(P 018) COMPLETE RESPONSE TO MODEST DOSE RADIATION IN OSTEOSARCOMA METASTASIS IN TWO PATIENTS WITH LI-FRAUMENI SYNDROME

Objective: BACKGROUND:
Li-Fraumeni Syndrome (LFS) is an autosomal dominantly inherited condition caused by mutations of the TP53 tumor suppressor gene encoding p53. P53, often described as “the guardian of the genome” is a transcription factor that regulates cell division and cell death. Loss of or damage to p53 function in patients with LFS renders these individuals highly susceptible to different cancers. In addition, radiation-induced second cancers have previously been reported among individuals with this TP53 mutation. However, a recent review found that in patients with Li-Fraumeni, there is no significant association between radiation therapy and secondary malignancies. Instead, the higher rate of reoccurrence or secondary malignancies is more likely a reflection of a more aggressive cancer, unrelated to an increased radiation sensitivity (Hendrickson et al., 2019).

OBJECTIVE:
To treat osteosarcoma (OST) specifically, high levels of radiation are typically necessary for complete treatment. Due to the known sensitivity to radiation in patients with LFS, radiation is often used at low doses for palliation and not typically a treatment option. Typical palliation doses have been reported in pediatric osteosarcoma cases as 40.0 Gy (range, 20.-60.4) with a median number of fractions per course as 15 (range 5-39) (Chen et al., 2019). Another institution reported the mean dose applied for palliation was 47 Gy (range, 26 Gy to >70 GyE), and for cure was 59 Gy (range, 45 Gy to >70 GyE) (Oertel et al., 2018).
We report two cases of successful responses to modest dose radiation in osteosarcoma metastasis in patients with Li-Fraumeni Syndrome. As far as we know, this is the first reporting of a complete response for patients with osteosarcoma to moderate dose radiation.

Methods: A literature review limited to the last 15 years was conducted on Google Scholar using the keywords: “Li-Fraumeni”, “osteosarcoma”, “radiation”, and “checkpoint inhibitors.”

CASE REPORT:

Patient 1 is a 12-year-old male with known LFS, previously healthy, who presented with a 7.8 x 9.0 x4.8 cm mass of the distal tibial mass with metastasis to the T12 vertebrae and right fourth rib, evident on PET. He was diagnosed with osteoblastic osteosarcoma and started conventional chemotherapy with methotrexate, doxorubicin, and cis-platinum, but all the masses progressed after 3 months on bone scan. He was switched to a palliative paradigm and started on pembrolizumab every three weeks with concurrent stereotactic radiotherapy (SBRT) 36 Gy to the right foot, T12, and right fourth rib lesion. Four months later he had a right, below-the-knee amputation. Pathology showed no viable cells, 100% necrotic. A follow-up PET scan showed new areas of disease in the T4 and T5 vertebrae, but no uptake at the previously irradiated T12 lesion. He continued on systematic therapy of zoledronic acid, oral lenvatinib, and nivolumab for 8 more months with concurrent 25Gy SBRT to T4-T5 paraspinal masses. Both areas showed sustained radiologic response at 6 and 12 months.


Patient 2 is an 18-year-old male with known LFS, previously healthy, who presented with a 6.3 x 4.3 x 4.8 cm mass of the distal femur mass without metastasis. He was diagnosed with osteoblastic osteosarcoma and started conventional chemotherapy with methotrexate, doxorubicin, and cis-platinum. He achieved remission with surgery at 3 months (80% necrosis) followed by 6 cycles of the same chemotherapy given in the adjuvant setting.
Four months after completing therapy, he had a lung relapse and large sacral relapse (12 x 8 x 7.6cm) involving multiple nerve roots. The lung lesion was resected. The sacral lesion was unresectable without a hemipelvectomy which the patient refused. He also refused more chemotherapy so was started on nivolumab 3mg/kg IV every 2 weeks, lenvatinib 12 mg daily, and zoledronic acid 4 mg IV every and concurrent SBRT, 50 Gy to the sacral lesion.
Like patient 1, he also experienced diffuse relapse but not in the radiated field.
A follow-up at 12 months verified a complete response by PET to the irradiated area (figure 2).

Results: With doses typically used for palliation, we observed two patients with a complete response. One patient had a complete response shown by PET, confirmed histologically, and the other had a complete response based on PET scan (fig 1 and 2).

Conclusion: In patients with LSF, radiation has historically been omitted out of concern for inducing a second malignancy. Despite a strong theoretical rationale, however, there may be inadequate clinical data to support this concern (P. Hendrickson et al., 2020.) We show two examples of excellent responses to moderate dose radiation in OST with LFS. Both patients were treated with checkpoint inhibitors, which have been proven effective in several other cancer types, but their efficacy in treating OST specifically is still under review (S. Miwa et al., 2019). Treatment of OST with low to moderate doses of radiation in combination with TP53 checkpoint inhibitors in patients with Li-Fraumeni is worthy of consideration due to increased radiation sensitivity. Radiation in OST should be considered in patients where surgery is not an option and may be especially effective in patients with LFS or with concurrent checkpoint inhibitors.