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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3650-3652 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.6719
Dose Selection in Phase I Studies: Why We Should Always Go for the Most EffectiveMelbourne Oncology Group, Cabrini Health, Malvern; and Monash University, Melbourne, Australia To the Editor: In their recent editorial, Sleijfer and Wiemer1 ask one of the current key questions in clinical oncology: "In this era of molecularly targeted drugs, does dose selection based on outcomes from biomarker studies alone suffice or, as with chemotherapy, do we still need to establish the maximum tolerated dose (MTD)?" They then state that we need randomized studies to answer this question and that these studies are very scarce at present. However, the clinical data that they use to support their assertion that we should still aim to establish the MTD of all molecularly targeted drugs and "always go for the top" seems rather flimsy and needs to be analyzed carefully. This is emerging as an important issue in oncology and is starting to be debated in opinion-leading journals2,3 and newspapers.4 They start by correctly asserting that the only data available for mammalian target or rapamycin inhibitors shows no relationship between dose and efficacy.5 They then analyze three recent phase I studies of the mammalian target or rapamycin inhibitor everolimus (RAD001) that used biomarkers rather than MTD to determine dose recommendations for additional studies6-8 and, quite reasonably, state that extensive translational research is needed in considerable numbers of patients to fully appreciate the value of biomarkers. However, to underpin their argument that MTD should still be the goal of phase I studies of small molecule targeted therapies, they interpret what they call the "robust data" on imatinib in advanced GI stromal tumors (GISTs) as showing that higher doses produce better outcomes. They make this assertion by referring to a 2007 abstract of a meta-analysis of the 1,640 assessable patients in the two large prospectively randomized multicenter studies that compared two doses of imatinib. It showed a small increase in estimated median progression-free survival (mPFS) of 0.37 years. The P value of .41 just attained significance and there was no difference in overall survival (OS) between the patient groups.9 However, the assessment of PFS used the unreliable Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria in both studies rather than the significantly more accurate Choi criteria.10-12 The first of these two large randomized studies was by the European Organisation for Research and Treatment of Cancer and compared 400 versus 800 mg daily in 946 patients overall. It reported a small improvement in mPFS favoring the MTD (800 mg) over 400 mg in the initial analysis at a median follow-up of 25 months.13 However, a subsequent analysis of this study at a median follow-up of 40 months published more than 2 years ago and also published in abstract form only showed that there was no longer any difference in mPFS, even by RECIST criteria, between the two groups and there was still no difference in OS.14 Even PFS for those patients requiring a dose reduction to 300 mg daily "did not seem to differ from that seen for patients at higher doses." In addition, and importantly, toxicity was considerably higher for the patients receiving the higher dose, with 50% v 32% having at least one grade 3 to 4 toxic event. Edema, rash, lethargy, nausea, bleeding, diarrhea, and dyspnea were significantly more frequent in the patients within the higher dose arm. The second of these large randomized studies, the Intergroup SO33 study, reported its results in Journal of Clinical Oncology on February 1, 2008.15 It was identical in basic design and randomly assigned 746 patients imatinib doses of 400 or 800 mg daily. At a median follow-up of 4.5 years, it also revealed no statistically significant differences in objective response rates, PFS, or OS. Serious adverse events and treatment-related deaths were more common on the high-dose arm, with 63% v 43% experiencing grade 3 to 5 toxicities and 3% v 1% experiencing treatment-related death. One hundred thirty-three of the 345 patients randomly assigned on the lower dose arm who experienced disease progression by the unreliable RECIST criteria were crossed over to the higher dose arm. One hundred seventeen of these 133 were assessable; 3% of these achieved a partial remission and 28% achieved stable disease. Many of these may have been responding by Choi criteria when they were judged to have experienced disease progression and were crossed over. Any subsequent response may well have happened anyway while receiving continued lower dose treatment if they had been more accurately assessed by Choi criteria initially. The study manuscript concluded that 400 mg of imatinib daily is the standard of care for incurable GIST. Therefore, neither individual study showed any advantage for the higher dose of imatinib but both showed considerably more toxicity. To be