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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Cancer survivors are at excess risk of developing second primary cancers, but the precise level of risk in Japanese patients is not known. To investigate the risk of survivors developing second primary cancers, we conducted a retrospective cohort study using data from the Osaka Cancer Registry. The study subjects comprised all reported patients aged 0–79 years who were first diagnosed with cancer between 1985 and 2004 in Osaka and who survived for at least 3 months, followed-up through to December 2005. A metachronous second primary cancer was defined as any invasive second cancer that was diagnosed between 3 months and 10 years after the first cancer diagnosis. The main outcome measures were incidence rates per 100 000 person-years, cumulative risk and standardized incidence ratios (SIR) of second primary cancer. Metachronous second primary cancers developed in 13 385 of 355 966 survivors (3.8%) after a median follow-up of 2.5 years. Sex-specific incidence rates of metachronous second primary cancer per 100 000 person-years increased with age, and were higher among men than women (except for the 0–49 years age group), but these rates did not differ over the study period. The 10-year cumulative risk was estimated as 13.0% for those who first developed cancer at 60–69 years of age (16.2% for men, 8.6% for women). The SIR among those with first cancer diagnosed at 0–39 and 40–49 years of age were 2.13 and 1.52, respectively, in both sexes, whereas the SIR among cancers of the mouth/pharynx, esophagus and larynx were much higher than one as for site relationships. We showed that cancer survivors in Osaka, Japan, were at higher risk of second primary cancers compared with the general population. Our findings indicate that second primary cancers should be considered as a commonly encountered major medical problem. Further investigations are required to advance our understanding to enable the development of effective measures against multiple primary cancers. (Cancer Sci 2012; 103: 1111–1120)

Approximately 50% of men and 40% of women will develop a cancer during their lifetime,[1] and half of all cancer patients in Japan will survive for at least 5 years.[2] Because of the longer survival times for several forms of cancer and the aging of the population, it is estimated that 5–10% of all cancer patients develop a further, independent primary cancer.[3, 4] A better understanding of multiple primary cancers should yield greater insights into the shared etiological factors and basic mechanisms of carcinogenesis and could thus provide a more sound basis for the management of cancer patients, including the development of protective measures.[5]

In a previous study using data from the Osaka Cancer Registry (2000 Census population; 8.8 million), one of the largest population-based cancer registries in the world, we reported that 2.0% of cancer patients developed metachronous second primary cancer between 1966 and 1986.[4] We also calculated the 10-year cumulative risk for metachronous second primaries to be approximately 10% for those who developed their first cancer at 60–69 years of age between 1978 and 1983.[4] However, investigations into trends or site combinations could not be completed owing to the short cancer registration period. In the present study, we updated the data for the incidence of metachronous second primary cancers in Osaka, Japan, according to sex, age groups, calendar year at diagnosis, primary cancer sites, and follow-up interval. This was done not only to provide an insight into the etiology of cancer, but also to provide information for effective medical care by clinical oncologists.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Study subjects and definition of metachronous second primary cancer

The present study was designed as a retrospective cohort study. Individual case records were obtained from the Osaka Cancer Registry, which was founded in 1962 for the purpose of registering all malignant tumors and benign intracranial tumors arising in Osaka Prefecture.[6] The study subjects were all reported patients aged 0–79 years in Osaka who were initially diagnosed as having a first primary cancer between 1985 and 2004 and had survived for at least 3 months. The incidence of second primary cancers among the study subjects was examined through to the end of 2005 for a maximum of 10 years after the first cancer diagnosis.

Metachronous second primary cancer was defined as any invasive second cancer that was diagnosed between 3 months and 10 years after diagnosis of the first cancer. In situ carcinomas, benign intracranial tumors, and any third or fourth (or more) primaries were excluded. Each cancer site was categorized into 16 selected major groups according to International Classification of Diseases Tenth Revision (ICD-10)[7], to analyze the cancer site relationships between first and second cancer. The ICD-10 codes used in the present study are given as mouth/pharynx (C00-14), esophagus (C15), stomach (C16), colorectum (C18-20), liver (C22), gallbladder (C23, C24), pancreas (C25), larynx (C32), lung (C33, C34), breast (female) (C50), uterus (C53-55), ovary (C56), prostate (C61), kidney/urinary tract/bladder (C64-68), thyroid (C73) and blood (C81-85, C88, C90, C91-96).

