Mary J. MacKenzie

Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment : a randomised open-label trial

BACKGROUND Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment. METHODS We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079. FINDINGS 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia. INTERPRETATION Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. FUNDING Sanofi-Aventis.

External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study

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 Consortiums 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.

Imatinib Mesylate in Patients With Adenoid Cystic Cancers of the Salivary Glands Expressing c-kit: A Princess Margaret Hospital Phase II Consortium Study

PURPOSE This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases. PATIENTS AND METHODS In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks. RESULTS Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles. CONCLUSION Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.

Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

BACKGROUND The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). OBJECTIVE To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. DESIGN, SETTING, AND PARTICIPANTS We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. RESULTS AND LIMITATIONS The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p<0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22-1.62) for BMs, 1.42 (95% CI, 1.17-1.73) for LMs, and 1.82 (95% CI, 1.47-2.26) for both BMs and LMs compared with other metastatic sites (p<0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis were collected retrospectively. CONCLUSIONS The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.

A Phase II Trial with Pharmacodynamic Endpoints of the Proteasome Inhibitor Bortezomib in Patients with Metastatic Colorectal Cancer

Purpose: To evaluate the effects of the proteasome inhibitor bortezomib on tumor growth in patients with advanced colorectal cancer, and to explore the relationship between correlative studies and clinical outcome. Design: Bortezomib (1.3 mg/m2) was administered i.v. on days 1, 4, 8, and 11 of a 21-day cycle. Tumor response was assessed after every two cycles. Tumor biopsies were done prior to treatment and on day 9 of the first treatment cycle. Biopsies were examined for Ser32/36-IκB, Ser276-nuclear factor κB (NFκB), hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX), p53, and microvessel density using immunohistochemistry. Results: Nineteen patients received 42 cycles (range 1-4) of bortezomib. No objective response was seen; three patients had stable disease at cycle 2, two patients had progressive disease after cycle 1, and 11 patients had progressive disease at cycle 2. Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity. The median time to progression was 5.1 weeks (95% confidence interval, 5.1-11.1 weeks). There was a significant increase in the expression of HIF-1α relative to its transcriptional target CAIX following bortezomib, and a similar effect was also observed in a companion study using a human tumor xenograft model. Expression of p53, Ser276-NFκB, and Ser32/36-IκB was unchanged. Conclusion: Single agent bortezomib is inactive in metastatic colorectal cancer. Using this regimen, there was no detectable effect on NFκB, but a significant accumulation of HIF-1α was seen relative to CAIX. This suggests that proteasome inhibition alters the response to tumor hypoxia, and further investigation of this effect is indicated.

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy

BACKGROUND A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: Characterization of survival outcome and application of the International mRCC Database Consortium criteria

This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non–clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized.

Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study

BACKGROUND The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival--a measure that accounts for elapsed time since treatment initiation--for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies. METHODS We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival. FINDINGS In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0-34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41-47) at 0 months to 51% (46-55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8-15) at 0 months to 33% (18-48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41-47) to 68% (60-75) in the overall population and from 74% (68-79) to 90% (77-96) in the favourable group, 49% (45-53) to 57% (45-67) in the intermediate group, and 11% (8-15) to 73% (43-89) in the poor risk group. INTERPRETATION Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients. FUNDING The Trust Family Fund for Kidney Cancer Research.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials

BACKGROUND Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

A phase II trial of ZD1839 (Iressa™) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer

SummaryPurpose: The epidermal growth factor receptor (EGFR) appears relevant in the pathogenesis and progression of colorectal cancer. After completing a phase I pharmacodynamic trial of ZD1839, we undertook a dose expansion trial to examine the antitumour efficacy and adverse effect profile of this agent in a homogeneous group of patients with metastatic colorectal cancer (CRC). Experimental design: Eligible patients with metastatic or recurrent CRC received ZD1839 750 mg daily by mouth. This dose was selected based on a phase I trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Treatment was continued until unacceptable toxicity or disease progression. Results: Twenty-eight patients were enrolled at three NCIC CTG centers. Twenty-three patients had received prior chemotherapy; 12 patients had received three or more regimens. No objective responses were observed in 24 evaluable patients, although 8 patients had stable disease (median duration of 2.2 months). The most frequent drug related adverse events were diarrhea, rash and nausea. Eleven patients required dosing modification (hold or reduction), while 3 patients discontinued therapy because of toxicity. There were no treatment related deaths. Conclusions: ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.