Lecture 22 Radiobiological aspects of alternative dose delivery system

1. Lecture 22 Radiobiological aspects of alternative dose delivery system

2. Protons High LET sources BNCT Stereotactic radiosurgery/radiotherapy, IMRT, IORT: Dose distribution and dose heterogeneity

3. Alternative Radiation Modalities The early recognition that X-rays could produce local tumor control in some patients and not in others led to the notion that other forms of ionizing radiations might be superior. In the case of neutrons, they give up their energy to produce recoil protons, alpha-particles, and heavier nuclear fragments. Consequently, their biologic properties differ from those of X-rays: reduced OER, little or no repair of sublethal damage, and less variation of sensitivity through the cell cycle. Protons have radiobiologic properties similar to those of X-rays; Negative π-mesons and heavy ions were introduced with the hope of combining the radiobiologic advantages attributed to neutrons with the dose distribution advantage characteristic of protons.

4. Alternative Radiation Modalities Neutrons - superior to X-rays in a limited number of situations, specifically for prostate cancer, salivary gland tumors, and possibly soft-tissue sarcomas; Protons - used for treatment of uveal melanoma and tumors such as chordomas-they are located close to spinal cord and benefit from the localized dose distribution. The wider use of protons for broad- beam radiotherapy is being tested now. Negativeπ-mesons and heavy ions have been used to treat hundreds of patients, but the trials have never been completed to prove their superiority over conventional X-rays.

5. Fast Neutrons The first clinical use of neutrons

6. Alternative Radiation Modalities Fast Neutrons. Practical sources The only practical source of neutrons for clinical radiotherapy is a cyclotron. Cyclotron is an electric device capable of accelerating positively charged particles, such as protons or deuterons, to an energy of millions of volts

7. Alternative Radiation Modalities Fast Neutrons More recently, cyclotrons to produce neutrons have been built using the p+ Be reaction. The cyclotron can be small enough to be installed in a hospital. Neutron spectra produced by the two processes are shown

8. Percentage Depth Doses for Neutron Beams An essential factor in the choice of a neutron beam for clinical use is its ability to penetrate to a sufficient depth.

9. Current Efforts with Neutrons • Emphasis is being placed on two factors: • First, subgroups of patients with specific types of tumors • that may benefit from neutrons must be found. • Second, different fractionation patterns will be tried • for neutrons.

10. Current efforts with neutrons Emphasis will be placed on slowly growing tumors, in view of the observation of Breuer and Batterman that neutron RBE, measured from pulmonary metastases in patients, increases as tumor volume doubling time increases

11. Protons Protons are attractive for radiotherapy because of their physical dose distribution. The RBE of protons is undistinguishable from that of 250-kV X-rays, which means that they are 10 to 15% more effective than cobalt-60 gamma-rays or megavoltage X-rays generated by a linear accelerator. The OER for protons is undistinguishable from that for X-rays, namely about 2.5 to 3. These biologic properties are consistent with the physical characteristics of high-energy proton beams; they are sparsely ionizing.

12. Protons The dose deposited by a beam of monoenergetic protons increases slowly with depth, but reaches a sharp maximum near the end of the particle’s range in the Bragg peak. Proton beams ranging in energy from 150 to 200 MeV are of interest in radiotherapy because this corresponds to a range in tissue of 16 to 26 cm.

13. Protons The way the Bragg peak can be spread out to encompass a tumor of realistic size is shown. The spread-out Bragg peak can be made narrower or broader as necessary

14. Protons Many researchers consider protons to be the treatment of choice for choroidal melanoma. Protons have found a small but important place in the treatment of ocular tumors and also some specialized tumors close to the spinal cord

15. Protons Current proton therapy facilities worldwide, light- and heavy-charged- particle facilities, and the number of patients treated

16. Protons

17. Protons Most of the protons machines were built initially for physics research and were located in physics laboratories.

18. Protons High LET sources BNCT Stereotactic radiosurgery/radiotherapy, IMRT, IORT: Dose distribution and dose heterogeneity

19. Boron Neutron-Capture Therapy (BNCT) The basic idea behind boron neutron-capture therapy (BNCT) is elegant in its simplicity. The idea is to deliver to the cancer patient a boron-containing drug that is taken up only in tumor cells and then to expose the patient to a beam of low-energy (thermal) neutrons that themselves produce little radiobiologic effect but that interact with the boron to produce short-range, densely ionizing alpha-particles. Thus, the tumor is intensely irradiated, but the normal tissues are spared.

20. Boron Neutron-Capture Therapy (BNCT) • There are two problems inherent in this idea: • What is a “magic” drug that distinguish malignant cells • from normal cells? • The low-energy neutrons necessary for BNCT are poorly • penetrating in tissue

21. Boron Neutron-Capture Therapy (BNCT) Boron compounds • For BNCT to be successful, the compounds used should have • high specificity for malignant cells, with low concentrations • in adjacent normal tissues and in blood. • The two classes of compounds have been proposed: • Low-molecular weight agents that simulate chemical precursors • required for tumor cell proliferation, can traverse cell membrane • and be retained intracellularly.Two boron compounds, the • BSH and BPA, have been identified and used to treat brain tumors.

22. Boron Neutron-Capture Therapy (BNCT) Boron compounds • High molecular-weight agents such as monoclonal • antibodies and bispecific antibodies. • These are highly specofoc, but very small amounts reach • brain tumors following systemic administration. • Boron-containing conjugates of epidermal growth factor, the • receptor for which is overexpressed on some tumors, • also have been developed.