Statistical analysis

To estimate the risk for second primary cancer, person-years at risk were calculated as the time from 3 months after diagnosis of the first cancer until whichever of the following came first: (i) December 31, 2005; (ii) the date of diagnosis of the metachronous second primary cancer; (iii) the date of death; (iv) the date when a patient reached 80 years of age; or (v) the date 10 years after the diagnosis of the first cancer.[8]

The incidence rate per 100 000 person-years and cumulative risk[9] for metachronous second primary cancer were estimated according to sex, age group and calendar year at the time of diagnosis of the first cancer.

The observed number of metachronous second primary cancers was compared with the expected number according to sex, age group, selected site of the first and second cancer, and follow-up interval. A standardized incidence ratio (SIR) was then obtained by dividing the observed number of cases of a second primary cancer by the expected number. Thus, the SIR is used to estimate the risk of a cancer patient developing a second primary malignancy compared with the incidence of cancer among the general population. In the analyses for site relationship between the first and second cancer, we report only the cancer site combinations where more than 10 eligible metachronous second primary cancers were obtained. The significance and 95% confidence intervals (CI) for the SIR were tested by Poisson distribution analysis.

In Osaka, we used the rules suggested by the International Agency for Research on Cancer (IARC)[10] and the third edition of the ICD-O[11] to define the circumstance under which an individual is considered to have more than one cancer. The IARC's definition does not accept any tumors in the same site as a second primary cancer unless their major histological type differs from that of the first primary cancer. Therefore, the SIR for all sites will be underestimated, particularly in the case of first cancers with high person-years, such as cancer of the stomach, colorectum, liver, lung, and breast. To avoid such underestimations, we excluded both the observed and expected numbers of second primary cancer in the same site as the first cancer from the SIR calculations for all sites. Therefore, in the present study a second primary cancer of the same site (as defined by the three-digit rubric of the ICD with some exceptions according to the rules) was excluded even if its histological type differed from that of the first primary cancer when we used the variable of cancer site in the analyses.[8]

Probability values for statistical tests were two-tailed and P < 0.05 was considered significant. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

The total number of study subjects was 355 966, of whom 79.7% were histologically verified. During the follow-up period (median follow-up duration 2.5 years; mean 3.9 years), metachronous second primary cancers developed in 13 385 subjects (3.8%). Figure 1 shows age- and sex-specific incidence rates of metachronous second primary cancers per 100 000 person-years, in which study subjects were classified into four groups according to calendar year at diagnosis of the first cancer. The incidence rates increased remarkably with an increase in age and were higher among men than women, except in the 0–39 and 40–49 years age groups. In terms of calendar year at the time of diagnosis of the first cancer, age-specific incidence rates did not differ within either sex.

image

Figure 1. Age-specific incidence rates of metachronous second primary cancer per 100 000 person-years in (a) men and (b) women according to the calendar year at diagnosis of the first cancer, Osaka, 1985–2004.

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Table 1 shows the cumulative risks of metachronous second primary cancers according to age and calendar year at diagnosis of the first cancer. The 10-year cumulative risk was estimated as 13.0% for those who developed their first cancer at 60–69 years of age (16.2% for men, 8.6% for women). No difference or increasing trend was observed during the study period.

Table 1. Cumulative risk of metachronous second primary cancer (%), according to sex, age and calendar year at the time of diagnosis of the first cancer
Sex/age (years)DurationYear of diagnosis of first cancer
1985–19891990–19941995–19992000–2004Total
Male 
0–393 months–5 years0.40.91.00.90.8
3 months–10 years1.51.41.81.6
40–493 months–5 years2.22.02.12.32.1
3 months–10 years5.14.84.95.0
50–593 months–5 years4.94.14.64.54.5
3 months–10 years11.49.89.510.2
60–693 months–5 years7.27.37.97.57.5
3 months–10 years16.416.515.716.2
70–793 months–5 years9.210.110.810.210.2
3 months–10 years20.822.521.721.8
Female 
0–393 months–5 years0.70.60.90.80.7
3 months–10 years1.91.52.31.9
40–493 months–5 years1.51.91.91.61.7
3 months–10 years3.33.54.63.7
50–593 months–5 years2.72.72.82.62.7
3 months–10 years6.06.15.55.8
60–693 months–5 years4.03.94.33.94.1
3 months–10 years8.78.68.48.6
70–793 months–5 years4.94.75.65.55.2
3 months–10 years11.711.010.111.0
All patients 
0–393 months–5 years0.60.71.00.80.8
3 months–10 years1.71.52.11.8
40–493 months–5 years1.71.92.01.81.9
3 months–10 years3.94.04.74.2
50–593 months–5 years3.93.53.73.53.7
3 months–10 years8.88.17.58.1
60–693 months–5 years5.86.06.66.16.2
3 months–10 years12.813.312.913.0
70–793 months–5 years7.37.78.68.48.1
3 months–10 years16.417.216.817.0

