Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model for first-line pazopanib in metastatic renal carcinoma: the Spanish Oncologic Genitourinary Group (SOGUG) SPAZO study

BackgroundPatients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice.Patients and methodsData of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear-cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib (57.2% due to progression), 47.9% had received second-line targeted therapy, and 48.9% had died.ResultsAccording to IMDC prognostic model, 19.4% had favourable risk (FR), 57.2% intermediate risk (IR), and 23.4% poor risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1%, respectively (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model.ConclusionOur results validate the IMDC model for first-line pazopanib in mRCC and confirm the effectiveness and safety of this treatment.     

Sunitinib in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to International Metastatic Renal Cell Carcinoma Database Consortium Risk Group

Background

Sunitinib malate, a targeted tyrosine kinase inhibitor, is standard of care for metastatic renal cell carcinoma (mRCC) and serves as the active comparator in several ongoing mRCC clinical trials. In this analysis we report benchmarks for clinical outcomes on the basis of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups for patients treated with sunitinib for mRCC in a first-line setting.

First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium

Introduction/BackgroundApproval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.Patients and MethodsWe performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).ResultsWe identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.ConclusionPoor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.     

Prognostic Factors of Survival for Patients With Metastatic Renal Cell Carcinoma With Brain Metastases Treated With Targeted Therapy: Results From the International Metastatic Renal Cell Carcinoma Database Consortium

BackgroundThe outcomes and prognosis of patients with brain metastases from advanced renal cell carcinoma (RCC) are not well characterized in the targeted-therapy era.MethodsData from patients with metastatic RCC (mRCC) and brain metastases treated with targeted therapy were collected through the International Metastatic Renal Cell Carcinoma Database Consortium from 7 cancer centers.ResultsOverall, 106 (15%) of 705 patients with mRCC had brain metastases. Forty-seven patients had brain metastases at the start of first-line anti–vascular endothelial growth factor therapy, and the rest developed metastases during follow-up. Of the patients with brain metastases, 12%, 42% and 29% were in the favorable, intermediate, and poor prognosis groups, respectively, per the Heng criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 37% had a Karnofsky performance status (KPS) <80%, and 80% had neurologic symptoms at presentation. The median largest size and number of brain metastases was 1.8 cm (range, 0.2-6.6 cm) and one (range, 1 to innumerable), respectively. The patients were treated with sunitinib (n = 77), sorafenib (n = 23), bevacizumab (n = 5), and temsirolimus (n = 1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). On multivariable analysis, KPS < 80%, diagnosis to treatment with targeted therapy <1 year, and a higher number of brain metastases (>4) was associated with worse survival from the time of diagnosis with brain metastases.ConclusionsPatients with brain metastases from RCC are unlikely to be in the favorable risk group. KPS at the start of therapy, diagnosis to treatment time, and the number of brain metastases are prognostic factors for overall survival.     

A population-based validation of the prognostic model PREDICT for early breast cancer

Introduction

Predict (www.predict.nhs.uk) is a prognostication and treatment benefit tool developed using UK cancer registry data. The aim of this study was to compare the 10-year survival estimates from Predict with observed 10-year outcome from a British Columbia dataset and to compare the estimates with those generated by Adjuvant! (www.adjuvantonline.com).

Method

The analysis was based on data from 3140 patients with early invasive breast cancer diagnosed in British Columbia, Canada, from 1989-1993. Demographic, pathologic, staging and treatment data were used to predict 10-year overall survival (OS) and breast cancer specific survival (BCSS) using Adjuvant! and Predict models. Predicted outcomes from both models were then compared with observed outcomes.

Results

Calibration of both models was excellent. The difference in total number of deaths estimated by Predict was 4.1 percent of observed compared to 0.7 percent for Adjuvant!. The total number of breast cancer specific deaths estimated by Predict was 3.4 percent of observed compared to 6.7 percent for Adjuvant! Both models also discriminate well with similar AUC for Predict and Adjuvant! respectively for both OS (0.709 vs 0.712) and BCSS (0.723 vs 0.727). Neither model performed well in women aged 20-35.

Conclusion

In summary Predict provided accurate overall and breast cancer specific survival estimates in the British Columbia dataset that are comparable with outcome estimates from Adjuvant! Both models appear well calibrated with similar model discrimination. This study provides further validation of Predict as an effective predictive tool following surgery for invasive breast cancer.     

A prognostic model in patients who receive chemotherapy for metastatic or recurrent gastric cancer: validation and comparison with previous models

Purpose  

To make up for the limitations of previous prognostic models, we developed and validated a model in patients with metastatic or recurrent gastric adenocarcinoma (AGC), and to compare with previous models.     

