Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with renal insufficiency

BackgroundPatients with metastatic renal cell carcinoma (mRCC) with renal insufficiency are generally excluded from clinical trials, despite their increasing numbers. Thus, we evaluated the efficacy and toxicity of sunitinib in such patients.Patients and methodsKorean patients with mRCC with renal insufficiency who had received sunitinib as first-line treatment between January 2008 and May 2012 were included. Patient characteristics, clinical outcomes and toxicities were evaluated. Overall survival (OS) and progression-free survival (PFS) were determined according to the degree of renal impairment.ResultsThe median age of the 34 patients evaluated was 66 years, 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1 and the median glomerular filtration rate was 46.5 mL min⁻¹·1.73 m⁻² (range, 21.1–59.5). The starting sunitinib dose was 37.5 and 50 mg for 12 and 22 patients, respectively. A 4-weeks-on–2-weeks-off regimen was followed for 31 patients; a 2-weeks-on–2-weeks-off regimen, for one patient; and a daily regimen, for two patients. The best response was partial response in eight patients and stable disease in 12. Median OS and PFS times were 26.3 months (95% confidence interval [CI]: 17.1–35.3) and 12.2 months (95% CI: 10.2–13.2), respectively. Common non-haematologic adverse events (AEs) were stomatitis, rash, general oedema and fatigue. The most common AEs of ⩾grade 3 severity were fatigue, neutropenia and thrombocytopenia.ConclusionsIn patients with mRCC with renal insufficiency, sunitinib was efficacious and did not cause increased toxicity. Thus, clinicians should not hesitate to treat patients with mRCC with renal insufficiency with sunitinib.     

A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma

Treatment of metastatic renal cell carcinoma (mRCC) with sunitinib is often associated with toxicity necessitating dose reduction. Maintaining adequate dosing and drug levels are essential for optimising clinical efficacy. Standard sunitinib schedule is 4 weeks of treatment and 2 weeks of rest (schedule 4/2). Empirically, several mRCC patients at The Cleveland Clinic (CCF) have been changed from schedule 4/2 to 2 weeks of treatment/1 week off (schedule 2/1) after experiencing toxicity, in an attempt to maintain daily dosing.The medical records of 30 mRCC patients on sunitinib who were changed from schedule 4/2 to schedule 2/1 at CCF were retrospectively reviewed. Toxicity on each schedule was recorded during routine clinic visits and graded using Common Toxicity Criteria, version 4.0.97% of patients on schedule 4/2 had grade 3 or 4 toxicity that led to changing to schedule 2/1. There were no grade 4 toxicities on schedule 2/1, and 27% of patients experienced grade 3 toxicity (p = 0.0001). Two of the most common toxicities, fatigue and hand–foot syndrome (HFS), were significantly less frequent on schedule 2/1 than on schedule 4/2 (p = 0.0003; p = 0.0004, respectively). Median overall treatment duration on schedule 4/2 was 12.6 months (range 1.2 months–5.1 years) and median overall treatment duration on schedule 2/1 was 11.9 months (range 0.9+ to 73.3+ months).Treatment with sunitinib on schedule 2/1 is associated with significantly decreased toxicity in patients who experience grade 3 or greater toxicity on schedule 4/2, and can extend treatment duration considerably. Prospective clinical trials are required to define the optimal sunitinib schedule to balance efficacy and toxicity.     

Statins and survival outcomes in patients with metastatic renal cell carcinoma

BackgroundA growing body of evidence has demonstrated the anti-neoplastic activity of statins. The objective of this study was to investigate the effect of statin use on survival in patients with metastatic renal cell carcinoma (mRCC) treated in the modern therapy era.Patients and methodsWe conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression and the Kaplan–Meier method.ResultsWe identified 4736 patients treated with sunitinib (n = 1059), sorafenib (n = 772), axitinib (n = 896), temsirolimus (n = 457), temsirolimus + interferon (IFN)-α (n = 208), bevacizumab + temsirolimus (n = 393), bevacizumab + IFN-α (n = 391) or IFN-α (n = 560), of whom 511 were statin users. Overall, statin users demonstrated an improved overall survival (OS) compared to non-users (25.6 versus 18.9 months, adjusted hazard ratio [aHR] 0.801, 95% confidence interval [CI] 0.659–0.972, p = 0.025). When stratified by therapy type, a benefit in OS was demonstrated in statin users compared to non-users in individuals receiving therapy targeting vascular endothelial growth factor (28.4 versus 22.2 months, aHR 0.749, 95% CI 0.584–0.961, p = 0.023) or mammalian target of rapamycin (18.6 versus 14.0 months, aHR 0.657, 95% CI 0.445–0.972, p = 0.035) but not in those receiving IFN-α (15.6 versus 14.8 months, aHR 1.292, 95% CI 0.703–2.275, p = 0.410). Adverse events were similar between users and non-users.ConclusionsWe demonstrate that statin use may be associated with improved survival in patients with mRCC treated in the targeted therapy era. Statins could represent an adjunct therapy for patients with mRCC; however, this is hypothesis generating and requires prospective evaluation.     

Small tumour size is associated with new-onset chronic kidney disease after radical nephrectomy in patients with renal cell carcinoma

BackgroundTo investigate the impact of tumour size on postoperative glomerular filtration rate (GFR) in patients undergoing radical nephrectomy (RN) for renal cell carcinoma (RCC).MethodsWe retrospectively identified 1371 patients who underwent RN between 1995 and 2010. Serum creatinine levels were measured preoperatively, within 7 days of RN, at 3 months, 1 and 3 years. We divided patients into three groups based on tumour size: A: ⩽4 cm, B: 4–7 cm, C: >7 cm. The changes in GFR were compared and multivariate logistic regression was used to analyse the predictive value of tumour size for new-onset chronic kidney disease (CKD, GFR < 60 mL/min/1.73 m²).ResultsThe preoperative GFR was significantly different among the three groups (A: 83.0, B: 82.0, C: 79.4 ml/min/1.73 m², P = 0.040). The decrease in GFR from preoperative to within 7 days was greater in group A than in groups B and C (28.2 versus 24.2 versus 18.5 ml/min/1.73 m², P < 0.001). The GFR at 1 year postoperative was lower in group A than in group C (58.4 versus 61.5 ml/min/1.73 m², P = 0.009), in contrast to preoperative GFR. The incidence of GFR decrease >30% was higher in Group A than in Groups B and C at 1 year (52.4% versus 41.5% versus 33.7%, P < 0.001). On multivariate analysis Groups A and B had a 2.37-fold (95% confidence interval (CI) 1.56–3.60, P < 0.001) and 2.24-fold (95% CI 1.49–3.38, P < 0.001) higher risk of new-onset CKD compared with Group C.ConclusionsSmall tumour size is associated with CKD after RN. Partial nephrectomy should be considered in patients with tumour size 7 cm or less.     

An indirect comparison of the toxicity of sunitinib and pazopanib in metastatic clear cell renal cancer

BackgroundBoth sunitinib and pazopanib are widely used as first line therapy in metastatic renal cancer (mRCC). The efficacy of these agents appears similar but they may have distinct toxicity profiles. In this study we compare the severity of symptomatic and asymptomatic toxicity associated with sunitinib and pazopanib.MethodsTwo sequential prospective single arm phase II studies investigated either 12 weeks of sunitinib (n = 43) or pazopanib (n = 34) prior to nephrectomy in untreated mRCC. Toxicity was defined as either symptomatic (hand and foot syndrome, mucositis, nausea, fatigue, diarrhoea, oedema, headache, pain, anorexia and change in taste) or asymptomatic (liver toxicity or haematological toxicity). Pazopanib (800 mg once daily (OD)) and sunitinib (50 mg 4/2) were given. Regular Common Toxicity Criteria (CTC) toxicity assessment was performed during the first 12 weeks of therapy.ResultsThere was no significant difference in the overall number of toxic events (grade 1–4) for sunitinib and pazopanib (mean number of toxic events/patients: 1.97 versus 1.96: p > 0.05). Increased grade 2–4 symptomatic toxicity events occurred with sunitinib (hazard ratio (HR) 1.67 [95% confidence interval (CI): 1.11–2.56] p < 0.03). Sunitinib was associated with an increased grade 2–4 mucositis (16% versus 0% p = 0.02) and fatigue (42% versus 15% p = 0.01). Pazopanib was associated with more frequent grade 1 diarrhoea (39% versus 12%: p = 0.03). Dose reductions for symptomatic toxicity occurred more frequently with sunitinib (26% versus 6% p < 0.05). There was no difference in the occurrence of asymptomatic toxicity.ConclusionThis indirect analysis suggests sunitinib and pazopanib have distinct toxicity profiles which may help guide patient’s choice. Further comparative data from randomised trials are awaited.     

Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: Results from a large patient cohort

AimA number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, this study evaluates their outcome.MethodsPatients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS) – defined as the time from start of first-line to progression on third-line treatment – were estimated using the Kaplan–Meier method and curves were compared with log-rank test.ResultsA total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)–VEGFi–mTORi compared with those receiving VEGFi–mTORi–VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively).ConclusionsFew patients received three lines of TTs. The sequence VEGFi–VEGFi–mTORi was associated with improved survival with respect to VEGFi–mTORi–VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.     

Isolated loco-regional recurrence after radical nephrectomy for renal cell carcinoma: A study of 22 patients

ObjectiveThis study aimed to assess prognosis of isolated local recurrence (ILR) of renal cell carcinoma (RCC) after radical nephrectomy (RN).Patients and MethodsThis retrospective study involved 22 cases (16 men and 6 women) of ILR from two centers with a mean age of 60.1 ± 8.5 years. All cases were managed surgically.ResultsPrimary tumors were mainly clear cell carcinoma (n = 17). Nine patients had T3 and T4 tumors. Local recurrence involved mainly the operative bed (n = 17); 4 among them had nodal recurrence as well. The median interval to local recurrence was 13.5 months (7–25 months). Stages T3 and T4 were significantly associated with shorter interval. Complete excision was possible in 9 patients (41%); 8 tumors were irresectable. It was associated with significantly higher overall and median disease-free survival (DFS). Advanced disease stage (p = 0.002) and shorter interval to recurrence (p < 0.001) were associated with higher proportion of incomplete excision. The median overall survival and DFS were 15 months (95% CI: 4.4–25.6) and 10 months (95% CI: 4.5–15.5), respectively. Overall and DF survival were significantly better in patients with nodal recurrence only, complete excision of the recurrence and interval from nephrectomy to recurrence >15 months.ConclusionILR after radical nephrectomy for RCC is more common with more advanced stages, where interval to recurrence tends to be shorter. The management should be surgical, which was possible in nearly 60% of cases. Complete excision was associated with better overall and disease free survival.     

The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma

BackgroundSunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). The neutrophil to lymphocyte ratio (NLR), an index of systemic inflammation, is associated with outcome in several cancer types.AimsTo study the association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival (PFS) and overall survival (OS) of patients treated with sunitinib for mRCC.MethodsWe retrospectively studied an unselected cohort of patients with mRCC, who were treated with sunitinib. Logistic regression model was used to analyse response rate. Cox regression models were fitted to identify risk factors associated with PFS and OS. We investigated how pre-treatment NLR is associated with these clinical outcomes after adjusting for confounding covariates. Regression tree for censored data method was used to find the best NLR cut-off value.ResultsBetween 2004 and 2011, 133 patients with mRCC were treated with sunitinib. One hundred and nine were included in the NLR analysis, from which were excluded patients without available data on pre-treatment NLR or with comorbidities/recent treatments known to be associated with a change of blood counts. Factors associated with PFS were low NLR ⩽ 3 (HR = 0.285, p < 0.001), past nephrectomy (HR = 0.38, p = 0.035), sunitinib dose reduction/treatment interruption (HR = 0.6, p = 0.014) and the use of antiotensin system inhibitors (HR = 0.537, p = 0.008). Low NLR ⩽ 3 was associated with OS (HR = 0.3, p = 0.043).ConclusionsIn patients with mRCC treated with sunitinib, pre-treatment NLR may be associated with PFS and OS. This should be investigated prospectively, and if validated applied in clinical practice and clinical trials.     

Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: Relevance of age and dose as risk factors

PurposeThe long-term outcome of platinum-induced nephrotoxicity is unknown. This prospective single-centre longitudinal cohort study evaluated long-term changes following treatment in childhood.Methods63 children treated with platinum (27 cisplatin, 24 carboplatin and 12 both) were studied at the end of treatment (End), 1 year and 10 years later. No child received ifosfamide. Glomerular filtration rate (GFR), serum calcium and magnesium (Mg) were measured, and total nephrotoxicity score (N_s) was graded.ResultsThere was no significant overall change in renal function over time in any treatment group (cisplatin, carboplatin or combined). Apart from marginally reduced median GFR (84 ml/min/1.73 m²) and Mg (0.68 mmol/l) at End of cisplatin, median GFR, Ca and Mg were normal at all times in each group. At 10 years, GFR was <60 ml/min/1.73 m² in 11%, N_s grade was severe in 15% and oral Mg supplements were required in 7% cisplatin patients. After cisplatin, older age at treatment was correlated with lower GFR at 10 years (p = 0.005), and higher N_s at End and 10 years (both p = 0.02). After carboplatin treatment, older age was associated with lower GFR at all times, and with higher N_s at End and 1 year (all p < 0.03). Higher cisplatin dose rate (>40 mg/m²/day) was associated with higher N_s at 1 year (p = 0.02) and higher carboplatin dose with lower Mg at 1 year and with higher N_s at 1 and 10 years (all p < 0.008).ConclusionsPlatinum nephrotoxicity did not change significantly over 10 years. Its severity was correlated to older age at treatment, and at some time points to higher cisplatin dose rate and higher cumulative carboplatin dose.     

Lymphopenia and clinical outcome of elderly patients treated with sunitinib for metastatic renal cell cancer

ObjectiveLymphopenia is associated with toxicity and outcomes in several cancer types. We assessed the association between pre-treatment lymphopenia, toxicity, and clinical outcomes in elderly patients with metastatic renal cell cancer (mRCC) treated with first-line sunitinib. Prognostic factors in these patients were also evaluated.Patients and MethodsWe reviewed the clinical records of 181 patients with mRCC aged ≥ 70 years treated with first-line sunitinib in 17 Italian Oncology Units from February 2006 to September 2011. Baseline lymphopenia was defined as lymphocyte counts < 1000/μL.ResultsTwenty-nine (16%) patients had a baseline lymphocyte count < 1000/μL (group A) and 152 (84%) patients had a lymphocyte count ≥ 1000/μL (group B). Although no differences between the two groups were reported in terms of overall response rate (P = 0.207), dose reductions (P = 0.740), discontinuation due to adverse events (P = 0.175) or overall incidence of grade 3–4 toxicities (P = 0.112), more patients in the lymphopenia group had grade 3–4 neutropenia (P = 0.017), grade 3–4 thrombocytopenia (P = 0.017) and grade 3–4 diarrhea (P = 0.006). In multivariate analysis, performance status and Heng score were predictors of progression-free survival (P = 0.015 and P = 0.0006, respectively), while performance status, Heng score, and lymphopenia were found to be significantly associated with overall survival (P = 0.007, P < 0.0001 and P = 0.023, respectively).ConclusionsSunitinib appears to be safe and active in elderly patients with lymphopenia. Lymphocyte count is an independent prognostic factor for overall survival in elderly patients with mRCC treated with first-line sunitinib.     

A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma

BackgroundNanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle–drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC.Patients and methodsPatients with mRCC and 2–3 prior lines of therapy were randomized 1:1 to CRLX101 + bevacizumab versus SOC, defined as investigator’s choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety.ResultsIn total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0–4.3) and 3.9 months (95% confidence interval 2.2–5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel–Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified.ConclusionsDespite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned.Clinical trial identificationNCT02187302 (NIH).     

