Originally published as JCO Early Release 10.1200/JCO.2005.03.6723 on April 24 2006

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Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma

Mark J. Ratain, Tim Eisen, Walter M. Stadler, Keith T. Flaherty, Stan B. Kaye, Gary L. Rosner, Martin Gore, Apurva A. Desai, Amita Patnaik, Henry Q. Xiong, Eric Rowinsky, James L. Abbruzzese, Chenghua Xia, Ronit Simantov, Brian Schwartz, Peter J. O'Dwyer

From the University of Chicago, Chicago, IL; Royal Marsden Hospital, Surrey, United Kingdom; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; The University of Texas M.D. Anderson Cancer Center, Houston; Cancer Therapy and Research Center, San Antonio, TX; Bayer Pharmaceuticals Corporation, West Haven, CT

Address reprint requests to Mark J. Ratain, MD, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL 60637; e-mail: mratain{at}medicine.bsd.uchicago.edu

	ABSTRACT

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PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma.

PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with 25% tumor shrinkage continued open-label sorafenib; patients with 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib.

RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity.

CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.

	INTRODUCTION

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Sorafenib (BAY 43-9006) is an oral kinase inhibitor targeting both tumor cells and the tumor vasculature. It was originally developed as an inhibitor of Raf-1, a member of the Raf/MEK/ERK signaling pathway.^1,2 Sorafenib was subsequently found to have activity against B-Raf, vascular endothelial growth factor receptor–2, platelet-derived growth factor receptor, Fms-like tyrosine kinase-3 (Flt-3), and stem-cell growth factor (c-KIT).³ In phase I studies investigating various oral dosing schedules, sorafenib was generally well tolerated; the recommended dose for future trials was 400 mg bid continuously. Dose-limiting toxicities at continuous doses higher than 400 mg bid were diarrhea, fatigue, and skin toxicity.^4-7

Preclinical studies in xenograft models (colon, breast, lung) showed that the primary effect of sorafenib was inhibition of tumor growth rather than tumor shrinkage.³ These data suggested that, unlike cytotoxic agents, the primary clinical benefit of agents such as sorafenib may be disease stabilization. Therefore, classical oncology paradigms for phase II clinical evaluation (eg, single-arm noncontrolled studies using partial or complete response rate as the primary end point) would not adequately detect the activity of sorafenib.⁸ As duration of disease stabilization is affected by the natural history of the disease and the effect of any administered agent, drug effect is best measured through use of a placebo control, ideally with minimization of patient exposure to placebo.

The randomized discontinuation (or withdrawal) trial (RDT) design, first proposed in 1975, attempts to assess the clinical activity of a drug while minimizing the use of placebo.⁹ Since then, this design has been used in many therapeutic areas.^10-15 This is an enrichment design, in which all patients receive study drug for an initial run-in period, followed by random assignment of potential responders to either the study drug or placebo.^9,14 This design creates a controlled trial without upfront randomization, and decreases the heterogeneity of the randomly assigned population, resulting in increased statistical power with smaller patient numbers. This design was first implemented in oncology in a study of carboxyaminoimidazole for the treatment of metastatic renal cell carcinoma (RCC).^16,17

Our multicenter placebo-controlled RDT was performed to determine whether sorafenib inhibits tumor growth in patients with metastatic solid tumors who maintain stable disease after a 12-week run-in period. The original protocol focused on patients with metastatic colorectal carcinoma (CRC), based on the putative importance of Raf/MEK/ERK signaling in this tumor type.^18,19 However, the broad eligibility criteria of the protocol also enabled enrollment of patients with other malignancies. Early signs of antitumor activity in patients with RCC and low numbers of patients with CRC achieving the criteria for randomization after the 12-week run-in period led to a refocus of this study toward patients with RCC, as we have reported here.

