- Email: [email protected]
Initial Patterns of Care With Oral Targeted Therapies for Patients With Renal Cell Carcinoma
Renal Cancer Initial Patterns of Care With Oral Targeted Therapies for Patients With Renal Cell Carcinoma Christopher P. Filson, Bruce G. Redman, Rodney L. Dunn, and David C. Miller OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
To characterize the contemporary use of oral-targeted therapies (ie, sunitinib, sorafenib) among patients with renal cell carcinoma (RCC) and to assess the factors associated with short-term and sequential treatment. We used an administrative claims database of privately insured patients to evaluate oral-targeted therapy use among patients with RCC from 2006 to 2007. After identifying patients with RCC who had received sunitinib and/or sorafenib, we determined the prevalence of patients treated with short-term and/or sequential therapy. We performed bivariate and multivariate analyses to estimate the associations between the patient characteristics and receipt of short-term and/or sequential treatment regimens. We identified 938 patients with RCC who had initially been treated with sunitinib (n ⫽ 554) or sorafenib (n ⫽ 384). In this group, 36% and 23% of patients had received short-term or sequential therapy, respectively. Most patients (61%) who had received sequential therapy had undergone short-term treatment with ⱖ1 drugs, with second-line sorafenib more likely to be given as short-term therapy than sunitinib (63% vs 34%, P ⬍ .001). Short-term therapy was more common in female patients (odds ratio 1.53, 95% confidence interval 1.12-2.09) and patients in the Southern United States (odds ratio 1.71, 95% confidence interval 1.05-2.80). Sequential therapy was more common among patients receiving sorafenib first (odds ratio 2.30, 95% confidence interval 1.64-3.21). Short-term and sequential oral targeted therapy use was relatively prevalent among patients with RCC. For patients treated with sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the “real-world” clinical outcomes and economic effect associated with these treatment courses. UROLOGY 77: 825– 830, 2011. © 2011 Elsevier Inc.
T
he historical survival statistics for patients with metastatic renal cell carcinoma (RCC) have been dismal, reflecting the nearly ubiquitous resistance of this tumor to conventional chemotherapy and immunotherapy.1-3 More recently, however, new medications that target the molecular pathogenesis of RCC have been shown to significantly improve survival among patients with disseminated disease. From these data, the oral tyrosine kinase inhibitors (TKIs) sunitinib (January 2006)4 and sorafenib (December 2005)5 received Food and Drug Administration This research was supported by the National Institutes of Health Clinical Training Grant in Urology (NIH-T32-DK007782) to C. P. Filson, and the Edwin Beer Research Fellowship in Urology and Urology-Related Fields from the New York Academy of Medicine and the University of Michigan Cancer Center Munn Idea Grant to D. C. Miller From the Departments of Urology and Internal Medicine, Division of Hematology/ Oncology, University of Michigan, Ann Arbor, Michigan; and Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan Reprint requests: David C. Miller, M.D., M.P.H., Department of Urology, University of Michigan, Room 1031, Michigan House, 2301 Commonwealth Boulevard, Ann Arbor, MI 48105-2967. E-mail: [email protected] Submitted: August 25, 2010, accepted (with revisions): November 3, 2010
© 2011 Elsevier Inc. All Rights Reserved
approval and emerged as first-line therapeutic agents for most patients with metastatic RCC. Although the progression-free (sunitinib, sorafenib)6,7 and overall (sunitinib)8 survival benefits of oral-targeted therapies are indisputable, the available clinical trial data have indicated that these gains have been modest and have varied across individual medications and patient populations. Given this limited therapeutic margin, a better understanding is needed of whether the results of clinical trials have been translated into everyday clinical practice. Moreover, given the recent controversy surrounding coverage of these agents in the United Kingdom,9 data describing the use of oral TKIs is immediately relevant to several highprofile policy debates, including mandated versus evidencebased coverage decisions for novel biologic therapies,10 episode-based payments for cancer care, and reforms aimed at controlling Medicare spending for new cancer drugs.11 In this context, we sought to evaluate the initial patterns of treatment with the oral TKIs among a large and diverse sample of patients with RCC. We specifically assessed the 0090-4295/11/$36.00 doi:10.1016/j.urology.2010.11.003
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average duration of treatment with sunitinib and/or sorafenib, as well as the frequency of short-term and sequential use of the oral TKIs. Once available, these data will clarify the initial practice patterns using the oral TKIs and provide a context for efforts aimed at understanding the real-world clinical and cost-effectiveness of these important medications.
sunitinib or sorafenib). We defined sequential therapy as the presence of outpatient drug claims for both sunitinib and sorafenib; we considered the initial and subsequent drugs as first-line and secondline therapy, respectively. To better understand the relationships between sequential and short-term TKI therapy, we also categorized patients receiving sequential therapy into the following 4 groups: (a) short-term use of first-line TKI only; (b) short-term use of second-line TKI only; (c) short-term of both TKIs; and (d) no short-term use.
MATERIAL AND METHODS Statistical Analysis Analytic Cohort The MarketScan Commercial Claims and Encounters (CCE) Research Database included the inpatient, outpatient, and pharmaceutical insurance claims from nearly 29 million persons covered by employer-sponsored private health insurance plans.12 Using the CCE data from 2003 through 2007, we used a 4-step process to identify a cohort of patients with both a diagnosis of RCC and pharmacy claims specifying treatment with sunitinib and/or sorafenib. First, we identified all patients who had had either an inpatient or outpatient insurance claim that included an “International Classification of Diseases, 9th edition, Clinical Modification” diagnosis code corresponding to RCC (list available from on-line Appendix). Next, we excluded from this group patients with ⬍90 days of benefit plan enrollment after the date of their first claim with an RCC diagnosis and those with missing or incomplete outpatient pharmacy claims data. This step ensured that we included only those patients with longitudinal pharmacy coverage and the corresponding claims data. For the remaining subjects, we used the Food and Drug Administration National Drug Codes to identify all patients with outpatient pharmacy claims for sunitinib and/or sorafenib (list available from on-line Appendix). Finally, we excluded patients who only had claims specifying a diagnosis of gastrointestinal stromal tumor (“International Classification of Diseases, 9th edition, Clinical Modification” code 171.5 or 238.1, n ⫽ 34), the only other condition for which the use of sunitinib has been approved by the Food and Drug Administration.
Study Variables Next, we used the patient-level information included in the CCE database to ascertain the age (at the first claim with an RCC diagnosis), sex, geographic residence, and insurance benefit plan (eg, health maintenance organization) for each patient in our analytic cohort. We also used the inpatient or outpatient procedure claims to determine whether each of these patients had undergone kidney cancer surgery and/or RCC-directed immunotherapy (ie, interleukin-2 or interferon-␣) before their first pharmacy claim for oral TKI therapy (list available from online Appendix). The CCE database does not provide information regarding cancer severity (eg, stage, grade).
Outcomes We defined the duration of therapy for each medication as the total number of days supplied by all consecutive outpatient prescriptions. For instance, if a patient had 2 pharmacy claims for sunitinib that had both specified a 28-day course, we defined the treatment duration as 56 days (regardless of the interval between the dates for the 2 claims). Our primary outcome of interest was the prevalence of short-term and/or sequential use of oral TKIs. We classified as short-term therapy any treatment regimen that lasted ⬍60 days (a period roughly equivalent to 2 cycles of 826
Chi-square tests were used to determine whether differences existed for patient factors according to the first TKI prescribed (sunitinib or sorafenib), whether the subjects had received shortterm (⬍60 days) or long-term (ⱖ60 days) therapy, and whether the subjects had received monotherapy or sequential therapy. Of those receiving sequential therapy, the duration of each therapy was compared by the first TKI prescribed using a chi-square test. Finally, multivariate logistic regression models were used to determine the independent effect of the initial TKI (sunitinib vs sorafenib) on both short-term and sequential TKI use, after adjusting for age, sex, benefit plan type, geographic region, year of RCC diagnosis, previous kidney surgery (yes vs no), previous immunotherapy (yes vs no), and year of first TKI therapy. All statistical analyses were performed with 2-sided tests at the 5% significance level using SAS, version 9.2 (SAS Institute, Cary, NC).
RESULTS We identified 938 patients with a diagnosis of RCC and ⱖ1 pharmacy claim for sunitinib and/or sorafenib. The median duration of first-line TKI treatment was 90 days (range 2-690) and 120 days (range 14-690) for sunitinib and sorafenib, respectively. The patient characteristics are listed in Table 1, stratified by the initial therapeutic agent. Overall, nearly 3 of 4 patients (73%) treated with sunitinib and/or sorafenib were men, 57% were 51-60 years old, and 43% had claims for previous kidney cancer surgery. Of these patients treated with oral TKIs, 47% lived in the Southern United States. Compared with those treated in 2006, the patients starting treatment in 2007 were significantly more likely to receive first-line sunitinib (73% vs 49%, P ⬍ .001). Figure 1 presents the prevalence of short-term and sequential therapy among the patients with RCC and treated with oral TKIs. The short-term use of oral TKIs was common, with nearly 4 of 10 (36%) patients receiving first-line treatment lasting ⬍60 days; the prevalence of initial shortterm therapy use did not differ according to the initial drug prescribed (37% sunitinib vs 33% sorafenib, P ⫽ .177). Overall, 23% of patients received sequential therapy, which was more common among patients who had received firstline sorafenib (34% first-line sorafenib vs 16% first-line sunitinib, P ⬍ .001). The distribution of short-term and sequential therapy according to the patient characteristics and the results from the multivariate analyses evaluating the independent associations between the patient characteristics and receipt of short-term or sequential TKI therapy are listed in Table 2. Compared with sorafenib, patients starting therapy with sunitinib were not more likely to receive short-term therapy UROLOGY 77 (4), 2011
Table 1. Patient characteristics Characteristic Initial treatment date 2006* 2007 Initial RCC diagnosis date 2003 2004 2005 2006 2007 Age (y) 19-40 41-50 51-60 61-65 Sex Male Female Benefit plan† Basic/comprehensive HMO Other‡ Geographic region§ Northeast North-Central South West Previous kidney surgery Yes No Previous immunotherapy Yes No
Total (n ⫽ 938)
Sunitinib (n ⫽ 554)
Sorafenib (n ⫽ 384)
537 401
261 (49) 293 (73)
276 (51) 108 (27)
96 111 173 366 192
53 (55) 51 (46) 89 (51) 216 (59) 145 (76)
43 (45) 60 (54) 84 (49) 150 (41) 47 (24)
51 184 531 172
28 (55) 111 (60) 315 (59) 100 (58)
23 (45) 73 (40) 216 (41) 72 (42)
686 252
407 (59) 147 (58)
279 (41) 105 (42)
94 136 685
55 (59) 75 (55) 408 (60)
39 (41) 61 (45) 277 (40)
97 233 444 153
52 (54) 147 (63) 267 (60) 83 (54)
45 (46) 86 (37) 177 (40) 70 (46)
402 536
250 (62) 304 (57)
152 (38) 232 (43)
47 891
26 (55) 528 (59)
21 (45) 363 (41)
P Value ⬍ .001 ⬍ .001
.905
.783 .632
.260
.092 .592
RCC, renal cell carcinoma; HMO, health maintenance organization. Data presented as numbers, with percentages in parentheses. * Included 1 case from 2005. † Unknown in 23 cases. ‡ Included preferred provider organizations, exclusive provider organizations, point-of-service, and consumer-driven healthcare plans. § Unknown in 3 cases.
(odds ratio [OR] 0.90, 95% confidence interval [CI] 0.671.21). Short-term therapy was more common among the female patients (OR 1.53, 95% CI 1.12-2.09) and patients who resided in the Southern United States (OR 1.71, 95% CI 1.05-2.80). Patients aged 51-60 years were significantly less likely to receive short-term therapy (OR 0.52, 95% CI 0.28-0.95) than patients aged 19-40 years. Sequential therapy was more common among patients treated with sorafenib first (OR 2.30, 95% CI 1.64-3.21) and those aged 51-60 years (OR 2.52, 95% CI 1.07-5.91). In the analyses that jointly assessed sequential and shortterm therapy, we observed that 61% of patients treated with sequential oral TKIs had received a short-term regimen with ⱖ1 of the 2 medications. As illustrated in Figure 2, the patients who had received first-line sunitinib were significantly more likely to had received a short-term regimen with one or both oral TKIs (73% vs 52%, P ⬍ .001). Compared with second-line sunitinib, second-line sorafenib was significantly more likely to have been prescribed for ⬍60 days (63% vs 34%, P ⬍ .001). Furthermore, of the 59 patients who had received first-line sunitinib for ⬎60 days, 36 (61%) were treated with second-line sorafenib for ⱕ60 UROLOGY 77 (4), 2011
days. In contrast, only 30 (32%) of 93 patients receiving first-line sorafenib for ⬎60 days had received short-term second-line sunitinib.
COMMENT The present study had several findings that have clarified the initial use patterns for the oral TKIs among patients with RCC. Because it has highlighted a potentially significant disconnect between the efficacy and true clinical benefit of sunitinib and sorafenib, our most consequential finding might have been the relatively high prevalence (36%) of short-term treatment regimens. The most likely explanations for a short course of oral TKI therapy include adverse drug reactions, disease progression, and/or death. In the large clinical trials of sunitinib and sorafenib, in which patient eligibility and accrual is strictly controlled, adverse event-related discontinuation of these TKIs occurred in only 6-10% of patients.6,7,13 Moreover, only 15% of patients in these trials stopped treatment within 2 months of initiating oral TKI therapy.6,7 However, our observation that nearly 40% of patients continued their 827
Figure 1. Initial patterns of oral TKI use among patients with RCC. *P ⫽ .177 for comparison between patients receiving initial sunitinib versus initial sorafenib. **P ⬍ .001 for comparison between patients receiving initial sunitinib versus initial sorafenib. The X axis corresponds to groups of patients in our analytic cohort who received either short-term therapy (ie, ⬍60 days) or sequential therapy (ie, both sunitinib and sorafenib); y axis corresponds to proportion who received treatment courses of interest. Black bars represent proportion who were treated with sunitinib first, and white bars, those who received sorafenib first.
