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Unformatted text preview: Applications of Proton Beam Radiation Radiation Jean Paul Font, MD Vicente Resto, MD, Ph.D. University of Texas Medical Branch Department of Otolaryngology Grand Rounds Presentation June 18, 2008 History of Radiation Therapy History First accidental radiobiological experiment – Becquerel in 1898 Left 200 mg of radium in his vest pocket for 6 Left hours – resulted in erythema and ulceration of his skin that took weeks to heal skin During the early 1900’s, During – Bergonie and Tribondeau Bergonie radiosensitivity was highest in tissues with the highest mitotic index History of Radiation Therapy History Fractionation – Researchers in Paris Researchers Beneficial effects of fractionation on normal tissues tissues – By irradiating the testes of rams using a By fractionated technique, these animals were made sterile while relatively sparing their skin made – Giving them one big dose of radiation did not Giving sterilize these animals without causing a severe skin reaction severe History of Radiation Therapy History Further advances in the 1950s – Allowed higher energy radiation units to Allowed be built to allow further penetration of tissues with greater skin sparing tissues – Linear accelerators – faster & higher Linear energy radiation beams energy History of Proton Therapy History Dr Robert Wilson – A Harvard University physicist who played a Harvard central role on the development of the atomic bomb bomb – Published a paper in 1946 that first proposed Published the medical use of protons for cancer therapy the In 1954 – The University of Berkeley began using proton The technology after the construction of a cyclotron to treat cancer patient cyclotron Proton Therapy Proton As of 5/20/08, 55,000 patients have been treated with proton therapy As World Wide World In the United State there are five facilities offering this treatment Approximately 20,000 patients have been treated between two of this Approximately facilities facilities – The Harvard cyclotron laboratory at Massachusetts General The Hospital – The Proton Treatment Center at Loma Linda University Medical The Center (LLUMC) The other three new centers providing this service in the US are – M.D. Anderson Proton Therapy Center in Houston – University of Florida's Shands Medical Center in Jacksonville University – University of Pennsylvania's proton facility in Philadelphia Mechanism of radiation therapy Mechanism Electromagnetic radiations (x-rays and Electromagnetic gamma rays) gamma – Produce biological damage indirectly – They release their energy by colliding with They cells producing fast-moving electrons – Their energy is converted into heat in the form Their of thermal energy which breaks chemical bonds bonds – These weak chemical bonds that are broken These lead to cell death lead Mechanism of Radiation Therapy Mechanism X-rays reach their tissues it takes some distance X-rays for the interactions to summate and reach a maximum maximum This fact accounts for the skin sparing properties This of conventional radiation – the maximum dose occurs below the skin surface occurs After which the energy of the beam dissipates by After a constant fraction per unit depth constant Mechanism of Proton therapy Mechanism Protons pass near orbiting electrons, pulling them Protons out of their orbits causing ionization out Changes the characteristics of the atom and of the Changes molecule Damaging the DNA destroys specific cell functions, particularly the ability to divide or proliferate particularly While both normal and cancerous cells go through While this repair process, a cancer cell's ability to repair molecular injury is frequently inferior molecular This permits selective destruction of bad cells This growing among good cells growing among Particles Particles Electron beams – Lower energy beams Lower Maximal effect upon reaching skin and subcutaneous tissue Energy dissipates rapidly after reaching these tissues Energy More appropriate for skin and clearly visible mucosal More cancers cancers – This becomes important when irradiating certain This neck lymphadenopathy neck – These electron beams are able to reach the lymph These nodes fairly well but then their energy drops off quickly so that the spinal cord is spared of radiation radiation Neutrons and Protons Neutrons The energy required to accelerate these The particles is quite high particles The machines are quite expensive thus The these beams are not commonly available these