Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors

R. S. Allodji; R. C. Reulen; I. Diallo; D. L. Winter; G. Vu-Bezin; S. Bolle; M. Locquet; F. Bagnasco; E. Bárdi; E. A.M. Feijen; D. Alessi; M. M. Fidler-Benaoudia; S. Høgsholt; C. J. Bright; H. Linge; B. Fresneau; N. Haddy; C. Veres; D. Llanas; N. Journy; C. Demoor-Goldschmidt; J. Byrne; D. Bejarano-Quisoboni; D. Grabow; W. Zrafi; T. Gudmundsdottir; G. Michel; W. Gunnes; P. Kaatsch; C. Rubino; H. Jenkinson; M. Kaiser; R. Skinner; R. Aho Glele; C. Ducos; N. Aba; T. Cole; N. Waespe; S. Nordenfelt; T. Charrier; M. Zidane; M. Jankovic; T. Lähteenmäki; M. M. Maule; H. J.H. van der Pal; C. M. Ronckers; F. E. van Leeuwen; J. Teepen; M. Terenziani; T. Wiebe; C. Sacerdote; Z. Jakab; R. Haupt; P. M. Lähteenmäki; L. Zadravec Zaletel; C. E. Kuehni; J. F. Winther; L. C. Kremer; L. Hjorth; M. M. Hawkins; F. de Vathaire

doi:10.1016/j.esmoop.2026.108313

Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors

R. S. Allodji
, R. C. Reulen
, I. Diallo
, D. L. Winter
, G. Vu-Bezin
, S. Bolle
, M. Locquet
, F. Bagnasco
, E. Bárdi
, E. A.M. Feijen
, D. Alessi
, M. M. Fidler-Benaoudia
, S. Høgsholt
, C. J. Bright
, H. Linge
, B. Fresneau
, N. Haddy
, C. Veres
, D. Llanas
, N. Journy

C. Demoor-Goldschmidt, J. Byrne, D. Bejarano-Quisoboni, D. Grabow, W. Zrafi, T. Gudmundsdottir, G. Michel, W. Gunnes, P. Kaatsch, C. Rubino, H. Jenkinson, M. Kaiser, R. Skinner, R. Aho Glele, C. Ducos, N. Aba, T. Cole, N. Waespe, S. Nordenfelt, T. Charrier, M. Zidane, M. Jankovic, T. Lähteenmäki, M. M. Maule, H. J.H. van der Pal, C. M. Ronckers, F. E. van Leeuwen, J. Teepen, M. Terenziani, T. Wiebe, C. Sacerdote, Z. Jakab, R. Haupt, P. M. Lähteenmäki, L. Zadravec Zaletel, C. E. Kuehni, J. F. Winther, L. C. Kremer, L. Hjorth, M. M. Hawkins, F. de Vathaire

Group Kremer

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Previous studies of risk factors for subsequent soft-tissue sarcoma (STS) among childhood cancer survivors had small numbers and were unable to comprehensively investigate the dose–response relationships with radiation from radiotherapy and with cumulative exposure to specific cytotoxics. Patients and methods: We conducted a nested case-control study, encompassing 275 subsequent STS cases and 275 matched controls, within the Pan-European cohort of 69 460 5-year survivors from 12 countries. Odds ratios (ORs) and 95% confidence intervals (CIs) for subsequent STS were calculated for different levels of radiation dose to the STS location (in Gy) and for cumulative doses of specific chemotherapeutic agents (in g/m²). Additionally, excess ORs per Gy (EOR/Gy) or per g/m² (EOR/g/m²) were calculated to assess dose–response relationships. Results: The OR for subsequent STS was 22-fold [95% CI 6.9-95.4] higher in soft tissue exposed to ≥30 Gy and remained in excess with exposure to 5-9 Gy [OR = 3.8, 95% CI 1.3-12.0] compared with no radiation. The EOR/Gy was 0.86 [95% CI 0.35-2.16], with a particularly high risk observed in survivors of neuroblastoma [EOR/Gy = 5.52, 95% CI 0.71-52.31] or bone sarcoma [EOR/Gy = 4.16, 95% CI 0.40-24.72], and in females [EOR/Gy = 2.35; 95% CI 0.65-8.14]. For patients who had received a cumulative procarbazine dose of ≥6.0 g/m², the OR was 4.7 [95% CI 1.3-25.1] compared with non-exposure after controlling for radiation. No association was found for other alkylating agents or other specific cytotoxic drugs. Conclusion: Although high radiation doses remain the primary risk factor for secondary STS, our findings suggest a possible increase in risk at lower doses (5-9 Gy) and following procarbazine treatment among childhood cancer survivors. These observations warrant further investigation and may merit consideration in treatment planning and long-term follow-up guidelines for cancer survivors.

Original language	English
Article number	108313
Journal	ESMO Open
Volume	11
Issue number	8
DOIs	https://doi.org/10.1016/j.esmoop.2026.108313
Publication status	Published - Aug 2026

Keywords

chemotherapy
childhood cancer survivors
procarbazine
radiation therapy
subsequent soft-tissue sarcoma

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10.1016/j.esmoop.2026.108313

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Allodji, R. S., Reulen, R. C., Diallo, I., Winter, D. L., Vu-Bezin, G., Bolle, S., Locquet, M., Bagnasco, F., Bárdi, E., Feijen, E. A. M., Alessi, D., Fidler-Benaoudia, M. M., Høgsholt, S., Bright, C. J., Linge, H., Fresneau, B., Haddy, N., Veres, C., Llanas, D., ... de Vathaire, F. (2026). Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors. ESMO Open, 11(8), Article 108313. https://doi.org/10.1016/j.esmoop.2026.108313

@article{3ae8f57075af403f984a37f57575b3f8,

title = "Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors",

abstract = "Background: Previous studies of risk factors for subsequent soft-tissue sarcoma (STS) among childhood cancer survivors had small numbers and were unable to comprehensively investigate the dose{\textendash}response relationships with radiation from radiotherapy and with cumulative exposure to specific cytotoxics. Patients and methods: We conducted a nested case-control study, encompassing 275 subsequent STS cases and 275 matched controls, within the Pan-European cohort of 69 460 5-year survivors from 12 countries. Odds ratios (ORs) and 95\% confidence intervals (CIs) for subsequent STS were calculated for different levels of radiation dose to the STS location (in Gy) and for cumulative doses of specific chemotherapeutic agents (in g/m2). Additionally, excess ORs per Gy (EOR/Gy) or per g/m2 (EOR/g/m2) were calculated to assess dose{\textendash}response relationships. Results: The OR for subsequent STS was 22-fold [95\% CI 6.9-95.4] higher in soft tissue exposed to ≥30 Gy and remained in excess with exposure to 5-9 Gy [OR = 3.8, 95\% CI 1.3-12.0] compared with no radiation. The EOR/Gy was 0.86 [95\% CI 0.35-2.16], with a particularly high risk observed in survivors of neuroblastoma [EOR/Gy = 5.52, 95\% CI 0.71-52.31] or bone sarcoma [EOR/Gy = 4.16, 95\% CI 0.40-24.72], and in females [EOR/Gy = 2.35; 95\% CI 0.65-8.14]. For patients who had received a cumulative procarbazine dose of ≥6.0 g/m2, the OR was 4.7 [95\% CI 1.3-25.1] compared with non-exposure after controlling for radiation. No association was found for other alkylating agents or other specific cytotoxic drugs. Conclusion: Although high radiation doses remain the primary risk factor for secondary STS, our findings suggest a possible increase in risk at lower doses (5-9 Gy) and following procarbazine treatment among childhood cancer survivors. These observations warrant further investigation and may merit consideration in treatment planning and long-term follow-up guidelines for cancer survivors.",

keywords = "chemotherapy, childhood cancer survivors, procarbazine, radiation therapy, subsequent soft-tissue sarcoma",

author = "Allodji, \{R. S.\} and Reulen, \{R. C.\} and I. Diallo and Winter, \{D. L.\} and G. Vu-Bezin and S. Bolle and M. Locquet and F. Bagnasco and E. B{\'a}rdi and Feijen, \{E. A.M.\} and D. Alessi and Fidler-Benaoudia, \{M. M.\} and S. H{\o}gsholt and Bright, \{C. J.\} and H. Linge and B. Fresneau and N. Haddy and C. Veres and D. Llanas and N. Journy and C. Demoor-Goldschmidt and J. Byrne and D. Bejarano-Quisoboni and D. Grabow and W. Zrafi and T. Gudmundsdottir and G. Michel and W. Gunnes and P. Kaatsch and C. Rubino and H. Jenkinson and M. Kaiser and R. Skinner and \{Aho Glele\}, R. and C. Ducos and N. Aba and T. Cole and N. Waespe and S. Nordenfelt and T. Charrier and M. Zidane and M. Jankovic and T. L{\"a}hteenm{\"a}ki and Maule, \{M. M.\} and \{van der Pal\}, \{H. J.H.\} and Ronckers, \{C. M.\} and \{van Leeuwen\}, \{F. E.\} and J. Teepen and M. Terenziani and T. Wiebe and C. Sacerdote and Z. Jakab and R. Haupt and L{\"a}hteenm{\"a}ki, \{P. M.\} and \{Zadravec Zaletel\}, L. and Kuehni, \{C. E.\} and Winther, \{J. F.\} and Kremer, \{L. C.\} and L. Hjorth and Hawkins, \{M. M.\} and \{de Vathaire\}, F.",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s)",