first-line TKI for ⬍60 days—and that the median treatment course was only 90-120 days—suggests that the results from these landmark trials have not been translated into everyday clinical practice. Thus, an understanding of the basis for this disconnect between the clinical trial results and routine clinical practice is needed. Both patient and provider factors could explain the observed discrepancy in the average length of treatment between our analytic cohort and the patients in the published clinical trials. Although not evaluated in the present study, an immediate explanation is the potential liberalization of treatment indications to include patients who would have been excluded from the clinical trials owing to the severity of either their cancer or their comorbidity (and who would be therefore less likely to respond to and/or tolerate these medications). Several factors might have promote this trend, including the relative ease of oral TKI administration (compared with intravenous chemotherapy) and an understandable “therapeutic imperative” for high-risk patients with few existing treatment options.14 Furthermore, it is likely that some patients in our analytic cohort had RCC with nonclear cell histologic features. Although small retrospective studies have suggested similar efficacy for the targeted therapies among patients with papillary and chromophobe RCC, the data have been inconclusive.15,16 Because the clinical trials for sunitinib and sorafenib were limited to patients with clear cell RCC, the observed discrepancy between our results and the reported clinical trial findings could be explained, in part, by the inclusion of patients with non-clear cell RCC. The relatively high prevalence of short-term therapy might also have reflected lower provider thresholds for the 828
discontinuation of the oral TKIs owing to unexpected and/or difficult-to-manage side effects and/or greater patient preference for stopping the medications in the absence of the intensive follow-up and support provided in most clinical trials. Although we could not address this question empirically, the high prevalence of short-term therapy also suggested the infrequent use of a dose reduction as a strategy for managing adverse events and prolonging therapy. This approach was implemented as a method for continuing therapy in 32% of patients in the treatment arm of the Phase III sunitinib trial.6 Additional investigation of these factors using multi-institutional and population-based studies (including qualitative research) is necessary to confirm the validity of our findings and reduce the prevalence of shortterm treatment regimens, thereby, optimizing the implementation of oral TKIs in “real-world” clinical practice.17 In addition, the not-infrequent use of sequential therapy (a practice pattern more prevalent among patients initially treated with sorafenib) has also highlighted important issues concerning real-world use of the oral TKIs. In theory, patients might have received both sunitinib and sorafenib because they experienced either intolerable side effects or disease progression while receiving the first-line TKI. Although the results from small retrospective case series18,19 and a recent prospective Phase II trial20 have suggested that sequential therapy with sunitinib and sorafenib is safe and possibly beneficial, no results from randomized Phase III trials are available to support the efficacy of sequential oral TKI treatment algorithms compared with the best supportive care. Our data have indicated that 6 of every 10 sequential therapy patients who tolerated first-line sunitinib (ie, those patients whose initial treatment course with sunitinib was ⬎60 days) received only a short course of second-line sorafenib, a finding consistent with sorafenib’s limited effectiveness in this clinical setting.21 Taken together, our findings highlight the need for indepth and prospective studies that can accurately assess patient outcomes and better characterize the clinical and “real-world” cost-effectiveness of short-term and sequential treatment regimens among patients with metastatic RCC. In reality, however, such studies would be exceedingly unlikely, given the increasingly rapid introduction of newer targeted therapies and the availability of established clinical trials for patients in whom treatment with sunitinib or sorafenib fails. Nonetheless, we believe it of interest to patients, physicians, and policymakers that these unproven sequential practice patterns not only exist but are actually fairly common among patients with advanced RCC. Several additional findings raised important hypotheses for future research in this area. For instance, we observed that the prevalence of short-term and sequential therapy varied according to patient age, sex, and geographic region. These associations can be explained by a number of factors, including the unmeasured differences in patient comorbidity, performance status, and/or cancer-severity. These and other hypotheses could be tested in future studies using more comprehensive clinical data sets. Finally, the prevaUROLOGY 77 (4), 2011
Table 2. Characteristics of patients receiving short-term and sequential oral tyrosine kinase inhibitor therapy
Variable Initial treatment date 2006*† 2007 Initial RCC diagnosis date 2003-2005* 2006 2007 Age (y) 19-40* 41-50 51-60 61-65 Sex Male* Female Benefit plan‡ Basic or comprehensive* HMO Other§ Geographic region¶ Northeast* North-Central South West Previous kidney surgery Yes* No Previous immunotherapy Yes* No
Short-Term Use (n ⫽ 334) Total Patients P Adjusted (n ⫽ 938) (n) Value OR 95% CI
Sequential Use (n ⫽ 216) Patients P Adjusted (n) Value OR 95% CI ⬍ .001
.011 537 401
170 (32) 164 (41)
380 366 192
122 (32) 125 (34) 87 (45)
51 184 531 172
24 (47) 67 (36) 175 (33) 68 (40)
686 252
227 (33) 107 (42)
94 136 685
34 (36) 59 (43) 236 (34)
97 233 444 153
29 (30) 77 (33) 178 (40) 46 (30)
402 536
148 (37) 186 (35)
47 891
18 (38) 316 (35)
1.00 1.27
— 170 (32) 0.89-1.81 46 (11)
1.00 1.12 1.51
— 0.81-1.54 0.95-2.37
1.00 0.64 0.52 0.73
— 7 (14) 0.33-1.23 39 (21) 0.28-0.95 128 (24) 0.38-1.41 42 (24)
1.00 1.53
— 160 (23) 1.12-2.09 56 (22)
1.00 1.34 0.86
— 20 (21) 0.75-2.37 33 (24) 0.53-1.39 160 (23)
1.00 1.22 1.71 1.07
— 0.72-2.09 1.05-2.80 0.60-1.89
1.00 0.92
— 102 (25) 0.70-1.22 114 (21)
1.00 0.59
— 17 (36) 0.31-1.12 199 (22)
.005
⬍ .001
99 (26) 97 (27) 20 (10)
.124
1.00 0.34
— 0.21-0.54
1.00 1.26 1.02
— 0.88-1.80 0.52-1.99
1.00 1.96 2.52 2.42
— 0.79-4.85 1.07-5.91 0.98-6.00
1.00 1.01
— 0.70-1.47
1.00 1.47 1.57
— 0.74-2.93 0.88-2.79
1.00 1.27 0.91 1.12
— 0.69-2.33 0.52-1.62 0.59-2.14
1.00 0.74
— 0.53-1.02
1.00 0.53
— 0.26-1.06
.338
.008
.723
.140
.866
.092
.326 21 (22) 61 (26) 91 (20) 39 (25)
.503
.140
.693
.028
OR, odds ratio; CI, confidence interval; other abbreviations as in Table 1. Data in parentheses are percentages. * Reference group. † Included 1 case from 2005. ‡ Unknown in 23 cases. § Included preferred provider organizations, exclusive provider organizations, point-of-service, and consumer-driven healthcare plans. ¶ Unknown in 3 cases.
