Renal 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 early-stage 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%.(4)
Immunoreactive cytokines, interferon-α (IFN-α) and interleukin-2 (IL-2) were the treatment mainstay for mRCC.(5) Interferon-α offers a small but significant advantage in OS.(6) However, cases of complete remission (CR) by IFN-α 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.(10) In previously untreated, advanced RCC patients, sunitinib and temsirolimus have shown superior efficacy in OS over IFN-α in phase-III trials in the US and Europe.(11,12) Therefore, IFN-α as a single therapeutic agent is no longer considered as a standard first-line treatment for mRCC. However, in the era of targeted agents, mRCC is still incurable. Targeted agents are rarely associated with CR, and the duration of efficacy is limited.
Interferon-α may show enhanced efficacy when combined with other drugs, particularly anti-angiogenic agents. Recently, two phase-III trials(13,14) have shown improved PFS and increased objective response rate (ORR) with bevacizumab plus IFN-α, when compared with IFN-α alone, as first-line treatment. The combination of IFN-α plus bevacizumab has now become one of the standard first-line treatments for favorable- to intermediate-risk mRCC patients.
The antitumor effects of cimetidine, cyclooxygenase-2 (COX-2) inhibitor and renin-angiotensin-system (RAS) inhibitor (angiotensin-converting-enzyme [ACE] inhibitor or angiotensin-II type-1 receptor [AT1R] antagonist) have been recognized in previous studies.(15–21) Of note is the fact that all three drugs have shown anti-angiogenic activity. We have recently reported three cases in which favorable responses to a combination treatment comprising cimetidine, COX-2 inhibitor and RAS inhibitor in mRCC were observed with a relatively long duration of the effects, at least 1 year of time to progression.(22) In view of the potential synergistic effects of these three agents and IFN-α (I-CCA therapy), we conducted a phase-II trial to characterize the efficacy and toxicity of I-CCA therapy for the treatment of patients with advanced RCC.
Materials and Methods
Patients. Japanese patients with metastatic or unresectable RCC, diagnosed by pathological examinations or imaging, were eligible for the study. The patients were required to have at least one evaluable lesion, an Eastern Cooperative Oncology Group (ECOG) performance status of three or less, estimated survival of 3 months or longer and no severe complications. Adequate cardiopulmonary, bone marrow, liver and renal function was another inclusion criteria. Exclusion criteria comprised immunosuppressive agents used within 3 weeks of study; previous or concomitant therapies, including chemotherapy or radiotherapy within 30 days of study initiation; an active peptic ulcer; other types of cancers that were not cured or had been cured within 1 year, and psychogenic diseases including depression.
Study design. The primary end-point was the ORR, and the secondary end-points included clinical benefit, PFS, OS and safety. Institutional review boards of Tokyo Medical and Dental University had approved the study protocol. This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. All patients provided written informed consent.
Treatment plan. Natural IFN-α (Sumiferon; Dainippon Sumitomo Pharma Co. Ltd, Osaka, Japan or OIF; Otsuka Pharmaceutical Co. Ltd, Tokyo, Japan) was administered at 3–6 million U subcutaneously thrice a week. Cimetidine (Tagamet; Dainippon Sumitomo Pharma) was administered at 800 mg orally daily in two divided doses. A selective COX-2 inhibitor, meloxicam (Mobic; Daiichi Sankyo Co. Ltd, Tokyo, Japan) was administered at 10 mg/day orally. As for the renin-angiotensin-system inhibitor, ACE inhibitor perindopril erbumine (Coversyl; Daiichi Sankyo) 4 mg/day orally was initially used, but as described in results, it frequently caused a cough. Therefore, in March 2004, it was replaced by an AT1R antagonist candesartan cilexetil (Blopress; Takeda Pharmaceutical Co. Ltd, Osaka, Japan) at 4 mg/day. The treatment was given on an outpatient basis. The patients received treatments until the disease obviously progressed, adverse effects were not tolerated, or patients refused the treatment. In this study, continuation of I-CCA therapy was allowed even after disease progression because no targeted agents were available at the start of this trial.
Criteria for evaluation of antitumor effects. Tumor responses were evaluated after 2–3 months, and every 3 months thereafter. Radiological evaluation was undertaken with computed tomography (CT) scans and/or MRI. Responses to the therapy were evaluated according to criteria of the World Health Organization (WHO)(23): CR was defined as the disappearance of all signs of disease for a minimum of 8 weeks; partial response (PR), 50% or greater decrease in the sum of the products of the greatest perpendicular diameters of measurable lesions, no increase in lesion size and no new lesions; stable disease (SD), less than a partial response with no disease progression for at least 8 weeks; and progressive disease (PD), 25% or more increase in the sum of the products of the longest perpendicular diameters of measurable lesions or development of new lesions. Lesions identified and measured at baseline were evaluated using the same technique by two investigators.
