Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma.

OBJECTIVE: To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib. PATIENTS AND METHODS: We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables. RESULTS: Seventy-one patients received sunitinib sequential therapy. Median duration of follow-up after starting sunitinib was 9.3 months. Median PFS was 5.8 months; median OS was not reached. Significantly higher ORR was seen in patients with normal hemoglobin (25.6%) [defined as >12 gm/dl for female; >13 gm/dl for male]. In addition, a shorter PFS for patients with low hemoglobin, and patients with time from diagnosis to first treatment ≤ 1 year was found. There was a shorter OS for patients ≥ 60 years old, with brain metastasis, low hemoglobin, and time from diagnosis to treatment ≤ 1 year. There was no difference in ORR, PFS, or OS in patients who started sunitinib after or within a 30-day period. CONCLUSIONS: Metastatic clear-cell RCC patients with anemia have less clinical benefit from sequential sunitinib after failure of bevacizumab or sorafenib. Other factors associated with poor outcome include brain metastases, older age, and <1 year between diagnosis and first treatment. Importantly, no difference in outcomes was observed if sequential therapy was initiated within or after 30 days. External validation and prospective evaluation are needed to confirm these findings.

Renal toxicity in patients with multiple myeloma receiving zoledronic acid vs. ibandronate: a retrospective medical records review.

AIMS: This retrospective study investigated the rates of renal impairment in patients with multiple myeloma treated with zoledronic acid and ibandronate. MATERIALS AND METHODS: We retrospectively reviewed medical records in a German oncology clinic, from May 2001 to December 2005. Creatinine measurements were analyzed from baseline (before zoledronic acid or ibandronate treatment) to last evaluation for each patient. A total of 84 patients were included. RESULTS: Zoledronic acid increased the risk of renal impairment by approximately 3-fold compared with ibandronate (renal impairment rates: zoledronic acid 37.7% vs. ibandronate 10.5%, relative risk [RR]=3.6, P=0.0029 serum creatinine [SCr]; 62.3% vs. 23.7%, RR=2.6, P=0.0001 glomerular filtration rate [GFR]). Ibandronate-treated patients switched from zoledronic acid had a significantly higher risk of renal impairment than patients receiving ibandronate monotherapy (zoledronic acid over ibandronate 39.1% vs. ibandronate monotherapy 6.7%, RR= 5.9, P=0.028 [SCr]; 65.2% vs 26.7%, RR=2.4, P=0.022 [GFR]). Multivariate analysis found significantly higher hazard ratios for zoledronic acid over ibandronate (SCr: Cox = 4.38, P=0.01; Andersen-Gill=8.22, P < 0.01; GFR: Cox = 4.31, P < 0.01; Andersen-Gill = 3.71, P < 0.01). CONCLUSIONS: Overall, this retrospective study suggests that multiple myeloma patients are more likely to experience renal impairment with zoledronic acid than with ibandronate. The risk of renal impairment increased if patients had received prior therapy with zoledronic acid.

Angiogenesis inhibitor therapies for metastatic renal cell carcinoma: effectiveness, safety and treatment patterns in clinical practice-based on medical chart review.

OBJECTIVE: To assess the effectiveness, safety, and treatment patterns of anti-angiogenic agents in metastatic renal cell carcinoma (mRCC) in tertiary clinical practice settings. PATIENTS AND METHODS: We retrospectively reviewed the medical records in two tertiary oncology centres in the USA for all patients treated while off clinical trials from April 2003 to June 2008 who met the entry criteria and received one or more prescriptions for sunitinib or sorafenib, or one or more intravenous administrations of bevacizumab (off-label) as first-line anti-angiogenic treatment. The objective response rate (ORR) reviewed by independent physicians, adverse events (AEs), and treatment modifications were assessed. RESULTS: Among 144 patients receiving sunitinib (57), sorafenib (62) and bevacizumab (25), the median treatment duration was 10.5, 8.1 and 7.9 months, and the ORR was 37%, 9% and 13%, respectively. The ORR was lower for patients with metastases to bone, brain, lungs or lymph nodes. Common AEs (all grades) for sunitinib were fatigue (53%), diarrhoea (37%); for sorafenib, diarrhoea (50%), fatigue (40%); for bevacizumab, fatigue (40%), nausea (24%). In all, 34 (60%), 51 (82%) and 20 (80%) patients receiving sunitinib, sorafenib and bevacizumab, respectively, discontinued treatment; 10 (18%), 11 (18%) and four (16%) discontinued due to AEs; 21%, 40% and 12% had a dose interruption, and 30%, 35% and 0% had a dose reduction. CONCLUSIONS: Currently available anti-angiogenic agents had considerable effectiveness in clinical practice. However, the response rates appeared to be low in certain subgroups, but sample sizes were small. Patients had significant rates of AEs, many of which led to treatment modifications. The findings from this retrospective study suggest that there is a need for better-tolerated therapies for mRCC.

Cost implications of IV versus oral anti-angiogenesis therapies in patients with advanced renal cell carcinoma: retrospective claims database analysis.

OBJECTIVE: Angiogenesis inhibitors (AI) are promising novel treatments for patients with renal cell carcinoma (RCC). However, IV therapy may impose infection risk from IV catheters, and will include increased costs due to administration and transportation costs. This study evaluated the incremental costs associated with IV administration of selected AI therapies (bevacizumab off-label) compared to oral therapies (sunitinib or sorafenib) for the treatment of RCC. METHODS: Patients with > or =2 RCC claims (ICD-9: 189.0, 198.0) were identified from a US commercial health insurance claims database from 1/2004 to 12/2007. Patients receiving bevacizumab (n = 109) were matched 1:1 to patients receiving sorafenib or sunitinib, and observed from their first AI therapy claim until the last treatment date. AI, inpatient, outpatient and pharmacy costs were calculated on a per-patient per-month (PPPM) basis over the treatment period. Costs were compared between the IV AI group and each separate oral AI group using multivariate Tobit regressions for each category separately, adjusting for demographic and baseline clinical characteristics. This study assessed costs of treatment and did not evaluate the cost-effectiveness of AIs. RESULTS: Mean total medical costs were $13,351, $6998, and $8213 PPPM for bevacizumab, sorafenib, and sunitinib, respectively (p <0.05 for equality). Adjusted incremental total cost for the bevacizumab group was $4951 PPPM compared to sorafenib and $4610 PPPM compared to sunitinib (both p < 0.05). Bevacizumab patients incurred incremental PPPM outpatient services cost compared to sorafenib and sunitinib of $2772 and $2548, respectively (both p < 0.05). CONCLUSIONS: Assuming median progression-free survival of 8.5 months as shown for bevacizumab (Bukowski, et al., J Clin Oncol 2007), the incremental costs would be estimated at $39 188-42 080 per patient compared to those treated with sunitinib or sorafenib. Assuming similar efficacies, oral AI therapies may result in cost savings to patients and healthcare payers over IV therapies.

Risk of renal impairment after treatment with ibandronate versus zoledronic acid: a retrospective medical records review.

PURPOSE: This retrospective study compared renal impairment rates in breast cancer, multiple myeloma, prostate cancer and non-small cell lung cancer patients treated with ibandronate or zoledronic acid. STUDY DESIGN: Medical records in two German oncology clinics from May 2001 to March 2006 were retrospectively reviewed. Creatinine measurements were analyzed from baseline (before bisphosphonate treatment) to last available measurement for each patient. The Cox proportional hazards model and the Andersen-Gill extension of the Cox model for multiple events analysis were used for multivariate analysis, which controlled for age, clinic site, primary cancer type, baseline SCr or GFR value, prior bisphosphonate use, concomitant use of drugs associated with acute renal failure, and renal-related comorbidities. RESULTS: Of 333 patients, 109 received ibandronate and 256 received zoledronic acid (32 patients had both drugs). Compared with ibandronate, the zoledronic acid group had a significantly better baseline renal function and fewer patients had a history of renal disease. Zoledronic acid treatment increased the relative risk (RR) and the incidence rate (IR) of renal impairment by approximately 1.5-fold in all assessed patients (all tumors) compared with ibandronate. Multivariate analysis found significantly higher hazards ratios for zoledronic acid over ibandronate (two to sixfold), after adjusting for differences in characteristics between the two treatment groups. CONCLUSIONS: In this retrospective review, patients were significantly more likely to experience renal impairment with zoledronic acid than with ibandronate.

Symptom assessment in relapsed small cell lung cancer: cross-validation of the patient symptom assessment in lung cancer instrument.

