Yuan JM, Castelao JE, Gago-Dominguez M, Ross RK, Yu MC.
Hypertension, obesity and their medications in relation to renal cell carcinoma.
Br J Cancer. 1998 May;77(9):1508-13. doi: 10.1038/bjc.1998.248.
Abstract/Text
A population-based, case-control study was conducted in Los Angeles County, California, to investigate the inter-relationships of obesity, hypertension and medications in relation to renal cell carcinoma (RCC) risk. A total of 1204 RCC patients and an equal number of neighbourhood controls were included. Obesity was a strong risk factor for RCC. A fourfold increase in risk was observed for those with usual body mass index (kg m(-2)) of > or = 30 vs < 22. A history of hypertension was another strong, independent risk factor for RCC [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.8, 2.6]. There was little evidence that use of diuretics was directly related to RCC development. Use of diuretics for reasons other than hypertension (primarily for weight control) was unrelated to risk among self-reported normotensive subjects (OR = 1.2; 95% CI = 0.7, 2.2). Among hypertensive subjects, heavy users of diuretics experienced similar risk as light users (OR = 0.9 among subjects with lifetime dose of > or = 137 g compared with those with lifetime dose of < 43 g). Similarly, normotensive subjects who took non-diuretic antihypertensives regularly showed no increased risk for RCC (OR = 1.1; 95% CI = 0.6-1.8), and intake among hypertensive subjects did not further increase their risk. Regular use of amphetamine-containing diet pills was associated with a twofold increase in RCC risk (95% CI = 1.4-2.8) and the risk increased with increasing dose of amphetamines. However, the fraction of cases possibly related to this exposure is small (population-attributable risk = 5%).
Waalkes S, Merseburger AS, Kramer MW, Herrmann TR, Wegener G, Rustemeier J, Hofmann R, Schrader M, Kuczyk MA, Schrader AJ.
Obesity is associated with improved survival in patients with organ-confined clear-cell kidney cancer.
Cancer Causes Control. 2010 Nov;21(11):1905-10. doi: 10.1007/s10552-010-9618-2. Epub 2010 Jul 22.
Abstract/Text
OBJECTIVES: Obesity increases the risk of developing renal cell carcinoma (RCC); however, it remains unclear whether obesity is associated with RCC aggressiveness and survival. We assessed whether different body mass index (BMI) levels at the time of surgery had an effect on long-term prognosis of RCC patients.
METHODS: We evaluated 1,338 clear-cell RCC patients with complete information about their BMI, who had undergone surgery for renal cell cancer at the University Hospitals in Hannover and Marburg between 1991 and 2005. The mean follow-up was 5.1 years.
RESULTS: Underweight, normal weight, pre-obesity, and obesity were diagnosed in 14 (1.0%), 444 (33.2%), 593 (44.3%), and 287 (21.4%) RCC patients, respectively. A lower BMI was significantly associated with higher age, tumor grade, and the rate of metastasis at diagnosis. Overweight patients had a significantly lower risk of cancer-related death; their median 5-year tumor-specific survival rate was 70.9% (pre-obese), 74.0% (obese grad I), and 85.6% (obese grad ≥II) as opposed to 63.8% for patients with a BMI below 25 (p < 0.001). Interestingly, subgroup analysis revealed that the positive association between overweight and survival was found in organ-confined RCC only.
CONCLUSION: We identified overweight as an independent prognostic marker of improved cancer specific survival in patients with organ-confined but not advanced RCC. Basic research is required to resolve the dilemma of why, if a higher BMI predisposes to RCC, it concurrently prolongs survival after patients have undergone (partial) nephrectomy.
Chow WH, Dong LM, Devesa SS.
Epidemiology and risk factors for kidney cancer.
Nat Rev Urol. 2010 May;7(5):245-57. doi: 10.1038/nrurol.2010.46.
Abstract/Text
After more than two decades of rising rates, in recent years the total kidney cancer incidence worldwide has shown signs of stabilizing, or even decreasing. In adults, kidney cancer consists of renal cell carcinoma (RCC), the predominant form, and renal transitional cell carcinoma (RTCC); these types primarily arise in the renal parenchyma and renal pelvis, respectively. Although temporal trends by kidney cancer type are not well established worldwide, incidence of RCC in the US has continued to rise, mainly for early-stage tumors, while that of RTCC has declined, and total kidney cancer mortality rates have leveled. Stabilization of kidney cancer mortality rates has also been reported in Europe. These trends are consistent with reports of increasing incidental diagnoses and a downward shift in tumor stage and size in clinical series. The changing prevalence of known risk factors for RCC, including cigarette smoking, obesity, and hypertension, is also likely to affect incidence trends, although their relative impact may differ between populations. Accumulating evidence suggests an etiologic role in RCC for physical activity, alcohol consumption, occupational exposure to trichloroethylene, and high parity among women, but further research is needed into the potential causal effects of these factors. Genetic factors and their interaction with environmental exposures are believed to influence risk of developing RCC, but a limited number of studies using candidate-gene approaches have not produced conclusive results. Large consortium efforts employing genome-wide scanning technology are underway, which hold promise for novel discoveries in renal carcinogenesis.
Chow WH, Gridley G, Fraumeni JF Jr, Järvholm B.
Obesity, hypertension, and the risk of kidney cancer in men.
N Engl J Med. 2000 Nov 2;343(18):1305-11. doi: 10.1056/NEJM200011023431804.
Abstract/Text
BACKGROUND: Obesity and hypertension have been implicated as risk factors for the development of renal-cell cancer.
METHODS: We examined the health records of 363,992 Swedish men who underwent at least one physical examination from 1971 to 1992 and were followed until death or the end of 1995. Men with cancer (renal-cell cancer in 759 and renal-pelvis cancer in 136) were identified by cross-linkage of data with the nationwide Swedish Cancer Registry. Poisson regression analysis was used to estimate relative risks, with adjustments for age, smoking status, body-mass index, and diastolic blood pressure.
RESULTS: As compared with men in the lowest three eighths of the cohort for body-mass index, men in the middle three eighths had a 30 to 60 percent greater risk of renal-cell cancer, and men in the highest two eighths had nearly double the risk (P for trend, <0.001). There was also a direct association between higher blood pressures and a higher risk of renal-cell cancer (P for trend, <0.001 for diastolic pressure; P for trend, 0.007 for systolic pressure). After the first five years of follow-up had been excluded to reduce possible effects of preclinical disease, the risk of renal-cell cancer was still consistently higher in men with a higher body-mass index or higher blood pressure. At the sixth-year follow-up, the risk rose further with increasing blood pressures and decreased with decreasing blood pressures, after adjustment for base-line measurements. Men who were current or former smokers had a greater risk of both renal-cell cancer and renal-pelvis cancer than men who were not smokers. There was no relation between body-mass index or blood pressure and the risk of renal-pelvis cancer.
CONCLUSIONS: Higher body-mass index and elevated blood pressure independently increase the long-term risk of renal-cell cancer in men. A reduction in blood pressure lowers the risk.
Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P.
Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies.
Int J Cancer. 2005 Mar 10;114(1):101-8. doi: 10.1002/ijc.20618.
Abstract/Text
Renal cell carcinoma (RCC) accounts for 3% of adult deaths from cancer. The risk factors for its development are still under intense investigation. Although tobacco smoke is a risk factor, the data are inconsistent and the extent of the increased risk is unclear. Estimates from 19 case-control and 5 cohort studies were used. The case-control reports included 8,032 cases and 13,800 controls; the cohort estimates were based on 1,457,754 participants with 1,326 cases of RCC. The relative risk (RR) for RCC for ever smokers as compared to lifetime never smokers was 1.38 (95% confidence interval [CI] = 1.27-1.50). The RR for male smokers was 1.54 (95% CI = 1.42-1.68) and for female smokers was 1.22 (95% CI = 1.09-1.36). For men and women there was a strong dose-dependent increase in risk. Ever smoker men who had smoked 1-9, 10-20 or 21 or more cigarettes/day had a RR of 1.60 (95% CI = 1.21-2.12), 1.83 (95% CI = 1.30-2.57), or 2.03 (95% CI = 1.51-2.74), respectively. For women, the relative risks were 0.98 (95% CI = 0.71-1.35), 1.38 (95% CI = 0.90-2.11), or 1.58 (95% CI = 1.14-2.20), respectively. The advantages of smoking cessation were confirmed by a reduction in RR for those who had quit smoking for >10 years as compared to those who had quit for 1-10 years. Inhaled tobacco smoke is clearly implicated in the etiology of RCC, with a strong dose-dependent increase in risk associated with numbers of cigarettes smoked per day and a substantial reduction in risk for long-term former smokers.
Kaelin WG Jr.
The von Hippel-Lindau tumor suppressor gene and kidney cancer.
Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6290S-5S. doi: 10.1158/1078-0432.CCR-sup-040025.