The ORR was defined as the proportion of patients with confirmed CR and PR in the intent-to-treat population. Assessments of responses required confirmatory radiological evaluation at 4 or more weeks after the initial determination of a response. Progression-free survival was defined as the time from treatment initiation to disease progression (radiological or clinical) or death, whichever occurred first. Overall survival was defined as the time from treatment initiation until death, and censored at the last date the patient was known to be alive. The clinical benefit rate was the percentage of patients achieving CR, PR or SD for at least 24 weeks.
Safety evaluation. The study was designed to detect commonly occurring adverse events. Patients were evaluated for adverse events on the basis of version 3.0 of National Cancer Institute Common Terminology Criteria for Adverse Events weekly in the first month, and monthly thereafter. Treatment-related adverse events were those not present at baseline or those present but worsening in severity and/or frequency during treatment.
Statistical analysis. For time-to-event end-points, medians and 95% confidence intervals (CI) were estimated using the Kaplan–Meier method and differences were assessed using the log rank test. The prognostic impact of variables was evaluated using the Cox proportional hazards model with P < 0.05 indicating significance for all analyses. Statistical analyses were performed using jmp 6.0-J (SAS Institute, Tokyo, Japan).
This phase-II study has shown that I-CCA therapy provides favorable responses and low toxicity profiles in patients with advanced RCC, indicating a definitively good scope as a first-line treatment. In our patients, the ORR was 22%, CR was 8%, the clinical benefit rate was 67%, median PFS was 12 months and median OS was 30 months. Better survival was noted in the patients who achieved clinical benefit with I-CCA therapy, although none of the MSKCC risk group, number of metastatic sites or organs, or only lung metastases or not was associated with the prognosis. Of note is the fact that none of the patients received targeted agents after the study.
Our results are apparently better than the reported efficacy of IFN-α monotherapy, by which an ORR of 10–15% and PFS of 5 months are generally achieved.(6–8,24) The efficacy of I-CCA is comparable with the current standard first-line treatments of sunitinib or IFN-α plus bevacizumab.(12–14,25) The I-CCA therapy seems to be effective even in patients for whom cytokine therapy is generally considered ineffective. In the current study, four of 10 (40%) patients in the poor-risk group and two of six (33%) patients with hepatic metastases showed an objective response, and the median PFS and OS in the poor-risk patients were 7 and 19 months, respectively. Motzer et al.(8) previously reported a median OS of only 5 months for poor-risk patients treated with cytokine therapy. We believe that CCA elements enhance the efficacy of IFN-α. We have previously reported a patient with multiple metastases of RCC origin including a 10-cm liver metastasis who received only CCA therapy.(22) All metastases showed good PR, which continued for 12 months. Our results suggest that I-CCA therapy could be a first-line therapy even for patients with poor prognostic factors.
In this study, four (8%) patients achieved CR: one had inferior vena cava invasion and multiple liver and lung metastases (Fig. 4), two had lung metastases and one had local recurrence at the initiation of I-CCA therapy. None of these four patients relapsed during follow up. Notably, three of the four patients maintained CR for more than 5 years, achieving durable CR. It is generally considered that durable CR rarely occur by cytokines or targeted agents except for high-dose IL-2.(26) However, a recent large-scale study reported that IFN-α 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.(19) Inhibition of COX-2 has been shown in both preclinical and clinical studies to inhibit angiogenesis and carcinogenesis in solid tumors, including mRCC. Shinohara et al.(20) conducted a phase-II trial of combined treatment with natural IFN-α plus meloxicam for mRCC patients, and recently reported its excellent efficacy. In the 43 patients, the ORR was 37% and an additional 33% of patients had SD. The median time to progression was 14 months. The combination of IFN-α and COX-2 inhibitors might be particularly beneficial in poor risk patients. A high ORR of 70% in the MSKCC poor-risk patients was reported in Shinohara et al.’s(20) study. Since the number of poor-risk patients was small (10 patients in both our and Shinohara et al.’s studies), further investigation in a large patient group is needed to confirm the results. In contrast, Rini et al.(19) conducted a phase-II trial of combined treatment with recombinant IFN-α plus celecoxib, an oral COX-2 inhibitor, for mRCC. The observed median PFS was 3.3 months, indicating that the addition of celecoxib to IFN-α did not increase the ORR or PFS. To date, it remains unclear why these two trials showed conflicting results: the different types of IFN-α and COX-2 inhibitors used in these studies could be a presumable cause for the difference.
