Halperin7e_CH29

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S E C T I O N I I  Techniques, Modalities, and Modifiers in Radiation Oncology

noted in 2 patients with each isotope, and 1 patient in the 188 Re-HEDP group experienced grade II thrombocytopenia. Grade I leukopenia was noted in 1 patient in each group. All cases of thrombocytopenia and leukopenia reversed within 12 weeks after therapy. Similar findings have been reported by other investigators. 119,120 FUTURE PERSPECTIVES In order for RIT to be successful, quite simply, an increased dose of high-LET radiotherapy must be delivered to the tumor and a lower dose delivered to normal tissue: 1. Tumor Specificity : To date, there are no true tumor-spe- cific antigens or targets. This is important considering the toxicity of radionuclides. The field must move toward tumor-specific processes. This will result in greater doses to the tumor and less to normal tissue. For example, aptamers can be designed to target tumor cells and then counter selected against normal tissue to produce a “true” tumor-specific targeting construct. 2. High-LET Radiation : Beta radiation is sparsely ioniz- ing and may be effective against hematologic malignan- cies but not against solid tumors (carcinoma). High-LET radiation will be required to combat solid tumors. Alpha radiation will be very effective but potentially toxic. Auger radiation will be very effective with limited toxicity. The caveat, the Auger radionuclide, must enter the nucleus and/or bind DNA. 3. Fractionation : Currently, the successful RIT agents (Zevalin, Bexxar) have been delivered in a single fraction. These agents however have treated radiosensitive hema- tologic malignancies. RIT must be delivered in multiple fractions for solid tumors. For example, platinum-based chemotherapy, used to treat germ cell tumors, was not curative as a single fraction. Multiple fractions were deliv- ered with a noted “log fold” decrease in tumor markers with each fraction (cycle). Potentially survival advanta- geous results seem to be occurring with the multiple frac- tion regimens of Xofigo and Lutathera. 4. Multiple Radionuclides : Individual radionuclides deposit their energy over a known path length. In order to be maximally effective, radionuclides need to deposit their energy over a wide range of micrometastatic and tumor sizes. The effectiveness of multiple radionuclides seems to have come to fruition with peptide therapy ( 90 Y and 117 Lu). The use and incorporation of high-LET radionuclide are quite necessary. One can calculate that the following radionuclide combinations will encompass a subcellular level to tumor level coverage: 125 I, 33 P, 131 I, 32 P. REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin 2016;66:7–30. 2. Torre LA, Bray F, Siegel R, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87–108. 3. Siddiqui M, Rajkumar SV. The high cost of cancer drugs and what we can do about it. Mayo Clin Proc 2012;87:935–943. 4. American Society of Clinical Oncology. Potential approaches to sustainable, long-lasting payment reform in oncology. J Oncol Pract 2014;10:254–258. 5. Abbas AK, Lichtman AH, Pillais S, eds. Cellular and Molecular Immunology . Philadelphia: Saunders Elsevier, 2007. 6. Campoli M, Ferrone S. Cancer immune surveillance and tumor escape mechanisms. In: Speer TW, ed. Targeted Radionuclide Therapy . Philadelphia: Lippincott Williams & Wilkins, 2011:3–21. 7. Liu X,William CC. Precision medicine in immune checkpoint blockade therapy for non-small cell lung cancer. Clin Translat Med 2017;6:1–4. 8. Prehn RT. On the nature of cancer and why anticancer vaccines don’t work. Cancer Cell Int 2005;5:1–5. 9. Jeoung DI. Employing SEREX for identification of targets for anticancer tar- geted therapy. In: Speer TW, ed. Targeted Radionuclide Therapy . Philadelphia: Lippincott Williams & Wilkins, 2011:159–167.

Additionally, all patients received “best standard of care.” The primary end point was overall survival, and the second- ary end points were time to first symptomatic skeletal event and various biochemical end points (median time to increase in alkaline phosphatase [AP] and PSA; ≥30% reduction in AP; normalization of AP). Entry criterion included castrate-resis- tant adenocarcinoma of the prostate (serum testosterone ≤1.7 nmol/L), at least two symptomatic bone metastases, no known visceral disease, PSA ≥5 with at least two consecutive rises, ECOG performance status of 0 to 2, malignant lymphadenopa- thy ≤3-cm short axis, and appropriate hematologic criteria (initial criteria per Bayer;ANC ≥1.5; platelet ≥100; hemoglobin ≥10).The overall survival in the Xofigo group was 14.9 months versus 11.3 months in the placebo group ( P < .001 ). All sec- ondary end points had a benefit from Xofigo versus placebo ( P < .001). 114 Subsequently, many questions regarding the use and sequencing of chemotherapy with Xofigo remained. In a prespecified subgroup analysis of the ALSYMPCA trial, Xofigo appeared to be equally effective before or after docetaxel, concerning overall survival. 115 A separate analysis of patients in the ALSYMPCA trial receiving chemotherapy after Xofigo was performed. The conclusion was that chemotherapy fol- lowing Xofigo, regardless of prior docetaxel, is feasible and appears to be well tolerated. 116 Current areas of research include using higher activities per injection, increased overall number of doses, use in other nonprostate metastatic bone disease processes, and CMT with EBRT. Rhenium-186 HEDP (Etidronate) Physical Properties: t ½ = 3.8 days; radiation decay: β (1.07 MeV maximum and 0.336 mean); γ (0.137 MeV maximum). Clinical Utility : Although not commercially available in the United States, 186 Rh-HEDP has been studied in phase I trials in Europe in association with autologous peripheral blood stem cell rescue in the management of hormone-refractory prostate cancer metastatic to bone. Phase I/II trials using 186 Rh-HEDP for castrate-resistant prostate cancer have indi- cated the potential for prolonged survival. 117 Rhenium-188 HEDP (Etidronate) Physical Properties : t ½ = 16.9 hours; radiation decay: β (2.1 MeV maximum and 0.779 mean); γ (0.155 MeV maximum and 0.061 mean). Clinical Utility : Although not commercially available in the United States, 188 Re-HEDP has been studied in Europe for some time. The agent is produced by a generator simi- lar to that used to produce 99m Tc, enabling wide availabil- ity at relatively low cost. Liepe et al. 118 reported treatment of 46 patients with multiple bone metastases from breast and prostate cancer with pain. Thirty-one patients received 188 Re-HEDP (3,300 MBq) and 25 patients received 153 Sm-EDTMP (37 MBq/kg of body weight). All patients had a single injection of isotope. Patients with prostate cancer received hormone therapy for 6 months before isotope ther- apy and during the postisotope observation period. Thirty- nine patients received bisphosphonates for 6 months prior to study treatment with discontinuance of the agents 1 month prior to isotope administration. In posttherapy evalu- ation, only the 188 Re-HEDP group had a statistically signifi- cant improvement in the Karnofsky performance score. Pain relief within 2 weeks of treatment was noted in 77% of the 188 Re-HEDP group and in 73% of the 153 Sm-EDTMP group. These results were not statistically significant, and there was no significant difference between responses in the patients with prostate or breast cancer. A brief flare reaction was noted in 17% of patients in both groups within 14 days of therapy, and the majority of patients demonstrated a maxi- mum of grade I anemia within 12 weeks of therapy based on the 1979 WHO criteria. Grade I thrombocytopenia was