Radiotherapy-Induced Malignancies: Review of Clinical Features, Pathobiology, and Evolving Approaches for Mitigating Risk

Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. After resection, patients were classified as having average-risk medulloblastoma ( 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Intensity-modulated radiation therapy (IMRT) allows dose to be concentrated in the tumor volume while sparing normal tissues. However, the downside to IMRT is the potential to increase the number of radiation-induced second cancers. The reasons for this potential are more monitor units and, therefore, a larger total-body dose because of leakage radiation and, because IMRT involves more fields, a bigger volume of normal tissue is exposed to lower radiation doses. Intensity-modulated radiation therapy may double the incidence of solid cancers in long-term survivors. This outcome may be acceptable in older patients if balanced by an improvement in local tumor control and reduced acute toxicity. On the other hand, the incidence of second cancers is much higher in children, so that doubling it may not be acceptable. IMRT represents a special case for children for three reasons. First, children are more sensitive to radiation-induced cancer than are adults. Second, radiation scattered from the treatment volume is more important in the small body of the child. Third, the question of genetic susceptibility arises because many childhood cancers involve a germline mutation. The levels of leakage radiation in current Linacs are not inevitable. Leakage can be reduced but at substantial cost. An alternative strategy is to replace X-rays with protons. However, this change is only an advantage if the proton machine employs a pencil scanning beam. Many proton facilities use passive modulation to produce a field of sufficient size, but the use of a scattering foil produces neutrons, which results in an effective dose to the patient higher than that characteristic of IMRT. The benefit of protons is only achieved if a scanning beam is used in which the doses are 10 times lower than with IMRT.

Information concerning radiation-induced malignancies comes from the A-bomb survivors and from medically exposed individuals, including second cancers in radiation therapy patients. The A-bomb survivors show an excess incidence of carcinomas in tissues such as the gastrointestinal tract, breast, thyroid, and bladder, which is linear with dose up to about 2.5 Sv. There is great uncertainty concerning the dose-response relationship for radiation-induced carcinogenesis at higher doses. Some animal and human data suggest a decrease at higher doses, usually attributed to cell killing; other data suggest a plateau in dose. Radiotherapy patients also show an excess incidence of carcinomas, often in sites remote from the treatment fields; in addition there is an excess incidence of sarcomas in the heavily irradiated in-field tissues. The transition from conventional radiotherapy to three-dimensional conformal radiation therapy (3D-CRT) involves a reduction in the volume of normal tissues receiving a high dose, with an increase in dose to the target volume that includes the tumor and a limited amount of normal tissue. One might expect a decrease in the number of sarcomas induced and also (less certain) a small decrease in the number of carcinomas. All around, a good thing. By contrast, the move from 3D-CRT to intensity-modulated radiation therapy (IMRT) involves more fields, and the dose-volume histograms show that, as a consequence, a larger volume of normal tissue is exposed to lower doses. In addition, the number of monitor units is increased by a factor of 2 to 3, increasing the total body exposure, due to leakage radiation. Both factors will tend to increase the risk of second cancers. Altogether, IMRT is likely to almost double the incidence of second malignancies compared with conventional radiotherapy from about 1% to 1.75% for patients surviving 10 years. The numbers may be larger for longer survival (or for younger patients), but the ratio should remain the same.