Angiotensin-II plays a fundamental role not only as a vasoconstrictor but also as a mitogenic factor through AT1R in cardiovascular cells. Furthermore, there is increasing evidence that RAS is implicated in the development of various cancers.(27) There have been several reports that RAS inhibitors, AT1R antagonist or ACE inhibitor can act as novel anti-angiogenic, anti-invasive and anti-growth agents in neoplastic tissues.(15) AT1R antagonist prevented lung metastatic nodules of RCC in a mouse model along with inhibition of neovascularization and VEGF expression.(18) Furthermore, in a mouse model, the ACE inhibitor perindopril enhanced the effect of IFN-β to attenuate hepatocellular carcinoma development and angiogenesis.(28) In addition, a few recent clinical studies have suggested that RAS inhibitors can improve prognoses of cancer patients when combined with standard chemotherapies. In a retrospective cohort study of advanced non-small-cell lung cancer, RAS inhibitors were statistically associated with longer survival when used with first-line platinum-based chemotherapy.(29)
Cimetidine, the prototypical histamine H2 receptor antagonist, has shown antitumor activity against colon, gastric and kidney cancers and melanomas.(17) Multiple potential mechanisms have been indicated: (i) a direct inhibitory effect on tumor growth by blocking the cell-growth-promoting activity of histamine; (ii) an indirect effect by inhibiting tumor-associated angiogenesis; and (iii) a cell-mediated immunomodulation by enhancing the host’s immune responses to tumor cells. The Hoosier Oncology Group evaluated high-dose cimetidine in mRCC patients. There were two CR in 38 patients.(16) Kinouchi et al.(30) conducted a non-randomized study combining IFN-α with cimetidine for advanced RCC with pulmonary metastases, in which the ORR and the 5-year survival were both 41%. They conducted a prospective randomized phase-III trial of combination therapy with IFN-α plus cimetidine versus IFN-α monotherapy in 71 patients with advanced RCC with pulmonary metastases. However, the combined treatment did not result in a significant improvement in response rates or time to progression compared with the IFN-α monotherapy.(24)
To date, it has been unclear which of the CCA agents contributes the most, but concomitant use of these drugs might allow interruption of important cancer pathways at more than one point or synchronous inhibition of separate but cross-communicating systems. Smith and Missailidis(31) reported that blockade of the AT1R in synergy with anti-inflammatory agents should cause regression of most solid tumors. They also hypothesized that a combination therapy consisting of AT1R antagonist, non-steroidal anti-inflammatory drugs (NSAIDs) and immune therapy should provide a novel and successful treatment for solid tumors, supporting the concept of I-CCA therapy. Toxicity of I-CCA therapy is relatively low. Most of the adverse events, including fatigue, depression and anorexia, are associated with IFN-α, except for coughing that occurs with the ACE inhibitor. These symptoms were usually manageable with supportive care or drug-dose reduction. Although only one patient required hospitalization for interstitial pneumonia (grade 1), there were no grade 3 or 4 events and treatment-related deaths due to I-CCA therapy. Six (12%) patients discontinued the study drug mainly because of grade 1 or 2 adverse events related to IFN-α. Low toxicity profiles observed in this study are probably because of the use of low-dose IFN-α (3–6 million U thrice/week). In the Avastin for renal cell cancer (AVOREN) trial,(13) the IFN-α dose was reduced from 9 million U thrice/week to 6 or 3 million U with the development of IFN-attributed toxicity in 131 (41%) of 322 patients in the bevacizumab plus IFN-α arm. Bevacizumab plus reduced-dose IFN-α was well tolerated, with a substantial decrease in the rate of adverse events following the dose reduction. Importantly, reducing the dose of IFN-α did not reduce the PFS when compared with PFS in those receiving the full-dose IFN-α, suggesting that the dose of IFN-α can be reduced to manage side-effects while maintaining efficacy in mRCC patients who are receiving this combination.(32)
The I-CCA therapy is also advantageous over targeted agents with respect to cost. There have been some criticisms that targeted agents impose an enormous economic burden on patients and societies. In Japan, sorafenib and sunitinib cost around US $6500–6800 per month, which is over thrice more than I-CCA therapy, which costs approximately US $2100. The cost of the CCA element is only US $100 per month.