lence of previous kidney surgery among our analytic cohort (43%) was far lower than the nephrectomy rates (90%) among the patients in the TKI clinical trials. Although measurement error could have contributed to this discrepancy (eg, some patients underwent nephrectomy in the years before our available claims data), it is also possible that some clinicians have been prescribing sunitinib and/or sorafenib to patients with intact primary tumors. Although, at present, the implications of this practice pattern remain unclear,22 the survival benefits of cytoreductive nephrectomy before targeted therapy are being investigated in an active clinical trial (ie, the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA)).23 The present study had several limitations. First, as stated, we could not measure the tumor characteristics, patient performance status, and other risk-related covariates. Thus, our analyses might not have adequately characterized or adjusted for important patient-specific determinants of the use of oral TKIs. Second, our findings might not be generalizable to older patients (eg, Medicare eligible) with RCC who were not included in our analysis. Third, we recognized UROLOGY 77 (4), 2011
that patients might have switched benefit plans or stopped coverage during the study interval, potentially leading to measurement error in our estimates of short-term and sequential therapy. Fourth, we recognized that some patients might have received therapeutic kidney cancer surgery that was not identified by this claims database, either because the operation took place before 2003 or while a patient was enrolled in a different health insurance plan. Fifth, we did not assess the frequency of dose reduction among the patients in our analytic cohort. Future studies evaluating the prevalence of dose reduction of TKIs among patients with RCC might help explain the discrepancies between the published clinical trials and our findings. Sixth, as mentioned, we did not have information on the tumor histologic type, which can affect the response to treatment with oral TKIs. Finally, our findings might not reflect the practice patterns for the more recently introduced oral medications for patients with RCC (eg, everolimus). Despite these limitations, our findings have provided useful insight regarding the initial practice patterns with the oral targeted therapies for patients with RCC. 829
Figure 2. Patterns of short-term therapy among patients receiving sequential therapy (ie, both sunitinib and sorafenib). (A) Patients who received sunitinib followed by sorafenib. and (B) Patients treated with sorafenib followed by sunitinib. Black portions of pie charts represent proportions of patients who received short-term sunitinib (first-line, Fig. A vs second-line, Fig. B) but had received sorafenib for ⬎60 days. White segments represent patients who received both medications for ⬍60 days. Dark gray areas represent patients who received short-term sorafenib (second-line, Fig A; first-line, Fig B) but had received sunitinib for ⬎60 days. Light gray portions represent patients who received both drugs for ⬎60 days.
CONCLUSIONS After their introduction, the initial use of sorafenib and sunitinib was characterized by relatively prevalent shortterm and sequential treatment regimens among patients with RCC. For patients treated with both sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences exist in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the “real-world” clinical outcomes and economic effect associated with these treatment courses. References 1. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335:865-875. 2. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol. 2000;163:408-417. 3. Gupta K, Miller J, Li J, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34:193-205. 4. Goodman V, Rock E, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367-1373. 5. Kane R, Farrell A, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12:72717278. 6. Motzer R, Hutson T, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356: 115-124. 7. Escudier B, Eisen T, Stadler W, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 8. Motzer R, Hutson T, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27:3584-3590. 9. Steinbrook R. Saying no isn’t NICE—the travails of Britain’s National Institute for Health and Clinical Excellence. N Engl J Med. 2008;359:1977-1981.
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10. Bach PB. Limits on Medicare’s ability to control rising spending on cancer drugs. N Engl J Med. 2009;360:626-633. 11. Pollack A. As Pills Treat Cancer, Insurance Lags Behind. New York Times. Availabe from: www.nytimes.com/2009/04/15/business/ 15pill.html. Accessed July 3, 2010. 12. Health Research Data for the Real World: The MarketScan Databases. Available from: www.support.thomsonhealthcare.com/ uploadedFiles/docs/2008HealthResearchDatafortheRealWorldThe% 20MarketScanDatabases(1).pdf. Accessed July 3, 2010. 13. Gore M, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10:757-763. 14. Kocs D, Fendrick AM. Effect of off-label use of oncology drugs on pharmaceutical costs: the rituximab experience. Am J Manag Care. 2003;9:393-400. 15. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26:127-131. 16. Strumburg D. Efficacy of sunitinib and sorafenib in non-clear cell renal cell carcinoma: results from expanded access studies. J Clin Oncol. 2008;26:3469. 17. Dougherty D, Conway PH. The “3T’s” road map to transform US health care: the “how” of high-quality care. JAMA. 2008;299:2319-2321. 18. Dudek AZ, Zolniernek J, Dham A, et al. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. J Clin Oncol. 2009;115: 61-67. 19. Eichelberg C, Heuer R, Chun FK, et al. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis. Eur Urol. 2008;54:1373-1378. 20. Di Lorenzo G, Carteni G, Autorino R, et al. Phase II Study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27:4469-4474. 21. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29-34. 22. Pantuck AJ, Belldegrun AS, Figlin RA. Cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of targeted therapy? Clin Cancer Res. 2007;13:693s-696s. 23. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). Available from: www.clinicaltrials.gov/ct2/show/ NCT00930033. Accessed July 3, 2010.
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Appendix. Codes for identification of analytic cohort, surgical procedures, and treatment with immunotherapy Codes of Interest Diagnosis of RCC* 189, 189.0, 189.00, 189.01 236.9, 236.90, 236.91, 236.99, 239.5, 239.9 235.4, 237.2, 238.1, 238.8 189.8, 189.9 211.8, 223.0, 223.1, 223.89, 223.9 194.0 171.5 195.2 158.0 Prescription of oral TKI¶ 69055030, 69055038, 69077030, 69077038, 69098030, 69098038, 54569598200, 54569598300 26848858 Receipt of cancer surgery储 50045 50200 50205 50225 50230 50545 50240 50543 50220 50234, 50236 50546, 50548 50250 50280 50541 50542 50549 50592 Receipt of immunotherapy# J9015 J9213, J9214
Description Malignant neoplasm of kidney except renal pelvis† Neoplasm of uncertain behavior of kidney and ureter, other specified urinary organ, unspecified urinary organ‡ Neoplasm of uncertain behavior of retroperitoneum, adrenal gland, connective/soft tissue, other specified site§ Malignant neoplasm of other or unspecified site, urinary tract origin Benign neoplasm of retroperitoneum, kidney, and other urinary organ, kidney except pelvis, other urinary organ, unspecified urinary organ Malignant neoplasm of adrenal gland Malignant neoplasm of connective and soft tissue of abdomen Malignant neoplasm of abdomen Malignant neoplasm of retroperitoneum Sunitinib malate Sorafenib Nephrotomy, with exploration Renal biopsy, percutaneous Renal biopsy, open Nephrectomy Complicated, open Radical, open Radical, laparoscopic Partial, open Partial, laparoscopic Simple, open Nephrectomy, open Nephrectomy, laparoscopic Ablation, open Excision/unroofing of cyst of kidney Laparoscopic Ablation, laparoscopic Unlisted laparoscopy procedure, renal Ablation (radiofrequency ablation) Aldesleukin (interleukin-2) Interferon-alpha
RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor. * Using diagnosis codes from “International Classification of Diseases, 9th edition, Clinical Modification.” † Represented 79% of analytic cohort. ‡ Represented 12% of analytic cohort. § Represented 3% of analytic cohort. ¶ From Food and Drug Administration National Drug Codes. 储 From Current Procedural Terminology (CPT) codes. # From Healthcare Common Procedure Coding System (HCPCS) procedure codes.
