CORRESPONDENCE

Re: Lung Cancer Mortality in the Mayo Lung Project: Impact of Extended Follow-up

Rajendra A. Badwe

Correspondence to: Rajendra A. Badwe, M.D., Department of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, India 400012 (e-mail: tmhcrs{at}vsnl.com)

The Mayo Lung Project article by Marcus et al. (1) and the accompanying editorial by Black (2) made a valiant effort to underplay the statistically insignificant 13% excess mortality (P = .09) in the screened arm. It is shocking that this excess mortality in the screened arm has been interpreted as "No lung cancer mortality benefit evident at the end of the study" (1). A 13% reduction in mortality in the screened arm would have been interpreted as a benefit of intervention that did not reach statistical significance. However, calling the 13% excess mortality no benefit is a tribute that statistical honesty pays to the oncologic optimism of saving lives by screening. Excess deaths in the screened arm in the study by Marcus et al. (1) appear to be increasing with time according to the mortality curve of lung cancer deaths from follow-up years 5–20 [Fig. 1 of Marcus et al. (1)]. Similarly, a Czechoslovakian lung cancer screening study compared chest x-ray with the control arm and also found excess mortality in the screened arm (3). Two other randomized lung cancer screening trials (4), the Johns Hopkins and Memorial-Sloan Kettering studies, have not yet published annual cumulative mortality.

The accompanying editorial by Black goes overboard blaming overdiagnosis for the coexistence of survival benefit and excess mortality in the screened arm. It is most inappropriate to discuss survival in a randomized screening trial because the primary purpose of a randomized screening trial is to overcome the lead time bias. Ignoring the mistake, an important interpretation of the coexistence of survival benefit and excess mortality has been completely overlooked. Blaming overdiagnosis acknowledges that diagnosis itself can affect the natural history of disease, analogous to the impact observation has on the observed. The impact of diagnosis on natural history challenges the paradigm of biological predeterminism and makes way for a new paradigm, referred to as the surgical dissemination/autonomy paradigm. The new paradigm suggests that micrometastases are either disseminated at the time of surgery or that removal of the primary tumor bestows autonomy on pre-existing micrometastases. The surgical dissemination/autonomy paradigm would be ideally tested in a randomized trial comparing surgery with no surgery. However, such a trial would be unethical. Randomized screening trials offer the next best opportunity to test the surgical dissemination/autonomy paradigm. In screening trials for solid tumors, surgery is advanced in the screened arm compared with the control arm. The early years of follow-up after randomization should, therefore, offer an opportunity to compare immediate surgery (screened arm) with the natural progression of the disease for a few years (control arm). Because historically surgery as an event is thought to have little influence on the natural history of cancer, we would predict fewer, if not similar, deaths in the screened arm during the early years of follow-up. If, on the other hand, the surgical dissemination/autonomy paradigm was correct, there should be an excess of deaths in the screened arm during the early years of follow-up. Such excess mortality is indeed evident in the screening trials for lung (1,3), colon (5), and prostate (6) cancers. A meta-analysis of the breast cancer screening trials (7) demonstrated an early excess mortality in the screened arm for the first year of follow-up in women greater than 50 years of age, whereas in women less than 50 years of age, the excess mortality persisted for the first 7 years of follow-up. Thus, published data of screening trials suggests that early intervention apparently has a detrimental effect on the natural history of common solid tumors in the initial years of follow-up.

It would be ideal if a meta-analysis of the annual cumulative mortality by arm of randomization is performed for all lung cancer screening trials. This would allow early detrimental effect and late benefit, if any, to be determined with an adequate sample size.

REFERENCES

1 Marcus PM, Bergstralh EJ, Fagerstrom RM, Williams DE, Fontana R, Taylor WF, et al. Lung cancer mortality in the Mayo Lung Project: impact of extended follow-up. J Natl Cancer Inst 2000;92:1308–16.[Abstract/Free Full Text]

2 Black WC. Overdiagnosis: an underrecognized cause of confusion and harm in Cancer screening [editorial]. J Natl Cancer Inst 2000;92:1280–2.[Free Full Text]

3 Kubik A, Parkin DM, Khlat M, Erban J, Polak J, Adamec M. Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial of a population of high risk males in Czechoslovakia. Int J Cancer 1990;45:26–33.[Medline]

4 Miller AB. Screening for lung cancer. Chest 1986;89(suppl):324S–6S.[Medline]

5 Mandel JS, Bond JH, Church TR, Snover DC, Bradley GM, Schuman LM, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993;328:1365–71.[Abstract/Free Full Text]

6 Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38:83–91.[Medline]

7 Elwood JM, Cox B, Richardson AK. The effectiveness of breast cancer screening by mammography in younger women. Online J Curr Clin Trials 1993; Doc 32.



             
Copyright © 2001 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement