Development and current status of proton therapy for lung cancer in Korea

Thoracic Cancer ISSN 1759-7706 INVITED REVIEW Development and current status of proton therapy for lung cancer in Korea Myonggeun Yoon Department of Radiological Science, College of Health Science, Yonsei University, Wounju, Korea Keywords Dose volume histogram; IMRT; proton; secondary dose. Correspondence Myonggeun Yoon, Department of Radiological Science, College of Health Science, Yonsei University, Yonseidae-Ro, Heungup-myun, Wounju 220-710, Korea. Tel: +82 33 760 2412 Fax: + 82 33 760 2562 Email: radioyoon@yonsei.ac.kr Received: 23 September 2011; accepted: 7 October 2011. doi: 10.1111/j.1759-7714.2011.00085.x Abstract The aim of this study was to examine the current status of proton therapy in Korea and to review the dosimetric benefits of proton beam therapy (PBT) over intensitymodulated radiotherapy (IMRT) for lung cancer treatment. Data from patients treated between March 2007 and February 2011 in Korea using proton therapy were analyzed retrospectively. For comparison, IMRT and PBT in the scattering mode were planned for lung cancer patients. Dosimetric benefits and organ-specific radiation-induced cancer risks were based on comparisons of dose volume histograms (DVH) and secondary radiation doses, respectively. On average, the doses delivered by PBT to the lung, esophagus and spinal cord were 17.4%, 2.5% and 43.6% of the prescription dose, respectively, which were lower than the doses delivered by IMRT (31.5%, 11.8% and 45.3%, respectively). Although the average doses delivered by PBT to the lung and spinal cord were significantly lower than those by IMRT, these differences were reduced in the esophagus. While the average secondary dose from PBT (measured at 20 50 cm from the isocenter) was 1.33 0.86 msv/gy, the average secondary dose from IMRT was 3.3 1.0 msv/gy. Compared with IMRT techniques, PBT showed improvements in most dosimetric parameters for lung cancer patients, with lower secondary radiation doses. Introduction Lung cancer remains one of the most frequent causes of cancer-related deaths in both men and women. About 40% of locally advanced lung cancer patients require combinedmodality treatment including radiotherapy. Although conventional photon radiotherapy such as 3-D conformal radiotherapy delivers 60 to 70 Gy to the tumor, this technique has been associated with a 40 to 50% local regional failure rate in stage III non-small-cell lung cancer cases. 1 Many studies have reported a benefit of dose escalation to the tumor based on a clinical outcome associated with both survival rate and local control in patients with either early-stage or locally advanced lung cancer. 1,2 However, non-negligible side effects associated with the organ at risk (OAR) such as lung, esophagus and spinal cord limit the potential of dose escalation. Advanced photon radiotherapy such as intensitymodulated radiation therapy (IMRT) and tomotherapy seems to offer the benefit of dose escalation without causing greater toxicity to the surrounding OAR. 3,4 Using the optimization technique, these treatment modalities have been able to deliver radiation maximally to a tumor while protecting normal tissue. However, even with advanced photon radiotherapy, significant toxicity is still a dose-limiting factor, particularly for extensive disease such as stage IIIB lung cancer. 5,6 Compared with advanced photon techniques, a better or comparable dose conformity with decreased low-dose volume can be achieved using proton beam therapy (PBT). This is because protons can penetrate the body and deposit most of their energy at the Bragg Peak, resulting in reduced proton doses to normal tissue, with better conformation of the dose to the target volume. 7 11 These unique dose characteristics of protons may reduce the risk of acute as well as late side-effects. This means that proton therapy has the potential to improve the therapeutic ratio for lung cancer by allowing for an escalation in radiation dose without a substantial increase in side-effects. Although a great deal of evidence supports this concept, only limited clinical studies have compared protons to photons in lung cancer. As a result, the increasing enthusiasm for the use of Thoracic Cancer 3 (2012) 1 7 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd 1