UROLOGY 77 (4), 2011
830.e1
METHODS
RESULTS
CONCLUSIONS
To characterize the contemporary use of oral-targeted therapies (ie, sunitinib, sorafenib) among patients with renal cell carcinoma (RCC) and to assess the factors associated with short-term and sequential treatment. We used an administrative claims database of privately insured patients to evaluate oral-targeted therapy use among patients with RCC from 2006 to 2007. After identifying patients with RCC who had received sunitinib and/or sorafenib, we determined the prevalence of patients treated with short-term and/or sequential therapy. We performed bivariate and multivariate analyses to estimate the associations between the patient characteristics and receipt of short-term and/or sequential treatment regimens. We identified 938 patients with RCC who had initially been treated with sunitinib (n ⫽ 554) or sorafenib (n ⫽ 384). In this group, 36% and 23% of patients had received short-term or sequential therapy, respectively. Most patients (61%) who had received sequential therapy had undergone short-term treatment with ⱖ1 drugs, with second-line sorafenib more likely to be given as short-term therapy than sunitinib (63% vs 34%, P ⬍ .001). Short-term therapy was more common in female patients (odds ratio 1.53, 95% confidence interval 1.12-2.09) and patients in the Southern United States (odds ratio 1.71, 95% confidence interval 1.05-2.80). Sequential therapy was more common among patients receiving sorafenib first (odds ratio 2.30, 95% confidence interval 1.64-3.21). Short-term and sequential oral targeted therapy use was relatively prevalent among patients with RCC. For patients treated with sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the “real-world” clinical outcomes and economic effect associated with these treatment courses. UROLOGY 77: 825– 830, 2011. © 2011 Elsevier Inc.
T
he historical survival statistics for patients with metastatic renal cell carcinoma (RCC) have been dismal, reflecting the nearly ubiquitous resistance of this tumor to conventional chemotherapy and immunotherapy.1-3 More recently, however, new medications that target the molecular pathogenesis of RCC have been shown to significantly improve survival among patients with disseminated disease. From these data, the oral tyrosine kinase inhibitors (TKIs) sunitinib (January 2006)4 and sorafenib (December 2005)5 received Food and Drug Administration This research was supported by the National Institutes of Health Clinical Training Grant in Urology (NIH-T32-DK007782) to C. P. Filson, and the Edwin Beer Research Fellowship in Urology and Urology-Related Fields from the New York Academy of Medicine and the University of Michigan Cancer Center Munn Idea Grant to D. C. Miller From the Departments of Urology and Internal Medicine, Division of Hematology/ Oncology, University of Michigan, Ann Arbor, Michigan; and Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan Reprint requests: David C. Miller, M.D., M.P.H., Department of Urology, University of Michigan, Room 1031, Michigan House, 2301 Commonwealth Boulevard, Ann Arbor, MI 48105-2967. E-mail: [email protected] Submitted: August 25, 2010, accepted (with revisions): November 3, 2010
© 2011 Elsevier Inc. All Rights Reserved
approval and emerged as first-line therapeutic agents for most patients with metastatic RCC. Although the progression-free (sunitinib, sorafenib)6,7 and overall (sunitinib)8 survival benefits of oral-targeted therapies are indisputable, the available clinical trial data have indicated that these gains have been modest and have varied across individual medications and patient populations. Given this limited therapeutic margin, a better understanding is needed of whether the results of clinical trials have been translated into everyday clinical practice. Moreover, given the recent controversy surrounding coverage of these agents in the United Kingdom,9 data describing the use of oral TKIs is immediately relevant to several highprofile policy debates, including mandated versus evidencebased coverage decisions for novel biologic therapies,10 episode-based payments for cancer care, and reforms aimed at controlling Medicare spending for new cancer drugs.11 In this context, we sought to evaluate the initial patterns of treatment with the oral TKIs among a large and diverse sample of patients with RCC. We specifically assessed the 0090-4295/11/$36.00 doi:10.1016/j.urology.2010.11.003
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average duration of treatment with sunitinib and/or sorafenib, as well as the frequency of short-term and sequential use of the oral TKIs. Once available, these data will clarify the initial practice patterns using the oral TKIs and provide a context for efforts aimed at understanding the real-world clinical and cost-effectiveness of these important medications.
sunitinib or sorafenib). We defined sequential therapy as the presence of outpatient drug claims for both sunitinib and sorafenib; we considered the initial and subsequent drugs as first-line and secondline therapy, respectively. To better understand the relationships between sequential and short-term TKI therapy, we also categorized patients receiving sequential therapy into the following 4 groups: (a) short-term use of first-line TKI only; (b) short-term use of second-line TKI only; (c) short-term of both TKIs; and (d) no short-term use.
MATERIAL AND METHODS Statistical Analysis Analytic Cohort The MarketScan Commercial Claims and Encounters (CCE) Research Database included the inpatient, outpatient, and pharmaceutical insurance claims from nearly 29 million persons covered by employer-sponsored private health insurance plans.12 Using the CCE data from 2003 through 2007, we used a 4-step process to identify a cohort of patients with both a diagnosis of RCC and pharmacy claims specifying treatment with sunitinib and/or sorafenib. First, we identified all patients who had had either an inpatient or outpatient insurance claim that included an “International Classification of Diseases, 9th edition, Clinical Modification” diagnosis code corresponding to RCC (list available from on-line Appendix). Next, we excluded from this group patients with ⬍90 days of benefit plan enrollment after the date of their first claim with an RCC diagnosis and those with missing or incomplete outpatient pharmacy claims data. This step ensured that we included only those patients with longitudinal pharmacy coverage and the corresponding claims data. For the remaining subjects, we used the Food and Drug Administration National Drug Codes to identify all patients with outpatient pharmacy claims for sunitinib and/or sorafenib (list available from on-line Appendix). Finally, we excluded patients who only had claims specifying a diagnosis of gastrointestinal stromal tumor (“International Classification of Diseases, 9th edition, Clinical Modification” code 171.5 or 238.1, n ⫽ 34), the only other condition for which the use of sunitinib has been approved by the Food and Drug Administration.
Study Variables Next, we used the patient-level information included in the CCE database to ascertain the age (at the first claim with an RCC diagnosis), sex, geographic residence, and insurance benefit plan (eg, health maintenance organization) for each patient in our analytic cohort. We also used the inpatient or outpatient procedure claims to determine whether each of these patients had undergone kidney cancer surgery and/or RCC-directed immunotherapy (ie, interleukin-2 or interferon-␣) before their first pharmacy claim for oral TKI therapy (list available from online Appendix). The CCE database does not provide information regarding cancer severity (eg, stage, grade).
