Review on Tumour Doubling Time (DT) Objective To review the studies that measuring the actual tumour doubling time for human cancers. Methods We searched the Medline database from January 1966 to January 2006 with the key words or Medical Subject Headings (MeSH) neoplasms, doubling time, growth rate, volume increase or Td. All the studies were limited to human cancers and English literature. We also performed a manual search of reference cited in the original articles and the reviews. Results We identified 128 relevant studies in the literature. Their characteristics are described in Table 1. Figure 1 shows that there are systematic differences in DT among different types of cancer (Kruskal-Wallis one way analysis of variance: Chi-square=172.5, p<0.0001. Two-sample Wilcoxon test is presented in Table 2) as well as wide dispersion of DTs within individual types of cancer. Figure 2 illustrates the distributions of DTs of breast cancer, lung cancer and head and neck cancer. The distribution of breast and head and neck cancer are approximately lognormal. For head and neck cancer, the distribution of DT is even broader. Figure 3 shows that in the selected sites where the necessary information was available, recurrent and metastatic cancers generally grow more rapidly than primary cancers. Conclusion Overall, the tumour doubling time is highly heterogeneous within as well as among different types of cancer. This finding precludes the development of disease-specific benchmarks for waiting time.
Table 1. Characteristics of studies describing the tumour doubling time Category No. of studies(%) Sample size N=128 Primary site Breast 11(8.59%) 1043 Prostate (PSA DT) 21(16.4%) 3335 Head neck 23(17.9%) 637 Lung 22(17.2%) 1041 Hepatic 12(9.4%) 312 Colorectal 9(7.0%) 234 Pancreatic 3(2.34%) 85 Renal 2(1.56%) 73 Gastric 3(2.34%) 33 Sarcoma 4(3.13%) 446 Others 18(14.06%) 832 Year 1966-1970 2(1.56%) 117 1971-1975 11(8.59%) 664 1976-1980 10(7.81%) 380 1981-1985 20(15.6%) 667 1986-1990 11(8.59%) 581 1991-1995 21(16.4%) 1091 1996-2000 24(18.75%) 950 2001-2006 29(22.65%) 3178 Sample size 1-10 17(13.3%) 94 11-50 76(59.3%) 1924 51-100 14(10.9%) 1061 >100 21(16.4%) 4714 Measure methods Tumor marker 26(20.3%) 3484 Plain X-ray 45(35.1%) 2737 CT scan or MRI 52(40.6%) 1241 Clinical or Pathological 5(3.9%) 331 Report 3 - Appendix 2
Table 2. Two Sample Wilcoxon Test of Distribution of Tumour Doubling Time site1 site2 Two-sample Wilcoxon Statistic P-value, Wilcoxon Test (Twosided) Report 3 - Appendix 2 Significance breast gastric 3011 0.01 + breast head/neck 2415 0.00 + breast hepatic 11703 0.00 + breast lung 63483 0.00 + breast pancreas 3990 0.00 + gastric colorectal 1136 0.72 - head/neck colorectal 1992 0.00 + hepatic colorectal 3742 0.01 + lung colorectal 6864 0.69 - pancreas colorectal 3147 0.00 + gastric head/neck 1429 0.00 + gastric pancreas 2226 0.00 + gastric hepatic 2662 0.14 - gastric lung 5083 0.84 - head/neck hepatic 2274 0.00 + head/neck lung 3945 0.00 + head/neck pancreas 2164 0.56 - lung hepatic 19251 0.00 + pancreas hepatic 4720 0.00 + lung pancreas 6668 0.00 +
35 30 24 18 13 8 6 Prostate Gastric Breast Colorectal Lung Hepatic Head/Neck Pancreas Fig.1. Tumour Doubling Time by Primary Cancer Site Figure 1 describes all the studies we identified in literature about the tumour doubling time. If the original studies provided the tumour doubling time of each case, they were combined and plotted (Black dots). The red strip is the median tumour doubling time of all the cases in each group; if the median and number of cases were provided, they were indicated by bubble, and the size of bubble was corresponding to the number of cases (Blue bubble); if the mean was provided, they were also plotted by using bubbles (Green bubble). The raw information about DT for prostate cancer is scarce so that the median DT was not plotted.
Fig.2. Distribution of Tumour Doubling Time Figure 2 illustrates the distribution of tumour doubling time on a log scale. The red curve is the normal density curve.
38 prostate Fig.3 Tumour Doubling Time for each cancer site 24 colorectal 9 8
8 1 headneck 8 30 breast 14
18 lung 13 11 hepatic 6
6 pancreas