	PATIENTS AND METHODS

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Patients
Patients with histologically or cytologically confirmed metastatic refractory cancer for which no approved effective therapy exists were eligible for this study. Originally, the study focused on patients with CRC, but allowed enrollment of patients with other solid tumor types. During the course of the study, evidence of tumor regression in many patients with RCC led to a protocol amendment, which extended recruitment of patients with RCC and terminated enrollment of patients with CRC.

Inclusion criteria included: patient age of at least 18 years; at least one measurable tumor; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; life expectancy of at least 12 weeks; and adequate bone marrow, liver, and renal function. Patients with other serious medical problems or CNS involvement were excluded. There was no limit on the extent of prior therapy, except for the exclusion of patients with previous exposure to a Ras pathway inhibitor.

Study Design
This RDT was conducted at five centers. Enrollment began on September 25, 2002. This report includes efficacy data up to December 31, 2004. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.

Sorafenib (Bayer Pharmaceuticals Corporation, West Haven, CT) was initially administered to all patients in a 12-week open-label run-in period using continuous oral dosing at 400 mg bid. Doses of sorafenib were delayed or reduced if clinically significant toxicities considered related to sorafenib occurred. After the 12-week run-in period, disease status was assessed based on change in bidimensional tumor measurements from baseline.²⁰ Patients with 25% tumor shrinkage continued to receive sorafenib until disease progression or toxicity, in order to avoid concerns about the random assignment of these patients. Patients with progressive disease ( 25% tumor growth or other evidence of progression) discontinued treatment. Patients who had a change in tumor size of less than 25% were randomly assigned to either sorafenib (at current dose) or matching placebo in a double-blinded fashion, using centralized allocation via a telephone randomization system. Patients who progressed at any time after randomization (progression was defined as a change in bidimensional tumor measurement from randomization of 25% or clinically assessed progression) were unblinded. Patients whose disease progressed while on placebo were offered sorafenib, and patients on sorafenib discontinued treatment.

Assessment of Efficacy
The primary end point was the percentage of randomly assigned patients who remained progression free at 12 weeks following random assignment (24 weeks after study entry).

Secondary end points included progression-free survival (PFS) after random assignment (randomized subset only); overall PFS (from start of treatment); tumor response rate; and safety. Tumor response was assessed at 12 weeks, and once every 6 weeks thereafter, in accordance with modified WHO guidelines for partial response (PR), stable disease (SD), and progressive disease (PD). Objective responses were confirmed at least 4 weeks after the original documentation. In order to verify investigator observations in an unbiased manner, independent assessment of radiologic scans was performed retrospectively for 152 (75%) of 202 patients. Some scans were not available for independent assessment, as a radiology charter specifying parameters for independent review was developed after the last patient was accrued. These independent radiographic assessments were performed by RadPharm (Princeton, NJ).

Assessment of Safety
Safety was assessed for the entire treatment period (run-in plus randomization). All patients who received at least one dose of the study drug and who had post-treatment data available were assessable for safety. Safety assessments were performed every 3 weeks during the run-in and randomization phases, and once every 4 weeks thereafter. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0), and their relationship to the study drug was recorded.

Statistical Analysis
Simulations for computing power and sample size assumed that tumor growth was exponential and that the distribution of tumor growth rates was log-normal. The mean growth rate in these simulations led to 43% of patients with SD and 57% of patients with PD after 12 weeks, assuming no treatment effect. With 50 patients randomly assigned to each group, the study had a power of 81% to detect a drug effect that corresponded to a reduction in the progression rate from 90% to 70%, 12 weeks after randomization. This simulation did not consider the possibility of tumor shrinkage.¹⁶

For the primary efficacy end point, the two treatment groups (based on an intention to treat) were compared using a Cochran–Mantel-Haenszel test stratified by baseline ECOG score; 95% CIs were computed using binomial distribution. PFS after randomization was summarized by the Kaplan-Meier method, and was compared between treatment groups using a log-rank test. We estimated PFS attributable to sorafenib by piecing together information from the various treatment groups and treatment periods. All patients contributed to the PFS estimate for the first 12 weeks of therapy. We combined the PFS estimate for the first 12 weeks with a similar estimate for all remaining weeks after the first 12 weeks, the latter assuming the patient was alive and progression free at 12 weeks. We estimated PFS after 12 weeks as a weighted average of group-specific PFS for the two groups treated with sorafenib for more than 12 weeks: the 79 patients who entered the open-label part of the trial and the 33 patients randomly assigned to continue on sorafenib. When combining the group-specific PFS estimates, the weights corresponded to the fraction of patients continuing on open-label sorafenib at 12 weeks (79 of 144 patients) and the proportion of randomly assigned patients who were progression free at 12 weeks (65 of 144 patients).

	RESULTS

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This study design permitted enrollment of patients with a variety of tumor types; 502 patients were enrolled onto the study, 501 of whom received the study drug. Early indications of activity in patients with RCC caused us to refocus our study on this patient population, resulting in RCC being the most predominant tumor type (202 patients [40%]).

The baseline demographics of these RCC patients are listed in Table 1. In the randomized phase, the distribution of men and women differed between the treatment groups. However, there were no significant differences between groups for this or any of the other measured baseline characteristics.

View larger version (9K): [in this window] [in a new window]   Fig 1. Changes from baseline in investigator-assessed, bidimensional radiographic measurements at 12 weeks for patients with renal cell carcinoma. These measurements were unconfirmed, and therefore do not represent confirmed responses according to modified WHO criteria. Mean change at 12 weeks was –18% (standard deviation, 33%).

Patient Disposition
The 12-week run-in was completed by 187 patients (93%). Of the 15 patients who discontinued treatment before the 12-week assessment, the majority (12 patients) did so because of adverse events; one patient withdrew consent, one patient was lost to follow-up, and one patient died (as a result of pneumonia and metastatic disease, unrelated to the study drug).

Of the 69 patients identified at 12 weeks with tumor growth or tumor shrinkage of less than 25% who were eligible for entry onto the randomized phase, two patients continued on open-label sorafenib (investigator protocol violation), and three patients withdrew (one patient each due to adverse events, to pursue other treatment options, and for clinical progression before random assignment). One patient who met the study criteria for PD at week 12 was randomly assigned instead of discontinuing treatment. Therefore, a total of 65 patients were randomly assigned to receive sorafenib (32 patients) or placebo (33 patients). Seventy-three patients with tumor shrinkage of at least 25% at the 12-week assessment entered into the open-label part of the trial, plus six additional patients who continued sorafenib, either at the discretion of the investigator or after being granted a waiver, despite having SD (n = 3) or PD (n = 2), or not receiving treatment for the entire run-in (n = 1). Therefore, a total of 79 patients continued open-label sorafenib. Forty-three patients, who completed the 12-week run-in, discontinued treatment at a later time point; 40 patients because of PD, and three patients who had SD (and withdrew from the study).

Antitumor Activity
Randomized phase. At 12 weeks postrandomization (24 weeks from study entry), 50% of patients (16 of 32 patients) receiving sorafenib were progression free, compared with only 18%of patients (six of 33) receiving placebo (P = .0077). Median PFS from 12-week randomization was also statistically significantly longer in the sorafenib group (24 weeks) compared with the placebo group (6 weeks; P = .0087; Fig 2).

View larger version (15K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of investigator-assessed progression-free survival from week 12 randomization for patients randomized to placebo (n = 33) or to sorafenib (n = 32).

Entire treatment period. A secondary objective of this study was to estimate overall PFS for all treated patients. The 79 patients who continued on open-label sorafenib after 12 weeks had a median PFS from baseline of 40 weeks. In patients who achieved tumor shrinkage of at least 25% at 12 weeks (n = 73), PFS was not appreciably different in those patients who had tumor shrinkage of at least 25% to less than 50% (38 weeks; n = 45) with those patients who had tumor shrinkage of at least 50% (47 weeks; n = 28). This suggests that patients with minor tumor shrinkage may have the same benefit as those with classic responses. For the entire population, median overall PFS was estimated (as described in Patients and Methods) to be 29 weeks (Fig 3).

