Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes.

The management of patients with cancer and Li-Fraumeni or heritable TP53-related cancer syndromes is complex because of their increased risk of developing second malignant neoplasms after genotoxic stresses such as systemic treatments or radiotherapy (radiosusceptibility). Clinical decision making also integrates the risks of normal tissue toxicity and sequelae (radiosensitivity) and tumour response to radiotherapy (radioresistance and radiocurability). Radiotherapy should be avoided in patients with cancer and Li-Fraumeni or heritable TP53 cancer-related syndromes, but overall prognosis might be poor without radiotherapy: radioresistance in these patients seems similar to or worse than that of the general population. Radiosensitivity in germline TP53 variant carriers seems similar to that in the general population. The risk of second malignant neoplasms according to germline TP53 variant and the patient's overall oncological prognosis should be assessed during specialised multidisciplinary staff meetings. Radiotherapy should be avoided whenever other similarly curative treatment options are available. In other cases, it should be adapted to minimise the risk of second malignant neoplasms in patients who still require radiotherapy despite its genotoxicity, in view of its potential benefit. Adaptations might be achieved through the reduction of irradiated volumes using proton therapy, non-ionising diagnostic procedures, image guidance, and minimal stray radiation. Non-ionising imaging should become more systematic. Radiotherapy approaches that might result in a lower probability of misrepaired DNA damage (eg, particle therapy biology and tumour targeting) are an area of investigation.

Radiation therapy and secondary malignancy in Li-Fraumeni syndrome: A hereditary cancer registry study.

BACKGROUND: Li-Fraumeni Syndrome (LFS) is a rare cancer-predisposing condition caused by germline mutations in TP53. Conventional wisdom and prior work has implied an increased risk of secondary malignancy in LFS patients treated with radiation therapy (RT); however, this risk is not well-characterized. Here we describe the risk of subsequent malignancy and cancer-related death in LFS patients after undergoing RT for a first or second primary cancer. METHODS: We reviewed a multi-institutional hereditary cancer registry of patients with germline TP53 mutations who were treated from 2004 to 2017. We assessed the rate of subsequent malignancy and death in the patients who received RT (RT group) as part of their cancer treatment compared to those who did not (non-RT group). RESULTS: Forty patients with LFS were identified and 14 received RT with curative intent as part of their cancer treatment. The median time to follow-up after RT was 4.5 years. Fifty percent (7/14) of patients in the curative-intent group developed a subsequent malignancy (median time 3.5 years) compared to 46% of patients in the non-RT group (median time 5.0 years). Four of seven subsequent malignancies occurred within a prior radiation field and all shared histology with the primary cancer suggesting recurrence rather than new malignancy. CONCLUSION: We found that four of14 patients treated with RT developed in-field malignancies. All had the same histology as the primary suggesting local recurrences rather than RT-induced malignancies. We recommend that RT should be considered as part of the treatment algorithm when clinically indicated and after multidisciplinary discussion.

Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes.

In recent years the use of radiation treatment for benign tumours has increased with the advent of stereotactic delivery and, in particular, single high dose gamma knife therapy. This has been particularly true for benign CNS (central nervous system) tumours such as vestibular schwannoma, meningioma, pituitary adenoma, and haemangioblastoma. While short term follow up in patients with isolated tumours suggests this treatment is safe, there are particular concerns regarding its use in childhood and in tumour predisposing syndromes. We have reviewed the use of radiation treatment in these contexts with particular regard to malignant transformation and new tumour induction. This review indicates that much more caution is warranted regarding the use of radiation treatment for benign tumours in childhood and in tumour prone conditions such as the neurofibromatoses.

Radiation therapy for choroid plexus carcinoma patients with Li-Fraumeni syndrome: advantageous or detrimental?

BACKGROUND: Choroid plexus carcinomas (CPCs) are rare pediatric tumors often associated with Li-Fraumeni Syndrome (LFS), a germline mutation in the TP53 tumor-suppressor gene, predisposing to cancer. MATERIALS AND METHODS: We performed a systemic literature review from 1990-2013 to evaluate the hypothesis that radiation therapy should be avoided in patients with CPC and LFS. Overall survival (OS) was compared using Kaplan-Meier curves and log-rank tests. RESULTS: Twenty-eight patients were documented with CPC and LFS. Eleven out of 17 patients received radiation therapy. The survival of patients receiving radiation was inferior to that of those without radiation [median (±95% confidence interval) 2-year OS=0.18 ± 0.12% versus 0.58 ± 0.12%]. The log-rank tests suggested the difference to be marginally significant (p=0.056). CONCLUSION: This finding provides evidence for pursuing treatment approaches that do not include radiation therapy for patients with LFS.

[Genetic predisposition and radiation sensitivity of normal tissue]. / Genetische Prädisposition und Strahlenempfindlichkeit bei normalen Geweben.

BACKGROUND: After radiotherapy there are always some patients who develop strong acute and late reactions in normal tissues. In these patients frequently a genetic predisposition is observed. There are found DNA-repair deficiencies and changes in the regulation of the cell cycle which are responsible for the increased radiosensitivity with enhanced cell killing. METHODS: The micronucleus test and the comet assay appear to be appropriate tests in order to measure this increased radiosensitivity. Both tests are characterized by being relatively quick and simple and can be performed with small cell numbers. It is possible to study blood lymphocytes and fibroblasts with these tests. RESULTS: Both tests can predict the radiosensitivity of normal tissues especially if they are applied in combination. CONCLUSIONS: Epidemiological studies with patients after radiotherapy show evidence that the increased radiosensitivity also causes an enhanced induction of secondary tumors by ionizing radiation. This is supported by corresponding animal models.