- Clin Cancer Res. 2006 Sep 1;12(17):5190-8.
Buckstein R, Kerbel RS, Shaked Y, Nayar R, Foden C, Turner R, Lee CR, Taylor D, Zhang L, Man S, Baruchel S, Stempak D, Bertolini F, Crump M.
Oncology, Toronto Sunnybrook Regional Cancer Centre, Sunnybrook and
Women's College, Medical Oncology, Princess Margaret Hospital, Ontario,
Angiogenesis is increased in aggressive histology non-Hodgkin's
lymphoma and may be a target with selective cyclooxygenase-2 inhibition
and metronomic chemotherapy.
EXPERIMENTAL DESIGN: We assessed response,
toxicity, and biomarkers of angiogenesis to low-dose cyclophosphamide
(50 mg p.o. o.d.) and high-dose celecoxib (400 mg p.o. b.i.d.) in adult
patients with relapsed or refractory aggressive non-Hodgkin's lymphoma
in a multicenter phase II prospective study.
RESULTS: Thirty-two of 35
patients (median age, 62 years) are evaluable for response. Patients
had primarily relapsed diffuse large B-cell lymphoma (63%) were heavily
pretreated (median of three regimens) and high risk (79% international
prognostic index, >or=2) and 34% were relapsed after autologous stem
cell transplant. With a median follow-up of 8.4 months, the overall
best response rate is 37% (2 complete clinical response/complete
clinical response unconfirmed and 9 partial response), with 22%
achieving stable disease. Median overall and progression-free survivals
are 14.4 and 4.7 months, respectively. The median response duration was
8.2 months. The most common toxicity was skin rash (40%);
myelosuppression and gastrointestinal side effects were uncommon. Three
patients developed deep vein thromboses and two heavily pretreated
patients developed treatment-related acute myelogenous leukemia or
myelodysplasia after 3.7 and 12 months of therapy. Circulating
endothelial cells and their precursors declined and remained low in
responders, whereas plasma vascular endothelial growth factor trended
to decline in responding patients but increase in nonresponders. Trough
celecoxib levels achieved targeted "antiangiogenic" levels.
CONCLUSIONS: Low-dose cyclophosphamide and high-dose celecoxib is well
tolerated and active in pretreated aggressive non-Hodgkin's lymphoma.
Close surveillance for arterial and venous thrombotic events is
recommended. The decline in circulating endothelial cells and their
precursors suggests that this combination may be working by inhibiting
angiogenesis but should be validated in a larger patient sample.