Boosting Effectiveness of Radiation Against Childhood Cancers

By Peter Anderson, MD, PhD

Osteosarcoma is the most common primary malignancy of the bone in children, adolescents and young adults. As osteosarcoma is a bone-forming tumor, bone formation in the specimen is the hallmark that clinches the pathologic diagnosis of this cancer by light microscopy. New bone formation also results in high uptake of the 99mTc-MDP tracer on standard bone scans, and bone-seeking radiopharmaceuticals provide opportunities for targeted therapy.

Bone-seeking radiopharmaceuticals as alpha particle therapy

These opportunities stem in part from multicenter studies I have been involved with for more than a decade. Our group showed that a 30× dose escalation of the bone-seeking radiopharmaceutical samarium (153Sm-EDTMP) was possible — if cryopreserved stem cells were given two weeks later — and that many patients had excellent responses.1 Gemcitabine, a radiosensitizer, subsequently increased the response rate further.2

Figure 1. Depiction of the mechanism of action of radiation therapy (DNA breaks) caused by beta particles and conventional photon radiotherapy versus protons and alpha particles. Beta particles and conventional radiotherapy are characterized by low mass and ionization potential, with rest mass energy of 0.5 MeV. In contrast, alpha particles and protons are characterized by high mass and ionization potential, with rest mass energy of 3,800 and 938 MeV, respectively.

Because 153Sm is a lower-energy beta (electron) emitter that causes single-stranded DNA breaks that are easy for cancer cells to repair (Figure 1), relapses were common within six to 18 months. Instead of continuing with samarium, a new kid on the block, the alpha- emitting radiopharmaceutical 223-radium (223Ra), was studied.

Since alpha particles are much more massive and energetic than beta emitters but act at shorter distances (0.1 mm), resistance to 223Ra should be less frequent and collateral damage to normal marrow much less than with samarium (Figure 1). Our group recently completed a study that escalated the 223Ra dose in osteosarcoma to 100 kBq/kg, which is twice as high as the level used for this agent’s FDA-approved indication for prostate cancer. Findings included:

• The first demonstration of activity against brain metastasis
• Clinical benefit in over half the patients (less pain, and improvement in scans)

The Na18F PET-CT was the most sensitive and specific scan to determine response. These results were presented at the 47th Congress of the International Society of Paediatric Oncology (SIOP) in Capetown, South Africa, Oct. 9, 2015.3 Future studies are planned to determine use of this “designer drug” for osteosarcoma with current chemotherapy.

Lymphocytes are important survival predictors in childhood cancers

Figure 2. Schema of how inflammation causes a (mal)adaptive immune response. In cancer, however, PD-1 and CTLA4 (red triangles and octagons) can inhibit lymphocyte function. Tumor growth and cancer may increase the (mal)adaptive immune response and increase PD-1 and CTLA4. The combination of anti-PD-1, anti-CTLA4 and radiotherapy (RT) may release immune checkpoint inhibition and allow T-cells to proliferate and more effectively kill tumor cells (bottom), resulting in better local control and possible out-of-field (abscopal) responses.

The speed and extent of recovery of lymphocytes after chemotherapy (improved absolute lymphocyte count) is associated with superior survival in childhood cancers including Ewing sarcoma, osteosarcoma and even acute lymphoblastic leukemia (ALL). Recovery of absolute lymphocyte count has been shown to be a more powerful independent predictor of survival than percent necrosis of osteosarcoma surgical specimens; it is also an independent and significant predictor compared with more complicated and expensive flow cytometry tests of minimal residual disease in ALL. Inflammation associated with cancer and cancer therapy can result in increased expression of PD-1 and CTLA4, immune checkpoint molecules associated with a (mal)adaptive downregulation of lymphocyte function (Figure 2). Antibodies against PD-1 and CTLA4 have offered new hope for patients, releasing the lymphocytes to function better and sometimes even resulting in out-of-field (abscopal) responses after radiotherapy (RT)4 (Figure 2). With greater precision now possible using stereotactic body RT, proton RT, and more precise RT with image guidance, RT should not only cause less inflammation but also become a potential tool to induce “vaccine effects.”

We have submitted a grant to study how using RT with checkpoint inhibitors could result in better immune function — i.e., “making lemonade out of lemons.” We think it is indeed possible that in the future, radiation will become something to be desired, instead of feared, in a childhood cancer therapy plan — and this may help RT act like a cancer vaccine.

References

1. Anderson PM, Wiseman GA, Dispenzieri A, et al. High-dose samarium-153 ethylene diamine tetramethylene phosphate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol. 2002;20:189-196.
2. Anderson PM, Wiseman GA, Erlandson
L, et al. Gemcitabine radiosensitization after high-dose samarium for osteoblastic osteosarcoma. Clin Cancer Res. 2005;11: 6895-6900.
3. Anderson P, Ladra M, Subbiah V, Murphy E, McAleer MF, Rohren E. Principles
and advances of 223-radium and proton particle therapy in bone-forming tumors including osteosarcoma. Pediatr Blood Cancer. 2015;62(suppl 4):S210. Abstract O-255.
4. Twyman-Saint Victor C, Rech AJ, Maity
A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer [letter]. Nature. 2015;520:373-377.

Additional references are available by contacting the author (andersp@ccf.org).

Dr. Anderson is a staff physician in the Department of Pediatric Hematology, Oncology and Blood & Marrow Transplantation.