Abstract/Text
The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in >50% of sporadic clear cell renal cell carcinomas. Germ-line VHL mutations give rise to VHL disease, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas) and renal cell carcinomas. In this setting, VHL inactivation gives rise to premalignant renal cysts. Additional genetic alterations are presumably required for conversion of these cysts to renal cell carcinomas. Restoration of VHL function in VHL-/- renal cell carcinomas is sufficient to inhibit tumorigenesis in vivo. On the basis of these and other data, VHL appears to be a critical gatekeeper with respect to the development of renal cell carcinoma. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL, accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor alpha. We have demonstrated that inhibition of HIF is necessary and sufficient for tumor suppression by pVHL in renal cell carcinoma nude mouse xenograft assays. This provides a rationale for treating VHL-/- renal cell carcinoma with inhibitors of HIF or its downstream targets. Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth.
Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, Nordenskjöld M, Hansen TV, Solly J, Maher ER; European BHD Consortium.
Birt-Hogg-Dubé syndrome: diagnosis and management.
Lancet Oncol. 2009 Dec;10(12):1199-206. doi: 10.1016/S1470-2045(09)70188-3.
Abstract/Text
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition characterised clinically by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cancer. The condition is caused by germline mutations in the FLCN gene, which encodes folliculin; the function of this protein is largely unknown, although FLCN has been linked to the mTOR pathway. The availability of DNA-based diagnosis has allowed insight into the great variation in expression of FLCN, both within and between families. Patients can present with skin signs and also with pneumothorax or renal cancer. Preventive measures are aimed mainly at early diagnosis and treatment of renal cancer. This Review gives an overview of current diagnosis and management of BHD.
Stewart JH, Vajdic CM, van Leeuwen MT, Amin J, Webster AC, Chapman JR, McDonald SP, Grulich AE, McCredie MR.
The pattern of excess cancer in dialysis and transplantation.
Nephrol Dial Transplant. 2009 Oct;24(10):3225-31. doi: 10.1093/ndt/gfp331. Epub 2009 Jul 8.
Abstract/Text
BACKGROUND: After transplantation, cancer risk varies from no increase for several common cancers to a many-fold increase for a number of, chiefly virus-associated, cancers. The smaller excess of cancer in dialysis has been less well described, but two studies suggested that impaired immunity might be responsible.
METHODS: In a population-based cohort study of 28 855 patients who received renal replacement therapy (RRT), we categorized incident cancers as end-stage kidney disease (ESKD) related, immune deficiency related, not related to immune deficiency, or of uncertain status, according to whether they were, or were not, increased in published reports of cancer in ESKD prior to starting RRT, organ transplantation or human immunodeficiency virus infection. Standardized incidence ratios for, and excess burdens of, cancer were calculated for all persons normally resident in Australia starting treatment by dialysis or renal transplantation from 1982 to 2003.
RESULTS: The risk for ESKD-related cancers was increased 4-fold in dialysis and during transplant function. For immune deficiency-related cancers, the increase was 1.5 (95% CI 1.3-1.6) times in dialysis, and 5-fold after transplantation. ESKD- or immune deficiency-related cancers contributed to approximately 90% of the excess burden of cancer, 48% and 36%, respectively, in dialysis, and 10% and 78% after transplantation. The remaining excess malignancy was contributed by cancers whose relationship with ESKD and immune deficiency is not yet certain.
CONCLUSIONS: In RRT, the increase in cancer is restricted, largely if not wholly, to cancers with origins in ESKD or related to immune deficiency. For the former, the cancer risk is similar in dialysis and transplantation, but for immune deficiency-related cancers, the relative risk is much greater after transplantation.
Ishikawa I, Honda R, Yamada Y, Kakuma T.
Renal cell carcinoma detected by screening shows better patient survival than that detected following symptoms in dialysis patients.
Ther Apher Dial. 2004 Dec;8(6):468-73. doi: 10.1111/j.1774-9987.2004.00192.x.
Abstract/Text
There is an apparent advantage to early or incidental diagnosis of renal cell carcinoma in the general population. We investigated whether the prognosis of dialysis patients with renal cell carcinoma is better if renal cell carcinoma is detected by screening of patients without symptoms rather than by examination after the appearance of the symptoms. Two groups in which renal cell carcinomas were detected by screening (N = 721) and by symptoms (n = 76) were compared. The model tested consisted of patient age and duration of dialysis in addition to the detection by screening or symptoms. Cox proportional hazard model was used to compare survival rates between the groups. The hazard ratio of death from all causes in patients with renal cell carcinoma detection by screening was 0.653 and the risk of death was reduced by 35%, compared with that in the group with detection due to symptoms. Moreover, the 50% survival rate in the group detected by symptoms was 80 months and the ratio of those detected by screening was 119 months. Therefore, screening provided a survival benefit of 39 months (3.3 years) in death from all causes after adjustment for age and duration of dialysis. The survival rate was best in young patients with a short duration of dialysis and renal cell carcinoma detected by screening. In dialysis patients with renal cell carcinoma, the survival rate in the group detected by screening was better than that in the group detected by symptoms. Especially, there was a large effect of screening for renal cell carcinoma in the young dialysis patients.
Levine E.
Acquired cystic kidney disease.
Radiol Clin North Am. 1996 Sep;34(5):947-64.
Abstract/Text
ACKD is characterized by the development of many fluid-filled renal cysts and sometimes neoplasms in the kidneys of individuals with chronic renal failure but without a history of hereditary cystic disease. The condition is seen mainly in dialysis patients, but often begins in patients with ESRD before dialysis is started. Most patients with ACKD are asymptomatic, but the disorder may be associated with such serious complications as retroperitoneal hemorrhage and metastatic renal cell carcinoma. The diagnosis of ACKD and its complications is best achieved by CT scanning, although US and MR imaging may be useful in evaluation, particularly in patients not treated with dialysis. Cyst hemorrhage is common in ACKD and may cause flank pain and hematuria. Hemorrhagic cysts may be recognized by their CT scan, sonographic, or MR imaging features. Hemorrhagic cysts may rupture into the perinephric space causing large perinephric hematomas. These can usually be treated-conservatively. Patients with ACKD, particularly those treated with dialysis, have an increased risk of renal cell carcinoma. Renal cell carcinoma may also develop in the native kidneys of renal transplant recipients with good graft function many years after transplantation. Annual imaging of the native kidneys of all dialysis patients or of transplant recipients for the development of carcinoma is not justified, however, because it has not been shown to have a significant effect on patient outcome. Screening may, however, be useful in selected dialysis patients with good general medical condition and who have known risk factors for renal cell carcinoma including prolonged dialysis, large kidneys, ACKD, and male gender. Screening of the native kidneys of transplant recipients may be performed when they are referred for US evaluation of the renal allograft.
Kawada S, Yonemitsu K, Morimoto S, Komura H, Shiraishi M, Tateyama Y, Kamikokuryo A, Arimura M, Uchizono H.
Current state and effectiveness of abdominal ultrasonography in complete medical screening.
J Med Ultrason (2001). 2005 Dec;32(4):173-9. doi: 10.1007/s10396-005-0054-y.
Abstract/Text
PURPOSE: The current state and effectiveness of abdominal ultrasonography (US) were investigated by reviewing statistical data for US of the kidney as part of complete medical screenings conducted at our institution between April 1994 and March 2004.
METHODS: Among 4339 individuals with US findings, computed tomography (CT) was performed on 129 individuals at our institution. Among these individuals, US findings and CT diagnoses were compared and analyzed.
RESULTS: US findings indicated renal tumors in 73 of the 129 subjects, and the breakdown of CT diagnoses for these 73 individuals was as follows: no lesion, n = 45 (61.6%); simple renal cyst, n = 13 (17.8%); complicated renal cyst, n = 5 (6.8%); suspected malignant tumor, n = 5 (6.8%); renal angiomyolipoma, n = 2 (2.7%); pelvic dilatation, n = 1 (1.4%); granuloma, n = 1 (1.4%); teratoma, n = 1 (1.4%). Magnetic resonance imaging (MRI) was performed on 4 of the 5 subjects with suspected malignant tumor, and surgery was performed in all 4 cases with suspected kidney cancer. Kidney cancer was histopathologically confirmed in 2 patients, resulting in a detection rate of 0.046% for kidney cancer by US as part of a complete medical screening. In the 2 patients with kidney cancer, differentiating cystic renal cell cancer from a renal cyst was not possible based on US findings alone in 1 patient, and no thorough examinations were performed in the 3 years leading up to surgery.
CONCLUSIONS: These results suggest that additional US and thorough examinations are necessary if a lesion cannot be confirmed as a simple renal cyst on initial US. Furthermore, to improve the skill levels of healthcare professionals who perform and interpret US, a feedback system should be established where data related to complete medical screenings are available to the personnel involved.
Lightfoot N, Conlon M, Kreiger N, Bissett R, Desai M, Warde P, Prichard HM.
Impact of noninvasive imaging on increased incidental detection of renal cell carcinoma.
Eur Urol. 2000 May;37(5):521-7. doi: 10.1159/000020188.
Abstract/Text
OBJECTIVE: To determine the impact of non-invasive imaging, specifically ultrasound imaging and computed tomography, on the incidental detection of renal cell carcinoma during two consecutive time periods, one prior and one subsequent to the acquisition of imaging equipment.
METHODS: All located patient charts (83% of 207) of renal cell carcinoma cases (n = 172) were reviewed, and categorized by presentation method as 'incidental' or 'nonincidental' cases, based on defined criteria. Clinical information was recorded, cases were staged, and survival estimates were calculated.
RESULTS: More than a third of the 172 cases were categorized as incidentally detected, most of which (82.5%) were detected during the latter time period. Either ultrasound or CT imaging was credited with detecting over 80% of the incidentally detected tumors.
CONCLUSION: Ultrasound and CT imaging have contributed to the incidental detection of renal cell carcinomas during the two time periods. Stage significantly predicted survival (p<0.001) in a Cox proportional hazard model that also controlled for presentation, sex, and age.
Einstein DM, Herts BR, Weaver R, Obuchowski N, Zepp R, Singer A.
Evaluation of renal masses detected by excretory urography: cost-effectiveness of sonography versus CT.
AJR Am J Roentgenol. 1995 Feb;164(2):371-5. doi: 10.2214/ajr.164.2.7839971.
Abstract/Text
OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of sonography and CT for the evaluation of renal masses discovered at excretory urography.
MATERIALS AND METHODS: The records of 225 patients with a renal mass shown by urography who then had either sonography or CT within 3 months were reviewed retrospectively. The number, location, and size of lesions; initial and subsequent imaging tests; and final diagnoses were determined. Using the current Medicare reimbursements for sonography and CT, we calculated the economic implications of using sonography or CT as the initial examination. Any effect of the location or size of the lesion on the most cost-effective examination was also determined.
RESULTS: Twenty-one percent of patients had both initial sonography and follow-up CT because of indeterminate findings or detection of a solid mass that required further staging. When CT was done first, CT findings were equivocal in 12%, necessitating follow-up sonography. At the prevailing charges, CT would have to be needed in 70% of patients initially imaged with sonography to justify the use of CT as the initial examination. The location and size of the lesion did not affect the need for CT at a rate (greater than 70%) that would economically justify use of CT as the first imaging test. Eighty-six percent of patients with a mass detected by urography had either a simple cyst or no evidence of a mass on sonography or CT.
CONCLUSION: Sonography is the most cost-effective imaging method for the workup of a renal mass detected at urography. The number of sonographic examinations in which findings are indeterminate or positive (for a solid mass) is not sufficiently high to warrant replacement of sonography by CT, regardless of the size and location of the lesion. CT should be reserved for a limited number of specific indications.
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK.
Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.
J Clin Oncol. 2009 Dec 1;27(34):5794-9. doi: 10.1200/JCO.2008.21.4809. Epub 2009 Oct 13.
Abstract/Text
PURPOSE: There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy.
METHODS: Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS.
RESULTS: The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73.
CONCLUSION: This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.
Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK.
External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study.
Lancet Oncol. 2013 Feb;14(2):141-8. doi: 10.1016/S1470-2045(12)70559-4. Epub 2013 Jan 9.
Abstract/Text
BACKGROUND: The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models.
METHODS: We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit.
FINDINGS: Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6-21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68-0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4-50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7-25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5-9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639-0·689). 672 patients had complete data to test all five models. The concordance index of the CCF model was 0·662 (95% CI 0·636-0·687), of the French model 0·640 (0·614-0·665), of the IKCWG model 0·668 (0·645-0·692), and of the MSKCC model 0·657 (0·632-0·682). The reported versus predicted number of deaths at 2 years was most similar in the Database Consortium model compared with the other models.
INTERPRETATION: The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis.
FUNDING: None.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, Feldman DR, Olencki T, Picus J, Small EJ, Dakhil S, George DJ, Morris MJ.
Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial.
J Clin Oncol. 2017 Feb 20;35(6):591-597. doi: 10.1200/JCO.2016.70.7398. Epub 2016 Nov 14.
Abstract/Text
Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23 to 44) for cabozantinib versus 12% (95% CI, 5.4 to 21) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators.
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.
N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21.
Abstract/Text
BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma.
METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk.
RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups.
CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, Pouliot F, Alekseev B, Soulières D, Melichar B, Vynnychenko I, Kryzhanivska A, Bondarenko I, Azevedo SJ, Borchiellini D, Szczylik C, Markus M, McDermott RS, Bedke J, Tartas S, Chang YH, Tamada S, Shou Q, Perini RF, Chen M, Atkins MB, Powles T; KEYNOTE-426 Investigators.
Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Epub 2019 Feb 16.
Abstract/Text
BACKGROUND: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.
METHODS: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.
RESULTS: After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.
CONCLUSIONS: Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
Copyright © 2019 Massachusetts Medical Society.
Joniau S, Vander Eeckt K, Van Poppel H.
The indications for partial nephrectomy in the treatment of renal cell carcinoma.
Nat Clin Pract Urol. 2006 Apr;3(4):198-205. doi: 10.1038/ncpuro0458.
Abstract/Text
Partial nephrectomy is performed more frequently for small, incidentally discovered, low-stage renal tumors. Importantly, one should distinguish the imperative indications for such surgery from the relative and elective indications, while taking contraindications to nephron-sparing surgery into account. The main advantage of partial nephrectomy over radical nephrectomy is the avoidance of renal insufficiency; the major disadvantages include the possibility of local recurrence and perioperative complications. In this article, the literature on nephron-sparing surgery was reviewed in order to put the management of renal cancer into a modern perspective.
Mitchell RE, Gilbert SM, Murphy AM, Olsson CA, Benson MC, McKiernan JM.
Partial nephrectomy and radical nephrectomy offer similar cancer outcomes in renal cortical tumors 4 cm or larger.
Urology. 2006 Feb;67(2):260-4. doi: 10.1016/j.urology.2005.08.057.
Abstract/Text
OBJECTIVES: To determine whether the type of surgery (partial nephrectomy [PN] versus radical nephrectomy [RN]) has any effect on cancer outcome for renal cortical tumors 4 cm or larger. PN outcomes for large renal cortical tumors have been shown to be worse than outcomes for smaller tumors, but the upper limit of tumor diameter amenable to PN remains controversial.
METHODS: We identified 33 patients from the Columbia University Comprehensive Urologic Oncology Database who underwent PN between 1988 and 2004 for renal cortical tumors 4 cm or larger. Each was matched with 2 patients undergoing RN on the basis of the tumor diameter. A survival analysis was conducted using the Kaplan-Meier method, and any differences between the two groups were compared using the log-rank test. The Cox regression model was used to determine which variables affected survival.
RESULTS: The estimated 5-year recurrence-free survival rate was 93.5% for the PN group and 83.3% for the RN group (P = 0.471). The estimated 5-year disease-specific survival rate was 96.2% for the PN group and 97.8% for the RN group (P = 0.893). Only tumor diameter had an impact on recurrence-free survival in the univariate (P = 0.005) and multivariate (P = 0.008) Cox regression models. Surgical technique had no impact on disease recurrence.
CONCLUSIONS: The results of our study have shown that cancer outcomes after PN do not differ from outcomes after RN for tumors of 4 cm or greater in diameter. The upper limit of 4 cm appears to have been determined arbitrarily. It is no longer advisable to restrict PN to patients with tumors smaller than 4 cm in diameter.
Uzzo RG, Novick AC.
Nephron sparing surgery for renal tumors: indications, techniques and outcomes.
J Urol. 2001 Jul;166(1):6-18.
Abstract/Text
PURPOSE: A contemporary review of the indications, techniques and outcomes is presented for nephron sparing approaches to solid renal masses, emphasizing their role for the treatment of renal cell carcinoma. We also reviewed the evolving role of minimally invasive forms of parenchymal sparing renal surgery.
MATERIALS AND METHODS: MEDLINE and CANCERLIT computerized literature searches, and manual bibliographic reviews were performed to identify published peer reviewed articles pertaining to nephron sparing surgery or partial nephrectomy from 1980 to 2000. Pertinent articles were collated and reviewed.
RESULTS: Nephron sparing surgery is increasingly being used to treat patients with solid renal lesions. The technical success rate of nephron sparing surgery is excellent, and operative morbidity and mortality are low. For renal cell carcinoma long-term cancer-free survival is comparable to that after radical nephrectomy, particularly for low stage disease. The overall incidence of local recurrence is low at 0% to 10%. For tumors 4 cm. or less local recurrence rates are even less at 0% to 3%. The risk of local recurrence depends primarily on the initial local pathological tumor stage. The reported incidence of multifocal renal cell carcinoma is approximately 15% and it also depends on tumor size, histology and stage. The risk of multifocal disease is low at less than 5% when the maximal diameter of the primary tumor is 4 cm. or less. Recent advances in renal imaging limit the radiographic evaluation necessary when planning complex nephron sparing approaches. Three-dimensional, volume rendered computerized tomography integrates all of the necessary information previously obtained by conventional computerized tomography, angiography, venography and pyelography into a single preoperative test, allowing better operative planning with maximal preservation of unaffected parenchyma in the remnant kidney. Minimally invasive modalities of tumor resection or destruction should be reserved for highly select patients and await improvements in technology, standardization of technique and long-term outcomes data before they may be completely integrated options.
CONCLUSIONS: Nephron sparing surgery provides effective therapy for patients in whom preservation of renal function is a relevant clinical consideration. The importance of meticulous operative technique for achieving acceptable oncological and functional outcomes is emphasized. Accumulating data in appropriately select patients suggest a long-term functional advantage gained by the maximal preservation of unaffected renal parenchyma without sacrificing cancer control.
McKiernan J, Simmons R, Katz J, Russo P.
Natural history of chronic renal insufficiency after partial and radical nephrectomy.
Urology. 2002 Jun;59(6):816-20. doi: 10.1016/s0090-4295(02)01501-7.
Abstract/Text
OBJECTIVES: To compare the incidence of newly developed chronic renal insufficiency after partial nephrectomy (PN) and radical nephrectomy (RN). Elective PN for renal tumors is intended to preserve renal function; however, studies of transplant donors suggest normal renal function is also maintained after unilateral nephrectomy.
METHODS: We retrospectively compared all patients undergoing PN or RN for renal tumors 4 cm or less in the presence of a normal contralateral kidney from 1989 to 2000. Creatinine failure was defined as a serum creatinine value greater than 2.0 mg/dL. Risk factors for renal insufficiency, including diabetes, hypertension, American Society of Anesthesiologists score, age, preoperative creatinine, and history of smoking tobacco, were compared between the two groups. We compared the two groups using the chi-square and Mann-Whitney U tests and the creatinine failure rates using the Kaplan-Meier method.
RESULTS: One hundred seventy-three patients met the criteria for analysis after RN and 117 did so after PN (median follow-up 25 months). The 5-year freedom from recurrence rate was 96.4% and 98.6% for PN and RN, respectively (P >0.05). The mean preoperative serum creatinine was 1.0 mg/dL (range 0.4 to 1.4) and 0.98 (range 0.6 to 1.5) for RN and PN, respectively (P = 0.4, not significant). The incidence of risk factors for renal insufficiency did not differ between the two groups. The mean postoperative serum creatinine in the RN and PN groups was 1.5 mg/dL (range 0.8 to 3.8) and 1.0 mg/dL (range 0.5 to 1.9), respectively (P <0.001). The chance of creatinine failure over time was significantly greater in the RN group (P = 0.008).
CONCLUSIONS: When controlled for preoperative risk factors for renal insufficiency, patients undergoing RN are at a greater risk of chronic renal insufficiency than a similar cohort of patients undergoing PN.
Lucas SM, Stern JM, Adibi M, Zeltser IS, Cadeddu JA, Raj GV.
Renal function outcomes in patients treated for renal masses smaller than 4 cm by ablative and extirpative techniques.
J Urol. 2008 Jan;179(1):75-9; discussion 79-80. doi: 10.1016/j.juro.2007.08.156. Epub 2007 Nov 13.
Abstract/Text
PURPOSE: We examined the effect of radical nephrectomy, partial nephrectomy and radio frequency ablation on renal function in patients with stage T1a renal masses.
MATERIALS AND METHODS: A total of 242 consecutive patients from July 1995 to March 2005 undergoing primary treatment for unilateral renal masses smaller than 4 cm and a normal contralateral kidney were identified. Renal function was calculated using the modified Modification of Diet in Renal Disease equation. The rate of decrease in the glomerular filtration rate below 60 ml per minute 1.73 m2 was compared among the 3 treatment modalities.
RESULTS: A total of 86, 85 and 71 patients were treated with radio frequency ablation, partial nephrectomy and radical nephrectomy, respectively. Preoperatively stage 3 chronic kidney disease (glomerular filtration rate less than 60 ml per minute per 1.73 m2) was identified in 65 patients (26.7%), including 26.7%, 27.1% and 26.8% who underwent radio frequency ablation, partial nephrectomy and radical nephrectomy, respectively. Following intervention the 3-year freedom from a glomerular filtration rate decrease of below 60 ml per minute per 1.73 m2 for radio frequency ablation, partial nephrectomy and radical nephrectomy was 95.2%, 70.7% and 39.9%, respectively (p <0.001). Multivariate analysis showed that radical nephrectomy was an independent risk factor vs radio frequency ablation and partial nephrectomy for stage 3 chronic kidney disease (HR 34.3, 95% CI 4.28-275 and 10.9, 95% CI 1.36-88.7, respectively).
CONCLUSIONS: Decreased renal function is prevalent in patients with small unilateral renal tumors even with a normal contralateral kidney. Ablative or extirpative nephron sparing techniques are effective for preserving renal function in these patients.
Patton MW, Salevitz DA, Tyson MD 2nd, Andrews PE, Ferrigni EN, Nateras RN, Castle EP.
Robot-assisted partial nephrectomy for complex renal masses.
J Robot Surg. 2016 Mar;10(1):27-31. doi: 10.1007/s11701-015-0554-8. Epub 2015 Dec 24.
Abstract/Text
To determine whether the approach for partial nephrectomy is influenced by tumor complexity and if the introduction of robotic techniques has allowed us to treat more complex tumors minimally invasively. Data from 292 patients who underwent partial nephrectomy for renal masses from November 1999 to July 2013 at a tertiary referral center were retrospectively reviewed. Nephrometry scores and perioperative outcomes were stratified based on when robotic techniques were introduced. Mean follow-up time was 2.6 years. Preoperative RENAL nephrometry scores and perioperative outcomes were analyzed. Of the 292 patients, 31.5 % underwent robot-assisted partial nephrectomy, 46.2 % laparoscopic partial nephrectomy and 22.9 % open partial nephrectomy. Robot-assisted partial nephrectomy mean nephrometry score was significantly higher than laparoscopic and equivalent to open. Significant perioperative differences were estimated blood loss (p = 0.0001), length of stay (p = 0.0001) and Clavien score (p = 0.0069), all favoring robot-assisted partial nephrectomy. Limitations include retrospective design and single center data. Robot-assisted partial nephrectomy is a safe and effective surgical modality that allows for complex renal tumors that were previously reserved for open partial nephrectomy in the pure laparoscopic era to be managed with a minimally invasive approach.
Gervais DA, McGovern FJ, Arellano RS, McDougal WS, Mueller PR.
Radiofrequency ablation of renal cell carcinoma: part 1, Indications, results, and role in patient management over a 6-year period and ablation of 100 tumors.
AJR Am J Roentgenol. 2005 Jul;185(1):64-71. doi: 10.2214/ajr.185.1.01850064.
Abstract/Text
OBJECTIVE: The objectives of our article are to review our experience with radiofrequency ablation of renal cell carcinoma and to assess size and location as predictors of the ability to achieve complete necrosis by imaging criteria.
MATERIALS AND METHODS: Over a 6-year period, 100 renal tumors in 85 patients underwent radiofrequency ablation at a single institution. The absence of enhancement on CT or MRI after radiofrequency ablation was interpreted as complete coagulation necrosis. Results were analyzed by tumor size and location using multivariate analysis. A p value of 0.05 or less was considered significant.
RESULTS: All 52 small (3 cm) and all 68 exophytic tumors underwent complete necrosis regardless of size, although many large tumors (> 3 cm) required a second ablation session. Using multivariate analysis, we found that both small size (p < 0.0001) and noncentral location (p = 0.0049) proved to be independent predictors of complete necrosis after a single ablation session. Location was a significant predictor (p = 0.015) of complete necrosis after any number of sessions, whereas size showed a strong trend (p = 0.059) toward predicting success after any number of sessions. Complications were either self-limited or readily treated and included hemorrhage (major, n = 2; minor, n = 3), inflammatory track mass (n = 1), transient lumbar plexus pain (n = 2), ureteral injury (n = 2), and skin burns (n = 1).
CONCLUSION: Radiofrequency ablation is a promising minimally invasive therapy for renal cell carcinoma in patients who are not good operative candidates. Small size and noncentral location are favorable tumor characteristics, although large tumors can sometimes be successfully treated with multiple ablation sessions.
McDougal WS, Gervais DA, McGovern FJ, Mueller PR.
Long-term followup of patients with renal cell carcinoma treated with radio frequency ablation with curative intent.
J Urol. 2005 Jul;174(1):61-3. doi: 10.1097/01.ju.0000162046.45024.2b.
Abstract/Text
PURPOSE: We defined the role of radio frequency ablation in the treatment of renal cell carcinoma.
MATERIALS AND METHODS: A total of 16 patients with biopsy proven renal cell carcinoma were treated with radio frequency ablation in an outpatient setting and followed for a minimum of 4 years.
RESULTS: Of the 16 patients 5 died before 4 years of followup of unrelated causes. All except 1 tumor was successfully treated. All patients with exophytic tumors were successfully treated.
CONCLUSIONS: Radio frequency ablation of exophytic renal cell carcinomas less than 5 cm in diameter is effective in eradicating the tumor and comparable to surgical extirpation at 4 years.
Varkarakis IM, Allaf ME, Inagaki T, Bhayani SB, Chan DY, Su LM, Jarrett TW, Kavoussi LR, Solomon SB.
Percutaneous radio frequency ablation of renal masses: results at a 2-year mean followup.
J Urol. 2005 Aug;174(2):456-60; discussion 460. doi: 10.1097/01.ju.0000165655.91152.c5.
Abstract/Text
PURPOSE: We describe our experience with and results of percutaneous computerized tomography guided radio frequency ablation (RFA) for small (less than 4 cm) renal tumors at a 2-year mean followup.
MATERIALS AND METHODS: A total of 49 patients (60 renal tumors) with a mean age of 63.9 years underwent percutaneous RFA. Indications for RFA were severe comorbidities or previous abdominal surgery precluding operative management, or hereditary conditions predisposing to multiple tumor recurrence. Persistent enhancement on initial followup imaging was considered incomplete treatment and all such patients underwent biopsy and were offered repeat RFA. Enhancement or enlargement on subsequent imaging was considered tumor recurrence and these patients were counseled regarding further therapy.
RESULTS: Three patients (4 tumors) were excluded from evaluation due to death from unrelated causes or loss to followup. A total of 46 patients (56 tumors) were available for evaluation at a mean followup of 27.5 months (range 12 to 48). Six tumors were incompletely treated with the first RFA and successfully treated with a second session. Recurrences after successful initial treatment were seen in 3 of 46 patients. These recurrences developed 24, 25 and 31 months following RFA, respectively, and all occurred in patients with a central tumor of 3.0 cm or greater. Overall local control was achieved in 94.6% of tumors (53 of 56).
CONCLUSIONS: RFA is an emerging alternative treatment modality for small renal tumors. Larger (greater than 3.0 cm) central tumors represent unique technical challenges, making these tumors more prone to recurrence. Long-term followup is needed to establish the oncological durability of this technique.
Gupta A, Raman JD, Leveillee RJ, Wingo MS, Zeltser IS, Lotan Y, Trimmer C, Stern JM, Cadeddu JA.
General anesthesia and contrast-enhanced computed tomography to optimize renal percutaneous radiofrequency ablation: multi-institutional intermediate-term results.
J Endourol. 2009 Jul;23(7):1099-105. doi: 10.1089/end.2008.0499.
Abstract/Text
INTRODUCTION: Percutaneous renal ablation is often performed under conscious sedation and without contrast-enhanced imaging. We evaluated intermediate-term outcomes of patients undergoing percutaneous contrast-enhanced computed tomography (CT)-guided radiofrequency ablation (RFA) under general anesthesia (GA) at two high-volume centers.
MATERIALS AND METHODS: Prospectively maintained Institutional Regulatory Board-approved databases were searched to identify patients treated with percutaneous RFA using contrast-enhanced CT under GA. A total of 163 masses in 151 patients were treated. Enhancement on imaging or a positive biopsy at 4 to 6 weeks was considered incomplete ablation. Positive findings beyond this interval were defined as local recurrence.
RESULTS: The median follow-up was 18 months (range, 1.5-70). Median tumor size was 2.3 cm (range, 1-5.4). Of the 130 (80%) masses with definitive pathology, 70% were renal cell cancer. Five masses had evidence of viable tumor at 4 to 6 weeks posttreatment for a complete initial ablation rate of 97%. Three of these five lesions were endophytic. Five masses (3.3%) showed evidence of local recurrence, and metastases developed in two patients (1.3%). Overall 1- and 3-year recurrence-free survival was 97% and 92%, respectively. Masses that were in the central region and were endophytic had the highest risk for recurrence (hazard ratio, 6.3; p = 0.016).
CONCLUSIONS: Intermediate-term outcomes of percutaneous RFA are excellent. GA-assisted, contrast-enhanced CT-guided percutaneous RFA demonstrates a high initial ablation success rate. However, endophytic and interpolar lesions are at higher risk for recurrence.
Kutikov A, Kunkle DA, Uzzo RG.
Focal therapy for kidney cancer: a systematic review.
Curr Opin Urol. 2009 Mar;19(2):148-53. doi: 10.1097/MOU.0b013e328323f7d7.
Abstract/Text
PURPOSE OF REVIEW: Surgical excision remains the standard of care for treatment of localized small renal masses (SRMs). Laparoscopic and percutaneous minimally invasive ablative technologies are being increasingly employed in current urologic practice. We review recent literature regarding focal ablative treatments of SRMs.
RECENT FINDINGS: Most cryoablations are performed using a laparoscopic approach, whereas radiofrequency ablation (RFA) of the SRM is more commonly administered percutaneously. Pretreatment biopsy is performed more often for lesions treated by cryoablation than RFA with a significantly higher rate of indeterminate or unknown pathology for SRMs undergoing RFA versus cryoablation (P < 0.0001). Currently available data suggest that cryoablation results in lower retreatments (P < 0.0001), less local tumor progressions (P < 0.0001) and may be associated with a decreased risk of metastatic progression compared with RFA. It is unclear whether these differences are a function of the technologies or their application. Given the excellent results reported for active surveillance of the SRM in selected patients, the extent to which focal ablation alters the natural history of SRMs has not yet been established.
SUMMARY: Currently, data on the ability of interventions for SRMs to affect the natural history of these masses are lacking. Prospective randomized evaluations of available clinical approaches to SRMs are needed.
Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B.
Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.
N Engl J Med. 2018 Aug 2;379(5):417-427. doi: 10.1056/NEJMoa1803675. Epub 2018 Jun 3.
Abstract/Text
BACKGROUND: Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies.
METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival.
RESULTS: A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group.
CONCLUSIONS: Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).
Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen JV, Blank CU, van Velthoven R, Del Pilar Laguna M, Wood L, van Melick HHE, Aarts MJ, Lattouf JB, Powles T, de Jong Md PhD IJ, Rottey S, Tombal B, Marreaud S, Collette S, Collette L, Haanen J.
Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.
JAMA Oncol. 2019 Feb 1;5(2):164-170. doi: 10.1001/jamaoncol.2018.5543.
Abstract/Text
IMPORTANCE: In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown.
OBJECTIVE: To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied.
INTERVENTIONS: Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy.
MAIN OUTCOMES AND MEASURES: Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points.
RESULTS: The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%).
CONCLUSIONS AND RELEVANCE: Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01099423.
Culp SH, Tannir NM, Abel EJ, Margulis V, Tamboli P, Matin SF, Wood CG.
Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy?
Cancer. 2010 Jul 15;116(14):3378-88. doi: 10.1002/cncr.25046.
Abstract/Text
BACKGROUND: The benefits of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) should outweigh surgical morbidity. Even when the generally agreed upon selection criteria for CN are met, some patients do poorly after surgery. The objective of this study was to identify preoperative factors that were prognostic of outcome in patients who were being considered for CN.
METHODS: The authors conducted a retrospective study to investigate the overall survival (OS) of patients who underwent CN using the OS of patients with mRCC who did not undergo CN as a referent group. Patients who underwent CN were divided into 2 groups based on when their OS diverged from that of nonsurgical patients. Chi-square analysis was used to identify variables that differed between the 2 surgical groups. Multivariate Cox proportional hazards regression was used to analyze those variables for the entire CN cohort. Risk factors were defined as preoperative variables that remained significant on multivariate analysis. The median OS and the overall risk of death were calculated based on the number of risk factors.
RESULTS: From 1991 to 2007, 566 patients who were eligible for or received systemic therapy underwent CN, and 110 patients received medical therapy alone. On multivariate analysis, independent preoperative predictors of inferior OS in surgical patients included a lactate dehydrogenase level greater than the upper limit of normal, an albumin level less than the lower limit of normal, symptoms at presentation caused by a metastatic site, liver metastasis, retroperitoneal adenopathy, supradiaphragmatic adenopathy, and clinical tumor classification>or=T3. Inferior OS and an increased risk of death were correlated positively with the number of risk factors. Surgical patients who had >or=4 risk factors did not appear to benefit from CN.
CONCLUSIONS: The authors of this report identified 7 preoperative variables that permitted them to identify patients who were unlikely to benefit from CN.
Copyright (c) 2010 American Cancer Society.
Heng DY, Wells JC, Rini BI, Beuselinck B, Lee JL, Knox JJ, Bjarnason GA, Pal SK, Kollmannsberger CK, Yuasa T, Srinivas S, Donskov F, Bamias A, Wood LA, Ernst DS, Agarwal N, Vaishampayan UN, Rha SY, Kim JJ, Choueiri TK.
Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium.
Eur Urol. 2014 Oct;66(4):704-10. doi: 10.1016/j.eururo.2014.05.034. Epub 2014 Jun 13.
Abstract/Text
BACKGROUND: The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.
OBJECTIVE: To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective data from patients with synchronous mRCC (n=1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.
RESULTS AND LIMITATIONS: Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p<0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52-0.69; p<0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.
CONCLUSIONS: CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.
PATIENT SUMMARY: We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.
Copyright © 2014. Published by Elsevier B.V.
Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D; Eastern Cooperative Oncology Group/Intergroup trial.
Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial.
J Clin Oncol. 2003 Apr 1;21(7):1214-22. doi: 10.1200/JCO.2003.02.005.
Abstract/Text
PURPOSE: To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma.
PATIENTS AND METHODS: A total of 283 eligible patients with pT3-4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate.
RESULTS: At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P =.09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P =.33). Performance status (P =.003), nodal status (N2 v N0, P <.0001), and tumor stage (P =.0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P =.009) and shorter time to recurrence (P <.0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment.
CONCLUSION: Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.
Pizzocaro G, Piva L, Colavita M, Ferri S, Artusi R, Boracchi P, Parmiani G, Marubini E.
Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study.
J Clin Oncol. 2001 Jan 15;19(2):425-31. doi: 10.1200/JCO.2001.19.2.425.
Abstract/Text
PURPOSE: Because interferon gave promising results in the management of metastatic renal cell carcinoma in the 1980s, a multicentric randomized controlled trial was planned to compare adjuvant recombinant interferon alfa-2b (rIFNalpha2b) with observation after radical nephrectomy in patients with Robson stages II and III renal cell carcinoma. Overall and event-free survival were to be evaluated together with prognostic factors.
PATIENTS AND METHODS: Overall and event-free survival curves for 247 patients (124 controls and 123 treated) were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox's multiple regression models were adopted to perform a joint analysis of treatment and prognostic factors.
RESULTS: The 5-year overall and event-free survival probabilities were 0.665 and 0.671, respectively, for controls and 0.660 and 0.567, respectively, for the treated group; the differences were not statistically significant (2P = .861 for overall and 2P = .107 for event-free survival with the log-rank test). Regarding prognostic factors, only grade, pT, and pN demonstrated a significant prognostic role. First-order interactions of treatment with pT and pN category were investigated; a significant interaction was found between pN and treatment. A harmful effect of rIFNalpha2b in the 97 treated pN0 patients and a protective effect in the 13 treated pN2/pN3 patients were statistically significant.
CONCLUSION: Adjuvant rIFNalpha2b is not indicated after radical nephrectomy for renal cell carcinoma. The protective effect in the small group of pN2/pN3 patients requires further investigation.
Atzpodien J, Schmitt E, Gertenbach U, Fornara P, Heynemann H, Maskow A, Ecke M, Wöltjen HH, Jentsch H, Wieland W, Wandert T, Reitz M; German Cooperative Renal Carcinoma Chemo-Immunotherapy Trials Group (DGCIN).
Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).
Br J Cancer. 2005 Mar 14;92(5):843-6. doi: 10.1038/sj.bjc.6602443.
Abstract/Text
We conducted a prospectively randomised clinical trial to investigate the role of adjuvant outpatient immunochemotherapy administered postoperatively in high-risk patients with renal cell carcinoma. In total, 203 renal carcinoma patients' status post radical tumour nephrectomy were stratified into three risk groups: patients with tumour extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0), patients with locoregional lymph node infiltration (pN+), and patients after complete resection of tumour relapse or solitary metastasis (R0). Patients were randomised to undergo either (A) 8 weeks of outpatient subcutaneous interleukin-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen (Atzpodien et al, 2004) or (B) observation. Two-, 5-, and 8-year survival rates were 81, 58, and 58% in the treatment arm, and 91, 76, and 66% in the observation arm (log rank P=0.0278), with a median follow-up of 4.3 years. Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39% in the treatment arm, and at 62, 49, and 49% in the observation arm (log rank P=0.2398). Stage-adapted subanalyses revealed no survival advantages of treatment over observation, as well. Our results established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immunochemotherapy compared to observation in high-risk renal cell carcinoma patients following radical tumour nephrectomy.
Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS.
Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.
Lancet. 2016 May 14;387(10032):2008-16. doi: 10.1016/S0140-6736(16)00559-6. Epub 2016 Mar 9.
Abstract/Text
BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence.
METHODS: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898.
FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity.
INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis.
FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Ravaud A, Motzer RJ, Pandha HS, George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ; S-TRAC Investigators.
Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.
N Engl J Med. 2016 Dec 8;375(23):2246-2254. doi: 10.1056/NEJMoa1611406. Epub 2016 Oct 9.
Abstract/Text
BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy.
METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety.
RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects.
CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).
Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T; KEYNOTE-564 Investigators.
Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.
N Engl J Med. 2021 Aug 19;385(8):683-694. doi: 10.1056/NEJMoa2106391.
Abstract/Text
BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence.
METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point.
RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred.
CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).
Copyright © 2021 Massachusetts Medical Society.
Antonelli A, Zani D, Cozzoli A, Cunico SC.
Surgical treatment of metastases from renal cell carcinoma.
Arch Ital Urol Androl. 2005 Jun;77(2):125-8.
Abstract/Text
INTRODUCTION: Even if the number of curable renal cancers increased during the last decades, there is still a considerable amount of patients with distant metastases, evidenced at diagnosis or during the follow-up, without real curative therapeutic options.
MATERIALS AND METHODS: In the period between January 1983 and December 2003 we observed 252 metastatic patients among the 1187 surgically treated for renal cancer (21.2%). The metastatic disease was evidenced at the diagnosis of renal tumour in 118 patients (9.9%), during the follow up at a mean distance of 18.6 months in 134 (11.3%) and was in a single organ in 200 patients, in multiple sites in 52. A surgical treatment of metastases was performed in 113 cases, associated with chemo-immunotherapy in 16. Conversely, 44 patients received chemo-immunotherapy alone, 18 radiotherapy, and in the remaining 77 cases no curative therapies were applied.
RESULTS: The patients with a single-site metastasis who underwent of metastases removal, especially when pulmonary or adrenal, showed a better prognosis than the ones otherwise treated, while in the patients with bony metastases, multiple-site metastases and the ones who did not receive any curative therapies an extremely dismal prognosis was evidenced. However, a large amount of the patients with a single-site metastasis (79% on 159 treated patients) had a relapse of the disease, even when surgically treated (69%).
CONCLUSIONS: At present, in the lack of any effective systemic therapies for metastatic renal cancer, surgery offers better survival rates than other choices (chemo-immunotherapy or radiotherapy). Thus, even if the initial bias in the selection of patients is surely significant, in our opinion, each patient with good performance status and a resectable metastatic lesion, better if pulmonary or adrenal, should undergo surgical treatment of metastases, that could provide long-term survival in a small part of the patients. The high rate of relapses remarks the actual need of an effective systemic therapy both for the patients who can and cannot undergo surgery for their metastatic disease.
Piltz S, Meimarakis G, Wichmann MW, Hatz R, Schildberg FW, Fuerst H.
Long-term results after pulmonary resection of renal cell carcinoma metastases.
Ann Thorac Surg. 2002 Apr;73(4):1082-7. doi: 10.1016/s0003-4975(01)03602-5.
Abstract/Text
BACKGROUND: Until now no conclusive data exist regarding the factors influencing long-term survival after pulmonary resection of renal cell carcinoma metastases. The aim of the present study, therefore, was to discover definitive prognostic factors for survival using a large and homogeneous single center patient cohort.
METHODS: Between 1980 and 2000, 105 patients, after curative resection of lung metastases from renal cell carcinoma, were followed in this long-term study. These patients underwent a total of 150 surgical procedures. Survival analysis was done using the Kaplan-Meier method and the log-rank test. Multivariate analysis of prognostic factors was performed using the Cox multivariate proportional hazard model.
RESULTS: Median survival after curative resection reached 43 months (range, 1 to 218 months). Survival at 3, 5, and 10 years was 54%, 40%, and 33%, respectively. Univariate analysis revealed that a complete resection, a less than 4-cm diameter of the metastases and tumor-free lymph nodes at the time of primary operation, were highly significant dependent prognostic factors (p < 0.001). These factors were also shown to be independent prognostic factors as suggested by multivariate analysis (p < 0.05).
CONCLUSIONS: The size of the metastatic nodule, the completeness of pulmonary resection, and the lymph node status at the time of nephrectomy are the most important prognostic factors that influence survival after resection of pulmonary metastases. Recurrence of resectable pulmonary metastases does not impair survival, thus favoring repeated resection in patients with recurrent disease.
Leibovich BC, Cheville JC, Lohse CM, Zincke H, Frank I, Kwon ED, Merchan JR, Blute ML.
A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.
J Urol. 2005 Nov;174(5):1759-63; discussion 1763. doi: 10.1097/01.ju.0000177487.64651.3a.
Abstract/Text
PURPOSE: We developed a clinically useful scoring algorithm to predict cancer specific survival for patients with clear cell metastatic renal cell carcinoma (RCC).
MATERIALS AND METHODS: We studied 727 patients treated with radical nephrectomy for clear cell RCC from 1970 to 2000 who had distant metastases at nephrectomy (285) or in whom metastases subsequently developed (442). A scoring algorithm to predict cancer specific survival was developed using the regression coefficients from a Cox proportional hazards model.
