Proton therapy for lung cancer - Wiley Online Library

Thoracic Cancer ISSN 1759-7706

INVITED REVIEW

Proton therapy for lung cancer Romaine C. Nichols Jr.1, Randal H. Henderson1, Soon Huh1, Stella Flampouri1, Zuofeng Li1, Abubakr A. Bajwa2, Harry J. D’Agostino3, Dat C. Pham4, Nancy P. Mendenhall1 & Bradford S. Hoppe1 1 2 3 4

University of Florida Proton Therapy Institute, Jacksonville, FL, USA Department of Medicine Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, Jacksonville, FL, USA Department of Surgery, University of Florida College of Medicine, Jacksonville, FL, USA Department of Medical Oncology, University of Florida College of Medicine, Jacksonville, FL, USA

Keywords literature review; lung cancer; proton therapy; radiation therapy; thoracic tumors. Correspondence Romaine C. Nichols Jr., University of Florida Proton Therapy Institute, 2015 North Jefferson Street, Jacksonville, FL 32206, USA. Tel: +1 904 588 1245 Fax: +1 904 588 1300 Email: [email protected] Received: 11 October 2011; accepted 29 November 2011. doi: 10.1111/j.1759-7714.2011.00098.x

Abstract Proton therapy is an emerging radiotherapy technology with the potential to improve the therapeutic index in the treatment of lung cancer patients. Since charged particles, such as protons, have a penetration length that can be modified by using different energies, protons offer the clinician the ability to modulate radiation dose deposition along the beam path. This facilitates an increase of the dose to the tumor target while minimizing the volume of normal tissue irradiation. Such precise delivery is particularly relevant in the setting of lung cancer where the targeted tissues are in close proximity to moderately radiation-sensitive organs like the spinal cord, heart, and esophagus, but are also effectively surrounded by the normal lung, which is extremely sensitive to radiation damage. Proton therapy has been investigated for the treatment of surgically curable yet medically inoperable patients as well as patients with regionally advanced disease.

An overview of proton therapy Over the past 6 decades, radiotherapy technology has advanced dramatically with significant improvements in clinical efficacy. These advancements have included the introduction of megavoltage beams,isocentric delivery techniques,customized cerrobend blocking, computerized tomography (CT)guided 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), and stereotactic radiosurgery. Radiation oncology teams can now fashion increasingly conformal radiotherapy dose distributions around targeted tissues. In conventional radiotherapy, X-rays deposit a high dose when entering tissues and a lower dose when exiting the targeted region, with most radiation dose deposition for any individual beam actually taking place outside of the target. Technologies that have improved the conformality of the radiation dose distribution deliver multiple beams from multiple angles, which all intersect upon the tumor target. This dose delivery necessarily pushes a significant dose to the periphery of the field, which results in lower-dose radiation to

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areas of the body that are not involved with the malignancy. The “low-dose bath” offers no benefit to the patient and may, in fact, be associated with various degrees of toxicity, or even an increased risk of iatrogenic malignancy. In contrast to X-rays, charged particles such as protons deliver the dose within a defined region known as the Bragg Peak, which occurs at the end of the proton’s path in matter. The entry dose for a proton beam is consequently low relative to the dose at the end of the path, and there is no exit dose beyond the Bragg Peak (Fig 1). Protons can be rendered useful in the clinical setting through the creation of a “spread-out Bragg Peak” (SOBP), which is formed by delivering an array of monoenergetic beams of different energies. The SOBP can be established at the depth of the tumor target with a much lower entry dose and no exit dose compared with X-ray radiotherapy (Fig 2). Because clinicians can control dose deposition along the beam path with protons, a conformal dose distribution around the tumor target can be achieved with fewer beams. Figure 3 demonstrates typical dose distributions achieved with 3DCRT, IMRT and protons for a patient with stage III non-small cell lung cancer.

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Proton therapy for lung cancer

R.C. Nichols Jr. et al.

Figure 1 The “Spread Out Bragg Peak” or “SOBP” is associated with a lower entrance dose and no exit dose when compared with X-rays. Image borrowed with permission from University of Florida Proton Therapy Institute.