The MD Anderson Cyclotron cost The approximately $150 million approximately 235MeV proton cyclotron used for proton cancer 235MeV therapy at Boshan, China Hydrogen plasma ion source inside of the accelerator Neutrons Neutrons Advantages Advantages – Neutron beams are less affected by tumor Neutron hypoxia and repair of sublethal damage is lessened lessened Disadvantage – Despite encouraging local control outcomes, Despite neutron studies have shown high rates of adverse effects and their use has been largely discontinue discontinue Protons vs Photons Protons Irradiate smaller volume Irradiate of normal tissues of Photon beam decreases Photon exponentially with depth in the irradiated tissues in Protons have a finite Protons range range Protons deposit most of Protons their radiation energy in what is known as Braggs peak peak Image courtesy of Annie Chan Protons vs Photons Protons Irradiate smaller volume Irradiate of normal tissues of Photon beam decreases Photon exponentially with depth in the irradiated tissues in Protons have a finite Protons range range Protons deposit most of Protons their radiation energy in what is known as Braggs peak peak Image courtesy of Dr Annie Chan, Dept of Radiation Oncology, MGH, Boston, MA Bragg’s Peak Bragg’s Described by William Described Bragg over 100 years ago ago Depth is dependent Depth on the energy of the proton beam proton This energy can be This control very precisely control Image courtesy of Dr Annie Chan, Dept of Radiation Oncology, MGH, Boston, MA beam entrance beam exit unecessary radiation in normal tissues beam exit rapid dose fall-off Tissue beyond the target receives very little or no radiation Image courtesy of Dr Annie Chan, Dept of Radiation Oncology, MGH, Boston, MA Improved therapeutic index Improved – Irradiate smaller volume of normal tissues Ability to intensify dose – Higher doses to target zone Improve dose conformation Image from Greco C. Current Status of Radiotherapy With Proton and Light Ion Beams. American CANCER society April 1, 2007 / Volume 109 / Number 7 IMRT IMRT Intensity modulated Intensity radiation therapy – Consist of radiation portals Consist – Target structures receive Target photon radiation from different portals to achieve desire dose desire – Adjacent structures Adjacent receive a “bath effect” before and beyond the target zone Image from CHAN A.. Proton Radiation Therapy for Head and Neck Cancer. Journal of Surgical Oncology 2008;97:697–700 IMPT IMPT Intensity modulated proton Intensity therapy (IMPT) – Radiation portals which adds Radiation more accuracy to target zone more – Also, in contrast to the twodimensionality of IMRT, dimensionality IMPT is able to modulate the Bragg peak allowing threeBragg dimensional optimization. dimensional Image from CHAN A.. Proton Radiation Therapy for Head and Neck Cancer. Journal of Surgical Oncology 2008;97:697–700 IMRT IMRT IMPT Image from CHAN A.. Proton Radiation Therapy for Head and Neck Cancer. Journal of Surgical Oncology 2008;97:697–700 Proton Therapy Proton Spread-out Bragg peaks (SOBP) – The dose peak may be ‘spread out’ to achieve a uniform dose Spot scanning method – Recently introduce – Small pencil beams of a certain energy Small deposit their peaks to obtain ‘dose-sculpting’ of the target of Dose Equivalent Dose Relative biological effectiveness (RBE) Relative – Ratio of the photon dose to the particle dose Ratio required to produce the same biological effect required An RBE value of 1.1 is generally accepted for An clinical use with proton beams clinical Gray equivalents (GyE) or cobalt Gray Gray equivalents (CGE) often used with protons equivalents – Gray multiplied by the relative biological Gray effectiveness (RBE) factor specific for the beam used used Carbon ions Carbon The RBE of carbon ions has a estimated The value of 3 Carbon ion therapy attempts to capture the ‘best of both worlds,’ – Presence of the proton’s Bragg peak Presence – Advantage of their high RBE to increase the Advantage tumor control probability tumor Uses of Proton radiation Uses Initially, the major emphasis in clinical research Initially, for proton and light ion therapy – Dose escalation for radioresistant tumors – Lesions adjacent to critical normal structures Since the advent of IMRT – Protocols aimed at morbidity reduction – Emphasis for reduced risk of radiation-induced Emphasis carcinogenesis with protons – In the pediatric setting Higher inherent susceptibility of tissues Benefits of protons Pediatric Malignancies Pediatric Depending on the