RESULTS: There were 606 deaths from clear cell RCC at a median of 1.0 years (range 0 to 14) following metastatic RCC. Constitutional symptoms at nephrectomy (+2), metastases to the bone (+2) or liver (+4), metastases in multiple simultaneous sites (+2), metastases at nephrectomy (+1) or within 2 years of nephrectomy (+3), complete resection of all metastatic sites (-5), tumor thrombus level I to IV (+3), and the primary pathological features of nuclear grade 4 (+3) and histological tumor necrosis (+2) were significantly associated with death from RCC. All patients started with a score of 0 and points were added or subtracted as indicated in parentheses. Cancer specific survival rates at 1 year were 85.1%, 72.1%, 58.8%, 39.0%, and 25.1%, respectively, for patients with scores of -5 to -1, scores of 0 to 2, scores of 3 to 6, scores of 7 or 8, and scores of 9 or more.
CONCLUSIONS: This scoring algorithm can be used to predict cancer specific survival for patients with metastatic clear cell RCC.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA.
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma.
N Engl J Med. 2007 Jan 11;356(2):115-24. doi: 10.1056/NEJMoa065044.
Abstract/Text
BACKGROUND: Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted.
METHODS: We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety.
RESULTS: The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001).
CONCLUSIONS: Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).
Copyright 2007 Massachusetts Medical Society.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial.
Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
N Engl J Med. 2007 May 31;356(22):2271-81. doi: 10.1056/NEJMoa066838.
Abstract/Text
BACKGROUND: Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.
METHODS: In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.
RESULTS: Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).
CONCLUSIONS: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).
Copyright 2007 Massachusetts Medical Society.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA.
Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
J Clin Oncol. 2009 Aug 1;27(22):3584-90. doi: 10.1200/JCO.2008.20.1293. Epub 2009 Jun 1.
Abstract/Text
PURPOSE: A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-alpha) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported.
PATIENTS AND METHODS: Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-alpha 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up.
RESULTS: Median overall survival was greater in the sunitinib group than in the IFN-alpha group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-alpha group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).
CONCLUSION: Sunitinib demonstrates longer overall survival compared with IFN-alpha plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM; TARGET Study Group.
Sorafenib in advanced clear-cell renal-cell carcinoma.
N Engl J Med. 2007 Jan 11;356(2):125-34. doi: 10.1056/NEJMoa060655.
Abstract/Text
BACKGROUND: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma.
METHODS: From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005.
RESULTS: At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo.
CONCLUSIONS: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).
Copyright 2007 Massachusetts Medical Society.
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK.
Pazopanib versus sunitinib in metastatic renal-cell carcinoma.
N Engl J Med. 2013 Aug 22;369(8):722-31. doi: 10.1056/NEJMoa1303989.
Abstract/Text
BACKGROUND: Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.
METHODS: We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.
RESULTS: Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).
CONCLUSIONS: Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).
Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, Walsh M, Olencki T, Picus J, Small EJ, Dakhil S, Feldman DR, Mangeshkar M, Scheffold C, George D, Morris MJ.
Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.
Eur J Cancer. 2018 May;94:115-125. doi: 10.1016/j.ejca.2018.02.012. Epub 2018 Mar 20.
Abstract/Text
BACKGROUND: The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS).
PATIENTS AND METHODS: Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases.
RESULTS: A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8-14.0) versus 5.3 months (95% CI 3.0-8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31-0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0-30.8) versus 9% (95% CI 3.7-17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6-not estimable) with cabozantinib and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR 0.80 [95% CI 0.53-1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib.
CONCLUSIONS: In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk.
TRIAL REGISTRATION NUMBER: NCT01835158.
Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators.
Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.
N Engl J Med. 2015 Nov 5;373(19):1814-23. doi: 10.1056/NEJMoa1510016. Epub 2015 Sep 25.
Abstract/Text
BACKGROUND: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.
METHODS: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.
RESULTS: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.
CONCLUSIONS: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).
Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, Donskov F, Roth BJ, Peltola K, Lee JL, Heng DYC, Schmidinger M, Agarwal N, Sternberg CN, McDermott DF, Aftab DT, Hessel C, Scheffold C, Schwab G, Hutson TE, Pal S, Motzer RJ; METEOR investigators.
Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.
Lancet Oncol. 2016 Jul;17(7):917-927. doi: 10.1016/S1470-2045(16)30107-3. Epub 2016 Jun 5.
Abstract/Text
BACKGROUND: Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis.
METHODS: In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747.
FINDINGS: Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1-21·1) in the cabozantinib group and 18·8 months (16·0-21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7-not estimable) with cabozantinib and 16·5 months (14·7-18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53-0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41-0·62]; p<0·0001) and objective response (17% [13-22] with cabozantinib vs 3% [2-6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration).
INTERPRETATION: Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications.
FUNDING: Exelixis Inc.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Permpongkosol S, Chan DY, Link RE, Sroka M, Allaf M, Varkarakis I, Lima G, Jarrett TW, Kavoussi LR.
Long-term survival analysis after laparoscopic radical nephrectomy.
J Urol. 2005 Oct;174(4 Pt 1):1222-5. doi: 10.1097/01.ju.0000173917.37265.41.
Abstract/Text
PURPOSE: This report assesses the long-term oncological efficacy of laparoscopic radical nephrectomy compared with open radical nephrectomy in patients with clinically localized renal cell carcinoma.
MATERIALS AND METHODS: We analyzed the data from 121 patients who underwent radical nephrectomy between 1991 and 1999 for clinical tumor stage T1/2 N0M0. The medical records of all patients were retrospectively reviewed with emphasis on tumor recurrence and survival. Statistical comparison was performed using Kaplan-Meier analysis.
RESULTS: The median followup was 73 months for the laparoscopic group and 80 months for the open group. Of the 67 patients who underwent laparoscopic surgery, 53 survived without any recurrence of disease, 2 are currently alive with metastasis, 2 died of metastatic disease in months 12 and 17, and 10 patients died without any disease recurrence. Laparoscopic port site metastasis did not develop in any patients. Of the 54 who underwent open surgery, 34 survived without any recurrence of disease, 1 currently has metastasis, 6 died of metastasis within 17 to 74 months, and 13 died without any disease recurrence. A comparison of the 5 and 10-year disease-free survival rates of the laparoscopic and open groups revealed no significant differences. In addition, the 5 and 10-year cancer specific and actuarial survival rates were not significantly different.
CONCLUSIONS: Based on long-term followup, our evaluation confirmed for clinical tumor stage T1/2 N0M0 that laparoscopic radical nephrectomy is oncologically equivalent to open radical nephrectomy.
Colombo JR Jr, Haber GP, Jelovsek JE, Lane B, Novick AC, Gill IS.
Seven years after laparoscopic radical nephrectomy: oncologic and renal functional outcomes.
Urology. 2008 Jun;71(6):1149-54. doi: 10.1016/j.urology.2007.11.081. Epub 2008 Mar 3.
Abstract/Text
OBJECTIVES: To compare the long-term oncologic and renal function outcomes in patients undergoing laparoscopic (LRN) versus open radical nephrectomy (ORN).
METHODS: The medical records of 116 patients undergoing radical nephrectomy for pathologically confirmed renal cell carcinoma before January 2000 were reviewed. Of these 116 patients, 63 underwent LRN and 53 ORN. The oncologic and renal functional data were obtained from the patient charts, radiographic reports, and direct telephone calls to the patients or their families.
RESULTS: The median follow-up was 65 months (range 19 to 92) in the LRN group and 76 months (range 8 to 105) in the ORN group. LRN was successfully completed in all patients without open conversion. The mean tumor size was 5.4 cm in the LRN group and 6.4 cm in the ORN group (P = 0.007). The 5-year overall survival (78% versus 84%, respectively; P = 0.24), cancer-specific survival (91% versus 93%, respectively; P = 0.75), and recurrence-free survival (91% versus 93%, respectively; P = 0.75) rates were similar between the LRN and ORN groups. At 7 years, the overall survival (72% versus 84%; P = 0.24), cancer-specific survival (91% versus 93%; P = 0.75), and recurrence-free survival (91% versus 93%; P = 0.75) rates were also comparable. No port site recurrence was noted in the laparoscopic group. The long-term renal function outcomes were similar in the LRN and ORN groups, with serum creatinine increasing by 33% and 25%, and the estimated creatinine clearance decreasing by 31% and 23% from baseline, respectively. Chronic renal insufficiency developed in 4% of patients in each group.
CONCLUSIONS: The results of our study have shown that LRN and ORN have comparable long-term oncologic and renal functional outcomes.
Hattori R, Osamu K, Yoshino Y, Tsuchiya F, Fujita T, Yamada S, Funahashi Y, Ono Y, Gotoh M.
Laparoscopic radical nephrectomy for large renal-cell carcinomas.
J Endourol. 2009 Sep;23(9):1523-6. doi: 10.1089/end.2009.0393.
Abstract/Text
OBJECTIVES: We retrospectively reviewed the clinical outcome and long-term cancer control of patients with localized large renal-cell carcinomas (RCCs) who underwent laparoscopic radical nephrectomy in comparison to open procedure.
PATIENTS AND METHODS: One hundred and thirty-one patients with RCCs greater than 7 cm who underwent radical nephrectomy between 1996 and 2008 were studied: 52 patients in the laparoscopy group and 79 in the open group. In this analysis patients who had metastasis or pT4 disease or tumor thrombus in the inferior vena cava were excluded. The median follow-up period was 41 months in the laparoscopy group and 51 months in the open group.
