CORRESPONDENCE

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

Tomotaka Sobue, Tomio Nakayama

Affiliations of authors: T. Sobue, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan; T. Nakayama, Department of Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Japan.

Correspondence to: Tomotaka Sobue, M.D., M.P.H., Cancer Information and Epidemiology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104–0045, Japan (e-mail: tsobue{at}ncc.go.jp).

In a recent article, Marcus et al. (1) updated findings from the Mayo Lung Project, extending the follow-up period to 25 years. The authors demonstrated that, even after a long follow-up, there was no difference in lung cancer mortality between the intervention and usual-care arms, although survival for lung cancer diagnosed before 1983 was better in the intervention arm. The authors suggested that overdiagnosis is the most plausible interpretation for the excess of lung cancer incidence observed in the intervention arm. However, alternative explanations for this excess are possible.

One possible explanation for the excess incidence in the intervention arm is an allocation failure, that is, randomization at baseline failed to allocate future lung cancer incidence cases equally into the two arms. An allocation failure, but not overdiagnosis, may explain the results shown in Table 5 of Marcus et al. (1), where there is higher incidence but no survival benefit for patients in the intervention arm with adenocarcinomas diagnosed before 1983. Furthermore, Black editorialized (2) that incidence imbalance could be the result of misdiagnosed occult metastatic adenocarcinomas from other organs, such as primary lung cancers, implying that the number of overdiagnosed cases of lung adenocarcinoma would diminish. For example, suppose that 14 excess deaths due to lung adenocarcinoma were actually due to metastatic adenocarcinoma, then the number of primary lung adenocarcinomas would be 45 and 38 for the intervention and the usual-care arms, respectively, resulting in seven excess cases in incidence in the intervention arm. Although this assumption may be extreme because the number of nonlung cancer deaths was already more in the intervention arm than in the usual-care arm [57 versus 37 cases, respectively; Table 3 in Marcus et al. (1)], it may imply that the majority of incidence excess in the intervention arm came from squamous cell carcinoma: 17 cases of squamous cell carcinoma [Table 5 in Marcus et al. (1)] compared with seven cases of adenocarcinoma. Because more than 70% of squamous cell carcinoma was detected by chest x-ray in the Mayo Lung Project (3) and overdiagnosis due to sputum cytology was not observed in the Memorial Sloan-Kettering and the Johns Hopkins trials (4,5), the excess incidence of squamous cell carcinoma in the study by Marcus et al. (1) could be mainly due to detection by chest x-ray. This contradicts the radiologic findings in Japan that squamous cell carcinomas usually show more rapid growth (6), which means overdiagnosis is less likely than adenocarcinomas. Therefore, when divided into histologic type, overdiagnosis alone could not explain incidence imbalance between the two arms.

It is still unknown whether an excess of lung cancer incidence in the intervention arm continued until the end of the observation period in 1996 because Marcus et al. (1) did not observe lung cancer incidence after 1983. There is a possibility that lung cancer with a relatively long preclinical detectable phase not diagnosed in the usual-care arm before 1983 would offset the difference in lung cancer incidence between the two arms at the end of the observation period in 1996 suggesting that no overdiagnosis exists. Marcus et al. (1) claimed that the incidence excess in the usual-care arm after 1983 is improbable because better survival among participants diagnosed after 1983 in the usual-care arm is unlikely. However, if there turns out to be no excess lung cancer incidence after 1983 in the usual-care arm, implying that lung cancer with a relatively long preclinical detectable phase did not exist in the trial, then lung cancer would consist of two distinct diseases: one with a short preclinical detectable phase and the other with a long preclinical detectable phase and corresponding to the overdiagnosed cases in the intervention arm. Again, these two distinct distributions contradict radiologic and pathologic findings that indicate that lung cancer is distributed in a continuous spectrum from aggressive to indolent characteristics in terms of tumor doubling time and pathologic appearance (6,7).

If the above-stated radiologic and pathologic findings in Japan can be applied to patients in the United States, then the lung cancer incidence imbalance that is observed in the Mayo Lung Project cannot be explained by overdiagnosis alone but may be due to a combination of multiple factors, including, but not restricted to, allocation failure, short observation period, underdiagnosis in the usual-care arm, and overdiagnosis in the intervention arm.

Currently, a disease-specific mortality rate is used as the primary endpoint in randomized controlled trials for evaluating cancer screening. Although there may be no alternatives, the disease-specific mortality rate tends to be affected by the intervention itself and, therefore, needs careful interpretation. It is inappropriate to overinterpret the findings from a single study.

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 Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR, et al. Screening for lung cancer. A critique of the Mayo Lung Project. Cancer 1991;67(4 Suppl):1155–64.[Medline]

4 Melamed MR, Flehinger BJ. Detection of lung cancer: highlights of the Memorial Sloan-Kettering Study in New York City. Schweiz Med Wochenschr 1987;117:1457–63.[Medline]

5 Tockman MS. Survival and mortality from lung cancer in a screened population: The Johns Hopkins Study. Chest 1986;89(suppl):324–5.[Medline]

6 Arai T, Kuroishi T, Saito Y, Kurita Y, Naruke T, Kaneko M. Tumor doubling time and prognosis in lung cancer patients: evaluation from chest films and clinical follow-up study. Japanese Lung Cancer Screening Research Group. Jpn J Clin Oncol 1994;24:199–204.[Abstract]

7 Noguchi M, Morikawa A, Kawasaki M, Matsuno Y, Yamada T, Hirohashi S, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 1995;75:2844–52.[Medline]


This article has been cited by other articles in HighWire Press-hosted journals:


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