Outcomes We defined the duration of therapy for each medication as the total number of days supplied by all consecutive outpatient prescriptions. For instance, if a patient had 2 pharmacy claims for sunitinib that had both specified a 28-day course, we defined the treatment duration as 56 days (regardless of the interval between the dates for the 2 claims). Our primary outcome of interest was the prevalence of short-term and/or sequential use of oral TKIs. We classified as short-term therapy any treatment regimen that lasted ⬍60 days (a period roughly equivalent to 2 cycles of 826
Chi-square tests were used to determine whether differences existed for patient factors according to the first TKI prescribed (sunitinib or sorafenib), whether the subjects had received shortterm (⬍60 days) or long-term (ⱖ60 days) therapy, and whether the subjects had received monotherapy or sequential therapy. Of those receiving sequential therapy, the duration of each therapy was compared by the first TKI prescribed using a chi-square test. Finally, multivariate logistic regression models were used to determine the independent effect of the initial TKI (sunitinib vs sorafenib) on both short-term and sequential TKI use, after adjusting for age, sex, benefit plan type, geographic region, year of RCC diagnosis, previous kidney surgery (yes vs no), previous immunotherapy (yes vs no), and year of first TKI therapy. All statistical analyses were performed with 2-sided tests at the 5% significance level using SAS, version 9.2 (SAS Institute, Cary, NC).
RESULTS We identified 938 patients with a diagnosis of RCC and ⱖ1 pharmacy claim for sunitinib and/or sorafenib. The median duration of first-line TKI treatment was 90 days (range 2-690) and 120 days (range 14-690) for sunitinib and sorafenib, respectively. The patient characteristics are listed in Table 1, stratified by the initial therapeutic agent. Overall, nearly 3 of 4 patients (73%) treated with sunitinib and/or sorafenib were men, 57% were 51-60 years old, and 43% had claims for previous kidney cancer surgery. Of these patients treated with oral TKIs, 47% lived in the Southern United States. Compared with those treated in 2006, the patients starting treatment in 2007 were significantly more likely to receive first-line sunitinib (73% vs 49%, P ⬍ .001). Figure 1 presents the prevalence of short-term and sequential therapy among the patients with RCC and treated with oral TKIs. The short-term use of oral TKIs was common, with nearly 4 of 10 (36%) patients receiving first-line treatment lasting ⬍60 days; the prevalence of initial shortterm therapy use did not differ according to the initial drug prescribed (37% sunitinib vs 33% sorafenib, P ⫽ .177). Overall, 23% of patients received sequential therapy, which was more common among patients who had received firstline sorafenib (34% first-line sorafenib vs 16% first-line sunitinib, P ⬍ .001). The distribution of short-term and sequential therapy according to the patient characteristics and the results from the multivariate analyses evaluating the independent associations between the patient characteristics and receipt of short-term or sequential TKI therapy are listed in Table 2. Compared with sorafenib, patients starting therapy with sunitinib were not more likely to receive short-term therapy UROLOGY 77 (4), 2011
Table 1. Patient characteristics Characteristic Initial treatment date 2006* 2007 Initial RCC diagnosis date 2003 2004 2005 2006 2007 Age (y) 19-40 41-50 51-60 61-65 Sex Male Female Benefit plan† Basic/comprehensive HMO Other‡ Geographic region§ Northeast North-Central South West Previous kidney surgery Yes No Previous immunotherapy Yes No
Total (n ⫽ 938)
Sunitinib (n ⫽ 554)
Sorafenib (n ⫽ 384)
537 401
261 (49) 293 (73)
276 (51) 108 (27)
96 111 173 366 192
53 (55) 51 (46) 89 (51) 216 (59) 145 (76)
43 (45) 60 (54) 84 (49) 150 (41) 47 (24)
51 184 531 172
28 (55) 111 (60) 315 (59) 100 (58)
23 (45) 73 (40) 216 (41) 72 (42)
686 252
407 (59) 147 (58)
279 (41) 105 (42)
94 136 685
55 (59) 75 (55) 408 (60)
39 (41) 61 (45) 277 (40)
97 233 444 153
52 (54) 147 (63) 267 (60) 83 (54)
45 (46) 86 (37) 177 (40) 70 (46)
402 536
250 (62) 304 (57)
152 (38) 232 (43)
47 891
26 (55) 528 (59)
21 (45) 363 (41)
P Value ⬍ .001 ⬍ .001
.905
.783 .632
.260
.092 .592
RCC, renal cell carcinoma; HMO, health maintenance organization. Data presented as numbers, with percentages in parentheses. * Included 1 case from 2005. † Unknown in 23 cases. ‡ Included preferred provider organizations, exclusive provider organizations, point-of-service, and consumer-driven healthcare plans. § Unknown in 3 cases.
(odds ratio [OR] 0.90, 95% confidence interval [CI] 0.671.21). Short-term therapy was more common among the female patients (OR 1.53, 95% CI 1.12-2.09) and patients who resided in the Southern United States (OR 1.71, 95% CI 1.05-2.80). Patients aged 51-60 years were significantly less likely to receive short-term therapy (OR 0.52, 95% CI 0.28-0.95) than patients aged 19-40 years. Sequential therapy was more common among patients treated with sorafenib first (OR 2.30, 95% CI 1.64-3.21) and those aged 51-60 years (OR 2.52, 95% CI 1.07-5.91). In the analyses that jointly assessed sequential and shortterm therapy, we observed that 61% of patients treated with sequential oral TKIs had received a short-term regimen with ⱖ1 of the 2 medications. As illustrated in Figure 2, the patients who had received first-line sunitinib were significantly more likely to had received a short-term regimen with one or both oral TKIs (73% vs 52%, P ⬍ .001). Compared with second-line sunitinib, second-line sorafenib was significantly more likely to have been prescribed for ⬍60 days (63% vs 34%, P ⬍ .001). Furthermore, of the 59 patients who had received first-line sunitinib for ⬎60 days, 36 (61%) were treated with second-line sorafenib for ⱕ60 UROLOGY 77 (4), 2011
days. In contrast, only 30 (32%) of 93 patients receiving first-line sorafenib for ⬎60 days had received short-term second-line sunitinib.
COMMENT The present study had several findings that have clarified the initial use patterns for the oral TKIs among patients with RCC. Because it has highlighted a potentially significant disconnect between the efficacy and true clinical benefit of sunitinib and sorafenib, our most consequential finding might have been the relatively high prevalence (36%) of short-term treatment regimens. The most likely explanations for a short course of oral TKI therapy include adverse drug reactions, disease progression, and/or death. In the large clinical trials of sunitinib and sorafenib, in which patient eligibility and accrual is strictly controlled, adverse event-related discontinuation of these TKIs occurred in only 6-10% of patients.6,7,13 Moreover, only 15% of patients in these trials stopped treatment within 2 months of initiating oral TKI therapy.6,7 However, our observation that nearly 40% of patients continued their 827
Figure 1. Initial patterns of oral TKI use among patients with RCC. *P ⫽ .177 for comparison between patients receiving initial sunitinib versus initial sorafenib. **P ⬍ .001 for comparison between patients receiving initial sunitinib versus initial sorafenib. The X axis corresponds to groups of patients in our analytic cohort who received either short-term therapy (ie, ⬍60 days) or sequential therapy (ie, both sunitinib and sorafenib); y axis corresponds to proportion who received treatment courses of interest. Black bars represent proportion who were treated with sunitinib first, and white bars, those who received sorafenib first.
