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Re: Adjuvant Sunitinib in High-risk Renal-cell Carcinoma after Nephrectomy
EURURO-7220; No. of Pages 2 EUROPEAN UROLOGY XXX (2017) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Adjuvant Sunitinib in High-risk Renal-cell Carcinoma after Nephrectomy Ravaud A, Motzer RJ, Pandha HS, et al N Engl J Med 2016;375:2246–54 Expert’s summary: In this phase 3 trial (S-TRAC, NCT00375674), 1 yr of adjuvant sunitinib was compared with placebo in patients who underwent full surgical resection of high-risk clear cell renal-cell carcinoma (RCC). Sunitinib was administered orally at a dose of 50 mg/d in the classic 4-wk on/2-wk off schedule. The primary endpoint was disease-free survival, which was significantly prolonged in the sunitinib arm (hazard ratio: 0.76, 95% confidence interval: 0.59–0.98, p = 0.03). There were no differences in overall survival (hazard ratio: 1.01, 95% confidence interval: 0.72–1.44, p = 0.94). The incidence of Grade 3 and 4 adverse events was 48% in the sunitinib arm and 12% in the placebo arm. Forty-six percent of patients in the sunitinib arm had dose reductions, of which > 90% were due to adverse events [1]. Expert’s comments: More than 50% of patients with high-risk RCC will recur following complete surgical resection [2], which is likely due to growth of microscopic metastases that are present at the time of diagnosis or which develop during the perioperative period. The aim of an adjuvant therapy is to eradicate these microscopic metastases, and ultimately improve disease-free and overall survival. Several adjuvant trials have been initiated to eradicate these possible microscopic tumour deposits, including trials with sunitinib, sorafenib, pazopanib, and axitinib. These therapies have been the standard of care in the palliative setting for about a decade; however, complete tumour eradication of visible metastases has rarely been reported. The present study showed that the risk for disease recurrence is reduced by 24% with adjuvant sunitinib, with a 5-yr disease-free survival rate of 59% in the sunitinib arm, and 51% in the placebo arm. This difference in disease-free survival developed within the 1st yr and remained relatively stable thereafter. Thus, it appears that sunitinib discontinuation after 1 yr does not lead to rebound growth of microscopic metastases due to revascularisation. Patients in the sunitinib arm did not have improved overall survival [1]; however, these data are crucial as sunitinib is frequently used as first line treatment after progression. According to
Ravaud et al [1], overall survival data as secondary endpoints were not yet mature. However, the hazard ratio for overall survival was close to 1, and no trend in favour of any arm was seen after a relatively long follow-up interval of 5+ yr. Given the fact that the majority of patients recurred within the 1st 2 yr and that the median overall survival time of patients with metastatic disease is about 2 yr, the author feels that the follow-up interval should be sufficient to demonstrate a trend. Thus, the author thinks that it is unlikely that an overall survival benefit will be demonstrated in this cohort. Adverse events under sunitinib were prevalent and frequently led to a dose reduction. In clinical practice, the management of patients with Grade 3 or 4 adverse events may be more difficult in the adjuvant than in the palliative setting. ASSURE (NCT00326898) compared adjuvant sunitinib or sorafenib to placebo in 1943 patients with high-risk RCC. In contrast to S-TRAC, the ASSURE trial was completely negative, with no significant differences among the three groups (hazard ratio: 1.02, p = 0.8 and hazard ratio: 0.97, p = 0.7). The selection of high-risk patients was slightly different in both trials, but these differences cannot explain the conflicting results. Comparably, a significant proportion of patients experienced Grade 3 or 4 adverse events. In ASSURE, there were five deaths related to treatment or occurring within 30 d of the end of treatment [2]. How should we proceed with high-risk RCC in clinical practice? The author agrees with the recent statement by the European Association of Urology Guidelines Group that, at present, sunitinib should not be recommended to highrisk patients after complete tumour removal [3]. Differences in disease-free survival may be minor or not present at all, and an overall survival benefit has not been demonstrated. Meta-analyses were attempted [4], but will not replace further trials. Finally, the risk of toxicities is not balanced by possible minor improvements in outcomes. Conflicts of interest: The author has nothing to disclose.
References [1] Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016;375: 2246–54. [2] Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN
http://dx.doi.org/10.1016/j.eururo.2017.01.026 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EURURO-7220; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2017) XXX–XXX
E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387:2008–16.
Tobias Klatte* Department of Urology, Medical University of Vienna, Vienna, Austria
[3] Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines regarding adjuvant therapy for renal cell carcinoma. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2016.11.034. [4] Gyawali B, Ando Y. Adjuvant sunitinib for high-risk resected renal cell carcinoma: a meta-analysis of ASSURE and S-TRAC trials. Ann Oncol. In press. http://dx.doi.org/10.1093/annonc/mdw667.
*Department of Urology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected].
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Adjuvant Sunitinib in High-risk Renal-cell Carcinoma after Nephrectomy Ravaud A, Motzer RJ, Pandha HS, et al N Engl J Med 2016;375:2246–54 Expert’s summary: In this phase 3 trial (S-TRAC, NCT00375674), 1 yr of adjuvant sunitinib was compared with placebo in patients who underwent full surgical resection of high-risk clear cell renal-cell carcinoma (RCC). Sunitinib was administered orally at a dose of 50 mg/d in the classic 4-wk on/2-wk off schedule. The primary endpoint was disease-free survival, which was significantly prolonged in the sunitinib arm (hazard ratio: 0.76, 95% confidence interval: 0.59–0.98, p = 0.03). There were no differences in overall survival (hazard ratio: 1.01, 95% confidence interval: 0.72–1.44, p = 0.94). The incidence of Grade 3 and 4 adverse events was 48% in the sunitinib arm and 12% in the placebo arm. Forty-six percent of patients in the sunitinib arm had dose reductions, of which > 90% were due to adverse events [1]. Expert’s comments: More than 50% of patients with high-risk RCC will recur following complete surgical resection [2], which is likely due to growth of microscopic metastases that are present at the time of diagnosis or which develop during the perioperative period. The aim of an adjuvant therapy is to eradicate these microscopic metastases, and ultimately improve disease-free and overall survival. Several adjuvant trials have been initiated to eradicate these possible microscopic tumour deposits, including trials with sunitinib, sorafenib, pazopanib, and axitinib. These therapies have been the standard of care in the palliative setting for about a decade; however, complete tumour eradication of visible metastases has rarely been reported. The present study showed that the risk for disease recurrence is reduced by 24% with adjuvant sunitinib, with a 5-yr disease-free survival rate of 59% in the sunitinib arm, and 51% in the placebo arm. This difference in disease-free survival developed within the 1st yr and remained relatively stable thereafter. Thus, it appears that sunitinib discontinuation after 1 yr does not lead to rebound growth of microscopic metastases due to revascularisation. Patients in the sunitinib arm did not have improved overall survival [1]; however, these data are crucial as sunitinib is frequently used as first line treatment after progression. According to
Ravaud et al [1], overall survival data as secondary endpoints were not yet mature. However, the hazard ratio for overall survival was close to 1, and no trend in favour of any arm was seen after a relatively long follow-up interval of 5+ yr. Given the fact that the majority of patients recurred within the 1st 2 yr and that the median overall survival time of patients with metastatic disease is about 2 yr, the author feels that the follow-up interval should be sufficient to demonstrate a trend. Thus, the author thinks that it is unlikely that an overall survival benefit will be demonstrated in this cohort. Adverse events under sunitinib were prevalent and frequently led to a dose reduction. In clinical practice, the management of patients with Grade 3 or 4 adverse events may be more difficult in the adjuvant than in the palliative setting. ASSURE (NCT00326898) compared adjuvant sunitinib or sorafenib to placebo in 1943 patients with high-risk RCC. In contrast to S-TRAC, the ASSURE trial was completely negative, with no significant differences among the three groups (hazard ratio: 1.02, p = 0.8 and hazard ratio: 0.97, p = 0.7). The selection of high-risk patients was slightly different in both trials, but these differences cannot explain the conflicting results. Comparably, a significant proportion of patients experienced Grade 3 or 4 adverse events. In ASSURE, there were five deaths related to treatment or occurring within 30 d of the end of treatment [2]. How should we proceed with high-risk RCC in clinical practice? The author agrees with the recent statement by the European Association of Urology Guidelines Group that, at present, sunitinib should not be recommended to highrisk patients after complete tumour removal [3]. Differences in disease-free survival may be minor or not present at all, and an overall survival benefit has not been demonstrated. Meta-analyses were attempted [4], but will not replace further trials. Finally, the risk of toxicities is not balanced by possible minor improvements in outcomes. Conflicts of interest: The author has nothing to disclose.
References [1] Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med 2016;375: 2246–54. [2] Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN
http://dx.doi.org/10.1016/j.eururo.2017.01.026 0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EURURO-7220; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2017) XXX–XXX
E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387:2008–16.
Tobias Klatte* Department of Urology, Medical University of Vienna, Vienna, Austria
[3] Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines regarding adjuvant therapy for renal cell carcinoma. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo. 2016.11.034. [4] Gyawali B, Ando Y. Adjuvant sunitinib for high-risk resected renal cell carcinoma: a meta-analysis of ASSURE and S-TRAC trials. Ann Oncol. In press. http://dx.doi.org/10.1093/annonc/mdw667.
*Department of Urology, Medical University of Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria. E-mail address: [email protected].