Proton therapy for lung cancer in Korea M. Yoon protons in lung cancer has been limited due to considerable concern. Some have doubted its usefulness to limit morbidity, and others have questioned its value relative to the cost. In addition, a higher potential risk of secondary malignancies associated with neutrons has been suggested in proton therapy compared to photon therapy. 12 29 In this study, we report the current status of proton therapy in Korea and evaluate the dosimetric benefits of PBT over IMRT for lung cancer treatment which supports the use of protons for lung cancer treatment. Methods Patient data and treatment planning For dosimetric comparison between IMRT and PBT, we randomly selected three patients with lung cancer who were to be treated with proton radiotherapy at a national cancer center in Korea. All patients underwent treatment planning computed tomography (CT) scans (Picker CT-Simulator, UltraZ, Philips Medical System, Best, the Netherlands) of the chest, lower neck and upper abdomen for identification of targets and normal neighboring organs. These CT images were directly linked to the 3-D planning system (AcQPlan, version 4.2, Philips Medical Systems), using a scan slice thickness of 5 8 mm (512 512 pixel resolution). An Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA, USA) was used for IMRT and PBT planning for each patient. The targets of all lung cancer patients were delineated in accordance with the International Commission on Radiation Units and Measurements Report (ICRU 50). In particular, the gross tumor volume (GTV) encompassed all detectable tumors and lymph nodes that were at least 1 cm in short-axis diameter, as observed on CT scans. Clinical target volume (CTV) included GTV and uninvolved mediastinal and ipsilateral hilar nodes. The planning target volume (PTV) included the GTV plus a 10 15 mm margin. Contouring of target volumes and OAR (esophagus, spinal cord and lung) was performed for each slice. All patients underwent 3-D treatment planning, and dose distribution was computed. Each patient received a total dose of 36 66 Gy, using different fractionation schemes, to the isocenter. The prescribed dose was specified at the ICRU reference point (isocenter) of the PTV. Table 1 lists the clinically relevant patient characteristics, treatment schemes, and target volume sizes. All treatment plans for lung cancer patients used three to five beams for IMRT and two to three beams for PBT. The proximal, distal, and transverse margins were 2 mm, 2 mm and 10 mm, respectively; the border smoothing and smearing margins were set to 0 mm and 3 mm, respectively. We used relatively small margins in planning, because various uncertainties had already been included in our PTV. Measurement of secondary dose during IMRT and proton treatment The secondary neutron dose was measured by using a CR-39 detector since it is relatively insensitive to photon irradiation and can accurately measure neutron doses at multiple sites simultaneously. The CR-39 and 3 He neutron detectors were calibrated as H* [11] dose equivalents using 252 Cf from the Korea Atomic Energy Research Institute (Daejeon, Korea). Before the experiments, we compared the dose measured by the CR-39 detectors with the neutron dose measured by the 3 He Swendi-2 neutron detector (Thermo Fisher Scientific Inc, Pittsburgh, PA, USA), using a 22-cm range and a 5-cm spread-out Bragg peak. We found that the maximum measurements from the CR-39 detectors were within 14% of those measured with the 3 He Swendi-2 neutron detector, indicating that the CR-39 detectors reliably measured the neutron dose. Secondary radiation during IMRT was assessed by measuring the ionization of the photon beam as a function of distance from the isocenter, because the contribution of the secondary neutron dose is negligible in 6-MV photon beams. These measurements were performed using a 0.6-cm 3 ionization chamber with a buildup cap for a 6-MV photon beam (Farmer-type chamber, PTW30013, 0.6 cm 3, PTW, Freiburg, Germany) at distances 20 50 cm from the beam isocenter on a solid phantom. For neutron based secondary dose measurement, the CR-39 detectors were attached at the same sites on the solid phantom to measure the secondary dose during PBT. In all treatments, the photon energy of 6 MV (Clinac 21EX, Varian Medical Systems) was used for IMRT, and the passive scattering mode was used for PBT (IBA, Louvain-la-Neuve, Belgium). The relative biological effectiveness or quality factor was set at 10 for all calculations of equivalent doses from neutron doses. Table 1 Patient characteristics, size of tumor volumes, prescribed dose and fraction size Treatment site Age (years) PTV (ml) Maximum field size (cm) Fractional size (Gy) No. of fractions Prescribed dose (Gy) Lung 86 232.2 15.4 15.4 2.4 27 64.8 Lung 54 56.1 11.0 11.0 3.0 22 66.0 Lung 42 634.6 24.0 24.0 2.0 18 36.0 2 Thoracic Cancer 3 (2012) 1 7 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