first-line TKI for ⬍60 days—and that the median treatment course was only 90-120 days—suggests that the results from these landmark trials have not been translated into everyday clinical practice. Thus, an understanding of the basis for this disconnect between the clinical trial results and routine clinical practice is needed. Both patient and provider factors could explain the observed discrepancy in the average length of treatment between our analytic cohort and the patients in the published clinical trials. Although not evaluated in the present study, an immediate explanation is the potential liberalization of treatment indications to include patients who would have been excluded from the clinical trials owing to the severity of either their cancer or their comorbidity (and who would be therefore less likely to respond to and/or tolerate these medications). Several factors might have promote this trend, including the relative ease of oral TKI administration (compared with intravenous chemotherapy) and an understandable “therapeutic imperative” for high-risk patients with few existing treatment options.14 Furthermore, it is likely that some patients in our analytic cohort had RCC with nonclear cell histologic features. Although small retrospective studies have suggested similar efficacy for the targeted therapies among patients with papillary and chromophobe RCC, the data have been inconclusive.15,16 Because the clinical trials for sunitinib and sorafenib were limited to patients with clear cell RCC, the observed discrepancy between our results and the reported clinical trial findings could be explained, in part, by the inclusion of patients with non-clear cell RCC. The relatively high prevalence of short-term therapy might also have reflected lower provider thresholds for the 828
discontinuation of the oral TKIs owing to unexpected and/or difficult-to-manage side effects and/or greater patient preference for stopping the medications in the absence of the intensive follow-up and support provided in most clinical trials. Although we could not address this question empirically, the high prevalence of short-term therapy also suggested the infrequent use of a dose reduction as a strategy for managing adverse events and prolonging therapy. This approach was implemented as a method for continuing therapy in 32% of patients in the treatment arm of the Phase III sunitinib trial.6 Additional investigation of these factors using multi-institutional and population-based studies (including qualitative research) is necessary to confirm the validity of our findings and reduce the prevalence of shortterm treatment regimens, thereby, optimizing the implementation of oral TKIs in “real-world” clinical practice.17 In addition, the not-infrequent use of sequential therapy (a practice pattern more prevalent among patients initially treated with sorafenib) has also highlighted important issues concerning real-world use of the oral TKIs. In theory, patients might have received both sunitinib and sorafenib because they experienced either intolerable side effects or disease progression while receiving the first-line TKI. Although the results from small retrospective case series18,19 and a recent prospective Phase II trial20 have suggested that sequential therapy with sunitinib and sorafenib is safe and possibly beneficial, no results from randomized Phase III trials are available to support the efficacy of sequential oral TKI treatment algorithms compared with the best supportive care. Our data have indicated that 6 of every 10 sequential therapy patients who tolerated first-line sunitinib (ie, those patients whose initial treatment course with sunitinib was ⬎60 days) received only a short course of second-line sorafenib, a finding consistent with sorafenib’s limited effectiveness in this clinical setting.21 Taken together, our findings highlight the need for indepth and prospective studies that can accurately assess patient outcomes and better characterize the clinical and “real-world” cost-effectiveness of short-term and sequential treatment regimens among patients with metastatic RCC. In reality, however, such studies would be exceedingly unlikely, given the increasingly rapid introduction of newer targeted therapies and the availability of established clinical trials for patients in whom treatment with sunitinib or sorafenib fails. Nonetheless, we believe it of interest to patients, physicians, and policymakers that these unproven sequential practice patterns not only exist but are actually fairly common among patients with advanced RCC. Several additional findings raised important hypotheses for future research in this area. For instance, we observed that the prevalence of short-term and sequential therapy varied according to patient age, sex, and geographic region. These associations can be explained by a number of factors, including the unmeasured differences in patient comorbidity, performance status, and/or cancer-severity. These and other hypotheses could be tested in future studies using more comprehensive clinical data sets. Finally, the prevaUROLOGY 77 (4), 2011
Table 2. Characteristics of patients receiving short-term and sequential oral tyrosine kinase inhibitor therapy
Variable Initial treatment date 2006*† 2007 Initial RCC diagnosis date 2003-2005* 2006 2007 Age (y) 19-40* 41-50 51-60 61-65 Sex Male* Female Benefit plan‡ Basic or comprehensive* HMO Other§ Geographic region¶ Northeast* North-Central South West Previous kidney surgery Yes* No Previous immunotherapy Yes* No
Short-Term Use (n ⫽ 334) Total Patients P Adjusted (n ⫽ 938) (n) Value OR 95% CI
Sequential Use (n ⫽ 216) Patients P Adjusted (n) Value OR 95% CI ⬍ .001
.011 537 401
170 (32) 164 (41)
380 366 192
122 (32) 125 (34) 87 (45)
51 184 531 172
24 (47) 67 (36) 175 (33) 68 (40)
686 252
227 (33) 107 (42)
94 136 685
34 (36) 59 (43) 236 (34)
97 233 444 153
29 (30) 77 (33) 178 (40) 46 (30)
402 536
148 (37) 186 (35)
47 891
18 (38) 316 (35)
1.00 1.27
— 170 (32) 0.89-1.81 46 (11)
1.00 1.12 1.51
— 0.81-1.54 0.95-2.37
1.00 0.64 0.52 0.73
— 7 (14) 0.33-1.23 39 (21) 0.28-0.95 128 (24) 0.38-1.41 42 (24)
1.00 1.53
— 160 (23) 1.12-2.09 56 (22)
1.00 1.34 0.86
— 20 (21) 0.75-2.37 33 (24) 0.53-1.39 160 (23)
1.00 1.22 1.71 1.07
— 0.72-2.09 1.05-2.80 0.60-1.89
1.00 0.92
— 102 (25) 0.70-1.22 114 (21)
1.00 0.59
— 17 (36) 0.31-1.12 199 (22)
.005
⬍ .001
99 (26) 97 (27) 20 (10)
.124
1.00 0.34
— 0.21-0.54
1.00 1.26 1.02
— 0.88-1.80 0.52-1.99
1.00 1.96 2.52 2.42
— 0.79-4.85 1.07-5.91 0.98-6.00
1.00 1.01
— 0.70-1.47
1.00 1.47 1.57
— 0.74-2.93 0.88-2.79
1.00 1.27 0.91 1.12
— 0.69-2.33 0.52-1.62 0.59-2.14
1.00 0.74
— 0.53-1.02
1.00 0.53
— 0.26-1.06
.338
.008
.723
.140
.866
.092
.326 21 (22) 61 (26) 91 (20) 39 (25)
.503
.140
.693
.028
OR, odds ratio; CI, confidence interval; other abbreviations as in Table 1. Data in parentheses are percentages. * Reference group. † Included 1 case from 2005. ‡ Unknown in 23 cases. § Included preferred provider organizations, exclusive provider organizations, point-of-service, and consumer-driven healthcare plans. ¶ Unknown in 3 cases.