INTRODUCTION: Lung cancer symptoms can be burdensome for patients with small cell lung cancer (SCLC). Patient Symptom Assessment in Lung Cancer (PSALC), a self-report scale for assessing SCLC symptom burden, was developed and validated previously using intravenous topotecan clinical trial data. This study cross-validates the PSALC using oral topotecan (OT) trial data. METHODS: Data were analyzed from a randomized, open-label, multicenter trial including 71 patients with relapsed SCLC receiving OT with best supportive care and 70 patients receiving best supportive care alone. PSALC and EQ-5D were administered at baseline and at 3-week intervals. Internal consistency, reliability, construct validity, and responsiveness were evaluated. RESULTS: Only one factor was indicated in factor analysis, hence PSALC total score (PSALC-TS) was used for psychometric analysis. Internal consistency was supported by Cronbach's alpha of 0.78. Construct validity was supported by significant associations of higher PSALC-TS (higher symptom burden) with worse Eastern Cooperative Oncology Group performance status and by correlations of PSALC-TS with EQ-5D utility index and visual analog scale score (all p < 0.001). Reliability was supported by intraclass correlation coefficient of 0.68 (using PSALC-TS before clinical status change) and concordance correlation coefficient of 0.69 (using PSALC-TS at baseline and before first visit). PSALC-TS was responsive to clinical status change from baseline to tumor response (responsiveness statistic = -0.99) and to tumor progression (responsiveness statistic = 0.94). CONCLUSIONS: Consistent with prior psychometric results, this cross-validation study using OT trial data showed acceptable validity, reliability, and responsiveness of the PSALC scale, further supporting its use to measure symptom burden in previously treated SCLC.

Psychometric validation of the Patient Symptom Assessment in Lung Cancer instrument for small cell lung cancer.

OBJECTIVE: Patient Symptom Assessment in Lung Cancer (PSALC) is a symptom scale developed for use in patients with small cell lung cancer (SCLC) to assess nine lung cancer symptoms (shortness of breath, cough, chest pain, hemoptysis, appetite loss, sleep interference, hoarseness, fatigue, interference with daily activities) scored from 1 (not at all) to 4 (very much). This study aims to retrospectively evaluate the psychometric properties of PSALC using clinical trial data. METHODS: Data were analyzed from a randomized, open-label, multicenter trial with 211 patients with SCLC receiving i.v. topotecan versus cyclophosphamide, doxorubicin, and vincristine. PSALC was evaluated at baseline and at 3-week intervals. Internal consistency, reliability, construct validity, and responsiveness were evaluated. RESULTS: Factor analysis indicated that one factor could represent all symptom items, so a PSALC total score (PSALC-TS) was used for psychometric validation. Internal consistency was supported by Cronbach's alpha of 0.74. Reliability of PSALC was supported by an intraclass correlation coefficient of 0.61 and concordance correlation coefficient of 0.72. Construct validity was supported by associations of lower PSALC-TS (less severe symptoms) with better ECOG performance status (p < 0.0001), and of PSALC-TS changes with clinical response. PSALC-TS was responsive to tumor progression (responsiveness statistic = 0.64). LIMITATIONS: The validation was performed retrospectively and was limited by small sample sizes at later assessment timepoints due to disease progression. CONCLUSIONS: A retrospective analysis suggests that the PSALC is a reliable, valid, and responsive instrument for measuring SCLC symptoms. If feasible in this population, a prospective validation study could be used to further evaluate these findings.

The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid.

BACKGROUND: Bisphosphonates have been used to treat bone metastases in hormone-refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005. METHODS: A comprehensive medical records review was performed in a major tertiary oncology center (n = 122 patients). The primary outcome of renal impairment was defined as an increase >or=0.5 mg/dL or >or=1.0 mg/dL over baseline creatinine value if the baseline value was <1.4 mg/dL or >or=1.4 mg/dL, respectively. A risk factor analysis was conducted using the Andersen-Gill extension to the Cox proportional hazards model. RESULTS: Renal impairment was observed in 23.8% of patients. The risk of renal impairment increased with an extended duration of zoledronic acid therapy (<6 months, 11.1%; >or=24 months, 26.3%) and previous pamidronate treatment (45.5% vs 19.0% for patients with no prior pamidronate). A significantly greater risk of renal impairment was associated with increasing age at zoledronic acid initiation, prior pamidronate use, and a history of renal disease, hypertension, or smoking (P