Table 2 shows the SIR according to sex, age at diagnosis of the first cancer, and follow-up interval. The SIR and 95% CI among those (of both sexes) who developed their first cancer at 0–39 and 40–49 years of age were 2.54 (1.43–3.66) and 1.75 (1.41–2.10), respectively, for the first year; 2.34 (1.86–2.82) and 1.61 (1.46–1.77), respectively, for the next 4 years; 1.90 (1.51–2.29) and 1.39 (1.25–1.53), respectively, for the next 5–10-year period; and 2.13 (1.84–2.43) and 1.52 (1.42–1.62), respectively, for all 10 years after diagnosis of the first cancer. These ratios were higher than those in the total and other age groups. During the period 1–5 years after the diagnosis of the first cancer, 38% and 48% excess risk of metachronous second primary cancers was observed among men and women, respectively, who developed their first cancer at 50–59 years of age. Women aged 50–79 years had a tendency for a higher SIR of metachronous second primaries than men aged 50–79 years, whereas women aged 0–49 years had a tendency for a lower SIR than men aged 0–49 years.

Table 2. Observed numbers and standardized incidence ratios of metachronous second primary cancer according to sex, age at diagnosis of the first cancer and years after diagnosis of the first cancer, 1985–2004
Age at diagnosis of the first cancer (years)Years after diagnosis of the first cancer
3 months–1 year1–5 years5–10 years*Total (3 months–10 years)
No. second primary cancersPerson-yearsSIR95% CINo. second primary cancersPerson-yearsSIR95% CINo. second primary cancersPerson-yearsSIR95% CINo. second primary cancers Person-yearsSIR95% CI
  1. CI, confidence interval. *Because of the high proportion of censored data, the low reliability of the standardized incidence ratios (SIR) among the population aged 70–79 years for the period 5–10 years after diagnosis of the first cancer should be kept in mind.

Male patients
0–3995 7394.591.59–7.593420 7373.882.58–5.192716 9372.341.46–3.237043 4143.152.41–3.88
40–493710 5571.811.23–2.3917035 2741.891.61–2.1816427 4661.501.27–1.7337173 2981.691.52–1.86
50–5928231 3821.531.35–1.7092793 3551.381.29–1.4773159 0661.221.13–1.301940183 8051.331.27–1.39
60–6965547 6441.050.97–1.132279130 2111.191.14–1.23131166 6781.071.01–1.134245244 5351.131.09–1.16
70–7963832 1680.930.86–1.01158165 7291.101.05–1.1634612 5261.191.06–1.312565110 4231.071.03–1.11
Total (0–79)1621127 4901.071.02–1.124991345 3051.211.18–1.242579182 6731.151.11–1.209191655 4751.171.14–1.19
Female patients
0–39118 8111.860.76–2.975734 4551.891.40–2.386528 1151.761.33–2.1913371 3831.821.51–2.13
40–496416 9431.721.30–2.1524767 1771.471.28–1.6522455 0391.321.15–1.49535139 1621.431.30–1.55
50–5914425 0981.641.37–1.9050386 8581.481.35–1.6138959 4691.341.21–1.481036171 4271.451.36–1.53
60–6921127 9301.241.07–1.4179988 0501.351.25–1.4452454 1281.171.07–1.271534170 1101.271.20–1.33
70–7924021 7901.140.99–1.2856849 6131.161.06–1.2514811 7231.201.01–1.3995683 1271.161.08–1.23
Total (0–79)670100 5731.311.21–1.412174326 1531.341.28–1.41350208 4741.271.20–1.334194635 2091.311.27–1.35
All patients (both sexes)
0–392014 5502.541.43–3.669155 1922.341.86–2.829245 0521.901.51–2.29203114 7962.131.84–2.43
40–4910127 5001.751.41–2.10417102 4511.611.46–1.7738882 5051.391.25–1.53906212 4601.521.42–1.62
50–5942656 4801.561.41–1.711430180 2131.421.34–1.491120118 5351.261.18–1.332976355 2321.371.32–1.42
60–6986675 5751.091.02–1.163078218 2601.221.18–1.271835120 8051.101.05–1.155779414 6451.161.13–1.19
70–7987853 9580.980.92–1.052149115 3421.121.07–1.1649424 2491.191.09–1.303521193 5501.091.05–1.13
Total (0–79)2291228 0631.131.08–1.187165671 4591.251.22–1.283929391 1471.191.15–1.23133851 290 6841.211.19–1.23

