For personal use. Only reproduce with permission from The Lancet publishing Group. recovery found that it did not identify those with significant CAD. This concern is reinforced by the use of overall mortality as an endpoint in these studies, despite its definite methodological advantages, 11 since there is no reason to believe that revascularisation will improve non- cardiovascular mortality. Finally, there are unresolved pathophysiological issues. The relation of abnormal heart- rate recovery to an abnormal heart-rate response to exercise, commonly termed chronotropic incompetence, and to -blocker therapy, is not yet fully defined. In one study, abnormal heart-rate recovery tended to be more powerful in the absence of chronotropic incompetence. Desai and colleagues 12 have suggested that most of the abnormality in heart-rate recovery is related to chronotropic incompetence, and that different criteria for abnormality are appropriate in patients taking -blockers. The impact of -blocker use has been variable. Thus, abnormal heart-rate recovery after exercise has great promise; it may ultimately add to the understanding of the proper interpretation of the exercise ECG, clarify the role of the parasympathetic nervous system in response to exercise, and assist in the prediction of outcomes (ie, risk stratification) of patients with CAD. However, unlike evidence for the Duke score, that for abnormal heart-rate recovery does not yet support its widespread application in the interpretation of the treadmill-exercise test for risk stratification of symptomatic patients with known or suspected CAD. Raymond J Gibbons Division of Cardiovascular Diseases and Internal Medicine, Mayo Foundation, Rochester, MN 55905, USA (e-mail: gibbons.raymond@mayo.edu) 1 Cole CR, Blackstone EH, Pashkow F, Snader CE, Lauer MS. Heart- rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999; 341: 1351–57. 2 Nishime EO, Cole CR, Blackstone EH, Pashkow FJ, Lauer MS. Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG. JAMA 2000; 284: 1392–98. 3 Cole CR, Foody JM, Blackstone EH, Lauer MS. Heart rate recovery after submaximal exercise testing as a predictor of mortality in a cardiovascularly healthy cohort. Ann Intern Med 2000; 132: 552–55. 4 Diaz LA, Brunken RC, Blackstone EH, Snader CE, Lauer MS. Independent contribution of myocardial perfusion defects to exercise capacity and heart rate recovery for prediction of all-cause mortality in patients with known or suspected coronary heart disease. J Am Coll Cardiol 2001; 37: 1558–64. 5 Watanabe J, Thamilarasan M, Blackstone EH, Thomas JD, Lauer MS. Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography. Circulation 2001; 104: 1911–16. 6 Shetler K, Marcus R, Froelicher VF, et al. Heart rate recovery: validation and methodologic issues. J Am Coll Cardiol 2001; 38: 1980–87. 7 Gibbons RJ, Balady GJ, Beasley JW, et al. ACC/AHA guidelines for exercise testing: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Exercise Testing). J Am Coll Cardiol 1997; 30: 260–315. 8 Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 1999; 33: 2092–97. 9 Krone RJ, Hardison RM, Chaitman BR, et al. Risk stratification after successful coronary revascularization: the lack of a role for routine exercise testing. J Am Coll Cardiol 2001; 38: 136–42. 10 Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994; 344: 563–70. 11 Lauer MS, Blackstone EH, Young JB, et al. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999; 34: 618–20. 12 Desai MY, de la Pena-Almaguer E, Mannting F. Abnormal heart rate recovery after exercise as a reflection of an abnormal chronotropic response. Am J Cardiol 2001; 87: 1164–69. THE LANCET • Vol 359 • May 4, 2002 • www.thelancet.com 1537 COMMENTARY Metastatic colorectal cancer: treatment challenges and quality of life See page 1555 Increasingly, researchers face situations in which patients may not benefit in terms of traditional endpoints, such as survival, but in terms of health- related quality of life (HRQOL). Some 20 years ago only a few reports mentioned HRQOL in patients with cancer. 1 However, over recent years, more and more studies report HRQOL as a key outcome. The worldwide incidence of colorectal cancer is estimated at 945 000 patients per year. Many of these patients present with metastases. The past decade has seen several extensive investigations into advanced colorectal cancer. However, most patients have limited improvement in long-term prognosis. Debate has surrounded the use of chemotherapy in patients with advanced disease. Recently a Collaborative Group systematic review 2 suggested that chemotherapy improves survival and HRQOL, albeit modestly. Regardless, for this population of patients, HRQOL is important, particularly when survival gains are low. In this issue of The Lancet, T S Maughan and colleagues report an impressive study in which survival, palliation, and HRQOL were compared in a multicentre randomised trial with three chemotherapy regimens. 905 patients with advanced colorectal cancer were randomised to receive one of: the de Gramont regimens, the Lokich regimens, or raltitrexed. The de Gramont regimen is folinic acid plus fluorouracil bolus and infusion; the Lokich regimen is a protracted infusion of fluorouracil. Although the investigators report greater toxicity and poorer HRQOL in the patients on raltitrexed, overall survival was similar in all three groups. For HRQOL, definitive results are often difficult to obtain. Researchers can be affected by methodological problems that are best avoided. 3–5 Fortunately, Maughan and colleagues avoided most of these by using two robust HRQOL tools: the EORTC QLQ-C30 and the HADS. Such usage gives confidence to the results. Although these are robust tools, they were supplemented by six trial-specific pretested questions. Some degree of caution is warranted here. There is no mention in the study about the psychometric validity and selection process of these six items. The use of items with limited psychometric properties is known to bias outcomes. 6 For all three treatment groups overall survival was about 10 months. In view of the nature of the design, whereby patients could be randomised to stop or continue chemotherapy after 12 weeks, HRQOL assessment was limited to a very short period. Although the results of this period are often critical to the interpretation of a trial, several influences or results from longer-term treatment effects would not be detected. For example, fatigue, which is an acute issue for many chemotherapy patients, frequently represents a significant long-term HRQOL issue. 7 Maughan and colleagues, by pooling scales and items to form single scores, attempt to simplify HRQOL results. For example, combining EORTC QLQ-C30 scales for fatigue, pain, insomnia, and appetite loss creates an overall symptom score. An overall toxicity score comprised EORTC QLQ-C30 scales for nausea and vomiting, dyspnoea, constipation, and diarrhoea with three trial-specific items on dry or sore mouth, problems with eating or drinking, and discomfort with