Protons are particularly well-suited for lung cancer treatment since tumor targets in the chest are surrounded by the normal lung, which is extremely sensitive to radiation damage. While it is generally accepted that gross tumor targets in the chest require radiotherapy doses in excess of 60 or 70 Gray (Gy) for control, subunits of normal lung parenchyma can generally tolerate no more than 10 or 20 Gy before they are rendered nonfunctional. With protons, the radiotherapy team can limit the number of beams directed at the tumor, and large volumes of normal lung parenchyma are completely spared exposure to ionizing radiation. The SOBP allows for safe escalation of the radiotherapy dose to the tumor targets with less normal-tissue dose. Protons may also allow for the target area to be expanded – covering regions of likely microscopic tumor extension that cannot always be safely treated with conventional X-ray beams. Proton therapy can be delivered utilizing either “passive scattering,”“uniform scanning,” or “spot scanning.” The term “pencil-beam scanning” is often used interchangeably with the term “spot scanning.” The term “intensity-modulated proton therapy (IMPT)” implies the use of “inverse treatment planning” software in conjunction with the use of spot scanning. In current practice, the vast majority of patients receiving proton therapy are treated with passive scattering. Simplistically, passive scattering utilizes a scattering foil and a beam flattening device to generate a uniform beam which can then be shaped by a brass aperture. This technique is associated with the lowest risk of under-dosage of moving tumor targets in the chest. The other techniques (uniform scanning, spot scanning) utilize electronic scanning devices to distribute the proton dose across the radiation field in sequential layers. Since tumors may move in and out of the field with respiration, these “scanned” techniques may be associated with a less predictable dose distribution. 110


Figure 2 In contrast to an X-ray beam (top), which deposits a high radiation dose at the point of entry as well as an exit dose beyond the tumor target, the spread-out Bragg peak (SOBP) of a proton beam (bottom) deposits a relatively low dose at the point of entry, an increased dose to conform to the target, and no exit dose beyond the target. Image borrowed with permission from University of Florida Proton Therapy Institute.

Conventionally in radiotherapy literature, normal-tissue exposure for a given treatment plan is quantified in terms of the percentage volume of the normal structure exposed to a given radiotherapy dose. For example, the “normal lung V20” would represent the percentage volume of the total lung not involved with cancer receiving a dose of 20 Gy or higher. This nomenclature will be used throughout this article.

Proton therapy for surgically curable disease Dosimetric analyses Several published dosimetric studies have evaluated the potential role of proton therapy in the treatment of localized, surgically curable lung cancers. These studies have emerged alongside studies in photon radiotherapy that demonstrate © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd



Figure 3 Typical dose distributions achieved with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) and protons for a patient with stage III non-small cell lung cancer. Reprinted with permission from Nichols RC, Huh SN, Henderson RH, Mendenhall NP, Flampouri S, Li Z, D’Agostino HJ, Cury JD, Pham DC, Hoppe BS. Proton radiation therapy offers reduced normal lung and bone marrow exposure for patients receiving dose-escalated radiation therapy for unresectable stage III non-small-cell lung cancer: A dosimetric study. Clin Lung Cancer. 2011 Jul;12(4):252-7. doi: 10.1016/j.cllc.2011.03.027. Epub 2011 Apr 27.

the superiority of hypofractionated stereotactic radiosurgery when compared to treatment with conventionally fractionated radiotherapy. Most of the proton studies demonstrate improvements in normal-lung sparing with proton therapy compared to stereotactic radiosurgery with photons. A study by Chang et al.1 at MD Anderson Cancer Center (Houston, TX) evaluated the treatment plans of 10 patients with stage I non-small-cell lung cancer. Patients were initially planned to receive a dose of 66 Gy with photon-based 3DCRT. Those same patients subsequently underwent proton treatment planning with the goal to deliver a dose of 87.5 cobalt Gy equivalent (CGE) to the same tumor target Thoracic Cancer 3 (2012) 109–116

volumes. Despite the higher radiotherapy dose planned with protons, normal lung V5 exposures were reduced from 31.8% to 13.4%, V10 exposures were reduced from 24.6% to 12.3%, and V20 exposures were reduced from 15.8% to 10.9%. Based on this dosimetric study, M.D. Anderson Cancer Center opened a clinical trial offering a dose of 87.5 CGE for patients with localized non-small-cell lung cancers. Georg et al.2 reported a comparative dosimetry study on 12 patients undergoing hypofractionated stereotactic body radiotherapy at Medical University Vienna (Austria). Passively scattered protons were compared with IMPT and 3DCRT. Patients received three 15-Gy fractions specified at © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

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the 65% isodose line. Both proton techniques achieved full sparing of the contralateral lung and superior sparing of the heart compared with 3DCRT. Passively scattered protons were associated with 7% to 9% less lung exposure at the V2 level compared to 3DCRT. IMPT was associated with a 10% reduction in V2 exposure compared to 3DCRT. Wang et al.3 evaluated the dosimetry of 24 stage I nonsmall-cell lung cancer patients undergoing proton beam therapy at the Proton Medical Research Center at the University of Tsukuba (Japan). Proton beam therapy was associated with significantly lower mean doses to the ipsilateral lung, total lung, heart, esophagus, and spinal cord compared to 3DCRT. Specifically, protons reduced the total lung V5 from 25.7% to 10.2%; the V10 from 14.5% to 8.5%; and the V20 from 7.4% to 5.3%. All differences were statistically significant at the P < 0.001 level. Macdonald et al.4 compared the dosimetry on eight patients with peripheral early-stage non-small-cell lung cancer. Photon-based stereotactic body radiotherapy (SBRT) plans were generated and compared with passively scattered and actively scanned proton beam plans. Actively scanned, 3-field proton plans reduced the mean lung dose from 3.29 Gy to 2.08 Gy (P = 0.001) and reduced the V5 from 14.3% to 7.8% (P = 0.004). The maximum doses to the skin and ribs were similar or higher with proton therapy; however, the median doses to those same structures were higher with stereotactic body radiotherapy. Hoppe et al.5 evaluated eight patients with medically inoperable, peripherally located stage I non-small-cell lung cancers who had previously been treated with photon-based SBRT to a dose of 48 Gy in 4 fractions. Using the same treatment volumes, 3D conformal double-scatter proton plans were generated. Compared with SBRT, protons reduced the median V5 from 21.9% to 13.7% (P = 0.01); the V10 from 16.5% to 12.2% (P = 0.01); the V20 from 9.7% to 8.4% (P = 0.01); the V40 from 3.8% to 3.5% (P = 0.05); and the mean lung dose from 5.7Gy to 3.9Gy (P = 0.01). Protons were additionally associated with dosimetric improvements involving the heart, esophagus, and bronchus. Kadoya et al.6 retrospectively generated photon-based SBRT plans on 21 patients with stage I non-small-cell lung cancer who had been treated with proton therapy at the Southern Tohoku Proton Therapy Center in Japan. All patients received 66 Gy in 10 fractions. Proton plans were associated with reduced normal lung exposure when compared to the photon plans. The mean lung dose was reduced from 7.8 Gy with photons to 4.6 Gy with protons. V5 was reduced from 32.0% to 13.2%; V10 was 21.8% with photons versus 11.4% with protons; V13 was 17.4% with photons versus 10.6% with protons; V15 was 15.3% with photons versus 10.1% with protons;V20 was 11.4% with photons and 9.1% with protons. Register et al.7 reported on 15 patients with centrally or superiorly located stage I non-small-cell lung cancers treated 112



clinically with photon SBRT. Patients received 50 Gy in 4 fractions. The photon plans were compared with passively scattered proton and IMPT plans. Compared with the photon SBRT plans, the passively scattered proton and IMPT plans significantly reduced the mean total lung dose from 5.4 Gy to 3.5 Gy (P < 0.001) and 2.8 Gy (P < 0.001) and reduced the total lung volume receiving 5 Gy, 10 Gy, and 20 Gy (P < 0.001).When the planning target volume was within 2cm of critical structures, the proton plans significantly reduced the mean maximal dose to the aorta, brachial plexus, heart pulmonary vessels, and spinal cord at the P < 0.001 level.

Clinical outcome data Chang et al.8 reported on the outcomes of 18 medically inoperable patients with central T1N0M0 or peripheral N0M0 tumors treated with proton therapy on a phase I-II study. Patients received a dose of 87.5 CGE at 2.5 CGE per fraction. Four-dimensional (4D) simulation was performed to establish the target volume. All patients underwent repeat 4D CT simulations during treatment to assess the need for adaptive replanning. At a median follow-up time of 16.3 months, no patient experienced grade 4 or grade 5 toxicity. Local control was achieved in 88.9% of patients; 11.1% of patients demonstrated regional lymph node failure; and 27.8% of patients demonstrated distant metastasis. Nakayama et al.9 reported on 55 medically inoperable patients with stage I non-small-cell lung cancer treated with proton beam therapy. A total of 58 tumors were treated. Peripherallylocated tumors were treated with a total dose of 60 CGE in 10 fractions and centrallylocated tumors with 72.6 CGE in 22 fractions. The overall survival, progression-free survival, and local control rates at two years were 97.8%, 88.7%, and 97.0%, respectively. Two patients experienced grade 3 pneumonitis and two additional patients were reported to have experienced non-specific deterioration of pulmonary function. Iwata et al.10 analyzed the clinical outcomes for 80 patients treated with particle therapy in Nagoya, Japan. Fifty-seven patients were treated with proton therapy and 23 with carbon ion therapy using three treatment protocols. In the first protocol, patients received 80 CGE in 20 fractions with protons. In the second protocol, patients received 60 CGE with protons in 10 fractions. Patients treated with carbon ions received 52.8 CGE in 4 fractions. Carbon ion therapy was started in 2005. After that point, both proton and carbon ion therapy plans were generated for each patient and the superior plan was utilized. The median follow-up period was 35.5 months. The 3-year overall survival, cause-specific survival and local control rates were 75%, 86%, and 82%, respectively. There were no significant differences in treatment results among the three protocols. Only one patient demonstrated grade III pulmonary toxicity. © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd



Table 1 Studies of proton therapy for lung cancer Study

No. of Patients

Total Dose‡

Local Control (%)

Overall Survival (%)

Chang et al.8 Nakayama et al.9

18 55

87.5 CGE 60 Gy(E) to 72.6 Gy(E)

88.9 at 16.3 months 97 at 2 years

54.5 at 2 years 97.8 at 2 years

Iwata et al.10

80†

52.8 Gy(E) to 80 Gy(E)

82 at 3 years

75 at 3 years

Hata et al.11 Nihei et al.12

21 37

60 Gy(E) 70 Gy(E) to 94 Gy(E)

95 at 2 years 80 at 2 years

74 at 2 years 84 at 2 years

Shioyama et al.13

51

49 Gy(E) to 93 Gy(E)

29 at 5 years

Bush et al.14

37

73.8 CGE

89 (stage IA) and 39 (stage IB) at 5 years 87 at 2 years

63 at 2 years

Toxicity

2 patients with grade 2 pneumonitis 1 patient with grade 3 pulmonary toxicity No grade 3 + toxicity 3 patients with grade 3 pulmonary toxicity 1 grade 3 and 1 grade 4 pulmonary toxicity No grade 3 + toxicity

†Of the 80 patients, 57 were treated with protons and 23 with carbon ions. ‡CGE and Gy(E) are synonymous, but study-investigator choice has been maintained in this table. Abbreviations: CGE, cobalt gray equivalent; Gy(E), gray equivalent; LC, local control; OS, overall survival.

