Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial

Gore, Martin; Griffin, Clare; Hancock, Barry W.; Patel, Poulam M.; Pyle, L; Aitchison, Michael; James, Nicholas D.; Oliver, R. T. D.; Mardiak, Jozef; Hussain, Tahera; Sylvester, Richard; Parmar, Mahesh; Royston, Patrick; Mulders, Peter F.A.

doi:10.1016/s0140-6736(09)61921-8

Cited by 108 publications

(57 citation statements)

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“…Our results are apparently better than the reported efficacy of IFN-a monotherapy, by which an ORR of 10-15% and PFS of 5 months are generally achieved. (6)(7)(8)24) The efficacy of I-CCA is comparable with the current standard first-line treatments of sunitinib or IFN-a plus bevacizumab. (12)(13)(14)25) The I-CCA therapy seems to be effective even in patients for whom cytokine therapy is generally considered ineffective.…”

Section: (A) (B) (C) (D) (E) (F)mentioning

confidence: 93%

“…(26) However, a recent large-scale study reported that IFN-a monotherapy achieved durable CR in 2% of mRCC patients. (7) COX-2 is an enzyme involved in the formation of prostaglandin E2 from arachidonic acid. It is expressed in the majority of RCC and correlates with stage, grade and microvessel density and might promote RCC angiogenesis and tumor growth.…”

Section: (A) (B) (C) (D) (E) (F)mentioning

confidence: 99%

“…(6) However, cases of complete remission (CR) by IFN-a are rare and progression-free survival (PFS) is reported to be approximately 5 months. (7,8) High-dose immunotherapy with intravenous IL-2 results in generally durable CR in approximately 6% of patients, but significant toxicities can occur with this regimen, making it applicable to a limited number of patients. (9) Based on a better understanding of the biology and genetics of RCC, targeted agents have been developed and shown to have significant antitumor activities against RCC, resulting in dramatic paradigm shifts in the management of mRCC.…”

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Phase‐II trial of combination treatment of interferon‐α, cimetidine, cyclooxygenase‐2 inhibitor and renin‐angiotensin‐system inhibitor (I‐CCA therapy) for advanced renal cell carcinoma

Tatokoro

Fujii²,

Kawakami

et al. 2010

Cancer Science

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We have recently reported favorable responses to a combination treatment comprising cimetidine, a cyclooxygenase-2 inhibitor and a renin-angiotensin-system inhibitor in metastatic renal cell carcinoma (RCC). In view of the potential synergistic effects of these three agents and interferon-a (I-CCA therapy), we conducted a phase-II trial to examine the efficacy and toxicity of I-CCA as firstline treatment. Fifty-one patients with advanced RCC received natural interferon-a (3-6 million U thrice/week) and cimetidine (800 mg), cyclooxygenase-2 inhibitor meloxicam (10 mg), and renin-angiotensin-system inhibitor candesartan (4 mg) or perindopril (4 mg) orally daily. Memorial Sloan-Kettering Cancer Center prognostic categories were favorable, intermediate and poor in 10 (20%), 31 (61%) and 10 (20%) patients, respectively. The primary end-point was the objective response rate (ORR) and the secondary end-points included clinical benefit, progression-free survival (PFS), overall survival (OS) and safety. Median follow-up was 19 months. Complete response (CR) was observed in four patients (8%) and partial response in seven (14%), yielding an ORR of 22%. None of the four patients who achieved CR relapsed during the 16-to 81-month follow up. The ORR were 17% in the favorable-or intermediate-risk group and 40% in the poor-risk group. The other 24 patients (45%) had stable disease for at least 6 months, resulting in a clinical benefit rate of 67%. The median PFS and OS were 12 and 30 months, respectively. Grade 3/4 toxicities were never observed. The I-CCA therapy, providing favorable responses and low toxicity profiles, is worthy of further consideration as a firstline therapy for metastatic RCC. (Cancer Sci 2011; 102: 137-143) R enal cell carcinoma (RCC) is the most common renal malignancy and accounts for approximately 2% of all cancers.(1) Metastatic disease is present in around 30% of RCC patients when diagnosed, and 30-40% of patients with earlystage disease relapse with metastases following nephrectomy. Renal cell carcinoma is highly resistant to conventional cytotoxic chemotherapy and the prognoses in patients with metastatic RCC (mRCC) are poor, (2) with a median overall survival (OS) period of approximately 1 year (3) and a 5-year survival rate of <10%. Immunoreactive cytokines, interferon-a (IFN-a) and interleukin-2 (IL-2) were the treatment mainstay for mRCC.(5) Interferon-a offers a small but significant advantage in OS. (6) However, cases of complete remission (CR) by IFN-a are rare and progression-free survival (PFS) is reported to be approximately 5 months. (7,8) High-dose immunotherapy with intravenous IL-2 results in generally durable CR in approximately 6% of patients, but significant toxicities can occur with this regimen, making it applicable to a limited number of patients. Based on a better understanding of the biology and genetics of RCC, targeted agents have been developed and shown to have significant antitumor activities against RCC, resulting in dramatic paradigm shifts in the management of mRCC....

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Section: (A) (B) (C) (D) (E) (F)mentioning

confidence: 93%

Section: (A) (B) (C) (D) (E) (F)mentioning

confidence: 99%

mentioning

confidence: 99%

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Phase‐II trial of combination treatment of interferon‐α, cimetidine, cyclooxygenase‐2 inhibitor and renin‐angiotensin‐system inhibitor (I‐CCA therapy) for advanced renal cell carcinoma

Tatokoro

Fujii²,

Kawakami

et al. 2010

Cancer Science

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“…In a previous study, the treatment of advanced and metastasized RCC was attempted with a cytokine-based therapy with interferon-α and high-dose interleukin-2 (IL-2), under the presumption that an immune response could be triggered against RCC cells. However, this therapy offered little benefit with regard to the overall survival times of the patients (8). It is only in the last decade that a broader understanding of RCC tumor biology and the introduction of inhibitors of tyrosine kinase, multikinase and mammalian target of rapamycin (mTOR) have greatly improved the therapeutic means for metastatic RCC (9).…”

Section: Introductionmentioning

confidence: 99%

Rho GDP dissociation inhibitor‑β in renal cell carcinoma

et al. 2017

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Abstract. Rho GDP dissociation inhibitor-β (ARHGDIB) is an important mediator of cell signaling. The expression of ARHGDIB is associated with tumor growth and metastasis in a variety of non-genitourinary cancers; however, the role of ARHGDIB in renal cell carcinoma (RCC) has not yet been evaluated. In the present study, tissue samples from 105 patients undergoing surgery for RCC were obtained. The expression levels of ARHGDIB mRNA in normal kidney tissues and in corresponding cancer tissues were analyzed by reverse transcription-quantitative polymerase chain reaction. Differences in relative mRNA expression levels were assessed using paired two-sample t-tests. Expression levels were analyzed with respect to various clinical parameters, and associations were tested using a bivariate logistic regression model. Relative mRNA expression levels in healthy renal tissues compared with cancerous tissues from the same kidney were assessed using paired t-tests. Expression data were compared with respect to survival data by the Kaplan-Meier method/Cox regression analysis. The results revealed that the relative mRNA expression level of ARHGDIB was significantly higher in the lysates of RCC tumor tissues (P<0.001) when compared with healthy renal tissues in a paired analysis of 74 samples; this finding was consistent with the analysis of ARHGDIB mRNA expression levels in all RCC samples, as well as in the subset of clear cell RCC (ccRCC) samples. The relative mRNA expression level of ARHGDIB was also increased in ccRCC tissues compared with papillary RCC tissues (P<0.001). On univariate Cox regression analysis, recurrence-free survival (RFS) was significantly associated with metastasis, locally advanced disease and tumor grade (P=0.018, P=0.002 and P<0.001, respectively). Furthermore, in the subgroup of patients with ccRCC, increased ARHGDIB mRNA expression was significantly associated with a longer RFS time (P=0.001). In summary, the results indicate that ARHGDIB mRNA is highly expressed in RCC tissues in general and is positively associated with RFS in ccRCC. As ARHGDIB has a known effect on angiogenesis and immune modulation, the present study suggests that the functional analysis of ARHGDIB should be performed in the future.

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“…[9,10] Until recently, standard treatment for mRCC has consisted of immunotherapy with either interleukin-2 (IL-2) or interferon-a (IFNa), both of which are associated with overall response rates (ORRs) of 5-20%, and significant clinical toxicities. [11][12][13][14][15] In randomized controlled trials, IFNa has been associated with a median overall survival (OS) of 12-19 months, [16][17][18] and highdose IL-2 can result in disease cure in 5-10% of patients. [19] Additionally, treatment options were scarce for those patients who progressed on cytokine therapy.…”

Section: Introductionmentioning

confidence: 99%