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Japanese Journal of Clinical Oncology Advance Access originally published online on April 10, 2009
Japanese Journal of Clinical Oncology 2009 39(5):310-314; doi:10.1093/jjco/hyp022
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© The Author (2009). Published by Oxford University Press. All rights reserved

Efficacy of Adjuvant Interferon-alpha Therapy Following Curative Resection in Renal Cell Carcinoma: Before the Molecular Targeting Therapy Era

Fumitake Kai, Tatsuya Takayama, Takayuki Sugiyama, Hiroshi Furuse, Soichi Mugiya and Seiichiro Ozono

Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

For reprints and all correspondence: Tatsuya Takayama, Department of Urology, Hamamatsu University School of Medicine, 1-20-1 Higashi-ku Handayama, Hamamatsu, Shizuoka 431-3192, Japan. E-mail: ttakayam{at}hama-med.ac.jp

Received November 6, 2008; accepted February 20, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Objective: Although present treatment programs for renal cell carcinoma (RCC) typically involve molecular-targeting drugs, interferon-alpha (IFN-{alpha}) remains an important therapeutic drug for this cancer.

Methods: We evaluated the effect of adjuvant therapy in 508 patients with RCC following curative surgery. Patients were classified into one of the two categories based on the duration and the total dose of IFN-{alpha} treatment.

Results: Median follow-up time was 65.5 months. Overall survival rates at 5, 10, 15 and 20 years were 88.8%, 80.5%, 69.6% and 54.1%, respectively. Cause-specific survival rates at 5, 10, 15 and 20 years were 95.0%, 89.1%, 83.0% and 83.0%, respectively. Cox’s proportional hazard model revealed that C-reactive protein, T classification, histological grade and age were significantly independent factors indicative of a poor prognosis. Our examination of the 253 patients diagnosed as pT1-2N0M0 who underwent adjuvant IFN-{alpha} therapy following surgery found that the therapy was not significantly associated with either cause-specific or disease-free survival. With regard to effects of duration of therapy and total dose of IFN-{alpha}, patients with a total IFN-{alpha} exposure of ≥180 x 106 international units (IU) had a better prognosis than those exposed to <180 x 106 IU.

Conclusions: Adjuvant therapy using large doses of IFN-{alpha} may improve the prognosis of patients with RCC following curative resection, and the new possibility of IFN-{alpha} therapy merits further investigation.

Key Words: renal cell carcinoma • IFN-{alpha} • prognostic factor


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Although present treatment programs for renal cell carcinoma (RCC) typically involve molecular-targeting agents (1), interferon-alpha (IFN-{alpha}) remains an important therapeutic drug in treating this cancer (2).

Here, we performed a multivariate analysis of clinical variables in 508 patients with RCC to identify prognostic factors important for long-term survival. Further, we retrospectively investigated the effect of treatment with IFN-{alpha} on both cause-specific and disease-free survival in patients with RCC following curative resection.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
We retrospectively examined the medical records of 755 patients with RCC admitted to the Department of Urology at Hamamatsu University Hospital and affiliated hospitals between 1978 and 2004. We then identified the 508 patients diagnosed as pT1-2N0M0 as those with RCC following curative resection and evaluated the effect of adjuvant therapy with IFN-{alpha} in these patients.

Clinical characteristics of the 508 patients were gender, age, tumor laterality, Eastern Cooperative Oncology Group performance status (ECOG PS), mode of tumor discovery, C-reactive protein (CRP), T classification, cell type, histological grade, infiltration mode and venous invasion. The cut-off of CRP was based on the value of reference range in each hospital. Tumors were graded according to the criteria of the Japanese Urological Association (3) and the TNM system (4).

The Kaplan–Meier method was used to estimate survival rates. The log-rank test and Cox’s proportional hazard model were used for univariate and multivariate analysis, respectively. Differences were considered statistically significant at P < 0.05. All analyses were conducted using StatView ver. 5.0J (SAS Institute Inc., Cary, NC, USA).


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Of the 508 patients, the male-to-female ratio was 2.22. The mean patient age was 59.5 ± 12.7 years (range 15–86). With regard to kidney involvement, the right was involved in 284 (55.9%) and the left in 219 (43.1%). In one (0.2%) patient, RCC was bilateral. The mode of tumor discovery was incidental in 358 patients (70.5%), symptomatic in 143 (28.1%) and unknown in 7 (1.4%). CRP was negative in 370 patients (72.8%), positive in 118 (23.2%) and unknown in 20. Clinical and pathological characteristics of the patients are summarized in Table 1.


