| Researchers in the field of immunotherapy have | | | | Clinical trials in cancer patients are evaluated by |
| increasingly held out hope for therapeutic vaccines. | | | | criteria determined by either the World Health |
| However, a position paper published in the European | | | | Organization or RECIST (Response Evaluation Criteria |
| Journal of Cancer, May 2009,(1) questioned the | | | | in Solid Tumors) which define objective response |
| validity of vaccine trials and called for a critical | | | | rates as 30% to 50% decrease in lesions with no |
| appraisal of how the outcomes are determined and | | | | appearance of new lesions. "Mixed responses" in |
| understood. | | | | which some tumors decrease while others increase |
| Therapeutic vaccines, unlike prophylactic vaccines, are | | | | do not qualify as objective responses in either set of |
| designed to be administered after the onset of | | | | standard criteria. An example of deviating from the |
| disease so as to trigger an immune system response. | | | | standard criteria was seen in a study by Spanknebal |
| This emerging type of biological therapy is still mostly | | | | et al, which reported "10 objective responses in 46 |
| experimental, thus the vaccines are only available to | | | | evaluable patients after one course of IL-2 therapy." |
| patients enrolled in clinical studies. | | | | However, five of those were mixed responders |
| Steven Rosenburg, M.D., Surgery Chief at the | | | | meaning the true objective response rate was not |
| National Cancer Institute (NCI) in Bethesda, Maryland, | | | | 22%, but rather, 11%.(4) |
| argues that optimism about the clinical application of | | | | A classic case of misleading surrogate endpoints |
| therapeutic vaccines is unjustified. His research team | | | | occurred when studying the effect of ventricular |
| noted that cancer vaccine trials in 440 patients, | | | | arrhythmia after myocardial infarction. Arrhythmias |
| conducted at NCI Surgery Branch, had an overall | | | | are a known risk factor for sudden cardiac death and |
| objective response rate of only 2.6%. Much lower | | | | the drugs, encainide and flecainide are quite effective |
| than the 4.0% response rate reported in the 40 | | | | in suppressing them. Consequently, almost half a |
| studies that involved 756 patients. The team | | | | million patients in the US started receiving those |
| concluded that the more favorable study results | | | | drugs for that purpose. Researchers convinced |
| were based on surrogate end points rather than on | | | | cardiologists that it would be unethical to withhold |
| proof of anti-tumor effects.(2) | | | | these drugs from patients in the clinical study. |
| A surrogate endpoint is a "marker" – or measure | | | | Fortunately, a controlled study of encainide and |
| of effect of a particular treatment that may or may | | | | flecainide took place. Amazingly, the results showed |
| not correlate with a definitive endpoint that will | | | | that while both drugs suppressed arrhythmias |
| validate the study. Oftentimes, the primary endpoint | | | | effectively, the actual death rate tripled! Yes, the |
| of a study is an undesirable outcome – a full | | | | drugs had a positive effect on arrhythmias, but they |
| manifestation of disease or even death. So the | | | | also had an unintended and previously unrecognized |
| research team will zero in on "markers" that can | | | | adverse effect on overall survival.(5) Surrogate |
| serve as an alternative to test the benefit of a | | | | endpoints do have a place in clinical study but it |
| particular treatment. | | | | appears they should be used where they perform |
| The problem arises when the surrogate endpoint | | | | best – in preliminary screening and phase 2 trials. |
| "correlates" with the actual endpoint but doesn't have | | | | Definitive phase 3 trials should provide reliable |
| a guaranteed relationship. For instance, tumor | | | | evidence based on true objective clinical response. |
| response is frequently used as a surrogate end point | | | | Sources: |
| in therapeutic trials of cancer. The categories are: | | | | 1. Eggermont, AMM, "Therapeutic vaccines in solid |
| "complete response" (tumor not visible on | | | | tumours: Can they be harmful?", Eur J Cancer. 2009 |
| examination), "partial response" (a reduction in tumor | | | | May 22 |
| volume of 50% or more), and "no change of | | | | 2. Eggermont, AMM, "Therapeutic vaccines in solid |
| progression." Unfortunately, the measure of tumor | | | | tumours: Can they be harmful?", Eur J Cancer. 2009 |
| response is NOT a determinate of overall survival. | | | | May 22 |
| Which means that tumor response "correlates" to the | | | | 3. Moertel CG. "Improving the efficiency of clinical |
| subject at hand but has no real effect on mortality | | | | trials: a medical perspective", Stat Med. 1984; 3:455-68 |
| rates.(3) | | | | 4. Rosenberg SA, Yang JC, Restifo NP. "Cancer |
| The fact is, early-stage clinical trials usually involve | | | | immunotherapy: moving beyond current vaccines", |
| only a small number of patients, for which the results | | | | Nat Med 2004; 10:909–15 |
| are not always sustained in larger trials. Rarely is the | | | | 5. Fleming, Thomas R, "Surrogate Endpoints And |
| validity of a surrogate endpoint rigorously established | | | | FDA's Accelerated Approval Process", Health Affairs, |
| even though deviation from standard accepted | | | | 24, no. |
| criteria leads to considerable confusion. | | | | |