regarded as a significant advance in cancer therapy, any new treatment must either improve OS and/or quality of life measures for the treated group or reduce treatment-related toxicity and/or overall dollar costs for the treated group while matching OS. Higher doses of imatinib in GIST have not been shown yet to achieve any of these outcomes. Sleijfer and Wiemer then used a crossover analysis of a selected subset of patients,16 who started imatinib at 400 mg daily in the European Organisation for Research and Treatment of Cancer/Italian Sarcoma Group/Australasian Gastrointestinal Trials Group study13 and were crossed over to the MTD of 800 mg daily at progression, to claim that the dose increase allowed a "substantial number of patients to reach durable progression-free periods." This substantial number was the achievement, by RECIST criteria, of a partial remission (PR) for two of the 247 patients and stable disease for 36 of the 247 patients judged to have experienced disease progression while receiving 400 mg daily. The mPFS on the higher dose after crossover was 81 days and was achieved at the expense of "significantly worse anemia and fatigue." There are two major problems with these data and Sleijfer and Wiemer's interpretation of it. First, responses in this study were assessed by RECIST rather than by Choi criteria. It has been shown that Choi response criteria are more sensitive and more precise than RECIST in assessing the response of GISTs to imatinib mesylate because a significant number of responders by Choi criteria develop cystic changes that are incorrectly interpreted as progressive disease by RECIST criteria. Response by Choi criteria, unlike response by RECIST, correlates significantly with time to progression and disease-specific survival.10-12 Therefore, many of the patients receiving the 400-mg dose, who may have actually been responding to treatment by Choi criteria, were considered to have experienced disease progression by RECIST criteria and were changed to the higher dose of 800 mg, allowing them to subsequently demonstrate a "response by RECIST criteria." Second, Zalcberg et al16 concluded in their study that "a cross-over to high-dose imatinib is feasible and safe in GIST patients who progress on low-dose therapy." Importantly, and despite a detailed analysis of efficacy, Zalcberg et al did not claim that the higher dose was efficacious. In fact, they noted in the discussion that their analysis "has several limitations and should be considered as descriptive only. It can be used, however, to generate hypotheses regarding the role of the dose of imatinib for the treatment of secondary resistance in patients with advanced GIST." These study results and hypotheses for the treatment of GIST are hardly the "robust data" claimed by Sleijfer and Wiemer to support their contention that "we should always go for the top." Sleijfer and Wiemer then claim that "for other molecularly targeted drugs, such as sorafenib and sunitinib, evidence is accumulating that the higher the dose, the better the outcome." Again, this assertion is just not supported by the two studies cited. In the first study, Amato et al17 escalated the dose of sorafenib every 28 days from 800 mg daily to 1,600 mg daily in 46 patients with metastatic renal cell cancer. The study revealed a 52% complete response/PR rate overall. This shows that the drug has excellent biologic activity but gives no insights into the relationship between dose and response. A dose of 400 mg daily or significantly less may have achieved the same results. The second study, by Houk et al,18 looked at steady-state area under the curve for sunitinib maleate and its active metabolite SU12662, in three phase II and phase III studies, using doses of 25 to 62.5 mg daily. They noted increased PR rates, time to tumor progression and OS with increased area under the curve for patients with cytokine-refractory metastatic renal cell carcinoma. There were no data for treatment-naïve patients. They proposed that 50 mg daily would achieve PR in 62% of patients. As yet, this is no more than a hint of the possibility of a relationship between dose and benefit. In more than one million publications in clinical oncology during the last 60 years, no linear dose-palliation or dose-survival relationship has been demonstrated for any chemotherapy treatment in noncurable cancer or even for curable cancer. In our quest to improve the cure rates for various cancers during this time, we may have exposed some patients to more treatment than necessary for their cancers by concentrating too single-mindedly on the MTD of chemotherapy drugs. Treating patients with the MTD of any chemotherapy for incurable cancer probably contributes only increased toxicity and cost without any quality of life or survival benefit. The minimal effective dose (MED) of many commonly used chemotherapy drugs (such as gemcitabine, capecitabine, paclitaxel, docetaxel, oxaliplatin, irinotecan, and others) is quite possibly considerably lower than currently used. As biomarkers are increasingly revealing for biologic agents, there