Pioglitazone, etoricoxib, interferon-α, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial

Abstract

We enrolled 45 patients with metastatic renal cell carcinoma (RCC) at a progressive disease between March 2003 and April 2008 to assess the impact of an anti-inflammatory treatment regime in combination with metronomic low-dose chemotherapy. 42% of the patients had been systemically pre-treated. Therapy consisted of etoricoxib 60 mg daily plus pioglitazone 60 mg daily, day 1+, low-dose interferon-α 4.5 MU sc three times a week, week 1+ and low-dose capecitabine 1 g/m(2) twice daily orally for 14 days, every 3 weeks, day 1+, until disease progression. Objective response was observed in 35% of the patients (PR 27, CR 9%), which was paralleled by strong CRP decline for all patients with initially elevated CRP levels (n = 32). CRP values decreased from mean 42.3 mg/L (range 9.1-236), to 11.1 mg/L, (range 1.1-35.6), P = 0.006. Median overall survival and progression-free survival for the total cohort were 26.9 and 7.2 months for patients with elevated CRP 24.4 and 11.3 months (95% CI, 22.8-31.0/5.7-16.9) and 13.8-2.6 months (95% CI, 6.5-21.1/0.4-4.8) for the non-elevated CRP group, respectively (P = 0.082/0.017). Median observation time: 26.1 months; Overall survival at 5 years: 18%. Toxicity>WHO grade 3 was reported: Hand-foot syndrome in 16 patients (36%), diarrhea in 4, and pneumonia in 2 patients. Our data allow us to conclude that the control of tumor-associated inflammation is an important therapeutic principle in patients with metastatic RCC.

Proteomics and metabolomics identify molecular mechanisms of aging potentially predisposing for chronic lymphocytic leukemia

“…The expression of this transforming protein (82) in B-CLL cells not only indicates an adaptive response but may directly contribute to tumor promotion and thus represents a potential functional link between inflammatory signaling and increased risk for B-CLL formation. Furthermore, chronic inflammation may account for the presently observed downregulation of tumor suppressors (85) as well as the up- regulation of HMOX1 and ATOX1 (Fig. 1B) indicating a further resistance to radical stress.…”

Chemotherapy in metastatic renal cell carcinoma today? A systematic review

“…OR was observed in 35% of the patients and the median OS and PFS for the total cohort were 26.9 and 7.2 months, respectively, with better results for patients with elevated C-reactive protein before treatment. The author's conclusion was that the control of tumor associated inflammation is an important therapeutic principle and that this multitargeted approach could be a second-line therapy option in patients with mRCC who showed failure to previous tyrosine kinase inhibitor (TKI) therapy [55].…”

Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue

“…In a first trial, pioglitazone combined with metronomic chemotherapy and COX-2 inhibitor relatively poor response, mainly stable disease could be observed in > third line situation. The addition of low-dose interferon-α opened the possibility to induce histologically proven remission in resistant metastatic RCC, which translated in continuous complete remission, now lasting > 10 years in single patients [ 5 ].…”

“…Particularly, these clinical trials in patients with diabetes type II highlight the striking anti-inflammatory component of PPARα. The initial hypothesis that efficacious anti-inflammatory therapy may also control advanced cancer could be confirmed by introducing pioglitazone in treatment of refractory metastatic cancer [ 4 , 5 ]. From pre-clinical data, the appropriate PPARα agonist for cancer treatment has to be defined, yet [ 1 ].…”