M. Yoon Proton therapy for lung cancer in Korea Results Data of patients treated with proton therapy in Korea Table 2 lists statistical data for the number of patients treated with proton therapy at a national cancer center in Korea. Between March 2007 and February 2011, more than 400 patients were referred to the proton therapy center for prostate, lung, liver, brain and head and neck cancers. About 20% of the cancer patients were lung cancer patients, which was the second largest patient population after prostate cancer patients, among all patients treated at this national cancer center. Table 3 shows the detailed characteristics of lung cancer patients treated with proton therapy at this national cancer center in Korea. The mean age of lung cancer patients was 72 years. Histology analysis showed that 29.4% were adenocarcinoma and 54.9% were squamous cell carcinoma. About 30% of lung cancer patients were treated by proton therapy at stage I, revealing the largest patient population compared to other stages. The percentage of patients treated both with chemotherapy and radiotherapy was 34.7%. The percentage of dose per fraction that was greater than 3 Gy was 76.4%, showing that the dose per fraction was significantly higher than the dose per fraction used in photon radiotherapy. This indicates that the hypofractionated radiotherapy scheme is frequently applied for lung cancer treatment with proton therapy. Dosimetric comparison between IMRT and PBT Figure 1 shows the IMRT and PBT treatment plans for patient 2 in Table 1 and the corresponding coronal and axial views, with the dose distribution. This patient was representative of the three patients included in our study. As shown in Figure 1, the dose to normal tissue and OAR associated with PBT was lower than the dose distribution associated IMRT. The superior dose distribution of PBT compared to IMRT was due to two reasons. First, a smaller number of beams were used in the PBT plan compared to the IMRT plan, reducing the dose to normal tissue. Second, the dose in the lung or the Table 2 The number of patients treated with proton therapy at the National Cancer Center Korea between March 2007 and February 2011 Treatment sites Year 2007 2008 2009 2010 2011 Total Prostate 69 40 22 35 2 168 Lung 16 27 38 14 7 102 Liver 14 27 29 25 1 96 Brain 3 9 11 34 6 63 Head & neck 13 31 11 2 0 57 Table 3 Characteristics of lung cancer patients treated with proton therapy between March 2007 and February 2011 Variable Value Median age (y) 72 Sex Male 23.5% Female 76.5% Histology Adenocarcinoma 29.4% Squamous cell carcinoma 54.9% Non-small cell, unspecified 15.7% Stage I 29.4% II 5.9% IIIA 9.8% IIIB 9.8% IV 15.7% Recurrence 29.4% Variable Value Surgery No 76.5% Yes 23.5% Chemotherapy No 65.3% Yes 34.7% Total Prescribed dose (Gy) <50 78% 50 22% Dose per fraction (Gy) <3 23.6% 3 76.4% Fraction size <10 38% 10 62% dose beyond the tumor can be considerably smaller in PBT than in IMRT since there is no exit dose. Figure 2 shows typical the dose volume histogram (DVH) of lung cancer patients for IMRT and PBT. As seen in Figure 2, the slope of DVH for the PTV in PBT is steeper than that for IMRT, suggesting that the homogeneity associated with PBT is superior to that associated with IMRT. Figure 2 also shows that a smaller volume of the whole body was exposed with PBT compared with IMRT. Table 4 shows the comparison data of lung, esophagus and spinal cord dosimetry for IMRT and PBT. With PBT, the mean percentages of prescribed dose (PD) to the lung, spinal cord and esophagus were 17.4%, 2.5% and 43.6%, respectively, which are lower than the mean percentages of PD observed with IMRT (31.5%, 11.8% and 45.3%, respectively). While the mean doses delivered by PBT to the lung and spinal cord were significantly lower than those by IMRT, these differences were reduced in the esophagus. Table 4 also shows the OAR volume that received 50%, 30% and 10% of the PD. With Thoracic Cancer 3 (2012) 1 7 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd 3

Proton therapy for lung cancer in Korea M. Yoon Figure 1 Example of treatment plan for lung cancer, with dose distribution. (a) Axial view of an intensity-modulated radiotherapy (IMRT) plan; (b) axial view of a proton beam therapy (PBT) plan; (c) coronal view of an IMRT plan; and (d) coronal view of a PBT plan. Figure 2 Sample dose volume histograms (DVH) of two lung cancer patients using intensity-modulated radiotherapy (IMRT) and proton beam therapy. DVH of (a) patient 1 and (b) patient 2. 4 Thoracic Cancer 3 (2012) 1 7 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

M. Yoon Proton therapy for lung cancer in Korea Table 4 Comparison of lung, esophagus and spinal cord dosimetry for intensity modulated radiotherapy (IMRT) and proton beam therapy (PBT) IMRT PBT Lung (%) Mean dose 31.5% 17.4% V 50 16.7% 15.8% V 30 22.7% 22.9% V 10 41.4% 27.7% D 50% 9.3% 1.4% D 30% 25.7% 17.7% D 10% 59.7% 56.7% Spinal cord (%) Mean dose 11.8% 2.5% V 50 7.7% 8.5% V 30 20.1% 1.3% V 10 24.0% 0.9% D 10% 49.2% 8.7% D 5% 51.8% 10.6% D 2% 53.5% 16.0% Esophagus (%) Mean dose 45.3% 43.6% V 50 40.0% 42.4% V 30 45.2% 44.8% V 10 59.2% 49.1% D 10% 77.3% 70.2% D 5% 79.9% 71.2% D 2% 83.1% 73.3% PBT, the volumes that received 50%, 30% and 10% of PD to the lung were 15.8%, 22.9% and 27.7%, respectively, which are comparable or significantly lower than those observed with IMRT (16.7%, 22.7% and 41.4%, respectively). This result indicates that PBT is superior to IMRT in decreasing the low-dose volume (e.g. 10% of PD) and it may be comparable in high dose volumes (e.g. 50% of PD). As seen in Table 4, this trend holds for other OAR, showing a largest difference at V 10 between IMRT and PBT compared to V 30 or V 50. Discussion The findings presented here indicate that PBT results in improvements in most dosimetric parameters for lung cancer patients compared with the IMRT technique. Comparisons of dosimetric properties between IMRT and PBT used various parameters, including the OAR volume receiving 50%, 30% or 10% of the PD and homogeneity. Compared with IMRT, the PBT technique generally resulted in smaller doses delivered to normal tissue, but with the maintenance of a better dose homogeneity. This result provides further evidence that PBT reduces the risks of radiation side-effects for the treatment of lung cancer because of superior dosimetric properties. As expected,the normal tissue dose for the whole body was lower with PBT than with IMRT (Fig 2). Although the volume percentage receiving a high dose was similar, the low-dose volume was greater with IMRT,indicating that PBT was superior to the IMRT method in the sparing of normal tissue. One of the most notable late effects in radiotherapy is the occurrence of secondary malignant tumors in survivors who have been treated with radiotherapy. 30 36 Therefore, if proton therapy results in a higher risk of secondary malignancies, the advantage of this treatment technique will no longer be applicable. Although this is a very important issue, it is difficult to estimate the risks of developing radiogenic secondary cancers. Information about radiation-induced carcinogenesis was derived from data of atomic bomb survivors and medi- Comparison of secondary dose between IMRT and PBT Figure 3 shows that the average secondary dose from PBT in lung cancer patients (measured at 20 50 cm from the isocenter) was 1.33 0.86-mSv/Gy, and that the average secondary dose from IMRT in lung cancer patients was 3.3 1.0 msv/ Gy. As seen in Figure 3, the difference of the secondary dose between IMRT and PBT is largest at 20 cm and is approximately three times higher than for proton therapy. This difference decreases as the distance from the isocenter increases and is negligible at 50 cm. The findings indicate that the secondary radiation dose using the scattering mode in proton therapy was either lower than that observed in IMRT treatment or comparable to the secondary dose of the conventional IMRT treatment. Figure 3 Comparison of secondary doses from intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT) of patients with lung cancer. The X-axis and Y-axis denote the distance between the isocenter and the point of measurement and the normalized secondary dose compared to the dose in the isocenter, respectively. Thoracic Cancer 3 (2012) 1 7 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd 5

Proton therapy for lung cancer in Korea M. Yoon all types of cancer treatments with various modeling to accurately compare treatment modalities. 40,41 Conclusion We compared dosimetric parameters and secondary doses with the risks of secondary cancer produced by PBT using the scattering mode with those after IMRT in lung cancer patients. For the OAR near the tumor, we found that the average doses of PBT were lower than those of IMRT, suggesting that PBT may cause fewer side-effects compared to IMRT in lung cancer patients. We also found that the OED-based risks of secondary cancers in various organs, including the spinal cord, esophagus, bladder and thyroid, were higher when IMRT was used, compared with PBT. Figure 4 The organ equivalent dose (OED) of the spinal cord, esophagus, bladder and thyroid due to proton beam therapy in patients with lung cancer normalized to intensity-modulated radiotherapy (IMRT). cally exposed patients. In particular, the probability of cancer is linearly related to the absorbed dose of up to approximately 2.5 Sv, but this curve becomes less steep at higher doses, leading to some uncertainty regarding radiation-induced carcinogenesis. 37 39 In particular, relative cancer risk may be lower than expected at high radiation doses because of cell killing or a plateau effect. This has led to the concept of the organ equivalent dose (OED), expressed as linear exponential, plateau and linear dose response functions to estimate the secondary cancer risk to individuals. 38,39 The OED, a dose response weighted dose variable, is a useful concept for the estimation of cancer risk in populations, because the relationship between dose distributions and radiation-induced cancers in radiotherapy patients can be compared from DVH analysis. Figure 4 shows the secondary cancer risk of lung cancer based on organ-specific OED calculated by a plateau model, where organ-specific OED was higher for IMRT than for PBT. The relative OED for the spinal cord, esophagus, bladder and thyroid were normalized relative to those of the IMRT to determine the changes that may occur from the use of PBT. The relative secondary cancer risk of spinal cord and thyroid is less than 0.5, meaning that the secondary cancer risk associated with PBT is two times less than that with IMRT. Although the secondary cancer risk associated with PBT increases in the esophagus and bladder, it is still less than that with IMRT. This result shows that cancer risk due to secondary dose in PBT may be lower than that in IMRT for lung cancers. Although cancer risk due to secondary dose in PBT with scattering mode seems to be lower than that in conventional IMRT, more detailed studies should be carried out for Disclosure The author declares no conflict of interest. References 1 Curran W, Scott C, Langer C et al. Long term benefit is observed in a phase III comparison of sequential vs. concurrent chemo-radiation for patients with unresectable NSCLC: RTOG 9410. Proc Am Soc Clin Oncol 2003; 621a. 2 Kong F, Ten Haken R, Schipper Met al. High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 2005; 63: 324 33. 3 Murshed H, Liu H, Liao Z et al. Dose and volume reduction for normal lung using intensity-modulated radiotherapy for advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004; 58: 1258 67. 4 Yom S, Liao Z, Liu H et al. Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2007; 68: 94 102. 5 Bush DA, Slater JD, Shin BB et al. Hypofractionated proton beam radiotherapy for stage I lung cancer. Chest 2004; 126: 1198 203. 6 Widescott L, Amichetti M, Schwarz M. Proton therapy in lung cancer: clinical outcomes and technical issues. A systematic review. Radiother Oncol 2008; 86: 156 64. 7 Bush DA, Slater JD, Bonnet R et al. Proton-beam radiotherapy for early-stage lung cancer. Chest 1999; 116: 1313 9. 8 Fowler JF. What can we expect from dose escalation using proton beams? Clin Oncol (R Coll Radiol) 2003; 15: S10 S15. 9 Kagei K, Tokuuye K, Sugahara S et al. [Initial experience of proton beam therapy at the new facility of the University of Tsukuba]. Nippon Igaku Hoshasen Gakkai Zasshi 2004; 64: 225 30. 10 Tsujii H, Tsuji H, Inada T et al. Clinical results of fractionated proton therapy. Int J Radiat Oncol Biol Phys 1993; 25: 49 60. 6 Thoracic Cancer 3 (2012) 1 7 2011 Tianjin Lung Cancer Institute and Blackwell Publishing Asia Pty. Ltd

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