sites of irradiation – Growth, intelligence, cosmesis, endocrine Growth, function, fertility and organ function function, Radiation side effects become an even more Radiation serious concern for very young patients (age <3 years), whose tissues have been shown to be especially susceptible to radiation damage especially The most devastating long-term side effect of RT The remains the induction of a second malignancy (generally sarcomas) (generally Pediatric Malignancies Pediatric Bath effect IMRT pose a Bath concern – Integral dose to healthy Integral nontarget tissues may leads to higher risk of malignancies over the lifetime lifetime Image from Greco C. Current Status of Radiotherapy With Proton and Light Ion Beams. American CANCER society April 1, 2007 / Volume 109 / Number 7 Retinoblastoma Retinoblastoma Most common primary ocular malignancy Most in childhood in In 20% to 30% of cases the disease is In bilateral and associated with a germline mutation in the Rb tumor suppressor gene mutation In patients with hereditary retinoblastoma, In this risk of secondary malignancy has been reported to be as high as 51% at 50 years years Retinoblastoma Retinoblastoma Lee et al., a comparative planning study – Proton therapy provides superior target coverage with optimal sparing of orbital bone compared with 3D-CRT and IMRT Retrospective research has indicated 5 Gy as a Retrospective significant threshold for an increased risk of in-field sarcoma occurrence sarcoma The mean orbital bone volume exposed to 5 Gy was The 10% for protons vs 25% for 3D-CRT electrons vs 41% for a single 3D lateral photon beam vs 69% for photon IMRT photon Proton-beam irradiation in retinoblastoma – Potential to reduce radiation-induced malignancies – Reduce cosmetic outcomes hypoplasia of the Orbit Central nervous system tumors Central St. Clair et al. St. – Compared standard photons, IMRT, and Compared protons for craniospinal irradiation with a posterior fossa boost posterior – Substantial normal tissue sparing was seen Substantial with protons with The dose to 90% of the cochlea was reduced from 101% with standard photons, to 33% with IMRT, and to 2% with protons IMRT, Image from Greco C. Current Status of Radiotherapy With Proton and Light Ion Beams. American CANCER society April 1, 2007 / Volume 109 / Number 7 Sarcomas of the Base of Skull Sarcomas A large series of chondrosarcoma and chordomas of large the skull base was treated at MGH the A combination of proton and photon therapy to a combination median dose of 72.1 CGE was used median Local control rates for chondrosarcomas were 99% Local and 98% at 5 and 10 years and Patients with chordomas were found to have lower Patients rates of local control in spite of similar doses, with 59% and 44% at 5 and 10 years, respectively 59% The temporal lobe damage rate was 13.2% at 5 years. Sinonasal Malignancies Sinonasal Standard treatment- Combination of radical Standard surgery and postoperative radiatio surgery Total maxillectomy is the most commonly Total performed surgery performed Despite such aggressive therapy, the outcome is Despite poor, with fewer than half of the patients surviving at 5 years surviving In advanced tumors that involve the skull base, In survival is further reduced survival Sinonasal Malignancies Sinonasal Treatment failure at the primary site is the Treatment main pattern of failure, ranging from 30% to 100% to Higher radiation doses are associated with Higher improved local control, but the surrounding critical normal tissues in the skull base precludes the delivery of adequate tumoricidal doses tumoricidal Sinonasal Malignancies Sinonasal Due to the proximity of the optic structures to the Due tumors in the paranasal sinuses and skull base, radiation-induced late ocular toxicity such as retinopathy or optic neuropathy is very common retinopathy At the University of Florida, At – 27% of pts developed unilateral blindness 27% secondary to radiation retinopathy or optic neuropathy neuropathy – 5% developed bilateral blindness due to optic 5% neuropathy neuropathy Sinonasal Malignancies Sinonasal Other common ocular toxicities with Other conventional radiation therapy in sinonasal malignancies malignancies – Glaucoma – Cataract – Dry eye syndrome Sinonasal Malignancies Sinonasal Between 1991 and 2002, 102 pts with advanced sinonasal Between cancers have received proton radiation therapy at the MGH cancers – 33 SCCA, 30 carcinomas with neuroendocrine 33 differentiation, 20 adenoid cystic carcinomas, 13 soft tissue sarcomas, and 