Hata et al.11 reported on 21 patients with stage I non-smallcell lung cancer treated with high-dose proton beam therapy. Tumor sizes ranged from 10 to 42mm (median, 25mm) in maximum diameter. Most patients received a dose of 60 Gy in 10 fractions. The local progression-free and disease-free survival rates at two years were 95% and 79% respectively. No treatment-related grade 3 toxicity was observed. Nihei et al.12 reported on the outcomes of 37 patients with clinical stage I non-small-cell lung cancer who either refused surgery or were medically inoperable. Doses ranged from 70 to 94 Gy in 20 fractions. Fractions sizes ranged from 3.8 to 4.9 Gy. With a median follow-up period of 24 months, 2-year local progression-free and overall survival rates were 80% and 84%, respectively. The 2-year local-regional relapse-free survival rates in stage IA and stage IB patients were 79% and 60%, respectively. No serious acute toxicity was observed. Three patients demonstrated grade 3 pulmonary toxicity. Shioyama et al.13 reported on the outcome of 51 nonsmall-cell lung cancer patients treated with protons between 1983 and 2000. Most patients had stage I disease. A wide range of doses were delivered (range, 49.0 to 93.0 Gy). The 5-year overall survival rate was 29% for all patients. The 5-year infield local control rate was 89% for patients with stage IA disease. One patient demonstrated grade 3 pulmonary toxicity and another patient experienced grade 4 pulmonary toxicity. The investigators concluded that proton therapy is a safe and effective treatment for patients with early-stage nonsmall-cell lung cancer. Bush et al.14 reported on the outcomes of 37 medically inoperable patients with non-small cell lung cancer who were treated with proton therapy at Loma Linda University Medical Center (California). The majority of the patients had stage I and stage II disease. Eighteen patients were treated with a combination of protons and X-rays while 19 patients received proton beam therapy alone. With a median follow-up of 14 months, the actuarial disease-free survival rate in two years for the entire group was 63%. For stage I Thoracic Cancer 3 (2012) 109–116

patients, disease-free survival at two years was 86% and the local disease control rate was 87%. Two patients in the proton and X-rays arms developed pneumonitis that resolved with oral steroids. Table 1 summarizes the available studies on proton therapy for patients with localized disease.

Proton therapy for regionally advanced non-metastatic disease Dosimetric analyses Chang et al.1 reviewed 15 selected stage III lung cancer patients and generated 3DCRT plans and proton plans for dosimetric comparison. The 3DCRT plans delivered 63 Gy to the target volumes. The proton plans delivered 74 CGE to the target volumes. Normal lung exposure, despite the higher target doses, was lower in the proton plans compared to the photon plans. V5 was 54.1% with photons versus 39.7% with protons; V10 was 46.9% with photons versus 36.6% with protons; and V20 was 34.8% with photons versus 31.6% with protons. These differences were all statistically significant at the P = 0.002 level. In all cases, doses to the spinal cord, heart, esophagus, and integral dose were lower with proton therapy. Zhang et al.15 performed a similar comparison on 10 patients with stage IIIB non-small-cell lung cancer comparing IMRT, passively scattered proton therapy, and IMPT. Patients were selected based on their extensive disease and were considered to be unlikely to tolerate IMRT doses in excess of 60 to 63 Gy based on normal-tissue constraints.Compared with IMRT, IMPT spared more lung, heart, spinal cord, and esophagus, even with dose escalation from 63 Gy to 83.5 Gy. Nichols and Huh16 generated optimized 3D conformal photon, IMRT, and passively scattered proton plans for eight consecutive patients with unresectable stage III non-small-cell lung cancer, and compared radiation exposure to nontargeted normal structures. In comparison to the 3DCRT © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

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plans,protons offered a median 29% reduction in normal lung V20, a median 33% decrease in mean lung dose, and a median 30% reduction in the volume of bone marrow receiving a dose of 10 Gy. Compared with the IMRT plans, the proton plans offered a median 26% reduction in normal lungV20,a median 31% reduction in mean lung dose, and a median 27% reduction in the volume of bone marrow receiving 10 Gy. In a separate study, Nichols and Huh17 evaluated five consecutive patients with regionally advanced non-small-cell lung cancer to determine if the normal-tissue sparing offered by protons would allow for radiotherapy dose escalation as well as coverage of target areas at high risk of harboring microscopic disease. Four treatment plans were generated for each patient using (i) 3DCRT (photons) to treat positron emission tomography (PET)-positive gross disease only to 74 Gy; (ii) photons to treat high-risk nodes to 44 Gy and PET-positive gross disease to 74 Gy; (iii) protons to treat PET-positive gross disease only to 74CGE; and (iv) protons to treat high-risk nodes to 44CGE and PET-positive gross disease to 74CGE. High-risk nodes were defined as mediastinal, hilar, and supraclavicular nodal stations anatomically adjacent to the foci of PET-positive gross disease. Notwithstanding the larger volumes irradiated, median normal lung V10, V20, and mean lung dose were lower in the proton plans targeting gross disease and nodes when compared to the photon plans treating gross disease alone. The authors concluded that the proton plans demonstrated the potential to safely include high-risk nodes without increasing the volume of normal lung irradiation and without compromising dose escalation to the gross disease.

Clinical outcome data Although dosimetric data suggest a rather compelling advantage for protons over X-ray-based techniques, clinical outcome data for patients with stage III disease are limited. Available studies primarily demonstrate reduced acute toxicity with protons, but no mature data set is available in the literature to clearly demonstrate a survival advantage for proton therapy. Sejpal et al.18 compared treatment-related toxicities of patients with non-small-cell lung cancer receiving combined chemotherapy and radiation therapy. Three groups of patients were evaluated. The first group of 74 patients, treated between 2001 and 2003, received 3DCRT and chemotherapy. The second group of 66 patients, treated between 2003 and 2005, received IMRT and chemotherapy. The third group of 62 patients, treated between 2006 and 2008, received proton therapy and concurrent chemotherapy. All patients received weekly intravenous paclitaxel at 50 mg/m2 and carboplatin at an area under the curve of 2 mg/mL per minute. The primary end point of the study was toxicity. Median total radiation dose was 74 Gy for the proton group versus 63 Gy for the other groups. The rate of grade 3 pneumonitis and esophagi114



tis was lower in the proton group than in the 3-D conformal or IMRT group in spite of the higher radiation dose delivered. Specifically, grade 3 pneumonitis incidents were 2% in the proton group, 9% in the IMRT group and 30% in the 3-D CRT group. Grade 3 esophagitis was 5% in the proton group, 44% in the IMRT group and 18% in the 3-D CRT group. Chang et al.19 reported toxicity and survival data for 44 patients with stage III non-small cell lung cancer treated with proton therapy and weekly chemotherapy. Patients received 74 Gy in 37 fractions with weekly paclitaxel and 50 mg/m2 and carboplatin at an area under the curve of 2. The median overall survival was 29.4 months. No patient experienced grade 4 or 5 proton therapy-related adverse events. Grade 3 toxicities included dermatitis (n = 5), esophagitis (n = 5), and pneumonitis (n = 1). Nine (20.5%) patients experienced local disease recurrence, but local failure was isolated in only four (9.1%) patients. Nineteen (43.2%) patients developed a distant metastasis. The overall survival and progression-free survival rates were 86% and 63% at one year. Hoppe et al.20 reported on the outcomes of 16 patients with regionally advanced lung cancer treated at the University of Florida Proton Therapy Institute (Jacksonville, FL) from August 2008 through April 2010. All patients had mediastinal involvement. Chemotherapy regimens included carboplatin or cisplatin with either etoposide or a taxane. The median proton dose was 74 CGE. Twelve patients also received selective nodal proton therapy to high-risk nodal regions to a median dose of 40 CGE. With a median follow-up of 12 months,acute grade 3 toxicity developed in three patients.Late toxicity (at more than 90 days of follow-up) data was available for 12 patients, two of whom developed a grade 3 toxicity.

Technical challenges in proton therapy for lung cancer The penetration of protons into tissue is highly dependent on the density of the path traveled. While lung inhomogeneity corrections result in some changes in radiotherapy dose distribution with photons, dose distributions with protons are significantly more sensitive. As a result, if an intrathoracic tumor target shrinks significantly over a course of proton radiotherapy, the volume of normal tissue exposed downstream to the tumor increases. Adaptive replanning is consequently necessary when fractionated proton therapy is used for lung cancer treatment.21,22 In our clinical practice at the University of Florida Proton Therapy Institute, CT scans in the treatment position are performed weekly during proton therapy treatment. Verification plans are generated to confirm target dose distribution as well as normal-tissue exposures. The downstream dose also increases if the tumor moves significantly during the radiotherapy fraction due to breathing. Therefore, when designing proton plans, it is important © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd


to minimize the weighting of fields that pass through aerated lung if those fields might ultimately direct dose to a critical structure such as the spinal cord. Frequently, an optimal plan will make use of a heavily weighted posterior beam passing through the spinal cord in conjunction with lower weighted anterior oblique fields that avoid the spinal cord. These plans offer us a greater degree of certainty as to the true spinal cord dose than plans utilizing heavily weighted anterior fields passing through the lung before reaching the spinal cord. Using this technique allows us to achieve our prescribed target dose to the tumor while reliably keeping the spinal cord dose below 45 CGE in the setting of conventionally fractionated radiotherapy.