year = "2026",

month = aug,

doi = "10.1016/j.esmoop.2026.108313",

language = "English",

volume = "11",

journal = "ESMO Open",

issn = "2059-7029",

publisher = "Elsevier B.V.",

number = "8",

}

Allodji, RS, Reulen, RC, Diallo, I, Winter, DL, Vu-Bezin, G, Bolle, S, Locquet, M, Bagnasco, F, Bárdi, E, Feijen, EAM, Alessi, D, Fidler-Benaoudia, MM, Høgsholt, S, Bright, CJ, Linge, H, Fresneau, B, Haddy, N, Veres, C, Llanas, D, Journy, N, Demoor-Goldschmidt, C, Byrne, J, Bejarano-Quisoboni, D, Grabow, D, Zrafi, W, Gudmundsdottir, T, Michel, G, Gunnes, W, Kaatsch, P, Rubino, C, Jenkinson, H, Kaiser, M, Skinner, R, Aho Glele, R, Ducos, C, Aba, N, Cole, T, Waespe, N, Nordenfelt, S, Charrier, T, Zidane, M, Jankovic, M, Lähteenmäki, T, Maule, MM, van der Pal, HJH, Ronckers, CM, van Leeuwen, FE, Teepen, J, Terenziani, M, Wiebe, T, Sacerdote, C, Jakab, Z, Haupt, R, Lähteenmäki, PM, Zadravec Zaletel, L, Kuehni, CE, Winther, JF, Kremer, LC, Hjorth, L, Hawkins, MM & de Vathaire, F 2026, 'Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors', ESMO Open, vol. 11, no. 8, 108313. https://doi.org/10.1016/j.esmoop.2026.108313

TY - JOUR

T1 - Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors

AU - Allodji, R. S.

AU - Reulen, R. C.

AU - Diallo, I.

AU - Winter, D. L.

AU - Vu-Bezin, G.

AU - Bolle, S.

AU - Locquet, M.

AU - Bagnasco, F.

AU - Bárdi, E.

AU - Feijen, E. A.M.

AU - Alessi, D.

AU - Fidler-Benaoudia, M. M.

AU - Høgsholt, S.

AU - Bright, C. J.

AU - Linge, H.

AU - Fresneau, B.

AU - Haddy, N.

AU - Veres, C.

AU - Llanas, D.

AU - Journy, N.

AU - Demoor-Goldschmidt, C.

AU - Byrne, J.

AU - Bejarano-Quisoboni, D.

AU - Grabow, D.

AU - Zrafi, W.

AU - Gudmundsdottir, T.

AU - Michel, G.

AU - Gunnes, W.

AU - Kaatsch, P.

AU - Rubino, C.

AU - Jenkinson, H.

AU - Kaiser, M.

AU - Skinner, R.

AU - Aho Glele, R.

AU - Ducos, C.

AU - Aba, N.

AU - Cole, T.

AU - Waespe, N.

AU - Nordenfelt, S.

AU - Charrier, T.

AU - Zidane, M.

AU - Jankovic, M.

AU - Lähteenmäki, T.

AU - Maule, M. M.

AU - van der Pal, H. J.H.

AU - Ronckers, C. M.

AU - van Leeuwen, F. E.

AU - Teepen, J.

AU - Terenziani, M.

AU - Wiebe, T.

AU - Sacerdote, C.

AU - Jakab, Z.

AU - Haupt, R.

AU - Lähteenmäki, P. M.

AU - Zadravec Zaletel, L.

AU - Kuehni, C. E.

AU - Winther, J. F.

AU - Kremer, L. C.

AU - Hjorth, L.

AU - Hawkins, M. M.

AU - de Vathaire, F.

PY - 2026/8

Y1 - 2026/8

N2 - Background: Previous studies of risk factors for subsequent soft-tissue sarcoma (STS) among childhood cancer survivors had small numbers and were unable to comprehensively investigate the dose–response relationships with radiation from radiotherapy and with cumulative exposure to specific cytotoxics. Patients and methods: We conducted a nested case-control study, encompassing 275 subsequent STS cases and 275 matched controls, within the Pan-European cohort of 69 460 5-year survivors from 12 countries. Odds ratios (ORs) and 95% confidence intervals (CIs) for subsequent STS were calculated for different levels of radiation dose to the STS location (in Gy) and for cumulative doses of specific chemotherapeutic agents (in g/m2). Additionally, excess ORs per Gy (EOR/Gy) or per g/m2 (EOR/g/m2) were calculated to assess dose–response relationships. Results: The OR for subsequent STS was 22-fold [95% CI 6.9-95.4] higher in soft tissue exposed to ≥30 Gy and remained in excess with exposure to 5-9 Gy [OR = 3.8, 95% CI 1.3-12.0] compared with no radiation. The EOR/Gy was 0.86 [95% CI 0.35-2.16], with a particularly high risk observed in survivors of neuroblastoma [EOR/Gy = 5.52, 95% CI 0.71-52.31] or bone sarcoma [EOR/Gy = 4.16, 95% CI 0.40-24.72], and in females [EOR/Gy = 2.35; 95% CI 0.65-8.14]. For patients who had received a cumulative procarbazine dose of ≥6.0 g/m2, the OR was 4.7 [95% CI 1.3-25.1] compared with non-exposure after controlling for radiation. No association was found for other alkylating agents or other specific cytotoxic drugs. Conclusion: Although high radiation doses remain the primary risk factor for secondary STS, our findings suggest a possible increase in risk at lower doses (5-9 Gy) and following procarbazine treatment among childhood cancer survivors. These observations warrant further investigation and may merit consideration in treatment planning and long-term follow-up guidelines for cancer survivors.

AB - Background: Previous studies of risk factors for subsequent soft-tissue sarcoma (STS) among childhood cancer survivors had small numbers and were unable to comprehensively investigate the dose–response relationships with radiation from radiotherapy and with cumulative exposure to specific cytotoxics. Patients and methods: We conducted a nested case-control study, encompassing 275 subsequent STS cases and 275 matched controls, within the Pan-European cohort of 69 460 5-year survivors from 12 countries. Odds ratios (ORs) and 95% confidence intervals (CIs) for subsequent STS were calculated for different levels of radiation dose to the STS location (in Gy) and for cumulative doses of specific chemotherapeutic agents (in g/m2). Additionally, excess ORs per Gy (EOR/Gy) or per g/m2 (EOR/g/m2) were calculated to assess dose–response relationships. Results: The OR for subsequent STS was 22-fold [95% CI 6.9-95.4] higher in soft tissue exposed to ≥30 Gy and remained in excess with exposure to 5-9 Gy [OR = 3.8, 95% CI 1.3-12.0] compared with no radiation. The EOR/Gy was 0.86 [95% CI 0.35-2.16], with a particularly high risk observed in survivors of neuroblastoma [EOR/Gy = 5.52, 95% CI 0.71-52.31] or bone sarcoma [EOR/Gy = 4.16, 95% CI 0.40-24.72], and in females [EOR/Gy = 2.35; 95% CI 0.65-8.14]. For patients who had received a cumulative procarbazine dose of ≥6.0 g/m2, the OR was 4.7 [95% CI 1.3-25.1] compared with non-exposure after controlling for radiation. No association was found for other alkylating agents or other specific cytotoxic drugs. Conclusion: Although high radiation doses remain the primary risk factor for secondary STS, our findings suggest a possible increase in risk at lower doses (5-9 Gy) and following procarbazine treatment among childhood cancer survivors. These observations warrant further investigation and may merit consideration in treatment planning and long-term follow-up guidelines for cancer survivors.

KW - chemotherapy

KW - childhood cancer survivors

KW - procarbazine

KW - radiation therapy

KW - subsequent soft-tissue sarcoma

UR - https://www.scopus.com/pages/publications/105045735472

U2 - 10.1016/j.esmoop.2026.108313

DO - 10.1016/j.esmoop.2026.108313

M3 - Article

AN - SCOPUS:105045735472

SN - 2059-7029

VL - 11

JO - ESMO Open

JF - ESMO Open

IS - 8

M1 - 108313

ER -

Cancer treatments-related factors for subsequent soft-tissue sarcoma in childhood cancer survivors

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