23. Neutron Sources for BNCT During fission within the core of a nuclear reactor, neutrons are “born” that have a wide range of energies. Neutron beams can be extracted from the reactor. Current interest in the United States focuses on the use of epithermal neutron beams (1-10,000 eV), which have a greater than thermal neutrons (0.025 eV) depth of penetration. These neutrons do not themselves interact with the boron but are degraded to become thermal neutrons in the tissue by collisions with hydrogen atoms. The need for a nuclear reactor as a source for neutrons is a serious limitation and would preclude BNCT facilities in densely populated urban areas.

24. Protons • High LET sources • BNCT • Stereotactic radiosurgery/radiotherapy, • IMRT, IORT: Dose distribution and dose heterogeneity

25. Stereotactic radiosurgery/radiotherapy

26. Stereotactic radiosurgery/radiotherapy What is stereotactic radiosurgery? Stereotactic radiosurgery is a medical procedure that utilizes very accurately targeted, large “killing” doses of radiation. This noninvasive “operation”has proven to be an effective alternative to surgery or conventional radiation for treating many small tumors and a few other select medical disorders. Standard stereotactic techniques rely on a rigid metal frame fixed to a patient’s skull for head immobilization and target localization. However, such frame-based systems have numerous limitations, including: 1) restricting treatment to the brain, 2) limiting the possible angles which radiation could be delivered,3) causing considerable discomfort for the patient. In contrast to the standard frame-based radiosurgical instruments, the CyberKnife uses noninvasive image-guided localization, and a robotic delivery system. This combination of technologies enables the CyberKnife to overcome the limitations of older frame-based radiosurgery such as the Gamma Knife and LINAC.

27. Stereotactic radiosurgery/radiotherapy What is image-guided CyberKnife radiosurgery? The present design of the CyberKnife derives from the original concept of a frameless alternative to frame-based radiosurgery. The CyberKnife consists of three key components: 1) an advanced, lightweight linear accelerator (LINAC) (this device is used to produce a high energy (6MV) "killing beam" of radiation), 2) a robot which can point the linear accelerator from a wide variety of angles, and 3) several x-ray cameras (imaging devices) that are combined with powerful software to track patient position. The cameras obtain frequent pictures of the patient during treatment, and use this information to target the radiation beam emitted by the linear accelerator. The robot is instrumental in precisely aiming this device. When a patient moves during treatment, the change in position is detected by the cameras, and the robot compensates by re-targeting the linear accelerator before administering the radiation beam.

28. Stereotactic radio-surgery/radiotherapy This process of continually checking and correcting ensures accurate radiation targeting throughout treatment.In summary, the CyberKnife replaces the stereotactic head frame with a patient-friendly image-guided localization system. This technology has the added benefit of enabling the CyberKnife to be used for radiosurgical applications outside the brain and for staged radiosurgery. It is difficult if not impossible to perform these other procedures with standard frame-based radiosurgical systems

29. Stereotactic radio-surgery/radio-therapy Performance characteristics for gamma knife

30. Stereotactic radio-surgery/radio-therapy Test of the gamma-knife

31. Stereotactic Radiosurgeryinvolves a radiation treatment procedure designed to treat small intracranial tumors.  The radiation is produced by a linear accelerator that is collimated (focused) to create a small beam size and directed towards the center of the the treatment field.  The tumor's location is pinpointed in the intracranial space using a stereotactic method that accesses diagnostic images (CT scans) and markers to allow a positioning frame to be mounted on the patient's head for reference when treatment is started.     Radiation treatment beams are directed to the target by rotation of the therapy machine through various arcs around the patient's head. 

32. Example.The Novalis Shaped Beam Surgery system represents cutting-edge technology for the delivery of highly precise radiation treatments within the brain as well as other areas of the body.  The Novalis system will allow a multidisciplinary group of medical specialists to showcase the latest innovation in stereotactic radiosurgery.  The Novalis system features an image-guided localization technique to allow radiation oncologists to pinpoint tumors with sub-millimeter accuracy and to position patients automatically and with a higher degree of precision.  The Novalis system is able to precisely contour the shape of a tumor from any angle and achieves a more consistent superior dose distribution.  Radiosurgery is a proven alternative for many indications in the brain, head and neck and spine. The Novalis system represents an advancement that will allow neurosurgery, surgical and radiation oncology teams a wider ranger of applications for radiosurgery throughout the body.  

33. The Novalis system

34. The Novalis system

35. The Novalis system

36. IMRT The development of Intensity Modulated radiation Therapy (IMRT), tomography, and proton/light-ion beams results in greatly improved dose distributions, with more limited doses to normal tissues for comparable tumor doses. This suggests the attractive possibility of increasing the dose per fraction, since the need to spare late responding normal tissues by fractionation is reduced, because of the lower dose to these tissues

37. Photons IMRT A typical dose distribution that can be obtained with IMRT (intensity-modulated proton therapy) compared with intensity- modulated photon therapy is shown on the next slide. It is striking that with protons, the dose can be confined to the target volume, with much less irradiation of normal structures. With photons, a large fraction of the lungs are exposed to low doses of radiation.

38. Dose distribution obtained with Photons IMRT compared with Protons IMRT

39. Carbon Ion Radiotherapy There is a sufficient renaissance of interest in heavy-ion radiotherapy, in particular, on high- energy carbon ions. Depth-Dose Profiles The depth at which the Bragg peak occurs depends on the energy of carbon ions

40. Carbon Ion Radiotherapy RBE considerations For carbon ions RBE increases toward the end of the particle range. The rapid change of RBE with depth is shown