Comparison of survival rates in patients with metastatic renal cell carcinoma according to treatment era including cytokine and targeted therapy.

We compared the survival rates in patients with metastatic renal cell carcinoma between the cytokine and molecular targeted therapy era. The study included 321 patients who were diagnosed with metastatic renal cell carcinoma between 1987 and 2011. The patients were divided into two groups according to when they started therapy for metastatic renal cell carcinoma: in the cytokine era (1987-2007) and in the targeted therapy era (after 2008). The beginning of the follow-up period was defined as the time of discovery of metastasis occurrence. Cytokine and targeted therapy eras included 235 and 86 patients, respectively. Seventy-five percent of the patients in the cytokine era actually received cytokine therapy. Eighty-one percent of the patients in the targeted therapy era received targeted therapy and 14% received both cytokine and targeted therapy. There were no significant differences in overall survival rates (cytokine 29 months, targeted 38 months, P = 0.1789).


INTRODUCTION
Renal cell carcinoma (RCC) accounts for 2 -3% of all malignant tumors in adults in developed countries (1). The incidence rate of localized RCC has increased rapidly, whereas that of distant RCC has declined (2). However, the mortality rate has significantly increased for the localized stage and decreased for the distant stage (3). For patients with metastatic RCC, cytokine therapy including interferon-a (IFN-a) and interleukin-2 (IL-2) was widely used as first-line therapy. In recent years, targeted therapy including tyrosine kinase receptor inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) replaced cytokine therapy as the main therapeutic measure for metastatic renal cell carcinoma (mRCC). The results of randomized studies suggest that targeted therapies improve progression-free survival, but have not clarified whether such therapies measurably contribute to prolonging overall survival (OS) (4). It is difficult to set up a randomized study to evaluate survival rates in mRCC patients according to the absence or presence of systemic therapy including cytokine and targeted therapy because systemic therapy is now recognized as an effective measure against mRCC. Therefore, we retrospectively evaluated OS in patients with mRCC and compared the results based on the treatment era, including the cytokine era and the molecular targeted therapy era.

PATIENTS
This retrospective analysis examined 321 Japanese patients diagnosed with metastatic RCC at the Tokyo Women's Medical University Hospital between 1987 and 2012 and for whom data on follow-up time and outcome were available. Patients without sufficient follow-up data and those who underwent maintenance hemodialysis before being diagnosed with mRCC were excluded from this study. The patients were divided into two groups according to the period in which they were diagnosed with mRCC: Group 1, cytokine era (1987 -2007) and Group 2, targeted therapy era (after 2008). Targeted therapy included sorafenib, sunitinib, temsirolimus and everolimus. Patients' clinical-pathological data were retrieved from the medical record database at the Department of Urology. Tumor stage was established according to the 2009 TNM classification of the Union Internationale Contre le Cancer (UICC). Pathologic grade was determined according to the General Rules for Clinical and Pathological Studies on Renal Cell Carcinoma in Japan ( pathologic grade is classified as G1 -G3). Memorial Sloan-Kettering Cancer Center risk groups were used to define risk groups based on pretreatment features. In summary, low Karnofsky performance status (,80%), high lactate dehydrogenase (.1.5X upper limit of normal), low serum hemoglobin (,lower limit of normal), high corrected serum calcium (.10 mg/dl) and ,1 year interval from diagnosis to treatment onset were defined as independent prognostic factors. The presence or absence of these risk factors was used to stratify patients into three groups: favorable risk (0 factors), intermediate risk (1 or 2 risk factors) and poor risk (3 risk factors). The primary end point was the OS calculated from first diagnosis of mRCC to death or last follow-up.

STATISTICAL ANALYSIS
All statistical analyses were performed using JMP 8.0.1 software (SAS Institute, Cary, NC, USA). Quantitative parameters were compared using the Mann -Whitney U test, and qualitative parameters were compared using Fisher's exact test. The survival rate was calculated using the Kaplan -Meier method and statistical significance was determined by the log-rank test. P values of ,0.05 were considered to indicate the statistical significance.

RESULTS
The clinical and pathological features of the 321 patients included in this study are summarized in Table 1. Groups 1 and 2 consisted of 235 and 86 patients, respectively. In Group 1, 75% of the patients underwent cytokine therapy and 13 patients (6%) underwent targeted therapy. In Group 2, 70 patients (81%) received targeted therapy and 12 patients (14%) received cytokine therapy followed by targeted therapy. Gender and TNM distribution at first visit were not significantly different between the groups. Patients in Group 1 were significantly younger (P ¼ 0.0013) and were up for a longer period (P ¼ 0.0258) than those in Group 2. Histopathological features showed a decreasing tendency for clear-cell renal cell carcinoma (CRCC) and an increasing tendency for papillary renal cell carcinoma (PRCC). Moreover, there was an increasing tendency in G3 tumors (42%) and a decreasing tendency in G1 tumors (8%) in Group 2 compared with that in Group 1. The unfavorable risk group tended to decrease with the progression of era (Group 1: 15%, Group 2: 7%). Figure 1 shows the OS rates according to era. In the follow-up period, 175 patients (74%) died in Group 1 and 33 (38%) died in Group 2. The median survival time was 29 months in Group 1 and 38 months in Group 2. There were no significant differences in OS rates between the two groups (P ¼ 0.1789). Although the exact table is not shown, univariate analysis showed that T stage (P , 0.0001), distant metastasis at first visit (P ¼ 0.0002), non-CRCC histology (P , 0.0001), tumor grade (P ¼ 0.0001), history of metastectomy (P ¼ 0.0002) and MSKCC risk criteria (P , 0.0001) were significant predictors for overall mortality. A history of targeted therapy tended to improve the mortality rate, but it was not statistically significant (P ¼ 0.2093).

DISCUSSION
The years 1997 and 2008 were epoch making for mRCC therapy in Japan in terms of approval for marketing new therapies including IFN-a and targeted drugs. Both therapies changed the therapeutic strategy for metastatic RCC.
Cytokine therapy has been shown to provide a modest survival benefit in several articles (5 -7). The UK Medical Research Council's Renal Cancer Working Party reported the findings of their randomized trial comparing IFN-a with medroxyprogesterone acetate (MPA) (7). They reported a 28% reduction in the risk of death in the IFN-a group (hazard ratio 0.72, P ¼ 0.017) and a 12% improvement in 1-year survival (MPA 31% survival, IFN-a 43%). Moreover, high-dose IL-2 produced response rates of 15 -30%, including some long-term remissions, and was approved for the treatment of mRCC (8 -10). With regard to the Japanese multicenter retrospective analysis for prognosis of mRCC patients in the cytokine era, the median OS time was 21.4 months, which was approximately twice as long as that of previous studies from North America or Europe (11,12). The analysis speculated that this resulted from the higher rate of nephrectomy in Japan, the differences in metastatic number and site, the racial difference and the difference in the health insurance system. Moreover, the analysis proposed that early diagnosis of metastasis, nephrectomy, metastectomy and cytokine-based therapy seemed to improve the prognosis of RCC patients (12).
Targeted therapy has changed the treatment strategy for mRCC since 2008 when sorafenib was approved in Japan. Most prospective studies revealed that targeted therapy could prolong progression-free survival compared with interferon therapy (4,5,13,14), but whether targeted therapy contributed

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Renal cell carcinoma stage migration to improve OS rates is undetermined. In the AVOREN trials, although patients receiving bevacizumab plus IFN-a had significantly prolonged PFS compared with those receiving placebo plus IFN-a (P ¼ 0.0001), OS was not significantly different between the groups (P ¼ 0.0670) (13). Similarly, the superiority of sunitinib over IFN-a in PFS as first-line treatment for mRCC was reported (P , 0.001), but a statistically significant difference was not found in OS (P ¼ 0.056) (4). On the other hand, patients with poor-prognosis mRCC who received temsirolimus had longer OS (P ¼ 0.008) and PFS (P , 0.001) than did those who received IFN-a. Several articles have suggested that the prognosis in patients with mRCC has been improving (2,15). Patil et al. (15) compared OS rates in mRCC patients who were divided into six cohorts between 1975 and 2007 (1975 -1980, 1981 -1985, 1986 -1990, 1991 -1995, 1996 -2001 and 2001 -2007), and suggested that OS increased with each consecutive cohort year group (P , 0.0001). They also reported that the proportion of patients in the poor-risk group has become smaller, whereas the favorable risk group has increased, which would result from earlier detection and diagnosis. Sun et al. (2) computed age-adjusted incidence, survival and mortality rates using the Surveillance, Epidemiology and End Results (SEER) database between 1988 and 2006. Their analysis showed that overall age-adjusted mortality rates for mRCC decreased in a significant fashion over time: 1.8 per 100 000 in 1988 to 1.6 per 100 000 in 2006. They considered that this favorable phenomenon could be the result of a decrease in incidence rates of mRCC and improvement in treatment. Our results also showed a decrease in patients in the MSKCC unfavorable risk group and an increase in T1 patients at first visit, which is considered to have resulted from early detection in screening examinations. However, several articles have reported an increase in the number of grade 3/4 tumors, and decrease in the number of grade 1 tumors in large cohort studies (16,17). Similarly, our cohort was prone to an increase in the number of grade 3 tumors and a decrease in grade 1 tumors. It is not

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Renal cell carcinoma stage migration clear whether this was a true worsening of tumor aggressiveness, but it is clear that more careful screening examinations will be needed.
In the present study, the patients with mRCC in the targeted therapy era tended to show better survival rates than those in the cytokine era but there was no statistical significance despite the similar stage migration to that in previous studies (2,15). There would be several reasons for this. The cytokine era contained patients who also reaped the benefits of targeted therapy. Moreover, the follow-up period was significantly longer in the cytokine era than in the targeted therapy era. There is a possibility of reaching other results if patients in the targeted therapy era are followed for a longer duration.
The present study is a retrospective analysis, and the treatment strategy might have affected the survival rates. Moreover, several pathologists over the years were involved in examining specimens for this sample. A significant change in pathologists might explain some of the findings of the present study. Despite these limitations, the present study is the first analysis on the survival rates of mRCC including the cytokine and targeted therapy eras from an Asian country.

CONCLUSION
The present study did not show improvement in OS with the progression of eras, as reported in other articles. Further investigation and discussion are necessary to determine whether targeted therapy actually improves survival rates.