lence of previous kidney surgery among our analytic cohort (43%) was far lower than the nephrectomy rates (90%) among the patients in the TKI clinical trials. Although measurement error could have contributed to this discrepancy (eg, some patients underwent nephrectomy in the years before our available claims data), it is also possible that some clinicians have been prescribing sunitinib and/or sorafenib to patients with intact primary tumors. Although, at present, the implications of this practice pattern remain unclear,22 the survival benefits of cytoreductive nephrectomy before targeted therapy are being investigated in an active clinical trial (ie, the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA)).23 The present study had several limitations. First, as stated, we could not measure the tumor characteristics, patient performance status, and other risk-related covariates. Thus, our analyses might not have adequately characterized or adjusted for important patient-specific determinants of the use of oral TKIs. Second, our findings might not be generalizable to older patients (eg, Medicare eligible) with RCC who were not included in our analysis. Third, we recognized UROLOGY 77 (4), 2011
that patients might have switched benefit plans or stopped coverage during the study interval, potentially leading to measurement error in our estimates of short-term and sequential therapy. Fourth, we recognized that some patients might have received therapeutic kidney cancer surgery that was not identified by this claims database, either because the operation took place before 2003 or while a patient was enrolled in a different health insurance plan. Fifth, we did not assess the frequency of dose reduction among the patients in our analytic cohort. Future studies evaluating the prevalence of dose reduction of TKIs among patients with RCC might help explain the discrepancies between the published clinical trials and our findings. Sixth, as mentioned, we did not have information on the tumor histologic type, which can affect the response to treatment with oral TKIs. Finally, our findings might not reflect the practice patterns for the more recently introduced oral medications for patients with RCC (eg, everolimus). Despite these limitations, our findings have provided useful insight regarding the initial practice patterns with the oral targeted therapies for patients with RCC. 829
Figure 2. Patterns of short-term therapy among patients receiving sequential therapy (ie, both sunitinib and sorafenib). (A) Patients who received sunitinib followed by sorafenib. and (B) Patients treated with sorafenib followed by sunitinib. Black portions of pie charts represent proportions of patients who received short-term sunitinib (first-line, Fig. A vs second-line, Fig. B) but had received sorafenib for ⬎60 days. White segments represent patients who received both medications for ⬍60 days. Dark gray areas represent patients who received short-term sorafenib (second-line, Fig A; first-line, Fig B) but had received sunitinib for ⬎60 days. Light gray portions represent patients who received both drugs for ⬎60 days.
CONCLUSIONS After their introduction, the initial use of sorafenib and sunitinib was characterized by relatively prevalent shortterm and sequential treatment regimens among patients with RCC. For patients treated with both sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences exist in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the “real-world” clinical outcomes and economic effect associated with these treatment courses. References 1. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335:865-875. 2. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol. 2000;163:408-417. 3. Gupta K, Miller J, Li J, et al. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 2008;34:193-205. 4. Goodman V, Rock E, Dagher R, et al. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007;13:1367-1373. 5. Kane R, Farrell A, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12:72717278. 6. Motzer R, Hutson T, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356: 115-124. 7. Escudier B, Eisen T, Stadler W, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 8. Motzer R, Hutson T, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009; 27:3584-3590. 9. Steinbrook R. Saying no isn’t NICE—the travails of Britain’s National Institute for Health and Clinical Excellence. N Engl J Med. 2008;359:1977-1981.
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10. Bach PB. Limits on Medicare’s ability to control rising spending on cancer drugs. N Engl J Med. 2009;360:626-633. 11. Pollack A. As Pills Treat Cancer, Insurance Lags Behind. New York Times. Availabe from: www.nytimes.com/2009/04/15/business/ 15pill.html. Accessed July 3, 2010. 12. Health Research Data for the Real World: The MarketScan Databases. Available from: www.support.thomsonhealthcare.com/ uploadedFiles/docs/2008HealthResearchDatafortheRealWorldThe% 20MarketScanDatabases(1).pdf. Accessed July 3, 2010. 13. Gore M, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10:757-763. 14. Kocs D, Fendrick AM. Effect of off-label use of oncology drugs on pharmaceutical costs: the rituximab experience. Am J Manag Care. 2003;9:393-400. 15. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. J Clin Oncol. 2008;26:127-131. 16. Strumburg D. Efficacy of sunitinib and sorafenib in non-clear cell renal cell carcinoma: results from expanded access studies. J Clin Oncol. 2008;26:3469. 17. Dougherty D, Conway PH. The “3T’s” road map to transform US health care: the “how” of high-quality care. JAMA. 2008;299:2319-2321. 18. Dudek AZ, Zolniernek J, Dham A, et al. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. J Clin Oncol. 2009;115: 61-67. 19. Eichelberg C, Heuer R, Chun FK, et al. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis. Eur Urol. 2008;54:1373-1378. 20. Di Lorenzo G, Carteni G, Autorino R, et al. Phase II Study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27:4469-4474. 21. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29-34. 22. Pantuck AJ, Belldegrun AS, Figlin RA. Cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of targeted therapy? Clin Cancer Res. 2007;13:693s-696s. 23. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). Available from: www.clinicaltrials.gov/ct2/show/ NCT00930033. Accessed July 3, 2010.
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Appendix. Codes for identification of analytic cohort, surgical procedures, and treatment with immunotherapy Codes of Interest Diagnosis of RCC* 189, 189.0, 189.00, 189.01 236.9, 236.90, 236.91, 236.99, 239.5, 239.9 235.4, 237.2, 238.1, 238.8 189.8, 189.9 211.8, 223.0, 223.1, 223.89, 223.9 194.0 171.5 195.2 158.0 Prescription of oral TKI¶ 69055030, 69055038, 69077030, 69077038, 69098030, 69098038, 54569598200, 54569598300 26848858 Receipt of cancer surgery储 50045 50200 50205 50225 50230 50545 50240 50543 50220 50234, 50236 50546, 50548 50250 50280 50541 50542 50549 50592 Receipt of immunotherapy# J9015 J9213, J9214
Description Malignant neoplasm of kidney except renal pelvis† Neoplasm of uncertain behavior of kidney and ureter, other specified urinary organ, unspecified urinary organ‡ Neoplasm of uncertain behavior of retroperitoneum, adrenal gland, connective/soft tissue, other specified site§ Malignant neoplasm of other or unspecified site, urinary tract origin Benign neoplasm of retroperitoneum, kidney, and other urinary organ, kidney except pelvis, other urinary organ, unspecified urinary organ Malignant neoplasm of adrenal gland Malignant neoplasm of connective and soft tissue of abdomen Malignant neoplasm of abdomen Malignant neoplasm of retroperitoneum Sunitinib malate Sorafenib Nephrotomy, with exploration Renal biopsy, percutaneous Renal biopsy, open Nephrectomy Complicated, open Radical, open Radical, laparoscopic Partial, open Partial, laparoscopic Simple, open Nephrectomy, open Nephrectomy, laparoscopic Ablation, open Excision/unroofing of cyst of kidney Laparoscopic Ablation, laparoscopic Unlisted laparoscopy procedure, renal Ablation (radiofrequency ablation) Aldesleukin (interleukin-2) Interferon-alpha
RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor. * Using diagnosis codes from “International Classification of Diseases, 9th edition, Clinical Modification.” † Represented 79% of analytic cohort. ‡ Represented 12% of analytic cohort. § Represented 3% of analytic cohort. ¶ From Food and Drug Administration National Drug Codes. 储 From Current Procedural Terminology (CPT) codes. # From Healthcare Common Procedure Coding System (HCPCS) procedure codes.
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