is quite likely a dose-threshold effect rather than a dose-response effect for many chemotherapy drugs as well, where dosing beyond a certain level does not add clinical benefit. Even recently accepted phase I guidelines about the most appropriate dose-intensity and scheduling of chemotherapy drugs such as capecitabine and paclitaxel are being revised dramatically by modern assessment techniques.19-21 If the appropriate studies were done, the concept of treating many of our patients with the MTD rather than the MED of chemotherapy may be consigned to the museum for preservation with other superceded and/or extinct medical dogma. In this emerging era of translational research with biologically targeted therapies, MEDs are being—and will likely continue to be—identified by sophisticated biomarker analysis. Consequently, this may be an appropriate time to leave the clinical research treatment benchmark of exclusively treating with the MTD of new drugs to the medical archaeologists and historians. In the exciting future of clinical oncology drug research, let us always go for the most effective in every way possible—biologically, clinically (maintaining or improving both survival and quality of life), and economically. Our patients,22 our children (the next generation of patients) and our health care planners23 will almost certainly thank us. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Sleijfer S, Wiemer E: Dose selection in phase I studies: Why we should always go for the top. J Clin Oncol 26:1576-1578, 2008 2. Haines IE: A positive step forward, but more needed to maximize cost benefits of new-generation cancer therapies. J Clin Oncol 25:31e-32e, 2007 3. Haines IE, Miklos GL: Paclitaxel plus bevacizumab for metastatic breast cancer. N Engl J Med 358:1637-1638, 2008 4. Pollack A: Cutting dosage of costly drug spurs a debate. New York Times. http://www.nytimes.com/2008/03/16/business/16gaucher.html 5. Atkins MB, Hidalgo M, Stadler WM, et al: Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909-918, 2004 6. Tanaka C, O’Reilly T, Kovarik JM, et al: Identifying optimal biologic doses of everolimus (RAD001) in cancer patients based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26:1596-1602, 2008 7. O’Donnell A, Faivre S, Burris HA III, et al: A phase I pharmacokinetic and pharmacodynamic study of the oral mTOR inhibitor everolimus (RAD001) in patients with advanced solid tumors. J Clin Oncol 26:1588-1595, 2008 8. Tabernero J, Rojo F, Calvo E, et al: Dose- and schedule-dependent inhibition of the mTOR pathway with everolimus: A phase I tumor pharmacodynamic study in patients with solid tumors. J Clin Oncol 26:1603-1610, 2008 9. Van Glabbeke M, Owzar K, Rankin C, et al: Comparison of two doses of imatinib for the treatment of gastrointestinal stromal tumors (GIST): A meta-analysis based on 1640 patients. J Clin Oncol 25:546s, 2007 (suppl; abstr 10004) 10. Choi H, Macapinlac H, Burgess M, et al: Correlation of computerized tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate. Proc Am Soc Clin Oncol 22:819, 2003 (abstr 1359) 11. Choi H, Charnsangavej C, Faria S, et al: Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: Proposal of new computed tomography response criteria. J Clin Oncol 25:1753-1759, 2007 12. Benjamin RS, Choi H, Macapinlac HA, et al: We should desist using RECIST, at least in GIST. J Clin Oncol 25:1760-1764, 2007 13. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004[CrossRef][Medline] 14. Casali PG, Verweij J, Kotasek D, et al: Imatinib mesylate in advanced gastrointestinal stromal tumors (GIST): Survival analysis of the Intergroup EORTC/ISG/AGITG randomized trial in 946 patients. Eur J Cancer 3:201, 2005 (suppl; abstr 711) 15. Blanke CD, Rankin C, Demetri GD, et al: Phase III randomized, Intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 26:626-632, 2008 16. Zalcberg JR, Verweij J, Casali PG, et al: Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 41:1751-1757, 2005[CrossRef][Medline] 17. Amato RJ, Harris P, Dalton M, et al: A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). J Clin Oncol 25:241s, 2007 (suppl; abstr 5027)[CrossRef] 18. Houk BE, Bello CL, Michaelson MD, et al: Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach. J Clin Oncol 25:241s, 2007 (suppl; abstr 5027)[CrossRef] 19. Gonzalez-Angulo AM, Hortobagyi GN: Optimal schedule of paclitaxel: Weekly is better. J Clin Oncol 26:1585-1587, 2008 20. Traina TA, Theodoulou M, Feigin K, et al: Phase I study of a novel capecitabine schedule based upon the Norton-Simon mathematical model in patients with metastatic breast cancer. J Clin Oncol 26:1797-1802, 2008 21. Twelves CJ: Defining the optimal schedule of drug administration: Art or science? J Clin Oncol 26:1781-1782, 2008 22. Kolata G: Co-payments soar for drugs with high prices. New York Times. http://www.nytimes.com/2008/04/14/us/14drug.html 23. Mongan JJ, Ferris TG, Lee TH: Options for slowing the growth of health care costs. N Engl J Med 358:1509-1514, 2008
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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