Table 3 lists the SIR according to selected sites of the first cancer and the follow-up interval. There were no clear increasing or decreasing trends of SIR for any site of the first cancer for the duration of follow-up. The highest SIR (~2.0–2.5) were observed for cancers of the mouth/pharynx, esophagus, and larynx, followed by cancers of the lung, breast, uterus, ovary, thyroid, and blood (~1.4–1.7). The ratios for the remaining cancer sites were approximately 1.1–1.3 and usually > 1.0 regardless of the significance.

Table 3. Observed numbers and standardized incidence ratios of second primary cancer according to site of the first cancer and follow-up interval after diagnosis of the first cancer, 1985–2004, for both sexes combined
Site of the first cancerICD-10Follow-up interval after diagnosis of the first cancer
3 months–1 year1–5 years5–10 yearsTotal (3 months–10 years)
No. second primary cancersPerson-yearsSIR95% CINo. second primary cancersPerson-yearsSIR95% CINo. second primary cancersPerson-yearsSIR95% CINo. second primary cancersPerson-yearsSIR95% CI
  1. CI, confidence interval; SIR, standardized incidence ratios.

Mouth/pharynxC00–141075 5782.271.84–2.7036816 4392.662.39–2.931879 6212.261.93–2.5866231 6382.472.28–2.65
EsophagusC151095 4601.961.59–2.322059 5762.041.76–2.32863 5702.101.66–2.5540018 6062.031.83–2.23
StomachC1643247 5351.171.06–1.281522145 9801.331.26–1.39101396 0181.271.19–1.342967289 5361.281.24–1.33
ColorectumC18–2037636 1921.291.16–1.421301114 4951.361.29–1.4379366 3971.341.25–1.432470217 0851.341.29–1.39
LiverC2223922 8721.141.00–1.2961953 7311.191.10–1.2913813 6541.000.84–1.1799690 2581.151.08–1.22
GallbladderC23, C24343 6130.980.65–1.31816 2051.401.10–1.71342 7031.350.90–1.8114912 5221.271.06–1.47
PancreasC25363 8241.020.68–1.35453 7301.370.97–1.77131 3391.140.52–1.76948 8931.180.94–1.42
LarynxC32632 2692.321.75–2.902598 1582.522.22–2.831485 2202.031.70–2.3547015 6472.322.11–2.53
LungC33, C3428422 7051.321.16–1.4753339 0871.471.34–1.5916213 5711.241.05–1.4397975 3641.381.29–1.47
Breast (females)C5011525 2521.441.18–1.71509102 2821.491.36–1.6238370 0341.471.32–1.611007197 5711.481.38–1.57
UterusC53–55469 6061.250.89–1.6123236 0081.631.42–1.8420428 2031.661.43–1.8848273 8191.591.45–1.74
OvaryC56243 5921.781.07–2.506710 2121.811.38–2.24335 8401.541.01–2.0712419 6441.721.42–2.03
ProstateC61885 4361.030.82–1.2530215 8681.181.05–1.31954 7561.160.92–1.3948526 0611.151.04–1.25
Kidney/urinary tract/bladderC64–681289 8161.261.04–1.4849333 3301.421.30–1.5527220 3921.241.09–1.3989363 5391.341.25–1.43
ThyroidC73303 4321.811.16–2.469714 8931.361.09–1.638311 9531.431.12–1.7421030 2781.441.25–1.64
Blood

C81–85,

 C88, C90,

 C91–96

9310 1211.451.15–1.7425828 5281.561.37–1.7512615 6851.541.27–1.8047754 3341.531.39–1.67

Table 4 lists the SIR according to selected sites of the first and second primary cancers. Some specific associations were observed between the sites of the first and second primary cancers; specifically, the SIR for cancers of the mouth/pharynx, esophagus, and larynx were much higher. That is, the SIR between these three sites ranged between 4 and 22; however, the SIR for lung and the three sites was estimated to be approximately 2–3. The site relationships between breast, uterus, and ovary were relatively high, especially after first breast cancer (i.e. the SIR [95% CI] was 2.07 [1.71–2.43] for first breast to second uterus; 2.16 [1.62–2.70] for first breast to second ovary; 1.40 [1.10–1.71] for first uterus to second breast; and 1.43 [0.82–2.04] for first ovary to second breast). In addition, a high SIR for second thyroid cancer, but not first thyroid cancer, was observed.

