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- PATIENTS AND METHODS
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Sunitinib is an orally administered, multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3 and platelet-derived growth factor receptors α and β[1,2]. A randomized, prospective phase III clinical trial for systemic treatment-naïve metastatic RCC patients showed the superiority of sunitinib over interferon with respect to objective response rate (ORR) (31% vs 6%), progression-free survival (PFS) (11 vs 5 month) and overall survival (OS) (26.4 vs 21.8 months), with an acceptable safety profile [3,4]. These results indicate an improved prognosis in patients with RCC in the era of targeted therapy.
The first Japanese phase II study of single-agent sunitinib, which was conducted in 51 patients with metastatic RCC, also showed efficacy and tolerability comparable to that observed in Western patients . In that study, the ORR was 52.0% in treatment-naïve patients, 53.8% among cytokine-pretreated patients and 52.9% in the overall population . As a result of these findings, the multinational approvals of sunitinib for treatment of first- and second-line advanced RCC now include Japan.
However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease who are seen in ordinary clinical practice. Many patients with RCC do not meet the inclusion criteria, particularly those with a poorer prognosis. Patients with a poor performance status (PS), brain metastasis or other clinical parameters predicting shorter survival are often excluded from clinical trials. In the present study, we report the treatment efficacy and safety profile of sunitinib for patients with metastatic RCC in ordinary clinical practice. In addition, we also investigated the prognostic clinicopathological factors associated with OS in this population.
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- PATIENTS AND METHODS
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In the present study, we retrospectively analyzed the ORR, PFS, OS and prognostic factors in 63 native Japanese patients, suggesting that the results of the present study could reflect current clinical practice in metastatic RCC in our country. In this cohort, the ORR and clinical benefit (partial response plus stable disease >12 weeks) from sunitinib were 30% and 81%, respectively. These are somewhat lower than the results of a Japanese phase II study (52% and 78%)  but slightly better than the results from an expanded-access programme in Western countries (16% and 76%) . The estimated median PFS and OS in the present study were 9.3 and 32.2 months, respectively. These are also somewhat lower than the results of the Japanese phase II study (12.2 and 33.1 months for treatment-naïve patients and 10.6 and 32.5 months for cytokine-refractory patients) but slightly better than the results from the expanded-access programme in Western countries (10.9 and 18.4 months) [5,10,11]. In addition, it should be noted that 42% of the patients in the present study were still on treatment, which may have resulted in an underestimation of the ORR, as suggested by a recent analysis showing a higher ORR after longer follow-up [3,12].
It is remarkable that the median OS from the initial systemic therapy of the pretreated patients was 79.6 months. In a phase III randomized clinical trial, sunitinib showed longer PFS and OS compared to interferon-α as a first-line therapy for patients with metastatic RCC [3,4]. Interestingly, the OS was not significantly different between the treatment naïve patients and pretreated patients in the present study (not reached and 24.2 months), in the expanded-access programme (18.4 and 18.1 months)  and in the Japanese phase II study (33.1 and 32.5 months, respectively . These results suggest that sunitinib can give a favourable impact as a second-line therapy for patients refractory to cytokine therapy rather than for treatment-naïve patients.
All of the risk factors (ECOG PS >1, low Hb level, high corrected calcium level, high LDH level and ≤12 months between diagnosis and initial systemic therapy) were associated with worse OS in the MSKCC scores, which have been previously identified in patients treated with cytokines (Fig. 1A and Table 2) [8,9]. The application of the respect MSKCC models for the treatment naïve and refractory patients also distinctly separated the OS curves (Fig. 1). This is consistent with recent studies identifying patients who probably will benefit from tyrosine kinase inhibitors [12–15]. These results, as well as those obtained in the present study, indicate that MSKCC scores are associated with the behaviour of the disease rather than with specific forms of therapy. Therefore, MSKCC prognostic factors are still valid for predicting survival in metastatic RCC in the molecular targeted therapy era. However, the distribution of patients according to the MSKCC model is uneven: in the series from the present study, 13%, 62% and 25% of patients belonged to favourable, intermediate and poor risk groups, respectively. The disproportionately large number of patients in the intermediate group suggests that the outcome of this group may be somewhat heterogeneous. The prognostic significance of these factors remains to be verified in a larger study because the present study is only preliminary and has a small number of patients.
Apart from the MSKCC score, brain metastasis and no history of nephrectomy were also independently associated with poorer OS. The cumulative incidence of brain metastases is ≈10%, and these patients are considered to have a poor prognosis (median overall survival, 3–6 months) [16,17]. Although some studies have reported that sunitinib has activity against brain metastasis [18,19], and even against multiple brain lesions , there is insufficient information available about the activity of sunitinib for brain metastasis because most clinical trials have excluded patients with brain metastasis. Intracerebral haemorrhage in RCC patients with brain metastases should be considered as a cautious adverse effect to be treated with tyrosine kinase inhibitors, although the incidence of this remains to be reported. We consider radiotherapy as a primary treatment for patients with brain metastasis; thereafter, targeted therapies could be considered. However, in the present study, no patients suffered intracerebral haemorrhage.
Among the 49 patients who underwent nephrectomy, 22 patients did so as a cytoreductive strategy. Upfront cytoreductive nephrectomy, followed by systemic therapy, has been established as the standard care for metastatic RCC in the cytokine era [20,21]. Targeted agents, including sunitinib, have shown improved outcomes compared to cytokine therapy, transforming the treatment strategy of metastatic RCC. Although many studies focus on the role of cytoreductive nephrectomy in combination with targeted agents for patients with metastatic RCC, cytoreductive nephrectomy is still recommended at least for those patients with currently good PS.
All patients experienced treatment-related adverse events, most of which were grade 1 or 2 in severity, and most patients were able to resume therapy after treatment modification. In particular, the incidence of grade 3/4 haematological toxicities, including anaemia (20%), leucopaenia (9%) and thrombocytopaenia (48%), appears to be higher in the present study compared to the previous worldwide phase III clinical trial data [3,4], and also is consistent with the report from the Japanese phase II clinical trial [5,11].
In conclusion, sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice. The estimated median OS was >2 years with acceptable tolerability. In addition, it should be noted that the median OS from the initial systemic therapy of pretreated patients was >6 years. MSKCC prognostic factors appear to be still valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.