energy linear accelerators were introduced as the standard vehicle for radiotherapy delivery in the United States. Based on experiences with other initially expensive technologies, such as personal computers, computerized tomography, and magnetic resonance imaging, the fixed cost of proton facilities will probably decrease over time. Currently there are seven competing vendors delivering proton therapy systems, and there may be more as the demand increases. Additionally, as more facilities are built, the development costs for each vendor will be amortized over a larger number of projects, further reducing the cost of installation. Finally, while conventional linear accelerators have a median life expectancy in the range of seven to 10 years, it is estimated that currently installed cyclotrons should have a useful life span of 30 years or more.

Economics of proton therapy Many investigators raise questions about the costeffectiveness of proton therapy for the treatment of lung cancer and other common malignancies.23,24 At a time in the United States when healthcare costs approach 18% of the gross domestic product,25 it is understandable that questions of cost and benefit are being asked with regard to all new medical technologies. Any cost-benefit analysis will require a thorough understanding of the long-term costs of implementation as well as a comprehensive assessment of the potential benefits of proton therapy in relation to the alternative therapies available.

The costs of proton therapy Before we can argue for or against the economic relevance of proton therapy, we must understand the difference between the fixed and marginal costs of a technological innovation.The “fixed cost” will be a constant regardless of the number of patients treated.The“marginal cost”is the variable cost associated with the treatment of any individual patient. Proton therapy is a high fixed cost technology. A 3-gantry facility will cost in the range of $120 million before a single patient is treated. The marginal cost to treat an individual patient, however, does not appear to be greater than that associated with treating a patient at a state-of-the-art photon-based facility. Since fixed costs must be amortized over time and are higher in proton facilities, it is necessary that a proton facility, operate at full capacity. This is less critical for X-ray-based facilities. Proton therapy, by definition, is a centralized medical service. It is unlikely, at current cost levels, to be available outside of major cities. For patients to avail themselves of this technology, it is likely that they will experience a degree of inconvenience since they often will need to travel and possibly spend several weeks away from their homes. This is similar to the centralization of service that existed years ago when highThoracic Cancer 3 (2012) 109–116

The benefits of proton therapy The potential economic and quality-of-life benefits of proton therapy include: (i) the ability to safely escalate radiotherapy doses resulting in improved cure rates; (ii) normal-tissue sparing (resulting in reduced iatrogenic morbidity, lower lifetime medical costs for cured patients, and diminished incidence of radiation-induced malignancies); and (iii) reduced cost of treatment owing to physical improvements in the therapeutic index, allowing for hypofractionated radiation delivery. Time will tell if the postulated medical benefits of proton therapy will materialize. Similarly, it remains to be seen if the aforementioned economic and technological factors will result in reduced cost for the widespread implementation of proton therapy. Despite these uncertainties, many countries with national health insurance systems are moving toward the installation of proton therapy facilities.

Conclusions Dosimetric studies have demonstrated that proton therapy has the potential to improve the therapeutic ratio for patients receiving radiotherapy for lung cancer. Early data from clinical trials has demonstrated the feasibility of lung cancer treatment with protons with limited treatment-related toxicities. Future advances in the field are likely to include the development of more-sophisticated delivery systems possibly utilizing on-board cone-beam CT imaging, multileaf collimation, and improved spot scanning technology, which will allow for further exploitation of the physical advantages offered by protons.

Acknowledgments We would like to thank Jessica Kirwan and her staff at the University of Florida Department Of Radiation Oncology for editing and preparing the manuscript for submission. © 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

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Disclosure The authors have no conflicts of interest or disclosures.

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