War on cancer

On July 27, 2006, the European Union (EU) followed America's lead and gave conditional approve to Pfizer's new drug Sutent (sunitinib, formerly known as SU11248) as a treatment for advanced kidney cancer. The drug is also being used as a treatment for a rare type of cancer known as gastrointestinal stromal tumor (GIST). But how effective is it? Sutent is one of the latest crop of "targeted" therapies for various kinds of cancer. It is given as a 50 milligram (mg) pill once per day and contains small-molecule inhibitors of the tyrosine kinase portion of the VEGF and PDGF receptors. According to a June 2006 report from Memorial Sloan-Kettering Cancer Center (MSKCC), New York, 106 patients with advanced kidney cancer were treated there with Sutent. The objective partial response rate was 34%, while the median progression-free survival time was 8.3 months (ranging from 7.8 to 14.5 months). The most common adverse effects were fatigue (28%) and diarrhea (20%). Laboratory abnormalities seen in patients included neutropenia (white blood cell depletion) in 42% of patients, an elevation of the enzyme lipase (28%), and anemia (26%). The authors of this report call these findings proof of the "efficacy and manageable adverse-event profile" of Sutent in the treatment of advanced kidney cancer (Motzer 2006). However, the astute reader will notice that there is no mention of overall survival in the above report. Survival was in fact dropped even as a measurable endpoint for the study. Tbis is in line with US Food and Drug Administration (FDA) officials' increasingly frequent policy of approving drugs based on what are called "surrogate" (i.e.. substitute, or stand-in) endpoints, sucb as objective partial responses or progression-free survival, which do not equate to. or reflect, an improvement in overall survival. (An objective partial response is generally defined as the sbrinkage of measurable tumors by more than 50% for a period of one month or more. But simply because a patient's tumors have temporarily shrunk does not mean that the patient will live longer.) Since the MSKCC study of Sutent was a phase 11 non-randomized study, with no concurrent comparison group, it is not valid to draw the conclusion that these patients did better tban those who might have received an alternate treatment or no further treatment at all. At tbe 2006 meeting of the American Society for Clinical Oncology (ASCO), there was an additional report on a phase III trial comparing Sutent to a more traditional therapy, interferon-alpha, in previously untreated (socalled "treatment-naive") patients with metastatic renal cell carcinoma (RCC). Untreated patients who bad ciearcell, metastatic renal cell cancers received either Sutent or interferon-alpba. Sutent was given in six-week cycles of 50 mg orally once per day for four weeks, followed by two weeks off. The interferon-alpha patients received subcutaneous injections of nine million units (MU) given tbree times per week. Between August 2004 and October 2005, 750 patients were randomized to one or other of these two groups. The median progression-free-survival (PFS) was 47.3 weeks for Sutent vs. 24.9 weeks for interferon-alpba. (Progression-free survival is a term tbat describes tbe lengtb of tbe interval during which tbe disease is stabilized before it begins to advance again.) The respective objective response rates were 24.8% for Sutent vs. 8.8% for interferon-aipha i.e., 24.8% of the patients who were given Sutent exhibited a temporary sbrinkageof their tumors, whiletumor shrinkage was seen in only 8.8% of patients given interferon-alpha. At the time of the report, in June 2006, there had been 49 deaths out of 375 patients in tbe Sutent group vs. 65 deaths in the equally large interferon-alpha group. Overall survival was included as one of tbe primary endpoints in tbis study. However, when it came time to evaluate the study, tbe authors provided only figures on progressionfree survival and, curiously, none on overall survival. Since tbe survival trend did seem to favor Sutent, it is possible tbat some future evaluation may indeed demonstrate such an effect. New drugs to treat intractable forms of cancer, such as metastatic renal cell carcinoma, are always welcome. But what concerns me is that, once again, the FDA has approved a new drug without demanding any proof tbat it actually enbances tbe clinical outcome for patients. According to an astonisbingly candid admission on the FDA's own website, "At this time, it is not known whether Sutent will improve symptoms or help patients with tbis disease live longer." Yet, defying logic, tbe agency went ahead and approved it anyway. Tbe FDA website also provides a somewhat more complete picture of Sutent's possible adverse effects than tbe descriptions that appear in some of the rather sketchy meeting abstracts. Potential side effects include the following: