patients, the ACS will continue to promoteparticipation in these trials.”

LESS LETHAL SMOKING STILL A PIPE DREAM

The notion of tobacco harm reduction—that there may be a “safer” way to smoke—isone that holds great appeal for smokers unwill-ing or unable to kick the habit and for thetobacco companies that profit from it. But tworecent studies add weight to the argument thatquitting is still the only certain way to reducethe health risks of tobacco.

The first, published in BMJ (2004;328:72–80), compared lung cancer risk among smokersof high-tar, regular-tar, and reduced-tar ciga-rettes. Researchers from the Massachusetts In-stitute of Technology and the ACS found thatlow-tar and very low-tar cigarettes were no lessharmful than those with regular or medium-tarlevels.

“The data underscore that terms like ‘light’and ‘ultra light’ are misleading because theyimply less health risk but do not correspond toless hazardous cigarettes,” said coauthor Mi-chael J. Thun, MD, MS, Vice President ofEpidemiology and Surveillance Research atACS.

Nearly 1 million men and women (non-smokers, former cigarette smokers, and currentcigarette smokers) participating in the ACSCancer Prevention Study II were analyzed.The tar rating of the brand of cigarette smokedin 1982 was compared with mortality fromcancer of the lung, trachea, or bronchus overthe next six years. Cigarettes were categorizedas “very low tar” (0 to 7 mg tar per cigarette),“low tar” (8 to 14 mg tar per cigarette), “me-dium tar” (15 to 21 mg tar per cigarette), or“high tar” (22 mg or more per cigarette). Thestatistical analyses controlled for factors includ-ing age, race, education, marital status, diet,occupation (including asbestos exposure), andcardiovascular or respiratory comorbidities.

As expected, people who never smoked hadvirtually no risk of lung cancer. Those whosmoked high-tar brands (which typically areunfiltered) had the highest risk; compared withcurrent smokers of medium-tar cigarettes, theirhazard ratios were 1.44 for men and 1.64 forwomen.

But lung cancer risk among people whosmoked low-tar or very low-tar cigarettes wasindistinguishable from that of smokers ofmedium-tar brands. Hazard ratios were 1.17and 1.02 among men smoking very low-tar andlow-tar brands, respectively, and 0.98 and 0.95,respectively, among women. None of thesevalues were significantly different from the haz-ard ratio for smokers of medium-tar brands (setat 1.0 for this statistical analysis).

The way people smoke is the likeliest expla-nation for the findings, Thun said. The tar andnicotine content listed on cigarette labels isbased on measurements from a smoking ma-chine, but studies have shown “there’s a verypoor correlation between machine-measuredyield and what people are actually taking in,”he explained.

People who smoke reduced-tar cigarettesdon’t necessarily lower the amount of chemi-cals they inhale because they tend to inhaledeeper, hold the smoke longer, and puff moreoften than smokers of regular-tar brands. Theyalso tend to smoke more and may, inadver-tently or not, cover ventilation holes in thecigarette filter that are designed to dilute thesmoke with air.

Compensation in smoking behavior is alsothe most likely explanation for the findings of asecond study examining the effect of smokingfewer cigarettes on the level of carcinogens inthe body. Researchers from the University ofMinnesota Cancer Center TransdisciplinaryTobacco Use Research Center reported in theJournal of the National Cancer Institute (2004;96:107–115) that smoking fewer cigarettes did notresult in a proportional reduction in metabo-

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lites of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

“The reduction was just not as great as youwould have expected based on how much �thestudy participants� had cut back,” said lead re-searcher Stephen Hecht, PhD.

Hecht and colleagues enrolled more than150 people who smoked, on average, 23.7cigarettes a day. The study involved gradualcigarette reduction using nicotine replacementtherapy and brief counseling sessions. At eachstage of the program, urinary levels of theNNK metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and NNALglucuronides (NNAL-Gluc) were measured.The reductions in these biomarkers did notkeep pace with the reductions in cigarettes.

Cutting cigarette consumption by 53% ledto a reduction of only 29% in NNAL andNNAL-Gluc. Cutting cigarettes by 75% causedonly a 37% drop in the chemicals. Even peoplewho cut back to just 2.6 cigarettes a day, areduction of 90%, lowered their levels ofNNAL and NNAL-Gluc by only 46%.

Although these reductions in carcinogenswere statistically significant, for most smokersthe effect was modest and transient, Hecht said.As the study went on, NNAL and NNAL-Gluc increased again in many participants, eventhough they were still smoking fewer ciga-rettes. Compensatory smoking is probably thereason.

Thun and Hecht said their findings supportthe notion that giving up cigarettes entirely isthe best bet for reducing the health risks causedby tobacco. In the first study, quitting reducedlung cancer risk substantially; people who gaveup smoking before age 35 had almost the samelung cancer risk as nonsmokers, but even thosewho quit after age 55 saw a substantial reduc-tion. Hecht has done previous research show-ing that levels of NNAL and NNAL-Glucgradually decrease and eventually become un-detectable in people who quit smoking.

Moreover, no product or strategy designedto reduce the harm from smoking has yet beenshown to work, Hecht said

“I still think cessation is the way to go,clearly,” he said. “We don’t have conclusiveevidence that anything else works.”

VACCINE TRIALS SHOW ACTIVITY IN KIDNEY ANDLUNG CANCER

The recent successes of two therapeuticcancer vaccine trials have focused attention onthe recent progress and future potential of har-nessing the immune system’s power to fightcancer.

In a study published in the Journal of theNational Cancer Institute (2004;96:326–331),researchers from Baylor University MedicalCenter at Dallas and colleagues reported resultsof a Phase I/II multicenter trial involving 33patients with Stage II or IV nonsmall cell lungcancer. The vaccine caused complete responsesin three patients lasting six months, 18 months,and 22 months. In seven other patients, thedisease did not progress for a period rangingfrom five months to 28 months, while aneighth patient experienced a 30% reduction inthe size of the lung nodule.

The vaccine, called GVAX (Cell Genesys,Inc., San Francisco, CA), was made fromautologous tumor cells genetically modifiedto secrete human granulocyte-macrophagecolony-stimulating factor, a protein thatstimulates the lymphocytes to attack thecancer cells.

Lead researcher John Nemunaitis, MD, saidthis was the first time immune therapy alonehas been shown to be effective against meta-static nonsmall cell lung cancer. Nemunaitis,Director of the Mary Crowley Medical Re-search Center at Baylor and Director of the USOncology Phase I research program, called theresults promising for patients with this disease,which is frequently resistant to chemotherapy.

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