Table 4. Observed numbers and standardized incidence ratios of second primary cancer according to the site of first and second primary cancer, 1985–2004, in both sexes
First cancer siteSecond cancer siteNo. second primary cancersPerson-yearsSIR95% CI
  1. CI, confidence interval; SIR, standardized incidence ratios.

Mouth/pharynxEsophagus13732 48313.6211.34–15.90
Mouth/pharynxStomach8132 5711.381.08–1.68
Mouth/pharynxColorectum5332 5581.350.99–1.71
Mouth/pharynxLiver6632 5991.491.13–1.85
Mouth/pharynxGallbladder1132 6841.520.62–2.41
Mouth/pharynxPancreas1732 6841.570.82–2.31
Mouth/pharynxLarynx1232 6744.351.89–6.81
Mouth/pharynxLung11332 5622.452.00–2.90
Mouth/pharynxProstate1832 6571.730.93–2.53
Mouth/pharynxKidney/urinary tract/bladder1632 6561.300.66–1.94
Mouth/pharynxBlood2832 6612.391.50–3.27
EsophagusMouth/pharynx9419 04321.6317.26–26.00
EsophagusStomach5819 1281.320.98–1.66
EsophagusColorectum3319 1171.150.76–1.54
EsophagusLiver4019 1541.210.83–1.58
EsophagusPancreas1619 1932.001.02–2.97
EsophagusLarynx1419 1816.383.04–9.72
EsophagusLung6219 1291.711.29–2.14
EsophagusProstate1419 1811.510.72–2.30
EsophagusKidney/urinary tract/bladder1919 1732.001.10–2.90
EsophagusBlood1619 1741.890.97–2.82
StomachMouth/pharynx89294 6351.541.22–1.86
StomachEsophagus171294 5281.681.42–1.93
StomachColorectum563293 3991.401.28–1.51
StomachLiver486293 9781.070.97–1.16
StomachGallbladder91294 6931.170.93–1.41
StomachPancreas134294 7091.180.98–1.38
StomachLarynx39294 6851.360.94–1.79
StomachLung632294 0471.261.16–1.36
StomachBreast (female)126294 3971.631.34–1.91
StomachUterus35294 7421.090.73–1.45
StomachOvary15294 7791.040.51–1.56
StomachProstate157294 4971.361.15–1.57
StomachKidney/urinary tract/bladder163294 4331.261.07–1.45
StomachThyroid31294 6951.861.20–2.51
StomachBlood137294 6531.140.95–1.33
ColorectumMouth/pharynx47222 0161.130.81–1.45
ColorectumEsophagus95221 9491.311.05–1.57
ColorectumStomach558220 8241.281.17–1.39
ColorectumLiver352221 4541.070.96–1.19
ColorectumGallbladder58222 0350.970.72–1.22
ColorectumPancreas109222 0201.281.04–1.52
ColorectumLarynx29222 0101.500.96–2.05
ColorectumLung410221 5541.141.03–1.25
ColorectumBreast (female)91221 7741.220.97–1.47
ColorectumUterus50221 9611.641.19–2.10
ColorectumOvary34222 0482.431.61–3.24
ColorectumProstate107221 8861.311.06–1.56
ColorectumKidney/urinary tract/bladder120221 8051.301.07–1.53
ColorectumThyroid42221 9563.002.09–3.91
ColorectumBlood108221 9701.200.97–1.43
LiverMouth/pharynx3191 6281.510.98–2.04
LiverEsophagus5891 5981.561.16–1.96
LiverStomach26491 2231.221.08–1.37
LiverColorectum17091 3671.191.01–1.37
LiverGallbladder2291 6550.820.48–1.17
LiverPancreas3491 6470.850.57–1.14
LiverLung14691 5190.820.69–0.95
LiverBreast (female)2491 6331.260.75–1.76
LiverOvary1291 6583.231.40–5.06
LiverProstate4791 5971.090.78–1.41
LiverKidney/urinary tract/bladder5291 5851.130.82–1.44
LiverThyroid1191 6472.140.88–3.41
LiverBlood6791 6051.601.21–1.98
GallbladderStomach2712 6991.110.69–1.53
GallbladderColorectum3312 6691.921.26–2.57
GallbladderLiver1312 6960.740.34–1.14
GallbladderLung2712 7051.370.85–1.89
PancreasStomach148 9940.830.39–1.26
PancreasColorectum188 9911.550.83–2.26
PancreasLung188 9981.330.72–1.94
LarynxMouth/pharynx2616 4926.033.71–8.35
LarynxEsophagus4516 4715.563.94–7.19
LarynxStomach8416 2911.811.43–2.20
LarynxColorectum4116 4311.441.00–1.88
LarynxLiver4716 4721.320.94–1.70
LarynxGallbladder1016 5271.920.73–3.11
LarynxPancreas1216 5341.500.65–2.35
LarynxLung13616 3363.482.90–4.07
LarynxProstate1116 5171.100.45–1.75
LarynxKidney/urinary tract/bladder2016 4901.981.11–2.85
LarynxBlood1316 5251.540.70–2.38
LungMouth/pharynx3576 7732.141.43–2.84
LungEsophagus6076 7482.041.52–2.55
LungStomach25076 4621.391.22–1.57
LungColorectum14676 5331.241.04–1.44
LungLiver10776 6940.820.66–0.97
LungGallbladder3076 7981.270.82–1.73
LungPancreas4676 7891.360.96–1.75
LungLarynx2176 7782.511.44–3.58
LungBreast (female)3476 7241.661.10–2.21
LungUterus1176 8061.300.53–2.07
LungProstate6276 7131.671.26–2.09
LungKidney/urinary tract/bladder6476 7301.651.25–2.06
LungThyroid2076 7804.292.41–6.17
LungBlood4376 7771.220.86–1.59
Breast (female)Mouth/pharynx16200 6961.400.71–2.08
Breast (female)Esophagus20200 7021.921.08–2.76
Breast (female)Stomach180200 2921.401.20–1.61
Breast (female)Colorectum152200 3621.201.01–1.40
Breast (female)Liver88200 6201.180.93–1.43
Breast (female)Gallbladder36200 6861.280.86–1.69
Breast (female)Pancreas42200 7051.270.88–1.65
Breast (female)Lung103200 5631.241.00–1.48
Breast (female)Uterus126200 3892.071.71–2.43
Breast (female)Ovary61200 5742.161.62–2.70
Breast (female)Kidney/urinary tract/bladder26200 6311.240.77–1.72
Breast (female)Thyroid83200 3595.063.97–6.15
Breast (female)Blood43200 6821.080.76–1.41
UterusStomach5474 6751.060.78–1.35
UterusColorectum7574 5681.561.21–1.92
UterusLiver2974 7410.980.62–1.33
UterusGallbladder1974 7511.620.89–2.35
UterusPancreas2174 7531.630.93–2.32
UterusLung8274 6682.602.03–3.16
UterusBreast (female)8274 4971.401.10–1.71
UterusKidney/urinary tract/bladder1574 7351.860.92–2.80
UterusThyroid1374 7112.120.97–3.27
UterusBlood3574 7332.321.55–3.10
OvaryStomach1119 8580.990.40–1.57
OvaryColorectum3319 8023.042.00–4.07
OvaryLung1219 8761.730.75–2.71
OvaryBreast (female)2119 8441.430.82–2.04
OvaryBlood1319 8763.741.71–5.78
ProstateMouth/pharynx2126 8002.471.41–3.52
ProstateEsophagus1426 8330.820.39–1.25
ProstateStomach11926 6281.231.01–1.46
ProstateColorectum8026 6981.351.05–1.65
ProstateLiver5926 7410.870.65–1.09
ProstateGallbladder1626 8251.410.72–2.09
ProstatePancreas2126 8241.210.69–1.73
ProstateLung6226 7770.670.50–0.83
ProstateKidney/urinary tract/bladder5026 7632.211.60–2.83
ProstateBlood2226 8221.240.72–1.75
Kidney/urinary tract/bladderMouth/pharynx1765 1251.210.64–1.79
Kidney/urinary tract/bladderEsophagus3665 1181.410.95–1.88
Kidney/urinary tract/bladderStomach16764 8151.120.95–1.29
Kidney/urinary tract/bladderColorectum12264 8471.261.04–1.49
Kidney/urinary tract/bladderLiver11164 9751.000.81–1.19
Kidney/urinary tract/bladderGallbladder2565 1371.350.82–1.88
Kidney/urinary tract/bladderPancreas3365 1471.210.80–1.62
Kidney/urinary tract/bladderLung17764 9601.411.20–1.61
Kidney/urinary tract/bladderBreast (female)1265 1360.970.42–1.52
Kidney/urinary tract/bladderUterus1265 1162.321.01–3.64
Kidney/urinary tract/bladderProstate6465 0052.081.57–2.59
Kidney/urinary tract/bladderBlood3465 1081.180.78–1.58
ThyroidStomach3230 7111.240.81–1.67
ThyroidColorectum2730 6891.250.78–1.72
ThyroidLiver1230 7530.700.30–1.10
ThyroidLung2630 7161.430.88–1.98
ThyroidBreast (female)3730 6661.971.34–2.61
ThyroidBlood1330 7461.930.88–2.97
BloodMouth/pharynx1455 0122.181.04–3.32
BloodEsophagus1755 0271.610.84–2.37
BloodStomach7954 8981.200.94–1.47
BloodColorectum5554 9311.200.88–1.51
BloodLiver8254 9161.711.34–2.07
BloodLung7154 9571.381.06–1.70
BloodBreast (female)1055 0050.650.25–1.04
BloodProstate1955 0151.770.98–2.57
BloodKidney/urinary tract/bladder2454 9901.771.06–2.47
BloodThyroid1455 0175.542.64–8.43

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

The present study shows that in Osaka, Japan, 3.8% of study subjects (of both sexes) developed metachronous second primary cancers within 10 years of the first primary cancer between 1985 and 2005. Compared with our previous study, in which we reported that 2.0% of cancer patients developed metachronous second primary cancers between 1966 and 1986,[4] the proportion of multiple primary cancers has approximately doubled in the past 20 years. Although constantly elevated SIR was not observed in the first decade in our previous study,[4] elevated SIR for metachronous second primary cancers was observed among almost all sex and age groups over the study period in the present study. Almost all cancer patients were more likely to develop metachronous second primary cancers than the general population, as also found in another recent study in Australia.[12] A possible explanation for this finding could be the accumulation or concentration of cancer risk factors, such as smoking, alcohol drinking, radiotherapy treatment, and other potential factors, including genetic factors, within an individual. It may be difficult to improve cancer patients' lifestyle. For example, smoking cessation is challenging even for patients recovering from lung cancer with curative treatment because a significant proportion of smokers with cancer do not receive formal assistance to quit.[13] However, detection or surveillance bias may also play a part in the results, as evidenced in the elevated SIR of second thyroid cancer.[14]

We also found that the 10-year cumulative risk for second primaries was 13.0% for those who developed their first cancer at 60–69 years of age. Although this finding was slightly higher than our previous results, with an approximate 10% 10-year cumulative risk for second primaries for those who developed their first cancer at 60–69 years of age in 1978–1983,[4] we added sex-stratified information on cumulative risk for second primaries. Men with their first cancer diagnosed when they were at 60–69 years of age had a high cumulative risk of 16.2%, compared with an 8.6% risk in women. These figures clearly show that second primary cancer should be regarded as a problem commonly encountered in routine medical practice rather than a rare and unusual event to be described in case reports.

The SIR for metachronous second primary cancers from the first cancer of the mouth/pharynx, esophagus, and larynx, generally accepted as smoking and alcohol related, was higher than those from the other first cancers, including lung cancer. Robust site relationships of first and second primary cancers within these three cancer sites (mouth/pharynx to esophagus, mouth/pharynx to larynx, esophagus to larynx and each others) were found (see Table 4). Tobacco smoking is clearly one of the major causes of second primary cancers, as it is for first cancers.[15] Generally, cigarette smokers had an approximate 15–30-fold higher risk of lung cancer than non-smokers, whereas an approximate 2–10-fold higher risk of cancer of the mouth/pharynx, esophagus, or larynx has been reported for cigarette smokers.[16] In the present study, a lower SIR between smoking-related lung cancer and cancers of the mouth/pharynx, esophagus, or larynx was obtained than the SIR between these three sites. This may be due to combined effects of not only tobacco smoking, but also alcohol drinking, radiotherapy, or other potential factors,[17] as well as to the relatively lower relative risk of cigarette smoking for lung cancer in Japan than in Western countries (i.e. 4.4 for men and 2.8 for women in Japan).[18] The risk of developing a tobacco- or alcohol-related second cancer has been linked mainly to patients' habits before the onset of the initial cancer, although continued smoking and drinking may enhance the risk.[5, 19]

