Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BackgroundEverolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety.Patients and methodsData were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately.ResultsThe rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)].ConclusionsStomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines

Metastatic renal cell cancer treatments: An indirect comparison meta-analysis

Abstract Background Treatment for metastatic renal cell cancer (mRCC) has advanced dramatically with understanding of the pathogenesis of the disease. New treatment options may provide improved progression-free survival (PFS). We aimed to determine the relative effectiveness of new therapies in this field. Methods We conducted comprehensive searches of 11 electronic databases from inception to April 2008. We included randomized trials (RCTs) that evaluated bevacizumab, sorafenib, and sunitinib. Two reviewers independently extracted data, in duplicate. Our primary outcome was investigator-assessed PFS. We performed random-effects meta-analysis with a mixed treatment comparison analysis. Results We included 3 bevacizumab (2 of bevacizumab plus interferon-a [IFN-a]), 2 sorafenib, 1 sunitinib, and 1 temsirolimus trials (total n = 3,957). All interventions offer advantages for PFS. Using indirect comparisons with interferon-α as the common comparator, we found that sunitinib was superior to both sorafenib (HR 0.58, 95% CI, 0.38–0.86, P = < 0.001) and bevacizumab + IFN-a (HR 0.75, 95% CI, 0.60–0.93, P = 0.001). Sorafenib was not statistically different from bevacizumab +IFN-a in this same indirect comparison analysis (HR 0.77, 95% CI, 0.52–1.13, P = 0.23). Using placebo as the similar comparator, we were unable to display a significant difference between sorafenib and bevacizumab alone (HR 0.81, 95% CI, 0.58–1.12, P = 0.23). Temsirolimus provided significant PFS in patients with poor prognosis (HR 0.69, 95% CI, 0.57–0.85). Conclusion New interventions for mRCC offer a favourable PFS for mRCC compared to interferon-α and placebo

Сохраненное время качественной жизни, проведенное без клинических симптомов и проявлений токсичности (Q-TWiST), при лечении комбинацией ленватиниба и эверолимуса по сравнению с монотерапией эверолимусом у пациентов с распространенным почечно-клеточным раком

Введение. Комбинация ленватиниба и эверолимуса продемонстрировала увеличение беспрогрессивной выживаемости по сравнению с монотерапией эверолимусом в рандомизированном клиническом исследовании II фазы (РКИ 205). Цель исследования – сравнительный анализ сохраненного времени качественной жизни, проведенной без клинических симптомов и проявлений токсичности (quality-adjusted time without symptoms of disease progression or toxicity, Q-TWiST), при лечении комбинацией ленватиниба и эверолимуса и при монотерапии эверолимусом пациентов с распространенным почечно-клеточным раком после одной линии предшествующей антиангиогенной терапии.Дизайн исследования,  разработка и участники: вторичный анализ данных РКИ 205.Измерения и статистический анализ. Проведен анализ разделенной выживаемости с учетом 3 взаимоисключающих состояний: времени, проведенного с проявлением токсичности III или IV степени тяжести (TOX), времени до наступления прогрессирования заболевания и без проявлений токсичности III или IV степени тяжести (TWiST) и времени с момента наступления прогрессирования заболевания (REL). Показатели среднего времени, проведенного в каждом состоянии, корректировали с применением индексов взвешенности и суммировали для расчета Q-TWiST. С помощью метода непараметрической  статистики бутстрэп были составлены 95 % доверительные  интервалы.  В базовом сценарии индексам взвешенности для TWiST, TOX и REL были установлены значения, равные 1,0; 0,5 и 0,5 соответственно. При анализе чувствительности применяли альтернативные пороговые значения для индексов взвешенности REL, TOX и TWiST. Увеличение Q-TWiST в относительном выражении на ≥10 и ≥15 % было признано клинически значимым и явно выраженным клинически значимым соответственно.Результаты исследования и ограничения. Пациенты, получающие комбинацию ленватиниба  и эверолимуса (n = 51), по сравнению с группой монотерапии эверолимусом, имеют преимущество в виде значимого роста показателя Q-TWiST в абсолютном выражении на 3,7 мес (14,7 мес против 11,0 мес; 95 % доверительный интервал для различия 1,3–6,3), в относительном выражении на 24 %. В анализе чувствительности с использованием пороговых значений для индекса взвешенности TWiST, варьировавших от 0,55 до 0,9, и для индексов TOX и REL, равных 0,5, сохранялся относительный прирост Q-TWiST (в диапазоне от 11,0 до 21,2 %; все различия были достоверно значимыми) при различных значениях индекса. Ограничения исследования включают малый размер выборки, отсутствие измерения индексов состояния здоровья и данных о продолжительности нежелательных явлений в РКИ 205.Заключение. Комбинация ленватиниб + эверолимус продемонстрировала статистически значимое и явно выраженное клинически значимое увеличение времени сохраненной качественной жизни, проведенной до прогрессирования, по сравнению с монотерапией эверолимусом.Краткая информация для пациентов. У пациентов с распространенным раком почки, ранее получавших системную противоопухолевую терапию, было достигнуто явно выраженное клинически значимое улучшение показателя выживаемости с сохраненным качеством жизни при лечении комбинацией ленватиниб + эверолимус по сравнению с монотерапией эверолимусом

An approach to estimating prognosis using fractional polynomials in metastatic renal carcinoma

We present a prognostic model for metastatic renal cell carcinoma based on fractional polynomials. We retrospectively analysed 425 metastatic renal cell carcinoma patients treated with subcutaneous recombinant cytokine-based home therapies in consecutive trials. In our approach, we categorised a continuous prognostic index produced by the multivariable fractional polynomial (MFP) algorithm, using a strategy in which continuous predictors are kept continuous. The MFP algorithm selected five prognostic factors as significant at the 5% level in a multivariable model: lymph node metastases, liver metastases, bone metastases, age, C-reactive protein and neutrophils. The MFP model allowed us to divide patients into four risk groups achieving median overall survivals of 38 months (low risk), 23 months (low intermediate risk), 15 months (high intermediate risk) and 5.6 months (high risk). Our approach, based on categorising a continuous prognostic index produced by the MFP algorithm, allowed more flexibility in the determination of risk groups than traditional approaches

Surgical Treatment of Renal Cell Cancer Liver Metastases: A Population-Based Study

Background: To evaluate outcomes of surgical treatment in patients with hepatic metastases from renal-cell carcinoma in the Netherlands, and to identify prognostic factors for survival after resection. Renal-cell carcinoma has an incidence of 2,000 new patients in the Netherlands each year (12.5/100,000 inhabitants). According to literature, half of these patients ultimately develop distant metastases with 20% involvement of the liver. Resection of renal-cell carcinoma liver metastases (RCCLM) is performed in only a minority of patients. Hence, little is known about outcome of resectable RCCLM. Methods: Patients were retrieved from local databases of theNetherlands Task Force for Liver Surgery (14 centers) and from the Dutch collective pathology database. Survival and prognostic factors were determined by Kaplan-Meier analysis and log rank test. Results: Thirty-three patients were identified who underwent resection (n = 29) or local ablation (n = 4) of RCCLM in the Netherlands between 1990 and 2008. These patients comprise 0.5% to 1% of the total population of patients diagnosed with RCCLM in that period. There was no operative mortality. The overall survival at 1, 3, and 5 years was 79, 47, and 43%, respectively. Metachronous metastases (n = 23, P = 0.03) and radical resection (n = 19, P < 0.001) were statistically significant prognosticators of ov

Prognostic factors in metastatic renal cell carcinoma: metastasectomy as independent prognostic variable

Prognostic and predictive factors in patients with metastatic renal cell carcinoma (MRCC) have been evaluated from untreated patients or patients on several different treatment approaches. The aim of this analysis was to define prognostic and predictive factors in patients treated uniformly with a low-dose outpatient cytokine combination. The relationship between patient-, tumour-, and treatment-related factors was analysed in 99 patients with MRCC. These features were first examined in univariate analyses, then a stepwise modelling approach based on Cox regression was used to form a multivariate model. Nuclear grade, metastasectomy – even incomplete – C-reactive protein and lactate dehydrogenase were identified as independent prognostic factors for survival. Patients assigned to three different risk groups had statistically significant survival differences (30, 22 and 6 months, respectively). A total of 43.4% had undergone metastasectomy, mostly incomplete. Risk group affiliation was correlated with response to treatment. Our findings strongly suggest the consideration of metastasectomy in the management of patients with metastatic renal cell cancer undergoing either immunotherapy or targeted treatment

Metastatic renal carcinoma comprehensive prognostic system

The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-α2a (INF-α), s.c. interleukin-2 (IL-2) (n=102 pts), (B) s.c. IFN-α2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n=235 pts) or (C) s.c. IFN-α2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n=88 pts). Kaplan–Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count ⩾6500 cells μl−1, (4) serum lactate dehydrogenase level (LDH) ⩾220 U l−1, and (5) serum C-reactive protein level (CRP) ⩾11 mg l−1. Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio=1.9, P<0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio ⩽1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of 27%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials