Table 2.
Multivariable Cox proportional hazard regression analyses for subsequent breast cancer in female 5-year childhood cancer survivors (primary cancer diagnosis year 1946–2012)
| Characteristic | Total (n) | % | No. of SBC (n)c | % | Model Ia | Model IIb | ||
|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | HR | 95% CI | |||||
| Cumulative doxorubicin dose (mg m−²) | ||||||||
| 0 | 11,170 | 62.4 | 431 | 55.1 | 1.0 | Ref. | – | |
| <100 | 912 | 5.1 | 16 | 2.0 | 1.76 | 0.88–3.51 | ||
| 100–199 | 1,795 | 10.0 | 69 | 8.8 | 1.77 | 1.30–2.42 | ||
| 200–299 | 1,026 | 5.7 | 67 | 8.6 | 2.50 | 1.85–3.40 | ||
| 300–399 | 1,012 | 5.7 | 64 | 8.2 | 2.33 | 1.68–3.23 | ||
| ≥400 | 779 | 4.4 | 58 | 7.4 | 2.78 | 1.99–3.88 | ||
| Unknown | 1,209 | 6.8 | 77 | 9.8 | – | – | ||
| Continuous variable: cumulative doxorubicin dose (per 100 mg m−²) | – | – | – | – | – | – | 1.24 | 1.18–1.31 |
| Cumulative daunorubicin dose (mg m−²) | ||||||||
| 0 | 14,630 | 81.7 | 684 | 87.5 | 1.0 | Ref. | – | |
| <100 | 623 | 3.5 | 7 | 0.9 | 0.98 | 0.46–2.09 | ||
| 100–199 | 953 | 5.3 | 16 | 2.0 | 0.98 | 0.55–1.75 | ||
| ≥200 | 645 | 3.6 | 17 | 2.2 | 1.22 | 0.69–2.17 | ||
| Unknown | 1,052 | 5.9 | 58 | 7.4 | – | – | ||
| Continuous variable: cumulative daunorubicin dose (per 100 mg m−²) | – | – | – | – | – | – | 1.10 | 0.95–1.29 |
| Epirubicin | ||||||||
| No | 16,637 | 92.9 | 717 | 91.7 | 1.0 | Ref. | 1.0 | Ref. |
| Yes | 325 | 1.8 | 9 | 1.2 | 3.40 | 1.66–6.98 | 3.25 | 1.59–6.63 |
| Unknown | 941 | 5.3 | 56 | 7.2 | – | – | – | – |
| Chest radiotherapy field and dose | ||||||||
| No chest radiotherapy | 13,004 | 72.6 | 250 | 32.0 | 1.0 | Ref. | 1.0 | Ref. |
| High-dose mantle (≥36 Gy; median: 40 Gy, IQR: 39–44 Gy) | 698 | 3.9 | 238 | 30.4 | 8.99 | 7.00–11.53 | 9.12 | 7.09–11.75 |
| Low-dose mantle (<36 Gy; median: 26 Gy, IQR: 21–30 Gy) | 524 | 2.9 | 93 | 11.9 | 4.72 | 3.48–6.41 | 5.23 | 3.86–7.09 |
| Mediastinal (median: 26 Gy, IQR: 21–36 Gy) | 469 | 2.6 | 33 | 4.2 | 1.65 | 1.02–2.67 | 1.71 | 1.06–2.78 |
| TBI (median: 12 Gy, IQR: 11–13 Gy) | 371 | 2.1 | 22 | 2.8 | 7.05 | 4.11–12.10 | 7.18 | 4.18–12.33 |
| Whole lung (median: 16 Gy, IQR: 12–23 Gy) | 184 | 1.0 | 23 | 2.9 | 7.58 | 4.68–12.27 | 8.00 | 4.94–12.95 |
| Other (median: 28 Gy, IQR: 21–36 Gy) | 1,316 | 7.4 | 63 | 8.1 | 2.61 | 1.87–3.64 | 2.68 | 1.91–3.75 |
| Unknown | 1,337 | 7.5 | 60 | 7.7 | – | – | – | – |
| Pelvic radiotherapy ≥5 Gy | ||||||||
| No | 13,751 | 76.8 | 505 | 64.6 | 1.0 | Ref. | 1.0 | Ref. |
| Yes | 2,911 | 16.3 | 222 | 28.4 | 0.95 | 0.78–1.17 | 0.94 | 0.77–1.16 |
| Unknown | 1,241 | 6.9 | 55 | 7.0 | – | – | – | – |
| Age at primary childhood cancer diagnosis (year) | ||||||||
| <5 | 7,376 | 41.2 | 66 | 8.4 | 1.0 | Ref. | 1.0 | Ref. |
| 5–9 | 3,788 | 21.2 | 65 | 8.3 | 1.13 | 0.76–1.69 | 1.12 | 0.75–1.67 |
| 10–14 | 3,930 | 22.0 | 273 | 34.9 | 2.03 | 1.48–2.79 | 2.04 | 1.49–2.81 |
| 15–21 | 2,809 | 15.7 | 378 | 48.3 | 1.83 | 1.31–2.55 | 1.84 | 1.32–2.57 |
| CEDd (mg m−2) | ||||||||
| None | 7,951 | 44.4 | 301 | 38.5 | 1.0 | Ref. | 1.0 | Ref. |
| <6,000 | 3,069 | 17.1 | 94 | 12.0 | 0.87 | 0.67–1.14 | 0.95 | 0.73–1.25 |
| 6,000–17,999 | 3,899 | 21.8 | 192 | 24.6 | 1.02 | 0.82–1.27 | 1.07 | 0.86–1.32 |
| ≥18,000 | 1,117 | 6.2 | 47 | 6.0 | 1.20 | 0.83–1.74 | 1.23 | 0.85–1.77 |
| Unknown | 1,867 | 10.4 | 148 | 18.9 | – | – | – | – |
aModel I included categorical variables of cumulative doxorubicin and daunorubicin dose by steps of 100 mg m−2.
bModel II included continuous variables of cumulative doxorubicin and daunorubicin dose per 100 mg m−2.
cOne survivor had SBC before 5 years after primary cancer.
dCED calculation: CED (mg m−2) = 1.0 (cumulative cyclophosphamide dose (mg m−2)) + 0.244 (cumulative ifosfamide dose (mg m−2)) + 0.857 (cumulative procarbazine dose (mg m−2)) + 14.286 (cumulative chlorambucil dose (mg m−2)) + 15.0 (cumulative BCNU (carmustine) dose (mg m−2)) + 16.0 (cumulative CCNU (lomustine) dose (mg m−2)) + 40 (cumulative melphalan dose (mg m−2)) + 50 (cumulative Thio-TEPA (thiotepa) dose (mg m−2)) + 100 (cumulative nitrogen mustard dose (mg m−2)) + 8.823 (cumulative busulfan dose (mg m−2)).