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma

BackgroundTo determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study.MethodsThe relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan–Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test.ResultsIn the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P < 0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan–Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P < 0.0001).ConclusionsA positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.     

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer

BackgroundThis study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m² given over 90 min i.v. and l-leucovorin 200 mg/m² given over 120 min on day 1, followed by 5-FU 400 mg/m² bolus and then 2400 mg/m² infused over 46 h) in untreated metastatic colorectal cancer (mCRC).Patients and methodsIn this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1–6. Efficacy was a secondary objective.ResultsThirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n = 1), grade 4 neutropenia (n = 4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n = 1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5–79.7).ConclusionsThe MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.     

Sunitinib objective response in metastatic renal cell carcinoma: Analysis of 1059 patients treated on clinical trials

BackgroundRetrospective analyses were performed in patients with metastatic renal cell carcinoma (mRCC) to characterise the objective response (OR) rate to sunitinib and differentiate pretreatment features and outcomes of patients with early (response by ⩽12 weeks) versus late response, and responders versus non-responders.MethodsData were pooled from 1059 patients in six trials. Median progression-free survival (PFS) and overall survival (OS) were estimated by Brookmeyer and Crowley method and compared between groups by log-rank test. Baseline characteristics were compared by Fisher-exact, t-, or Wilcoxon rank-sum tests. Associations between characteristics and survival were investigated by Cox proportional regression analysis.Results398 patients (38%) had confirmed OR (12 complete responses); 26%, 61%, 79% and 86% responded by 6, 12, 18 and 24 weeks, respectively. Median (range) time to tumour response (TTR) was 10.6 (2.7–94.4) weeks and was similar in treatment-naïve and cytokine-refractory patients. Median response duration in early and late responders was 52.0 and 55.0 weeks, respectively. Median PFS in early versus late responders was 13.8 versus 20.2 months (P = 0.001); however, median OS did not significantly differ (37.8 versus 40.8 months; P = 0.144). Early responders had more lung metastases (P < 0.01), but baseline characteristics were otherwise mostly similar. Median PFS (16.3 versus 5.3 months) and OS (40.1 versus 14.5 months) were longer in responders versus non-responders (both P < 0.001); responders had more favourable prognostic factors.ConclusionsOR occurred in 38% of sunitinib-treated mRCC patients. Sixty-one percent of responses occurred by 12 weeks of therapy, and responders had favourable pretreatment features and significantly longer survival.     

Categories of response to first line vascular endothelial growth factor receptor targeted therapy and overall survival in patients with metastatic renal cell carcinoma

IntroductionSequential use of targeted therapy (TT) has improved overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC). The value of objective response (OR) as compared to stable disease (SD) is unclear. We aimed to investigate OR of first-line TT and its impact on OS.Material and methodsRetrospective analysis of OS among 331 mRCC patients with a first-line assessment according to RECIST 1.0. Characteristics between objective responders (complete response [CR] or partial remission [PR]), patients with SD and non-responders (progressive disease [PD] and toxicity [Tox]) were compared with the Chi-square test and the Kruskal–Wallis test. Kaplan–Meier analysis of OS and progression-free survival (PFS). Cox model analysis of Predictors of OS .ResultsBest response was CR, PR, SD, PD and Tox in 9 (2.7%), 61 (18.4%), 167 (50.5%), 80 (24.2%) and 14 (4.2%) patients respectively resulting in an OR rate of 21%. Median OS in months: CR 63.2; PR 37.6; SD 35.9; PD 14.6; TOX 22.5 (p < 0.0001). Median PFS for responders was 14.8, 11.5 for patients with SD and 2.5 for non-responders (p < 0.0001). Similarly median OS was 38.7, 35.9 and 15.5 (p < 0.00001). Primary resistance and a first-line PFS <6 months were the strongest independent predictors of OS. The achievement of OR as compared to SD did not impact OS.ConclusionsIn our cohort of unselected patients OR was not associated with superior OS as compared to SD.     

Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: Results from the Danish Renal Cancer Group (DARENCA) study-2

AimTo evaluate the implementation of targeted therapy on overall survival (OS) in a complete national cohort of patients with metastatic renal cell carcinoma (mRCC).MethodsAll Danish patients with mRCC referred for first line treatment with immunotherapy, TKIs or mTOR-inhibitors between 2006 and 2010 were included. Baseline and outcome data were collected retrospectively. Prognostics factors were identified using log-rank tests and Cox proportional hazard model. Differences in distributions were tested with the Chi-square test.Results1049 patients were referred; 744 patients received first line treatment. From 2006 to 2010 we observed a significant increase in the number of referred patients; a significant increase in treated patients (64% versus 75%, P = 0.0188); a significant increase in first line targeted therapy (22% versus 75%, P < 0.0001); a significant increase in second line treatment (20% versus 40%, P = 0.0104), a significant increased median OS (11.5 versus 17.2 months, P = 0.0435) whereas survival for untreated patients remained unchanged. Multivariate analysis validated known prognostic factors. Moreover, treatment start years 2008 (HR 0.74, 95% CI, 0.55–0.99; P = 0.0415), 2009 (HR 0.72, 95% CI, 0.54–0.96; P = 0.0277) and 2010 (HR 0.63, 95% CI, 0.47–0.86; P = 0.0035) compared to 2006, and more than two treatment lines received for patients with performance status 0–1 (HR 0.76, 95% CI, 0.58–0.99; P = 0.0397) and performance status 2–3 (HR 0.19, 95% CI, 0.06–0.60; P = 0.0051) were significantly associated with longer OS.ConclusionThis retrospective study documents that the implementation of targeted therapy has resulted in significantly improved treatment rates and overall survival in a complete national cohort of treated mRCC patients.     

Second line treatment of metastatic renal cell carcinoma: The Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients

BackgroundSequential treatment is currently the standard of care in metastatic renal cell carcinoma (mRCC). However, very little is known on how many patients (pts) can receive second line or further, and on how to predict those pts. The goal of this study was to evaluate these questions in a large series of pts treated in our institution.Patients and MethodsData from all mRCC patients treated at the IGR from 2005 to 2009 with first line targeted therapy (sunitinib (SU), sorafenib (SO), bevacizumab (B), temsirolimus or everolimus (pooled together as mammalian target of rapamycin – mTOR)) were analysed. Only patients with subsequent follow-up have been included in this analysis. Patients were defined as ‘non-eligible’ for second treatment if: they were (i) still on first line treatment, (ii) not showing progressive (durable stable disease or partial response or complete response) or (iii) if they refused a second line treatment.Results251 patients, median age 60 years, median follow-up 20.2 months were treated with targeted therapy with a median overall survival (OS) of 25.8 months. Median OS with SU (127), SO (60) or B (61) were 26.3, 16.4 and 32.5 months respectively. Only three patients received an mTOR inhibitor as first line. According to the eligibility criteria, the percentage of patients who received a second line was 59% (n = 61/103), 52% (n = 30/58) and 79% (n = 38/48) for Su, So and B, respectively. Memorial Sloan-Kettering Cancer Centre (MSKCC) classification (P = 0.02) and first line agent (P = 0.001) were significant predictive factor for receiving a second line of treatment. Overall, patients receiving B were in better general condition, with 77% of performance status score (PS) = 0 compared to SO (53%) and SU (48%) (P = 0.005). Among the 131 patients who received a second line, the median OS from the start of second line treatment was 20.8 months for a tyrosine kinase inhibitor (TKI) (n = 98; 75%) and 16.6 months for an mTOR (n = 32; 42%) (P = 0.12). Furthermore, the percentage of patients who received a third line was 56% (27/48), 28% (7/25) and 65% (13/20) for SU, SO and B, respectively.ConclusionThe median OS in patients treated with targeted therapies for mRCC in The Institut Gustave Roussy exceeds 2 years. The use of second line varies from 52% to 79%. Further studies are needed to validate the MSKCC groups and first line therapy as predictive factor for second line treatment.     

Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: Results of a pooled analysis of non-interventional studies

AimTo assess the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who failed one or two anti-VEGF therapies.Patients and methodsData from four prospective, non-interventional studies conducted in Germany, France, Greece and Austria were pooled for this analysis. Patients with mRCC of any histology (clear cell or non-clear cell) were included. VEGF-refractory patients received everolimus 10 mg/day until disease progression or unacceptable toxicity. The primary objective was to determine everolimus efficacy as measured by time to progression (TTP; from baseline to progression).ResultsThe overall population comprised 632 patients; 493 patients received everolimus in the second-line setting. Most patients were of favourable/intermediate MSKCC risk (91%), had clear cell mRCC (89%), and had undergone nephrectomy (89%). Median TTP was 6.3 months (95% confidence interval [CI], 5.9–6.8) for the overall population and 6.4 months (95% CI, 5.8–6.9) for the second-line everolimus population. Similarly, median progression-free survival was 5.5 months (95% CI, 5.0–6.1) for the overall population and 5.8 months (95% CI, 5.0–6.4) for second-line everolimus population. Best tumour response (n = 349) was complete or partial remission in 12% of patients and stable disease in 59% of patients. Overall population median overall survival (OS) was 11.2 months (95% CI, 9.0–not reached). Commonly reported adverse events (AEs) (any grade) were stomatitis (25%), anaemia (15%) and asthenia (11%).ConclusionsResults of this pooled analysis provide evidence of safety and effectiveness of second-line everolimus in routine clinical use and support everolimus as a standard of care for VEGF-refractory patients with mRCC.     

Long-term results of weekly paclitaxel carboplatin induction therapy: An effective and well-tolerated treatment in patients with platinum-resistant ovarian cancer

BackgroundWeekly paclitaxel/cisplatin is effective in platinum-resistant epithelial ovarian cancer (EOC). To reduce toxicity, paclitaxel/cisplatin was replaced by paclitaxel/carboplatin.Patients and methodsPatients with progressive EOC after prior 3-weekly paclitaxel/carboplatin were treated with six cycles weekly paclitaxel 90 mg/m² and carboplatin area under the curve (AUC) 4 mg/ml/min, followed by six cycles 3-weekly paclitaxel/carboplatin. End-points were progression free survival (PFS), overall survival (OS), response rate (RR) and toxicity.ResultsMedian progression free interval after last platinum was 9 (0–81) months in 108 patients; 43 were platinum-resistant, of whom 13 started weekly paclitaxel/carboplatin <6 months after progression. During 633 weekly cycles grade 3/4 toxicity included; thrombocytopenia 8%, neutropenia 30%, febrile neutropenia 0.5%. Non-haematologic toxicity was low. Treatment was delayed in 16%, and dose reduced in 2% of cycles. RR was 58% for platinum-resistant and 76% for platinum-sensitive patients, median PFS were 8 (range 1–21) and 13 (1–46) months, median OS 15 (1–69) and 26 (4–93) months, respectively. The 13 platinum-resistant patients with a platinum-therapy free interval <6 months had a significant shorter PFS (4 versus 10 months, p = 0.035) and OS (9 versus 15 months, p = 0.002).ConclusionSix cycles weekly paclitaxel/carboplatin followed by six 3-weekly cycles is well-tolerated and highly active in platinum-resistant and platinum-sensitive patients.     

A randomised,double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: Final overall survival results and safety update

BackgroundIn this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported.MethodsTreatment-naive or cytokine-pretreated mRCC patients (n = 435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover.FindingsThe difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR] = 0.91; 95% confidence interval [CI], 0.71–1.16; one-sided P = .224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR = 0.504; 95% CI, 0.315–0.762; two-sided P = .002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR = 0.43; 95% CI, 0.215–1.388; two-sided P = .172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events.InterpretationAlthough no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients.