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A Positive Step Forward, but More Needed to Maximize Cost Benefits of New-Generation Cancer Therapies

Melbourne Oncology Group, Cabrini Health; and the Department of Medicine, Monash University, Melbourne, Australia

To the Editor:

I wish to applaud the recent decision by the American Society of Clinical Oncology (ASCO) and the Journal of Clinical Oncology to only publish clinical trials that commence patient accrual after November 1, 2006, if they have been publicly registered.¹ Recent articles in medical journals and the popular press have revealed the concern that many in the medical community and general public share about aspects of clinical research.^2-18 As well as ensuring publication of all clinical studies, positive and negative, industry or nonindustry sponsored, this policy will help to highlight any research that helps slow the escalation of health care costs in the future without compromising patient care. We all want the best of care for all patients, but at the same time, we must attempt to address concerns about escalating cancer care costs. Many countries are currently noting exponential increases in health care costs as a percentage of GDP and are facing massive increases in health demands in the future from aging populations. It is important that ASCO and we, the oncology community, continue to provide strong leadership in all areas of clinical research. One important area where I believe some effort should be directed in the future is looking at finding minimum effective doses for our treatments. This is particularly important in this exciting new era of an increasing number of effective, targeted therapies in cancer treatment, which may be required for years for each patient to control cancer.

While evidence-based medicine has been increasingly embraced over the last 10 years as the gold standard of medical care, it also exposes some weaknesses and potential threats to the standard of medical care and to the economy. It has become increasingly difficult in the United States, Europe, and Australia for independent groups to fund large clinical research projects looking at these new agents. This has meant that the funding and control of clinical studies has been left to the pharmaceutical companies who produce the products. It would seem that pharmaceutical companies, understandably, are attracted to studies looking at the maximum tolerated dose of any treatments. This places in jeopardy studies that look at trying to find the minimum effective dose of these biologic agents and targeted therapies, as they do not usually cause increasing toxicity with increases in dose as is seen with chemotherapy.¹⁹ So the difference between minimum effective dose and maximum tolerated dose is potentially very large. This seems particularly true for agents such as transtuzumab, where the results of the smaller, government-funded Finland Herceptin (FINHER) study²⁰ appeared to mirror the results of the larger pharmaceutical company–sponsored Herceptin Adjuvant (HERA) study²¹ and caused significantly less cardiac toxicity with a much smaller overall dose.

The same may be said of bevacizumab, where the doses used have evolved from early studies looking at 3 mg/per kg²² to recent studies looking at 15 mg/per kg of body weight in the treatment of lung cancer.^23,24 Where will this trend end? Will we see trials in the future using hundreds of milligrams of bevacizumab per kg of body weight? The original phase I studies actually found that a dose of 3 mg/kg dramatically reduced serum-free vascular endothelial growth factor levels and could be safely combined with chemotherapy.^22,25 The recent phase III study by the Eastern Cooperative Oncology Group looking at oxaliplatin, leucovorin (LV), and fluorouracil (FU) regimen (FOLFOX4) with bevacizumab compared with FOLFOX4 alone or bevacizumab alone looked at overall survival as well as progression-free survival, response, and toxicity.²⁶ The dose chosen for bevacizumab was 10 mg/per kg every 2 weeks, a very expensive treatment. The authors stated that this dose was chosen because of studies showing that a dose of 10 mg/kg is active when combined with chemotherapy. However, the small studies they quote to support this dose looked at treatment in non–small-cell lung cancer (NSCLC) and renal cell cancer and, in fact, showed no statistically significant difference in time to progression or overall survival between 7.5 mg/kg and 15 mg/kg in the NSCLC studies^27,28 or between 3 mg/kg and 10 mg/kg in the renal cancer study.²⁹ In fact, a similar-sized and much more relevant study that they mentioned in their discussion compared 5 mg/kg every 2 weeks with 10 mg/kg every 2 weeks of bevacizumab combined with FU and LV compared with FU and LV alone in a three-arm study treating metastatic colorectal cancer.³⁰ This study showed no statistically significant benefit for the higher dose of bevacizumab, and in fact, the conclusion of this study was that the trial supported further study of bevacizumab 5 mg/kg combined with chemotherapy as first-line therapy for metastatic colorectal cancer.

The dose of rituximab of 375 mg/m² was based on a tiny phase I study of 20 patients, only 18 of whom were assessable.¹⁹ Patients received four courses of rituximab at weekly intervals using doses of 125 mg/m² body surface area (BSA), 250 mg/m2 BSA and 375 mg/m² BSA. The incidence and severity of adverse events were minimal and equal in the three groups as were response rates. The study, which was partly sponsored by the pharmaceutical company producing rituximab, concluded that 375 mg/m² given weekly for 4 weeks would be the dose used in phase II studies. The results of this study provide no firm foundation for this decision, and it is quite possible that the lowest effective dose of rituximab may be 125 mg/m² BSA or significantly less than that.

It is perhaps relevant to note that many of the authors in the above-quoted studies declared significant potential conflicts of interest, and many of the studies were sponsored by the manufacturer of the therapy or therapies being tested.

It is very important in these days of evidence-based medicine that we, the oncology community, do not relinquish control of the design, conduct, and reporting of clinical trials, which is the evidence gathering. The first 40 years of medical oncology as a specialty has repeatedly tested the hypothesis that greater and greater doses of chemotherapy will produce more cures or longer survival. This has rarely turned out to be the case. In this emerging era of targeted therapies, I urge that we make the search for minimum effective doses of these treatments one of the key goals of our research. This will help to retain public trust in clinical oncology research, provide leadership within the medical community generally, and perhaps attract more patients into clinical trials.

Over the next 40 years, we must strive to convince our government-funded research organizations or the sponsoring pharmaceutical companies with whom we work, to make the goal of finding minimum effective treatment doses, rather than maximum tolerated treatment doses, one of our primary aims. Otherwise, I fear that the most effective health care in the future will only be available to the wealthy.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Ensuring the public trust: JCO adopts clinical trials registration policy. ASCO News & Forum, April 2007, p 44

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19. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:3266-3274, 1997[Abstract]

20. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxel or vinorelbine with or without transtuzumab for breast cancer. N Engl J Med 354:809-820, 2006[Abstract/Free Full Text]

21. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Transtuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005[Abstract/Free Full Text]

22. Margolin K, Gordon MS, Holmgren E, et al: Phase IB trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: Pharmacologic and long-term safety data. J Clin Oncol 19:851-856, 2001[Abstract/Free Full Text]

23. Swindler A, Grey R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 355:2542-2550, 2006[Abstract/Free Full Text]

24. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomised phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 22:2184-2191, 2004[Abstract/Free Full Text]

25. Gordon MS, Margolin K, Talpaz G, et al: Phase I safety and pharmacokinetic study of recombinant human antivascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843-850, 2001[Abstract/Free Full Text]

26. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combinaqtion with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007[Abstract/Free Full Text]

27. Kabbinavar FF, Johnson D, Langmuir VK: Patterns of tumor progression during therapy with bevacizumab (BV) and chemotherapy (CT) for metastatic colorectal cancer (MCRC) and advanced non–small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20:277a, 2001 (abstr 1105)

28. Johnson DH, DeVore F, Kabbinavar F et al: Carboplatin (C) + paclitaxel (T) + RhuMab-VEGF (AVF) may prolong survival in advanced nonsquamous lung cancer. Proc Am Soc Clin Oncol 20:315a, 2001 (abstr 1256)

29. Yang JC, Haworth L, Sherry RM, et al: A randomised trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003[Abstract/Free Full Text]

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