Pathologic Predictors of Survival During Lymph Node Dissection for Metastatic Renal-Cell Carcinoma: Results From a Multicenter Collaboration

Purpose

To determine the therapeutic value of lymph node dissection (LND) during cytoreductive nephrectomy (CN) and assess predictors of cancer-specific survival (CSS) in metastatic renal-cell carcinoma.

Development and validation of prognostic models in metastatic breast cancer: a GOCS study.

The significance of several prognostic factors and the magnitude of their influence on response rate and survival were assessed by means of uni- and multivariate analyses in 362 patients with stage IV (UICC) breast carcinoma receiving combination chemotherapy as first systemic treatment over an 8-year period. Univariate analyses identified performance status and prior adjuvant radiotherapy as predictors of objective regression (OR), whereas the performance status, prior chemotherapy and radiotherapy (adjuvants), white blood cells count, SGOT and SGPT levels, and metastatic pattern were significantly correlated to survival. In multivariate analyses favorable characteristics associated to OR were prior adjuvant radiotherapy, no prior chemotherapy and postmenopausal status. Regarding survival, the performance status and visceral involvement were selected by the Cox model. The predictive accuracy of the logistic and the proportional hazards models was retrospectively tested in the training sample, and prospectively in a new population of 126 patients also receiving combined chemotherapy as first treatment for metastatic breast cancer. A certain overfitting to data in the training sample was observed with the regression model for response. However, the discriminative ability of the Cox model for survival was clearly confirmed.     

Prognosis and prognostic factors of patients with mesothelioma: a population-based study

Background:

It is important to regularly update survival estimates of patients with malignant mesothelioma as prognosis may vary according to epidemiologic factors and diagnostic and therapeutic management.

Methods:

We assessed overall (baseline) survival as well as related prognostic variables in a large cohort of 1353 patients with a confirmed diagnosis of malignant mesothelioma between 2005 and 2008.

Results:

About 50% of the patients were 70 years or older at diagnosis and the median latency time since start of asbestos exposure was 49 years. One year after diagnosis, 47% of the patients were alive, 20% after 2 years and 15% after 3 years. Prognostic variables independently associated with worse survival were: older age (HR=1.04 per year 95% CI (1.03–1.06)), sarcomatoid subtype (HR=2.45 95% CI (2.06–2.90)) and non-pleural localisation (HR=1.67 95% CI (1.26–2.22)).

Conclusion:

Survival of patients with malignant mesothelioma is still limited and depends highly on patient age, mesothelioma subtype and localisation. In addition, a substantial part of the patients had a long latency time between asbestos exposure and diagnosis.     

External validation of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer

Background:

For various malignancies, prognostic models have shown to be superior to traditional staging systems in predicting overall survival. The purpose of this study was to validate and compare the performance of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer.

Methods:

A multi-institutional epithelial ovarian cancer database was used to identify patients and to evaluate the predictive performance of two nomograms, a prognostic index and FIGO (International Federation of Obstetrics and Gynecology) stage. All patients were treated for advanced-stage epithelial ovarian cancer between January 1996 and January 2009 in 11 hospitals in the eastern part of The Netherlands.

Results:

In total, 542 patients were found to be eligible. Overall performance did not differ between the three prognostic models and FIGO stage. The discriminative performance for Chi''s model was moderately good (c indices 0.65 and 0.68) and for the models of Gerestein and Teramukai reasonable (c indices between 0.60 and 0.62). The c indices of FIGO stage ranged between 0.54 and 0.62. After recalibration, the three models showed almost perfect calibration, whereas calibration of FIGO stage was reasonable.

Conclusion:

The three prediction models showed general applicability and a reasonably well-predictive performance, especially in comparison to FIGO stage. To date, there are no studies available that analyse the impact of these prognostic models on decision-making and patient outcome. Therefore, the usefulness of these models in daily clinical practice remains to be investigated.     

Different prognostic models for different patient populations: validation of a new prognostic model for patients with oropharyngeal cancer in Western Europe

Objective:

The presence of human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant in prognostic risk modelling. Recently, a prognostic model was proposed in which HPV status, comorbidity and nodal stage were the most important prognostic factors to determine high-, intermediate- and low-risk survival groups. Here, we report on the validation of this model using an independent single-institutional cohort.

Methods:

A total number of 235 patients curatively treated for OPSCC in the period 2000–2011 at the MUMC (Maastricht University Medical Center, The Netherlands) were included. The presence of an oncogenic HPV infection was determined by p16 immunostaining, followed by a high-risk HPV DNA PCR on the p16-positive cases. The model variables included were HPV status, comorbidity and nodal stage. As a measure of model performance, the Harrell''s Concordance index (Harrell''s C-index) was used.

Results:

The 5-year overall survival (OS) estimates were 84.6%, 54.5% and 28.7% in the low-, intermediate- and high-risk group, respectively. The difference between the survival curves was highly significant (P<0.001). The Harrell''s C-index was 0.69 (95% confidence interval (CI): 0.63–0.75).

Conclusion:

In this study a previously developed prognostic risk model was validated. This model will help to personalise treatment in OPSCC patients. This model is publicly available at www.predictcancer.org.     

Safety and Efficacy of Pazopanib in First-Line Metastatic Renal-Cell Carcinoma With or Without Renal Failure: CORE-URO-01 Study

Background

Pazopanib has been approved for first-line treatment of patients with metastatic renal-cell carcinoma on the basis of clinical trials that enrolled only patients with adequate renal function. Few data are available on the safety and efficacy of pazopanib in patients with renal insufficiency. This study investigated the effect of kidney function on treatment outcomes in such patients.

Metastatic renal cell carcinoma: results of a population-based study with 25 years follow-up

BackgroundRenal cell carcinoma (RCC) is the sixth leading cause of death in developed countries. A third of all RCC patients are confronted with metastatic disease. Since their approval in 2005 and 2006 in the USA, new targeted therapies may lead to substantial progress. Thus, the aim of this cohort study was to present clinical characteristics and survival in metastatic RCC in a population-based sample before widespread implementation of these new therapies.MethodsPatients (2264) with metastatic RCC registered between 1978 and 2005 in the cancer registry of Munich, Bavaria were analysed.ResultsMedian survival and 5 year relative survival from the 1st metastases were 14.4 months and 21%, respectively. Median survival has slightly improved from 13.2 months in 1978–1987 to 15.6 months since 2002.ConclusionSurvival of patients with metastatic RCC did not substantially improve within the last three decades. Assuming that new targeted therapies are successful in the treatment of metastatic RCC, population-based data like these can provide a basis for assessing the progress shown in clinical studies and for surveying critically the future implementation of new therapies in routine care.     

External validation of a prognostic nomogram for overall survival in women with uterine leiomyosarcoma

BACKGROUND:

There is no validated system to identify prognostically distinct cohorts of women with uterine leiomyosarcoma (ULMS). By using an independent, pooled, multi‐institutional, international patient cohort, the authors validated a recently proposed ULMS nomogram.

METHODS:

The ULMS nomogram incorporated 7 clinical characteristics (age, tumor size, tumor grade, cervical involvement, locoregional metastases, distant metastases, and mitotic index (per 10 high‐power fields) to predict overall survival (OS) after primary surgery. Independent cohorts from 2 sarcoma centers were included. Eligible women, at minimum, underwent a hysterectomy for primary, locally advanced, or metastatic ULMS and received part of their care at 1 of the centers between 1994 and 2010.

RESULTS:

In total, 187 women with ULMS were identified who met the above criteria described above (median age, 51 years; median tumor size, 9 cm; median mitotic index, 20 per 10 high‐power fields). Tumors generally were high grade (88%), FIGO stage I or II (61%) without cervical involvement (93%) and without locoregional metastases (77%) or distant metastases (83%). The median OS and the 5‐year OS rate were 4.5 years (95% confidence interval, 3.2‐5.3 years) and 46%, respectively; and 65 women (35%) remained alive at last follow‐up. The nomogram concordance index was 0.67(standard error, 0.02), which was as high as the concordance index from the initial cohort used for nomogram development. The concordance between actual OS and nomogram predictions suggests excellent calibration because predictions were within 1% of actual 5‐year OS rates for patients with a predicted 5‐year OS of less than 0.68.

CONCLUSIONS:

The ULMS nomogram was externally validated using independent cohorts. These findings support the international use of the ULMS nomogram prognostic of OS in ULMS. Cancer 2013. © 2012 American Cancer Society.     

International incidence of oropharyngeal cancer: a population-based study

The incidence of oropharyngeal cancer is not well documented as it is rarely described according to the anatomic definition but usually grouped with oral cavity subsites. The aim of this study was to calculate oropharyngeal cancer incidence and compare it to oral cavity cancer incidence. Age-standardized incidence rates (ASR) of oropharyngeal cancer were calculated for the period between 1998 and 2002, based on data from Cancer Incidence in 5 Continents, Volume IX (CI5-IX). These ASRs were compared with previously published oral cavity cancer data. Among males, the highest ASRs were observed in France, Slovakia, Slovenia and Brazil. The highest oral cavity/oropharyngeal cancer rate ratio was observed in Pakistan, among males (6.2) and females (13.5). The results provide an overview of oropharyngeal cancer incidence and constitute a basis for the development of primary and secondary prevention, according to geographical variations and topography.