At present, there is accumulating evidence that the administration of targeted agents sequentially provides some clinical benefit in mRCC patients, and the use of sequential therapy has become a routine practice.(33) To our knowledge, the best sequence remains unknown, but cytokine-based therapy could be an option as first-line treatment in sequential therapy because many targeted agents including sorafenib, bevacizumab, sunitinib, axitinib and temsirolimus showed activity in patients with cytokine-refractory RCC,(33,34) whereas the efficacy of cytokines after targeted agents remains unknown. Very recently, Heng et al.(35) reported prognostic factors for OS in mRCC treated with vascular endothelial growth factor (VEGF)-targeted agents. Interestingly, prior immunotherapy did not undermine the efficacy of VEGF-targeted agents in this cohort. The median OS from the initiation of VEGF-targeted therapy in the case of 214 patients who had received prior immunotherapy was 22.7 months, which was equivalent to 21.3 months for 431 patients who received VEGF-targeted therapy as first-line treatment.
Escudier et al.(33) recently published an interesting review about sequential therapy in which the total PFS of each sequential therapy was speculated on the basis of the assumption that data from recent reports for the second-line setting could be extrapolated to the third-line setting. In this pure speculation, first-line IFN-α plus bevacizumab sequence seems to be a promising strategy. For example, the speculated total PFS of IFN-α plus bevacizumab (PFS, 10.2 months) – sorafenib (PFS, 6 months) – sunitinib (PFS, 6.5 months) – everolimus (PFS, 4 months) sequence is 26.7 months, which is longer than the total PFS of 19.5 months in the case of sunitnib (PFS, 11 months) – sorafenib (PFS, 4.5 months) – everolimus (PFS, 4 months) sequence. The I-CCA therapy, also a combination of IFN-α and anti-angiogenic agents with an achieved PFS of 12 months, could be an alternative to IFN-α plus bevacizumab as a first-line sequential therapy.
The current study has some limitations. First, it might be possible that our results are applicable only to Asian patients. Recent studies have suggested possible racial or ethnic differences in the survival rates of some cancers.(36,37) Aron et al.(38) reported that RCC in Asian/Pacific Islander patients had a significantly higher relative survival rate than all other races/ethnicities. Recently, the prognoses of 1463 Japanese patients with mRCC treated with cytokines were reported.(39) The median OS of Japanese mRCC patients was 21 months, which was approximately twice as long as those of North American or European counterparts previously reported.(8) The I-CCA therapy achieved a further longer median OS of 30 months in this study cohort. In Japan, metastatic foci might be detected early after nephrectomy because patients are usually subjected to a CT scan after nephrectomy at least annually, and this might contribute to the early detection of lung metastasis and treatment, leading to a better prognosis.(39) In this study cohort, 39% of patients had metastases in a single organ; in particular, 25% had only lung metastasis. However, the number of metastases, the number of metastatic organs or whether metastatic organs is limited to lung or not was not associated with the prognosis.
Second, there was no independent review of the radiographs. It is important to note that responses in this study were based on the investigators’ assessment. Because an independent review of scans can result in a lowering of the response rate relative to the investigator-assessed responses, this should be taken into consideration when interpreting the results of this trial. Third, in the present study, we used the WHO criteria without adopting the response evaluation criteria in solid tumor (RECIST) criteria. Our study started in 2001 when the RECIST criteria were relatively uncommon. Furthermore, clinicians have noted that the use of standard oncological criteria, such as RECIST, may not be sufficient for an accurate assessment of immunotherapy for mRCC.(40) In the current study, patients received candesartan 4 mg/day, the dose for normal cardiovascular treatment in Japan. Smith and Missailidis(41) reported that the inhibitory effects of blockade of AT1R in malignancy processes would be dose dependent. We would conduct a further combination trial including a higher dose of candesartan and other promising agents with potential synergistic effect with cytokine therapy. For example, several clinical studies found a combination of interleukin-2 and 13-cis retinoic acids to be beneficial in patients with several cancers including RCC.(41–43)
The I-CCA therapy is safe, cost-effective and its efficacy is comparable with that of targeted agents. It is worthy of further consideration as a first-line treatment for patients with mRCC. The availability of a variety of active agents could provide increased treatment options and the opportunity to provide several lines of therapy, potentially improving survival. Hence, it is necessary to conduct large-scale international randomized trials targeting mRCC in order to confirm our results.