RESULTS: Patients in the laparoscopy group had tumors similar in size to those in the open group (88 and 89 mm, respectively), lesser blood loss (245 and 663 mL p < 0.01), but more intraoperative complications (15% and 2.5%). One laparoscopy patient was converted to open surgery because of an injury to the inferior vena cava (IVC). The 5- and 10-year disease-free rates and patient-survival rates were comparable in both groups.
CONCLUSIONS: Laparoscopic nephrectomy is feasible for localized large RCC, although intraoperative complications were more frequent. No statistically significant differences were found in either disease-free or cause-specific patient survival rates between the laparoscopy and the open groups. Laparoscopic nephrectomy can be an alternative to the open procedure for localized large RCC. However, a longer follow-up period is necessary to confirm the oncological efficacy of this procedure.
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, Venugopal B, Kollmannsberger C, Negrier S, Uemura M, Lee JL, Vasiliev A, Miller WH Jr, Gurney H, Schmidinger M, Larkin J, Atkins MB, Bedke J, Alekseev B, Wang J, Mariani M, Robbins PB, Chudnovsky A, Fowst C, Hariharan S, Huang B, di Pietro A, Choueiri TK.
Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
N Engl J Med. 2019 Mar 21;380(12):1103-1115. doi: 10.1056/NEJMoa1816047. Epub 2019 Feb 16.
Abstract/Text
BACKGROUND: In a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.
METHODS: We randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.
RESULTS: A total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.
CONCLUSIONS: Progression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).
Copyright © 2019 Massachusetts Medical Society.
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Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators.
Lancet. 1999 Jan 2;353(9146):14-7.
Abstract/Text
BACKGROUND: Metastatic renal carcinoma has a 2-year survival of around 20% and is largely resistant to chemotherapy. The use of interferons in the treatment of metastatic renal carcinoma remains controversial. Although non-randomised studies suggest that biological therapy with interferons produces a small number of tumour responses, most clinicians judge such treatment to be ineffective. We have investigated the effect of treatment with interferon-alpha on survival in patients with metastatic renal carcinoma.
METHODS: In a multicentre, randomised trial, patients with metastatic renal carcinoma were randomly assigned subcutaneous interferon-alpha (three doses--5 MU, 5 MU, 10 MU--for the first week, then 10 MU three times per week for a further 11 weeks; n=174) or oral medroxyprogesterone acetate (MPA; 300 mg once daily for 12 weeks; n=176). The primary endpoint was overall survival. Analysis was by intention to treat. The trial used a triangular sequential design for early termination as soon as results were conclusive. The trial was stopped in November, 1997, when data were available for 335 patients (167 interferon-alpha, 168 MPA).
FINDINGS: A total of 111 patients have died in the interferon-alpha group, and 125 patients have died in the MPA group. There was a 28% reduction in the risk of death in the interferon-alpha group (hazard ratio 0.72 [95% CI 0.55-0.94], p=0.017). Interferon-alpha gave an improvement in 1-year survival of 12% (MPA 31% survival, interferon-alpha 43%), and an improvement in median survival of 2.5 months (MPA 6 months, interferon-alpha 8.5 months).
INTERPRETATION: The benefit of treatment with interferon-alpha should be weighed against the drug's toxic effects. Combination regimens of biological therapy and chemotherapy should now be compared with interferon-alpha monotherapy in randomised controlled trials.
Pyrhönen S, Salminen E, Ruutu M, Lehtonen T, Nurmi M, Tammela T, Juusela H, Rintala E, Hietanen P, Kellokumpu-Lehtinen PL.
Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer.
J Clin Oncol. 1999 Sep;17(9):2859-67. doi: 10.1200/JCO.1999.17.9.2859.
Abstract/Text
PURPOSE: The combination of interferon alfa-2a (IFNalpha2a) plus vinblastine (VLB) induces objective tumor responses in patients with advanced renal cell cancer. However, no prospective randomized trial has shown that this treatment prolongs overall survival. We compared overall survival after treatment with IFNalpha2a plus VLB versus VLB alone in patients with advanced renal cell cancer.
PATIENTS AND METHODS: We prospectively randomized 160 patients with locally advanced or metastatic renal cell cancer to receive either VLB alone or IFNalpha2a plus VLB for 12 months or until progression of disease. In both groups, VLB was administered intravenously at 0.1 mg/kg every 3 weeks, and in the combination group IFNalpha2a was administered subcutaneously at 3 million units three times a week for 1 week, and 18 million units three times a week thereafter for the second and subsequent weeks. For patients unable totolerate IFNalpha2a at 18 million units per injection, the dose was reduced to 9 million units.
RESULTS: Median survival was 67.6 weeks for the 79 patients receiving IFNalpha2a plus VLB and 37.8 weeks for the 81 patients treated with VLB (P =.0049). Overall response rates were 16. 5% for patients treated with IFNalpha2a plus VLB and 2.5% for patients treated with VLB alone (P =.0025). Treatment with the combination was associated with constitutional symptoms and abnormalities in laboratory parameters, but no toxic deaths were reported.
CONCLUSION: The combination of IFNalpha2a plus VLB is superior to VLB alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. This is the first study to demonstrate that survival can be prolonged by using IFNalpha2a for these patients.
Naito S, Yamamoto N, Takayama T, Muramoto M, Shinohara N, Nishiyama K, Takahashi A, Maruyama R, Saika T, Hoshi S, Nagao K, Yamamoto S, Sugimura I, Uemura H, Koga S, Takahashi M, Ito F, Ozono S, Terachi T, Naito S, Tomita Y.
Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients.
Eur Urol. 2010 Feb;57(2):317-25. doi: 10.1016/j.eururo.2008.12.026. Epub 2009 Jan 3.
Abstract/Text
BACKGROUND: Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients.
OBJECTIVES: We aimed to investigate the prognosis of Japanese patients and their prognostic factors.
DESIGN, SETTING, AND PARTICIPANTS: The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002.
MEASUREMENTS: The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features.
RESULTS AND LIMITATIONS: The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival.
CONCLUSIONS: The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.
Copyright 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC.
Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.
J Clin Oncol. 1995 Mar;13(3):688-96. doi: 10.1200/JCO.1995.13.3.688.
Abstract/Text
PURPOSE: To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma.
PATIENTS AND METHODS: Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients.
RESULTS: The overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesions. The median response duration for patients who achieved a CR has not been reached, but was 19.0 months for those who achieved a PR. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was the only predictive prognostic factor for response to IL-2. While treatment was associated with severe acute toxicities, these generally reversed rapidly after therapy was completed. However, 4% of patients died of adverse events judged to be possibly or probably treatment-related.
CONCLUSION: High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment-associated toxicities, IL-2 should be considered for initial therapy of patients with appropriately selected metastatic renal cell carcinoma.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P; CheckMate 025 Investigators.
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.
N Engl J Med. 2015 Nov 5;373(19):1803-13. doi: 10.1056/NEJMoa1510665. Epub 2015 Sep 25.
Abstract/Text
BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
METHODS: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.
RESULTS: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).
CONCLUSIONS: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M.
Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma.
J Clin Oncol. 2002 Jan 1;20(1):289-96. doi: 10.1200/JCO.2002.20.1.289.
Abstract/Text
PURPOSE: To define outcome data and prognostic criteria for patients with metastatic renal cell carcinoma (RCC) treated with interferon-alfa as initial systemic therapy. The data can be applied to design and interpretation of clinical trials of new agents and treatment programs against this refractory malignancy.
PATIENTS AND METHODS: Four hundred sixty-three patients with advanced RCC administered interferon-alpha as first-line systemic therapy on six prospective clinical trials were the subjects of this retrospective analysis. Three risk categories for predicting survival were identified on the basis of five pretreatment clinical features by a stratified Cox proportional hazards model.
RESULTS: The median overall survival time was 13 months. The median time to progression was 4.7 months. Five variables were used as risk factors for short survival: low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and time from initial RCC diagnosis to start of interferon-alpha therapy of less than one year. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two (intermediate risk), and those with three or more (poor risk). The median time to death of patients deemed favorable risk was 30 months. Median survival time in the intermediate-risk group was 14 months. In contrast, the poor-risk group had a median survival time of 5 months.
CONCLUSION: Progression-free and overall survival with interferon-alpha treatment can be compared with new therapies in phase II and III clinical investigations. The prognostic model is suitable for risk stratification of phase III trials using interferon-alpha as the comparative treatment arm.
Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators.
Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
N Engl J Med. 2021 Mar 4;384(9):829-841. doi: 10.1056/NEJMoa2026982.
Abstract/Text
BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.
METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.
RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.
CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).
Copyright © 2021 Massachusetts Medical Society.
Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Kopyltsov E, Méndez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators.
Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.
N Engl J Med. 2021 Apr 8;384(14):1289-1300. doi: 10.1056/NEJMoa2035716. Epub 2021 Feb 13.
Abstract/Text
BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.
METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.
RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.
CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
Copyright © 2021 Massachusetts Medical Society.