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  		Table 1. Clinical and pathological characteristics of 508 patients with RCC

 
The median follow-up time was 65.5 ± 52.0 months (range 1–283). Overall, cause-specific and disease-free survival rates at 5, 10, 15 and 20 years were 88.8%, 80.5%, 69.6% and 54.1%; 95.0%, 89.1%, 83.0% and 83.0%; and 94.5%, 88.2%, 83.2% and 83.2%, respectively (Fig. 1).


Figure 1
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  		Figure 1. Survival curves for 508 patients with renal cell carcinoma. Overall survival (OAS), cause-specific survival (CSS) and disease-free survival (DFS) rates at 5, 10, 15 and 20 years were 88.8%, 80.5%, 69.6% and 54.1%; 95.0%, 89.1%, 83.0% and 83.0%; and 94.5%, 88.2%, 83.2% and 83.2%, respectively.

 
Patients were divided into two groups based on the most significant difference according to the analysis of cause-specific survival rates (Table 2). Univariate analysis showed that the prognostic factors significant for survival were age, mode of discovery, CRP, T classification and histological grade. Multivariate analysis showed that four of the factors (CRP, T classification, histological grade and age) were independent of prognosis, the odds ratios of which were 3.873, 3.067, 3.237 and 2.438, respectively.


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  		Table 2. Prognostic significance for cause-specific survival in patients with RCC

 
With regard to disease-free survival, four prognostic factors (mode of discovery, CRP, T classification and infiltration mode) were found to be significant by univariate analysis (odds ratios 3.873, 3.067, 3.237 and 2.438, respectively) (Table 3), and two factors (CRP and T classification) were found to be independent of prognosis by multivariate analysis. In the present study, only CRP and T classification were significant prognostic factors in both cause-specific and disease-free survival.


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  		Table 3. Prognostic significance for disease-free survival in patients with RCC

 
Among the 508 patients who underwent curative resection, 480 underwent radical nephrectomy (including laparoscopic surgery in 27) and 28 had nephron-sparing surgery. Two hundred and fifty-three patients (49.8%) received adjuvant therapy by IFN-{alpha} and 255 (50.2%) without adjuvant therapy. This decision was made by the chief doctor based on examination of each patient.

During the follow-up period, 447 patients were alive, 28 died of cancer and 33 died of other diseases. Recurrence of RCC was seen in 43 patients (including lung only in 14, bone only in 10, multiple organs in 8 and opposite kidney in 3).

Univariate analysis showed that adjuvant therapy with IFN-{alpha} was not significantly associated with either cause-specific or disease-free survival (Table 2, 3). On dividing the 253 patients treated with adjuvant IFN-{alpha} therapy into two subgroups based on duration of treatment (<12 or ≥12 months), the duration of IFN-{alpha} therapy was not found to be significantly correlated with cause-specific or disease-free survival (Table 4). The 253 patients treated with adjuvant IFN-{alpha} therapy were also divided into two categories based on total dose of IFN-{alpha}. The median total dose in these patients was 180 x 106 international units (IU) (range = 6–4356 x 106 IU). As shown in Table 4, patients receiving a large total dose (≥180 x 106 IU) had a better prognosis for cancer-specific survival than those receiving a small dose (<180 x 106 IU), although the same relationship was not seen with disease-free survival. With regard to the large-dose group, we also examined the relationship between these results and CRP and T classification, significant prognostic factors for survival. As depicted in Fig. 2, the cause-specific survival among CRP-positive patients in the large-dose group was better than that of CRP-positive patients in the small-dose group. On dividing T classification into T1 and T2, the cause-specific survival among T1 status in the large-dose group was better than that of T1 status in the small-dose group. With regards to T2 status, the large-dose group appeared to be a trend toward better prognosis. Adjuvant therapy with IFN-{alpha} after curative resection in T1-2N0M0 patients was not significantly associated with either cause-specific or disease-free survival in our study.


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  		Table 4. Cause-specific and disease-free survival rates of 253 RCC patients with adjuvant therapy by IFN-{alpha}

 

Figure 2
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  		Figure 2. Cause-specific survival rates of 253 RCC patients who received adjuvant therapy with IFN-{alpha}. Large dose = total IFN-{alpha} dose of ≥180 x 106 IU; small dose, <180 x 106 IU. RCC, renal cell carcinoma; IFN, interferon; IU, international units.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
Our study conducted in 508 patients with RCC who underwent curative resection found that IFN-{alpha} therapy was not significantly associated with either cause-specific or disease-free survival. However, patients receiving a total IFN-{alpha} exposure of ≥180 x 106 IU had a better prognosis than those exposed to <180 x 106 IU. Molecular-targeting drugs now widely used in the treatment of advanced RCC, whereas the use of IFN therapy is gradually decreasing. However, IFN is safer and less expensive than molecular-targeting drugs. We are, moreover, familiar with IFN. Taken together, the usefulness of adjuvant IFN therapy in the treatment of RCC, particularly its effectiveness, duration of treatment and the volume of IFN, must be reconsidered.

Several studies have determined prognostic factors of RCC by multivariate analysis. Among prognostic factors, tumor stage, nuclear grade, DNA ploidy and nuclear morphometry, tumor size, lymph node metastasis, distant metastasis, tumor histology and venous invasion are generally thought to be important prognostic factors, whereas laboratory values such as an elevated erythrocyte sedimentation rate, hypercalcemia, anemia, elevated levels of lactate dehydrogenase, CRP and immunosuppressive acidic protein are associated with progression in RCC (5–11), and several recent reports have cited the influence of CRP presence in particular.

Masuda et al.’s (12) report documenting the prognostic factors of 320 patients with RCC treated at our institution between 1978 and 1995 found that age, N classification and M classification were the most important prognostic factors conducive to predicting long-term survival of these patients. A portion of these records were also included in the present study when we reviewed pT1-2N0M0 RCC patients who underwent curative surgery, with CRP and T classification as significant prognostic factors.

Gotoh et al. (13) investigated the long-term efficacy of adjuvant therapy with IFN-{alpha} in T1-3bN0M0 patients who underwent curative resection. Subjects were divided into three groups according to the IFN-{alpha} administration duration (≤6 months, from 6 months to <1 year and ≥1 year); however, results found no statistical significance with either cause-specific or disease-free survival. Similarly, we also found no significance between administration duration and survival. Basting et al. (14) reported that adjuvant therapy with IFN-{alpha} provided no significant benefit in the treatment of non-metastatic RCC and that tumor stage was not a suitable factor for selecting patients who may potentially respond well to IFN-{alpha} therapy. Migliari et al. (15) also studied the efficacy of adjuvant chemo-immunotherapy combining IFN-{alpha} and vinblastine in pT2-3N0M0 patients after curative resection, but found no significant benefit in the treatment.

With regard to the present study, we evaluated the efficiency of adjuvant therapy with IFN-{alpha} for pT1-2N0M0 RCC patients after curative resection. Although the therapy failed to exhibit a significant effect on either cause-specific or disease-free survival, patients in our study population receiving a total IFN-{alpha} administration of ≥180 x 106 IU had a better prognosis than those receiving <180 x 106 IU. Further, CRP-positive patients also appeared to enjoy a better prognosis. Careful examination of these data suggests that large-dose adjuvant IFN therapy may improve prognosis for patients with localized RCC.

Findings from the present study were similar to those of previous studies, showing that adjuvant IFN therapy was not effective as a prophylactic treatment for RCC patients after curative surgery. However, our findings do suggest that large-dose IFN-{alpha} treatment may improve the prognosis of RCC patients after curative resection, particularly among CRP-positive patients. New possibilities for the use of IFN-{alpha} therapy merit investigation, while simultaneously continuing current use of molecular-targeting drugs, such as sorafenib, sutent and other agents in the future.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This study was supported in part by a Grant-in-Aid for Scientific Research (C) (20591854) from The Ministry of Education, Culture, Sports, Science and Technology in Japan.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   Acknowledgments
 
We thank all the members for collecting clinical and pathological data to the present study, as follows: Kazuo Suzuki, Tomomi Ushiyama, Hiroshi Furuse, Nobuo Tsuru, Atsushi Otsuka, Hitoshi Shinbo, Masaki Harada, Takahiro Aoki and Masao Nagata, Hamamatsu University Hospital, Hamamatsu, Shizuoka; Yutaka Kurita and Takeshi Imanishi, JA Shizuoka Kohseiren Ensyu Hospital, Hamamatsu, Shizuoka; Tetsuya Watanabe, Maruyama Hospital, Hamamatsu, Shizuoka; Hiroyuki Ihara and Taisuke Suzuki, Kikugawa General Hospital, Kikugawa, Shizuoka; Toshimasa Nakanishi and Rikiya Matsumoto, Kosai General Hospital, Kosai, Shizuoka; Hiroshi Terada, Social Insurance Hamamatsu Hospital, Hamamatsu, Shizuoka; Nobutaka Ota, Makoto Suzuki, Shinsuke Hayami, Yoshitoku Tamashiro and Nariaki Nishijima, Yaizu City Hospital, Yaizu, Shizuoka; Akihiko Suzuki, Takuji Mizuno and Shin-ichi Akabane, Shinshiro Municipal Hospital, Shinshiro, Aichi; Sanki Takada, Public Morimachi Hospital, Mori, Shizuoka; Shigenori Sato and Daisuke Motoyama, Haibara General Hospital, Haibara, Shizuoka; Hiroshi Nagae, Shinsuke Hadano, Satoshi Maruyama and Toshiki Ito, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka; Shinya Kudo and Atsushi Sato, Seirei Hamamatsu General Hospital, Hamamatsu, Shizuoka; Takatoshi Usami and Takanori Uchida, Fukuroi Municipal Hospital, Fukuroi, Shizuoka; Yoshio Aso, Yasuhiro Hirano, Masanobu Aoki and Takashi Sato, Fujieda Municipal General Hospital, Fujieda, Shizuoka; Tomoyuki Kanbayashi and Kazuhiro Saisu, Iwata City Hospital, Iwata, Shizuoka; Hiroshi Sudoko, Toshiyuki Un-no and Shunsuke Nobata, Fujinomiya City General Hospital, Fujinomiya, Shizuoka, Japan.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
1 Chowdhury S, Larkin JM, Gore ME. Recent advances in the treatment of renal cell carcinoma and the role of targeted therapies. Eur J Cancer (2008) 44:2152–61.[CrossRef][Web of Science][Medline]

2 Naito S, Yamamoto N, Takayama T, Muramoto M, Shinohara N, Nishiyama K, et al. Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients. Eur Urol (2009) (January 3, Epub ahead of print).

3 Union international Contre le Cancer. TNM Atlas. (1997) 4th edn. Berlin: Springer-Verlag.

4 The Japanese Urological Association, the Japanese Society of Pathology, and Japan Radiological Society. General Rules for Clinical and Pathological Studies on Renal Cell Carcinoma. (1999) 3rd edn. Tokyo: Kanehara & Co. Ltd.

5 Yasunaga Y, Shin M, Miki T, Okuyama A, Aozasa K. Prognostic factors of renal cell carcinoma—a multivariate analysis. J Surg Oncol (1998) 68:11–8.[CrossRef][Web of Science][Medline]

6 Takashi M, Nakano Y, Sakata T, Miyake K, Hamajima N. Multivariate evaluation of prognostic determinants for renal cell carcinoma. Urol Int (1993) 50:6–12.[Web of Science][Medline]

7 Thrasher JB, Paulson DF. Prognostic factor in renal cancer. Urol Clin North Am (1993) 20:247–62.[Web of Science][Medline]

8 Strohmeyer T, Ackermann R. Classic and modern prognostic indication in renal cell carcinoma. Urol Int (1991) 47:203–12.[CrossRef][Web of Science][Medline]

9 Selli C, Hinshaw WM, Woodard BH, Paulson DF. Stratification of risk factors in renal cell carcinoma. Cancer (1983) 52:899–903.[CrossRef][Web of Science][Medline]

10 Nurmi M. Prognostic factor in renal cell carcinoma. An evaluation of operative findings. Br J Urol (1984) 56:270–5.[CrossRef][Web of Science][Medline]

11 Saito K, Tatokoro M, Fujii Y, Iimura Y, Koga F, Kawakami S, et al. Impact of C-reactive protein kinetics on survival of patients with metastatic renal cell carcinoma. Eur Urol (2009) 55:1145–1154.[CrossRef]

12 Masuda H, Kurita Y, Suzuki A, Kanbayashi T, Suzuki K, Fujita K. Prognostic factors for renal cell carcinoma: a multivariate analysis of 320 cases. Int J Urol (1997) 4:247–53.[Medline]

13 Gotoh A, Shirakawa T, Hinata N, Wada Y, Hara I, Fujisawa M, et al. Long-term outcome of postoperative interferon-{alpha} adjuvant therapy for non-metastatic renal cell carcinoma. Int J Urol (2004) 11:257–63.[CrossRef][Web of Science][Medline]

14 Basting R, Corvin S, Händel D, Hinke A, Schmidt D. Adjuvant immunotherapy in renal cell carcinoma—comparison of interferon alpha treatment with an untreated control. Anticancer Res (1999) 19–2c:1545–8.

15 Migliari R, Muscas G, Solinas A, Melis M, Ionta MT, Massidda B, et al. Is there a role for adjuvant immunochemotherapy after radical nephrectomy in pT2-3N0M0 renal cell carcinoma? J Chemother (1995) 7–3:240–5.


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This Article
Right arrow Abstract Freely available
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39/5/310    most recent
hyp022v1
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