Breast, uterine, and ovarian cancers had the next highest SIR for second primaries. Furthermore, we found that women aged 50–79 years had a higher SIR for second primaries than men aged 50–79 years. The site relationships between breast, uterus, and ovary were relatively high, especially after first breast cancer, whereas a robust site relationship between colorectal cancer and ovarian cancer was observed (see Table 4). These findings are consistent with previous evidence that women have slightly higher risk for second cancer compared with men because of the good survival rates for common female cancers.[3] Female-specific causes, such as hormonal environment due to menopause, may affect these relationships.[17] Although the constellation of multiple cancers of the breast, uterine corpus, ovary, and colon has long intrigued investigators, nutritional and hormonal interactions, such as dietary habits (e.g. high fat intake) and reproductive factors (e.g. nulliparity), may contribute to the development of multiple primaries at these sites.[5]

The risk of second primary cancer can be modified ostensibly by improving medical scrutiny and notification of cancer patients.[5] In our previous study, underestimation of the risk of second primary cancer may have been possible, with the incidence of second primaries differing substantially between 1966 and 1986. This may be due to the reliability of the registration indices because the number of cases registered by death certificate only and the number of cases verified histologically were not so favorable in Osaka during in the 1960s–1970s.[4] The present study shows that the incidence rates per 100 000 person-years for metachronous second primary cancers were approximately the same across all study periods (1985–2005) among both sexes in Osaka. This finding seems partly attributable to soundness of medical scrutiny and notification of cancer patients, as well as to stability in the registration indices.

One of the interesting relationships that emerged from the present analysis was that between hematological tumors and cancer of the mouth/pharynx, esophagus, uterus, ovary, and liver. Although there is evidence that hepatocellular carcinoma and lymphoma share a common risk factor, namely the hepatitis virus,[20] the relationships between hematological tumors and cancer of the mouth/pharynx, esophagus, uterus, and ovary have been relatively unclear. Because of the age distribution or potential etiologies of hematological tumors, analyses using disease types (lymphoma, leukemia, and myeloma) and specific age categories, such as childhood, adolescence, and young adults, should be considered in future research.[21] Although multiple primary cancers in some individuals provide a clue to understanding cancer etiology, including genetics,[5, 22] a number of associations remain without apparent explanation.[5] Because it is possible that other factors, such as socioeconomic status, genetics, lifestyle, or social network, may vary between people who have been diagnosed with cancer and those who have not,[23] further investigations are required to identify the mechanisms underlying these relationships in the incidence of multiple primary cancers for specific interventions.

There are several limitations to the present study. First, we should keep in mind the changes in the completeness of cancer registration in Osaka when we evaluate incidence. The percentage of cases registered by death certificate only, which is often regarded as an index of completeness, was approximately 10–15% and registration has been stable in the Osaka Cancer Registry for the most recent two decades.[24] Therefore, we considered that the effects of changes in completeness on incidence rates over the study periods are likely to be small. Second, some misclassifications for second primaries will be unavoidable in cancer registries, especially in cases registered by death certificate only. The IARC rules for second primaries are rather conservative compared with clinical practice; therefore, the risk for second primaries may be underestimated. Third, patients with second primary cancers may be followed-up in hospitals where the completeness of registration of cancer cases is higher than average compared with other hospitals in Osaka. This could result in an overestimation for second primaries to some degree. Fourth, patients with cancer differ in many respects from the general population, and these characteristics may affect the risk of subsequent cancer. For example, women with cervical cancer tend to smoke more, bear children at an earlier age, and are of lower socioeconomic status than women in the general population.[5] Because of the nature of cancer registries, these potential risk factors were not included in the data collection.

In conclusion, we have shown that cancer survivors in Osaka, Japan, are at higher risk of second primary cancer compared with the general population, in accordance with previous studies.[11, 25-27] More than one-tenth of cancer survivors aged over 60 years (specifically men over 50 years of age) will develop metachronous second primary cancer within 10 years of diagnosis of the first cancer. This clearly shows that second primary cancer should be considered as a commonly encountered major medical problem. The evaluation of second primary cancer identifies groups of cancer patients in need of increased surveillance for early cancer detection and management. Preventive measures are needed to reduce the occurrence of subsequent cancer and mortality.[5] Because we obtained acceptably stable statistics for second primary cancer in Osaka, further studies are required to advance our understanding of effective measures against multiple primary cancers.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

This study was supported by a Grant-in-Aid for Clinical Cancer Research from the Japanese Ministry of Health, Labour and Welfare (H22-011). The authors are grateful to all the medical institutions in Osaka and the Osaka Medical Association that provided us with cancer incidence data.

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  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
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