This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharma, S. Search for Related Content PubMed PubMed Citation Articles by Sharma, S.

Phase I Trials May Not Need to Be Viewed As Extraordinarily Different From Other Clinical Research

Nevada Cancer Institute, Las Vegas, NV

To the Editor:

I read the article by Joffe and Miller¹ with interest. I thank the authors for attempting to present a balanced view regarding risk-benefit assessment for phase I trials. However, I would like to discuss several points within their article.

The overall rate of severe toxicity to patients is very low in phase I trials. In a recent retrospective review,² the overall toxic death rate for 213 studies (involving 6,474 cancer patients) published in peer-reviewed journals was 0.54%, while the overall objective response rate was 3.8%. Toxic death rates decreased over the study period, from 1.1% over the first 4 years of the study (1991 to 1994) to 0.06% over the most recent 4-year period (1999 to 2002; P .01). It is not clear what the reduction in toxic death rates was from, but it could be related to better monitoring of patients, patient selection, and the advent of targeted therapy. Response rates also decreased but by proportionally much less. The article excluded patients with hematologic malignancies who were on phase I trials and were likely to have higher response rates.² These numbers are consistent with another analysis published recently³ where authors analyzed 460 trials involving 11,935 participants, all of whom were assessed for toxicity and 10,402 of whom were assessed for a response to therapy. The overall response rate (ie, for both complete and partial responses) was 10.6%. The overall rate of death due to toxic events was 0.49%. It is then debatable, in my opinion to opine that phase I trials afford no chance of therapeutic benefit. Thus, it is not clear that the authors' assertions that "Critics charge that in view of their emphasis on toxicity and dose finding, they ‘have no therapeutic content’ and offer participants no reasonable prospect of benefit."¹ It appears that the literature mentioned by the authors is relevant to all clinical research and should be part of informed consent.

Although phase I trials may not offer the same level of benefits as US Food and Drug Administration approved agents, it is not clear if they offer any lesser benefit than alternatively utilized therapies that many patients receive. In other words, if patients are not treated on phase I trials, they are often treated on other US Food and Drug Administration nonapproved chemotherapies or offered palliative care. It is not clear that phase I trials are an inferior option to either.

In addition, we need to realize that most patients with metastatic disease are not cured by current therapies. Thus, one way to think about risk and benefit is to realize that (at the outset) our patients have to deal with imperfect and toxic therapies, even when such therapies are US Food and Drug Administration approved. For example, docetaxel improves the median survival in second-line non–small-cell carcinoma from 4.6 to 7.5 months, but also carries a 2.8% risk of treatment-related deaths.⁴ In essence, all oncology treatments need to be articulated in terms of toxicity versus benefit.

Overall, I am in agreement with the idea that oncologists should clearly articulate various options available at every stage of treatment for our patients. I also agree that we have an ethical duty to inform patients about the risks and potential lack of benefit from any therapy they receive (including phase I trials). However, I would opine that phase I trials need not be an area of special consideration for therapeutic versus toxicity concerns because these trials are relatively nontoxic and potentially beneficial to patients.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Joffe S, Miller FG: Rethinking risk-benefit assessment for phase I trials. J Clin Oncol 24:2987-2990, 2006[Free Full Text]

2. Roberts TG Jr, Goulart BH, Squitieri L, et al: Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA 292:2130-2140, 2004[Abstract/Free Full Text]

3. Kuzrock R, Benjamin RS: Risks and benefits of phase 1 oncology trials, revisited. N Engl J Med 352:930-932, 2005[Free Full Text]

4. US Food and Drug Administration: Docetaxel prescribing information. 2003

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sharma, S. Search for Related Content PubMed PubMed Citation Articles by Sharma, S.