BERKELEY, CA (UroToday.com) - In a screening program, interval cancers are cancers which are diagnosed between two screening visits.
Therefore, interval cancers are either cancers that have developed after the previous screen, or cancers that were “missed” at the last screen.
The number of interval cancers and their impact on disease-specific survival is important to assess the efficacy of a screening program. If the disease-specific survival of men with interval cancer is superior to men with clinically detected cancer or similar to that of screen-detected cancers, it may indicate effectiveness of the applied screening algorithm. Adapting the screening algorithm towards a more aggressive strategy would probably not improve the screening effect. Instead, relatively more indolent cancers will be detected, especially in the setting of screening for cancers with a long preclinical detectable phase such as prostate cancer.
In contrast, if the disease-specific survival is similar or worse among interval cancers as compared to clinically detected cancers, the detection of interval cancers could be interpreted as a failure of screening. Furthermore, if interval cancers significantly contribute to disease-specific mortality, it will diminish the observed reduction of the disease-specific mortality in the screened population.
In prostate cancer screening literature, interval cancers are rarely mentioned and survival outcomes have not been reported previously. Therefore, within the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam, we evaluated the disease-specific survival of men with prostate cancer diagnosed during an interval, and compared it to that of men diagnosed with cancer in the control arm, which are clinically detected by definition. The results could have an impact on the interpretation of outcome data of the ongoing screening trials and development of future screening strategies.
The ERSPC is a multicenter, randomized, two-arm trial designed to evaluate the effect of screening on prostate cancer specific mortality. In the Rotterdam section, a total of 42,376 men identified from population registries (55-74 years of age) were randomized into a screening or control arm.
In the screening arm, men with PSA ≥3.0 ng/ml were recommended to undergo lateralized sextant prostate biopsy. The screening interval was 4 years. In the control arm, all men received standard medical care, which meant that the evaluation of symptoms, the diagnosis of prostate cancer, and subsequent treatment was provided by general practitioners and local urologists in line with clinical practice guidelines.
Interval cancers were defined as cases diagnosed in men who had a PSA test at the last screening round, either before the next scheduled screening round, or within a time period equal to the screening interval of 4 years for men who have reached the upper age limit for screening. Cancers were identified through linkage with the regional cancer registry. An independent cause-of-death committee determined the causes of death of men with prostate cancer who have died.
In this study, men with interval cancers were compared to men with prostate cancer in the control arm. The primary endpoint was disease-specific mortality; the secondary endpoint was overall mortality.
The median follow-up measured from randomization was 11.1 year. In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, 1,149 men were diagnosed of whom 128 died from prostate cancer. When comparing the two groups, there seems to be a trend of lower disease-specific mortality in men with interval cancer, compared to men with cancer in the control arm (hazard ratio=0.55; 95% CI 0.27-1.12; p=0.10). However, after controlling for age, prognostic factors, and treatment modality, no statistically significant difference in disease-specific mortality (hazard ratio=1.12; 95% CI 0.53-2.36; p=0.77) and overall mortality (hazard ratio=0.98; 95% CI 0.68-1.38; p=0.90) was found.
Our findings show that men with interval cancers have a similar disease-specific survival as compared to men with cancers diagnosed in the control arm. This could indicate that the detection of interval cancers in ERSPC Rotterdam could be regarded as a failure of the current screening algorithm.
Recently it has been shown that a third of the total prostate cancer deaths within the screening arm of ERSPC Rotterdam with 11 years of follow-up were men with interval cancer. Therefore, more benefit in disease-specific survival in the screening arm may be obtained by reducing the number of interval cancers.
The prognosis and outcome of interval cancers are likely to be strongly dependent on the sequential screening intervals. Cancers developing as interval cases missed at the prevalence screen may have a different disease-specific survival than those missed after subsequent screens. Therefore, a limitation of the study may be the follow-up, which is still too short to visualize the effect of repeat screening in the setting of ERSPC Rotterdam.
In conclusion, the disease-specific survival of men with interval cancer seems to be similar to that of men with prostate cancer in the control arm in the setting of population-based prostate cancer screening at 4-year intervals. To further improve the disease-specific survival in the screening arm of the ERSPC, one could attempt to reduce the occurrence of (potentially aggressive) interval cancers, provided that these cases significantly contribute to prostate cancer specific mortality. The balance between overdiagnosis and further mortality reduction should obviously be preserved.
Written by:
Xiaoye Zhu*, Pim J. van Leeuwen, Meelan Bul, Suzie J. Otto, Harry J. de Koning, Chris H. Bangma, Fritz H. Schröder, and Monique J. Roobol as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Urology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
*Corresponding author:
Xiaoye Zhu, MD
Department of Urology
Erasmus MC, University Medical Center Rotterdam
Room NH-227
P.O. Box 2040
3000 CA Rotterdam
The Netherlands
Tel. +31 10 703 2242
Fax. +31 10 703 5315
UroToday.com Prostate Cancer Section