8-A842A-2018-Multiple-00021-Chapter 29-ROUND1

559

Chapter 29 Chemical Modifiers of Radiation Response

87. Hanna TP, Kangolle AC. Cancer control in developing countries: using health data and health services research to measure and improve access, quality and efficiency. BMC Int Health Hum Rights 2010;10:24. 88. Knaul FM, Frenk J, Shulman LN, for the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries. Closing the cancer divide: a blueprint to expand access in low and middle income countries. Boston, MA: Harvard Global Equity Initiative, 2011. 89. World Health Organization. Cancer control: knowledge into action: WHO guide for effective programs; module 4. Diagnosis and treatment. Geneva: World Health Organization, 2008. 90. Anderson BO, Shyyan R, Eniu A, et al. Breast cancer in limited-resource coun- tries: an overview of the Breast Health Global Initiative 2005 guidelines. Breast J 2006;12(Suppl 1):S3–S15. 92. Macbeth FR, Abratt RP, Cho KH, et al. Lung cancer management in limited resource settings: guidelines for appropriate good care. Radiother Oncol 2007; 82:123–131. 93. Datta NR, Rajasekar D. Improvement of radiotherapy facilities in developing countries: a three-tier system with a teleradiotherapy network. Lancet Oncol 2004;5(11):695–698. 95. Coffey M, Engel-Hills P, El-Gantiry M, et al. A core curriculum for RTTs (radiation therapists/radiotherapy radiographers) designed for developing countries under the auspices of the international atomic energy agency (IAEA). Radiother Oncol 2006;81:324–325. 96. Podgorsak EB. Radiation oncology physics: a handbook for teachers and stu- dents. Vienna: IAEA, 2005.

97. Ribeiro RC, Pui CH. Saving the children–improving childhood cancer treatment in developing countries. N Engl J Med 2005;352(21):2158–2160. 98. Masera G, Baez F, Biondi A, et al. North-South twinning in paediatric haemato- oncology: the La Mascota programme, Nicaragua. Lancet 1998;352(9144):1923– 1926. 102. Peabody JW, Taguiwalo MM, Robalino DA, et al. Improving the quality of care in developing countries. In: Jamison DT, Breman JG, Measham AR, et al., eds. Disease control priorities in developing countries. Washington, DC: World Bank and Oxford University Press, 2006. 103. Borras C. Overexposure of radiation therapy patients in Panama: problem recog- nition and follow-up measures. Rev Panam Salud Publica 2006;20(2–3):173–187. 106. Mytton OT, Velazquez A, Banken R, et al. Introducing new technology safely. Qual Saf Health Care 2010;19(Suppl 2):i9–i14. 107. Newton RC, Mytton OT, Aggarwal R, et al. Making existing technology safer in healthcare. Qual Saf Health Care 2010;19(Suppl 2):i15–i24. 109. McArdle O, Kigula-Mugambe JB. Contraindications to cisplatin based chemora- diotherapy in the treatment of cervical cancer in Sub-Saharan Africa. Radiother Oncol 2007;83(1):94–96. 113. Frenk J, Chen L. Overcoming gaps to advance global health equity: a symposium on new directions for research. Health Res Policy Syst 2011;9(1):11. 117. Schreiner LJ, Kerr A, Salomons G, et al. The potential for image guided radia- tion therapy with cobalt-60 tomotherapy. In: Ellis RE, Peters TM, eds. Lecture notes in computer science: Proc. 6th Annual International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI). Vol 8. Heidelberg: Springer-Verlag, 2003:449–456.

Chapter 29 Chemical Modifiers of Radiation Response

David S. Yoo and David M. Brizel

Techniques, Modalities, and Modifiers in Radiation Oncology

causing an unacceptable level of morbidity. Conversely, when the two curves are closer together, the treatment may be less effective while causing an unacceptable level of morbidity. The second concept is the efficacy/toxicity profile of the putative chemical modifier, which can directly affect the TR. A radiosensitizing agent that exacerbates toxicity to the same extent that it improves efficacy (shifting both NTCP and TCP curves to the left) may leave the TR unchanged or worsened and not be clinically practical. Conversely, a radioprotective agent that also reduces RT efficacy against the tumor (shifting both NTCP and TCP curves to the right) also may not affect or even reduce the TR. The intrinsic toxicity of a radioprotector must also be considered when reduction of NTCP is the pri- mary goal of a given chemical modification strategy. A com- pound that causes significant side effects of its own may render it unsuitable even if it can reduce the treatment-induced toxic- ity in question. This chapter will explore chemical radiosensiti- zation and radioprotective strategies. The primary focus will be on treatments that have been clinically tested in head and neck cancer in order to amplify these concepts. The Oxygen Effect Tumor cell killing is produced by direct ionizations within criti- cal cellular targets as well as by the indirect effect of energy deposited in other cellular molecules including water. Ionizing radiation generates free radicals, which can lead to cellular death via the creation of single strand and double strand breaks in DNA. This damage can be fixed or repaired by the chemi- cal processes of oxidation and reduction, respectively. 1 The addition of molecular oxygen to target free radicals produces altered chemical structures that are potentially lethal. Tumor hypoxia reduces radiosensitivity in vitro and in vivo. 2,3 Well- oxygenated cells (partial pressure of oxygen or P o 2 > 10 mm Hg) are approximately 2.5 times more sensitive to a given dose of ionizing radiation than their hypoxic counterparts. Chemical Radiosensitization

Chemical agents have been administered in conjunction with radiotherapy (RT) for both the enhancement of antitumor ther- apeutic efficacy and the amelioration of treatment-induced toxicity. Two concepts are fundamental to understanding the rationale for chemical modification of radiation response and to interpreting the studies that have addressed this issue. The first is the therapeutic ratio (TR), which is defined as the TCP/ NTCP where TCP is the tumor control probability and NTCP is the normal tissue complication probability. Both of these parameters have sigmoid dose–response curves (Fig. 29.1). The horizontal separation between these two curves for any given treatment will often determine its overall utility. As the separation between these curves increases, the likelihood increases the odds that the treatment will be effective without

Therapeutic ratio

100%

100%

Probability of local tumor control

Probability of complications

( )

( )

0

0

Dose

Shifts in therapeutic ratio

Figure 29.1.  A graphic representation of the therapeutic index (TI). The tumor control probability (TCP) is to the left of the normal tissue complication probability (NTCP) and both are displayed as sigmoid dose–response curves. Larger separations are indicative of higher TIs. Ideally, normal tissue protection strategies would move the NTCP curve to the right with- out compromising TCP (moving the TCP curve to the right). Ideal therapeutic intensification strategies would move the TCP curve to the left without worsening NTCP (moving the NTCP curve to the left).