View larger version (8K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plot of estimated overall progression-free survival for all treated patients (n = 202) from day 1 of study drug dosing (excluding placebo-treated patient data). See Patients and Methods for details on the calculations.

	DISCUSSION

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It is notable that if this study had been a single-arm study, the conclusion may have been that sorafenib was inactive in metastatic RCC, as a 4% PR rate is generally considered to be indicative of an inactive agent. Sorafenib has now been confirmed to have significant benefit in a large phase III trial, demonstrating a 100% prolongation of PFS, and a 39% prolongation of overall survival.²¹ Of note, in this phase III study, the confirmed response rate was also less than 5%.

The RDT design also enables the assessment of tumor response in an uncontrolled setting by means of change in tumor measurements at the end of the run-in period (12 weeks). The majority of patients achieved some degree of tumor shrinkage at this time point, and tumor shrinkage of at least 25% (unconfirmed PR/minor response) was achieved in 36% of patients.

Elucidation of the different histologic subtypes of RCC indicates that there are distinct molecular mechanisms responsible for tumor growth, and that patients with different subtypes may have variable prognoses and may respond differently to treatment.²² However, in this study, the antitumor effect in papillary RCC seemed similar to that of the clear cell RCC population.

Although the RDT design prevents a direct analysis of PFS for patients initially treated with sorafenib, PFS of these patients was estimated by eliminating the number of patients randomly assigned to placebo and combining the estimates of conditional PFS to avoid bias. Using this approach, the median PFS at 29 weeks was longer than that observed in patients treated with bevacizumab (21 weeks), or with placebo in the same study (11 weeks).²³ The lack of a difference in median PFS between patients with 25% to 50% tumor shrinkage, with those with tumor shrinkage of more than 50% (ie, partial responders), further indicates the limited utility of standard response criteria for development of agents such as sorafenib.⁸

Importantly, this study shows that sorafenib is generally well tolerated when administered long term in a population of patients with metastatic cancer. Mild-to-moderate skin toxicity was common, and was reversed with treatment interruption and/or dose reduction. In addition, hypertension was frequent, and often required therapy with oral medications. It is expected that long-term sorafenib use will require administering antihypertensive therapy in many treated patients. Given that the drug is administered continuously without a break, the titration of antihypertensive therapy can be performed during the initial weeks of therapy and does not require frequent adjustment.

Sorafenib has demonstrated activity as a single agent in other solid tumors. In our study, tumor shrinkage was evident at 12 weeks in patients with soft tissue sarcoma and thyroid cancer.²⁴ Furthermore, sorafenib also appears to be active in advanced hepatocellular carcinoma.²⁵ The favorable safety profile of sorafenib lends itself well to combination with chemotherapy, as evidenced by the results of combining it with carboplatin and paclitaxel in metastatic melanoma.²⁶

This study was designed to evaluate the merits of the RDT design, which, as originally stated by Amery and Dony,⁹ allows increased statistical power and reduced patient numbers.²⁷ Enrollment onto this trial was rapid, with 202 RCC patients enrolled in 16 months at five study sites, reflecting patient acceptance of the study design. The large treatment difference between sorafenib and placebo was demonstrated with only 65 randomly assigned patients, 35% fewer than originally estimated, because the actual treatment effect was much greater than the hypothesized treatment effect. Not only does this study design allow detection of antitumor activity by standard response rate criteria, it enables assessment of disease stabilization, which would not be possible with a standard phase II study design. Therefore, because only a relatively small proportion of treated patients were randomly assigned, this underestimates the true efficiency of the RDT design. It is likely that the RDT design can be made even more efficient with modifications, such as using the full range of changes in tumor burden after random assignment, rather than a binary arbitrary criterion of "progression" as the primary end point.²⁸

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Mark J. Ratain Onyx Pharmaceuticals (A) Bayer Pharmaceuticals Corporation (C) Tim Eisen Bayer Pharmaceuticals Corporation (A); Onyx Pharmaceuticals (A) Bayer Pharmaceuticals Corporation (A); Onyx Pharmaceuticals (A) Bayer Pharmaceuticals Corporation (A) Walter M. Stadler Bayer Pharmaceuticals Corporation (B); Onyx Pharmaceuticals (B) Bayer Pharmaceuticals Corporation (B); Onyx Pharmaceuticals (B) Bayer Pharmaceuticals Corporation (C) Keith T. Flaherty Onyx Pharmaceuticals (B); Bayer Pharmaceuticals Corporation (A) Bayer Pharmaceuticals Corporation (A) Stan B. Kaye Bayer Pharmaceuticals Corporation (A) Bayer Pharmaceuticals Corporation (A) Martin Gore Bayer Pharmaceuticals Corporation (A) Bayer Pharmaceuticals Corporation (A) Bayer Pharmaceuticals Corporation (B) Eric Rowinsky ImClone Systems (N/R) Bayer Pharmaceuticals Corporation (C) Chenghua Xia Bayer Pharmaceuticals Corporation (N/R) Ronit Simantov Bayer Pharmaceuticals Corporation (N/R) Brian Schwartz Bayer Pharmaceuticals Corporation (N/R) Peter J. O'Dwyer Bayer Pharmaceuticals Corporation (A) Bayer Pharmaceuticals Corporation (A) Bayer Pharmaceuticals Corporation (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Mark J. Ratain, Stan B. Kaye, Gary L. Rosner, Amita Patnaik, Henry Q. Xiong, Eric Rowinsky, James L. Abbruzzese, Brian Schwartz Provision of study materials or patients: Mark J. Ratain, Tim Eisen, Walter M. Stadler, Keith T. Flaherty, Stan B. Kaye, Martin Gore, Amita Patnaik, Henry Q. Xiong, Peter J. O'Dwyer Collection and assembly of data: Mark J. Ratain, Tim Eisen, Keith T. Flaherty, Martin Gore, Henry Q. Xiong, Eric Rowinsky, Ronit Simantov, Brian Schwartz, Peter J. O'Dwyer Data analysis and interpretation: Mark J. Ratain, Tim Eisen, Walter M. Stadler, Apurva A. Desai, Henry Q. Xiong, James L. Abbruzzese, Chenghua Xia, Ronit Simantov, Brian Schwartz, Peter J. O'Dwyer Manuscript writing: Mark J. Ratain, Tim Eisen, Stan B. Kaye, Gary L. Rosner, Martin Gore, Apurva A. Desai, Henry Q. Xiong, Ronit Simantov, Peter J. O'Dwyer Final approval of manuscript: Mark J. Ratain, Tim Eisen, Walter M. Stadler, Keith T. Flaherty, Stan B. Kaye, Gary L. Rosner, Martin Gore, Apurva A. Desai, Amita Patnaik, Henry Q. Xiong, Eric Rowinsky, James L. Abbruzzese, Chenghua Xia, Ronit Simantov, Brian Schwartz, Peter J. O'Dwyer

 

	ACKNOWLEDGMENTS

 
We would like to acknowledge Ian Judson, Simon Pacey, and David Cunningham from the Royal Marsden Hospital (Surrey, United Kingdom) for their contribution to this study. Furthermore, this study would not have been possible without the efforts of Rachel Humphrey.

	NOTES

 
Supported by Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted August 8, 2005; accepted December 1, 2005.

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				M. Gomberg-Maitland Traditional and Alternative Designs for Pulmonary Arterial Hypertension Trials Proceedings of the ATS, July 15, 2008; 5(5): 610 - 616. [Abstract] [Full Text] [PDF]

				J. Autier, B. Escudier, J. Wechsler, A. Spatz, and C. Robert Prospective Study of the Cutaneous Adverse Effects of Sorafenib, a Novel Multikinase Inhibitor Arch Dermatol, July 1, 2008; 144(7): 886 - 892. [Abstract] [Full Text] [PDF]

				A. Sabir, R. Schor-Bardach, C. J. Wilcox, S. Rahmanuddin, M. B. Atkins, J. B. Kruskal, S. Signoretti, V. D. Raptopoulos, and S. N. Goldberg Perfusion MDCT Enables Early Detection of Therapeutic Response to Antiangiogenic Therapy Am. J. Roentgenol., July 1, 2008; 191(1): 133 - 139. [Abstract] [Full Text] [PDF]

				M. M. Hipp, N. Hilf, S. Walter, D. Werth, K. M. Brauer, M. P. Radsak, T. Weinschenk, H. Singh-Jasuja, and P. Brossart Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses Blood, June 15, 2008; 111(12): 5610 - 5620. [Abstract] [Full Text] [PDF]

				M. A. Tran, C. D. Smith, M. Kester, and G. P. Robertson Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development Clin. Cancer Res., June 1, 2008; 14(11): 3571 - 3581. [Abstract] [Full Text] [PDF]

				N. A.J.B. Peters, D. J. Richel, J. J.C. Verhoeff, and L. J.A. Stalpers Bowel Perforation After Radiotherapy in a Patient Receiving Sorafenib J. Clin. Oncol., May 10, 2008; 26(14): 2405 - 2406. [Full Text] [PDF]

				M. Muller, M. Obeyesekere, G. B. Mills, and P. T. Ram Network topology determines dynamics of the mammalian MAPK1,2 signaling network: bifan motif regulation of C-Raf and B-Raf isoforms by FGFR and MC1R FASEB J, May 1, 2008; 22(5): 1393 - 1403. [Abstract] [Full Text] [PDF]

				B. L. Frei and S. A. Soefje A Review of the Cardiovascular Effects of Oncology Agents Journal of Pharmacy Practice, April 1, 2008; 21(2): 146 - 158. [Abstract] [PDF]

				M. B. Thomas, J. P. O'Beirne, J. Furuse, A. T. C. Chan, G. Abou-Alfa, and P. Johnson Systemic Therapy for Hepatocellular Carcinoma: Cytotoxic Chemotherapy, Targeted Therapy and Immunotherapy Ann. Surg. Oncol., April 1, 2008; 15(4): 1008 - 1014. [Abstract] [Full Text] [PDF]

				C. K. Daugherty, M. J. Ratain, E. J. Emanuel, A. T. Farrell, and R. L. Schilsky Ethical, Scientific, and Regulatory Perspectives Regarding the Use of Placebos in Cancer Clinical Trials J. Clin. Oncol., March 10, 2008; 26(8): 1371 - 1378. [Abstract] [Full Text] [PDF]

				A. Dowlati and P. Fu Is Response Rate Relevant to the Phase II Trial Design of Targeted Agents? J. Clin. Oncol., March 10, 2008; 26(8): 1204 - 1205. [Full Text] [PDF]

				A. A. Garcia Small Molecules: Big Changes in the Cancer Treatment Paradigm Journal of Pharmacy Practice, February 1, 2008; 21(1): 17 - 35. [Abstract] [PDF]

				I. Tamaskar, R. Bukowski, P. Elson, A. G. Ioachimescu, L. Wood, R. Dreicer, T. Mekhail, J. Garcia, and B. I. Rini Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib Ann. Onc., February 1, 2008; 19(2): 265 - 268. [Abstract] [Full Text] [PDF]

				J. J. Hiles and J. M. Kolesar Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinoma Am. J. Health Syst. Pharm., January 15, 2008; 65(2): 123 - 131. [Abstract] [Full Text] [PDF]