6 adenocarcinomas sarcomas, The median dose was 71.6 G – 20% of patients had undergone complete resection before 20% proton radiation therapy proton A median follow-up of 6.6 years, the 5-year local control is 86% Distant metastasis was the predominant pattern of relapse for Distant squamous cell, neuroendocrine, and adenoid cystic carcinomas carcinomas These results compare very favorably to that achieved by IMRT These or three-dimensional conformal radiation therapy or Sinonasal Malignancies Sinonasal Adenoid cystic carcinoma- worst outcome For patients with inoperable tumors or gross For residual disease, the local control rate is 0–43% residual Neutron radiation therapy – Locoregional control rate of 23% for patients with Locoregional base of skull involvement base Proton radiation therapy Proton – Skull base adenoid cystic carcinoma Skull – 76 Gy, the locoregional control at 5 yrs is 93% Sinonasal Malignancies Sinonasal In multivariate analysis- decreased overall In survival survival – Change in vision at presentation Change – Involvement of sphenoid sinus and clivus With a median follow-up period of 52.4 months, With 5.6% of patients developed late ocular toxicity 5.6% There was no vascular glaucoma, retinal There detachment, or optic neuropathy detachment, Nasopharyngeal Carcinoma Nasopharyngeal Standard of care- Concurrent chemoradiation in Standard advanced nasopharyngeal carcinoma (NPC) advanced At the MGH, proton radiation therapy has been used At to treat very advanced NPC, particularly T4 to Between 1990 and 2002, 17 patients with newly Between diagnosed T4 N0-3 tumors received combined conformal proton and photon radiation. 12 pts (71%) had WHO type II or III histology had The median prescribed dose to the gross target The volume was 73.6 Gy volume Nasopharyngeal Carcinoma Nasopharyngeal 11 patients had accelerated hyperfractionated radiation therapy Ten patients received chemotherapy (induction or concurrent) Only one patient failed to complete the planned concurrent Only chemotherapy and radiation course chemotherapy With a median follow-up time of 43 months, only one patient With developed local recurrence and two patients developed distant recurrence No neck nodal recurrences were observed The locoregional control and relapse-free survival rates at 3 years were 92% and 79%, respectively. The 3-year overall survival rate was were 74%. 74%. Oropharyngeal Carcinoma Oropharyngeal The group at Loma Linda University Medical Center The (LLUMC) reported the results of re-irradiation of 16 patients with proton beam radiation with 59.4–70.2 Gy With a median follow-up of 24 months With – Overall survival and locoregional control rates at 2 years Overall were 50% were – Overall survival rates at 2 years for pts with optimal dosevolume histogram coverage versus suboptimal coverage volume were 83% and 17%, respectively (P= 0.006) were No central nervous system complications were No observed observed Oropharyngeal Carcinoma Oropharyngeal Investigators at LLUMC conducted an accelerated Investigators hyperfractionation study for stage II–IV oropharyngeal carcinoma oropharyngeal The LLUMC trial total dose of 75.9 Gy – Delivered in a shorter overall time of 28 days Only 25.5 Gy of the total dose was given with proton. Only None of the patients received concurrent chemotherapy chemotherapy The intent of the study – Increase tumor control probability by increasing the total Increase dose – Decrease the treatment time – Decrease treatment-related morbidity Oropharyngeal Carcinoma Oropharyngeal 29 pts accrue over a period of more than 10 years 29 All patients completed the prescribed dose without any interruption any With a median follow-up of 28 months, the 2-year With locoregional control and disease-free survival rates were 93% and 81% were The 2-year incidence of late RTOG Grade 3 toxicity The was 16% (vs >20% in IMRT) was Small study was performed over a prolonged period Small of time without the use of chemotherapy and employed proton radiation therapy for only 35% of the total dose the Other sites treated Other Paraspinal Tumors Lung Tumors Breast Ca Prostate Ca Conclusion Conclusion Proton therapy is a relatively new medical Proton advance advance Expensive and not widely available Very promising data on both tumor control, Very survival and prevention of side effects survival As head and neck surgeons we need to As familiarize with this technique as it could replace current management standards replace ...
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