Concomitant chemo‐radiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: A case–control study

Abstract

Radiotherapy and chemotherapy are associated with an increased risk of a second malignant neoplasm (SMN) after a cancer during childhood. This study specified the dose-effect relationship between radiotherapy, chemotherapy and the risk of a SMN, and investigated the effect of chemo-radiotherapy on the risk of SMN. A case-control study nested in a European cohort of 4,581 patients treated for a solid cancer during childhood was conducted. One hundred and fifty three cases with a SMN and 442 controls were matched according to sex, age at first cancer, calendar year, type of first cancer and follow-up. The local radiation dose was estimated at the site of the SMN, for each case and at the same site, for the matched controls. The local dose of radiation significantly increased the risk of a SMN. The best model was linear with an excess relative risk per Gray equal to 0.13 (95% CI, 0.06; 0.26). Any chemotherapy significantly increased the risk of a SMN, odd ratio(adjusted) (OR(adjusted)) = 2.4 (95% confidence interval (95% CI), 1.4-4.1), but no dose-effect relationship was observed between any drug category and the risk of a SMN. Patients who had received concomitant chemo-radiotherapy were significantly more at risk of developing a SMN than patients who had been treated with sequential chemo-radiotherapy, even after adjustment for the local dose of radiation and the 6 most frequently administered drugs, OR(adjusted) = 2.3 (95%CI, 1.1-4.8). Radiation was found to be the foremost treatment-related risk factor for the occurrence of a SMN. Compared to sequential treatment, concomitant chemo-radiotherapy may lead to a higher risk of a SMN.

Long-term Mortality from Second Malignant Neoplasms in 5-Year Survivors of Solid Childhood Tumors: Temporal Pattern of Risk according to Type of Treatment

“…Few previous studies have investigated the roles of radiotherapy (yes/no; refs. 18,38) or local radiation dose and chemotherapeutic drugs (20) as risk factors for mortality from SMN.…”

“…We converted the dose of each drug into the dose of a reference drug, based on either dose equivalence in terms of hematologic toxicity or substitution rules commonly used in clinical practice, a method we called "Equi-tox." A detailed description of the quantification of chemotherapy has already been published (20). We used a classic method of summing the dose (per square meter) for other drug categories.…”

“…On the other hand, it is a known fact that children treated with radiation, alkylating agents, epipodophyllotoxins, and antimetabolite therapy for a primary malignancy run an increased risk of developing a SMN (8,(13)(14)(15)(16)(17)(18), and few studies have estimated the radiation dose-response relationship (19,20).…”

Cancers secondaires des radiothérapies

“…Par exemple, ceux traité s pour une maladie d'Hodgkin semblent plus à risque de dé velopper ulté rieurement une leucé mie ou un cancer du sein [38], ceux traité s pour un neuroblastome semblent plus à risque de dé velopper un cancer de la thyroïde [34] ou du sein [36] et ceux traité s pour une tumeur germinale, un mé lanome [27]. D'autres pré dispositions de ce type seront probablement mises en é vidence dans le futur ; à dose de radiation et chimiothé rapie é gale, les anté cé dents familiaux de cancer augmentent le risque de second cancer [38] ; une é tude a montré , que, à doses de radiation et d'agents chimiothé rapiques é gales, le risque de cancer secondaire est plus important en cas d'administration concomitante qu'en cas d'administration sé quentielle de ces deux traitements [39]. Dans cette é tude, les enfants qui avaient reç u de maniè re concomitante la radiothé -rapie et la chimiothé rapie avaient un risque 2,3 fois plus important (IC 95 % = 1,1-4,8) de dé velopper ulté rieurement un autre cancer que ceux qui avaient reçu la mê me dose de radiothé rapie et de chimiothé rapie, mais de maniè re sé quentielle.…”

“…En effet, les deux é tudes qui ont estimé la relation entre la dose de radiation reç ue durant la radiothé rapie d'un cancer de l'enfant, et le risque de cancer secondaire, tous types confondus, sont parvenues à des ERR par Gray trè s infé rieures à ceux observé s chez les survivants d'Hiroshima et de Nagaski du mê me â ge, durant la mê me pé riode de suivi aprè s l'irradiation : ERR/Gy = 0,35 (IC 95 % : 0,14 à 0,81) dans la NCCRG [24], et ERR/Gy = 0,13 (0,06 à 0,27) dans EURO2K [39]. Ces faibles valeurs ne peuvent pas ê tre attribué es à des effets de mort cellulaire pour les hautes doses, car elles sont retrouvé es aussi dans des analyses aux seuls siè ges anatomiques ayant reç u moins d'un ou de quelques Grays.…”