously untreated patients were randomized to receive 12 (n ‫؍‬ 34) or 6 (n ‫؍‬ 31) CY pulses combined with CS. PAN and MPA were histologically proven or met ACR criteria. All patients presented >1 factor of severity according to the five factor score (FFS). CY pulses were administered every 2 weeks for 1 month, then every 4 weeks. The end point of the study was the number of events (relapses and/or deaths) occurring in each group, analyzed according to an intention-to-treat strategy. The outcome was evaluated by Cox proportional hazards analysis. Results. The baseline characteristics were similar for both groups. The mean (؎ SD) followup was 32 ؎ 21 months. Survival analysis showed a significantly lower relapse probability (P ‫؍‬ 0.02; hazards ratio [HR] ‫؍‬ 0.34) and higher event-free survival (P ‫؍‬ 0.02, HR ‫؍‬ 0.44) for the 12 CY-pulse group while the mortality rates were not significantly different (P ‫؍‬ 0.47). Conclusion. These results suggest that 6 CY pulses are less effective than 12 CY pulses to treat severe PAN and MPA, particularly with respect to the risk of relapses.

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“…A significant proportion of patients (perhaps 20-40%) appear to be "cured" by conventional therapy (2,6). However, disease flares following the tapering or discontinuation of treatment remain the rule, and treatment-induced side effects are a major source of morbidity and mortality (2,6,7).…”

mentioning

confidence: 99%

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

Stone¹

2003

Arthritis & Rheumatism

360

153

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Objective. To report baseline data on 180 patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET), and to examine demographic and clinical differences between patients with limited disease and those with severe disease.Methods. Definitions of limited and severe disease were agreed upon by consensus of the investigators at a pretrial meeting and were incorporated into the protocol as a stratification criterion. These data were applied prospectively to the WGET patient cohort, based on clinical features and the intention to treat patients according to disease activity. Data related to disease onset, date of diagnosis, clinical features, antineutrophil cytoplasmic antibody assays, tissue biopsy findings, and other medical history were collected on a baseline medical history form. Physician-investigators from each center participated in the development of this form, and all were certified in its use prior to the start of the trial. Selected data on patients who were screened for the trial but were not enrolled were also collected.Results. Several significant differences between the limited and severe disease subsets were observed. Patients with limited disease were nearly a decade younger at disease onset compared with patients with severe disease. Thirty-three percent of patients with severe disease were women, compared with 58% of those with limited disease. Despite their younger age at symptom onset, patients with limited disease tended to have longer disease duration, a greater likelihood of experiencing exacerbation of previous disease following a period of remission, and a higher prevalence of destructive upper respiratory tract disorders at the time of enrollment (e.g., saddle-nose deformity). Patients with limited WG were less likely than those with severe disease to have antibodies to either proteinase 3 or myeloperoxidase. Patients with severe disease had a higher likelihood of previous thyroid disease, particularly either Graves' disease or Hashimoto thyroiditis, suggesting the possibility of different pathogenetic factors within these disease subsets. Other observed differences between these subsets, such as the greater frequency of alveolar hemorrhage in the severe disease group, were related to the a priori definitions of limited and severe disease.Conclusion. There are significant differences between patients with limited WG and those with severe WG with regard to sex, age, the likelihood of recurrent disease, the risk of damage in certain organ systems, and, possibly, etiologic factors. These differences (and perhaps other differences that are currently unrecognized) in patient subsets may have implications for mechanisms of pathogenesis, prognosis, response to treatment, and the design of future clinical investigations.

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A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized wegener's granulomatosis

Cited by 469 publications

References 26 publications

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: A prospective trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in sixty‐five patients

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

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