RADIATION-INDUCED CANCERS FROM MODERN RADIOTHERAPY TECHNIQUES: INTENSITY-MODULATED RADIOTHERAPY VERSUS PROTON THERAPY

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 77, No. 5, pp , 2010 Copyright Ó 2010 Elsevier Inc. Printed in the USA. All rights reserved /$ see front matter CLINICAL INVESTIGATION Normal Tissues RADIATION-INDUCED CANCERS FROM MODERN RADIOTHERAPY TECHNIQUES: INTENSITY-MODULATED RADIOTHERAPY VERSUS PROTON THERAPY MYONGGEUN YOON, PH.D., SUNG HWAN AHN, PH.D., JINSUNG KIM, PH.D., DONG HO SHIN, PH.D., SUNG YONG PARK,PH.D., SE BYEONG LEE, PH.D., KYUNG HWAN SHIN, M.D., AND KWAN HO CHO, M.D. Proton Therapy Center, National Cancer Center, Goyang, Korea Purpose: To assess and compare secondary cancer risk resulting from intensity-modulated radiotherapy (IMRT) and proton therapy in patients with prostate and head-and-neck cancer. Methods and Materials: Intensity-modulated radiotherapy and proton therapy in the scattering mode were planned for 5 prostate caner patients and 5 head-and-neck cancer patients. The secondary doses during irradiation were measured using ion chamber and CR-39 detectors for IMRT and proton therapy, respectively. Organ-specific radiation-induced cancer risk was estimated by applying organ equivalent dose to dose distributions. Results: The average secondary doses of proton therapy for prostate cancer patients, measured 20 60cm from the isocenter, ranged from 0.4 msv/gy to 0.1 msv/gy. The average secondary doses of IMRT for prostate patients, however, ranged between 3 msv/gy and 1 msv/gy, approximately one order of magnitude higher than for proton therapy. Although the average secondary doses of IMRT were higher than those of proton therapy for head-andneck cancers, these differences were not significant. Organ equivalent dose calculations showed that, for prostate cancer patients, the risk of secondary cancers in out-of-field organs, such as the stomach, lungs, and thyroid, was at least 5 times higher for IMRT than for proton therapy, whereas the difference was lower for head-and-neck cancer patients. Conclusions: Comparisons of organ-specific organ equivalent dose showed that the estimated secondary cancer risk using scattering mode in proton therapy is either significantly lower than the cases in IMRT treatment or, at least, does not exceed the risk induced by conventional IMRT treatment. Ó 2010 Elsevier Inc. Organ equivalent dose, IMRT, Proton, Secondary dose, CR-39. INTRODUCTION Protons are used in radiotherapy because of their advantageous physical properties. These include a near-zero exit or distal dose just beyond the target volume, resulting in reduced proton doses to normal tissue, with better conformation of the dose to the target volume. Although the sharpness of the penumbra in proton beams decreases with the depth of penetration, the penumbra is generally smaller for proton than for photon beams, up to approximately 17 cm, resulting in higher conformity of the former (1 4). In general, tumors in cancer patients undergoing radiation treatment are exposed to high doses (prescription dose), whereas the surrounding normal tissues are exposed to intermediate doses, and the rest of the body is exposed to low doses. Exposure of normal tissues to intermediate doses is due to the primary radiation in the beam path, whereas exposure of the rest of the body to low doses is due primarily to out-of-field radiation resulting from scattering and leakage. Although intensity-modulated radiotherapy (IMRT) can produce the same level of dose conformity in the tumor, it may expose normal tissue to higher intermediate or low doses, resulting in higher secondary exposure (5). In contrast, although proton therapy may result in reduced exposure of adjacent normal tissue to intermediate doses, it may lead to an increase in low doses to the rest of the body, due to the number of neutrons produced by the scattering components of passively scattered proton beams, which may exceed that produced by conventional photon treatment. Thus, proton therapy may have a higher risk of radiationinduced secondary cancers than photon therapy, diminishing the superiority of proton therapy. To date, there have been many measurements and calculations of secondary neutron doses resulting from clinical proton beams (6 23). For example, a comparison of secondary neutron dose in proton treatment with secondary photon dose in photon radiation treatment found that proton therapy in the scattering mode yielded much higher secondary doses Reprint requests to: Myonggeun Yoon, Ph.D., Proton Therapy Center, National Cancer Center, 809 Madu 1-dong, Ilsandong-gu, Goyang , Korea. Tel: (+82) ; Fax: (+82) ; mxy131@ncc.re.kr Supported by Grant A from the Korea Healthcare Technology R&D Project, Ministry of Health, Welfare and Family 1477 Affairs, Republic of Korea; and Research Grant from the National Cancer Center, Korea. Conflict of interest: none. Received March 18, 2009, and in revised form July 3, Accepted for publication July 3, 2009.

2 1478 I. J. Radiation Oncology d Biology d Physics Volume 77, Number 5, 2010 Table 1. Patient characteristics, size of tumor volumes, prescription dose, and fraction size Tumor size Prescribed dose to PTV Patient Treatment site Age (y) PTV (ml) Maximum field size (cm) Fractional dose (Gy) No. of fractions Prescribed dose (Gy) 1 Prostate Prostate Prostate Prostate Prostate Oral cavity Buccal mucosa Nasopharynx Brain tumor Brain tumor Abbreviation: PTV = planning target volume. than did conventional IMRT (6). The neutron dose associated with conventional proton therapy, however, is highly facility dependent and is based on various factors, including initial beam, field-shaping devices, aperture, and treatment volume (8 11, 18 22). Calculations of secondary cancer should also include intermediate dose induced carcinogenesis, because the risk of radiation-induced carcinogenesis due to intermediate doses in the beam path (in-field) may be much higher than that due to low doses in the out-of-field region (8, 9, 18). Thus, intermediate dose may be more important than low dose for comparing secondary cancer risks among treatment modalities. The risks of proton therapy may therefore not exceed those of conventional IMRT treatment, because the intermediate dose of the former will be generally lower than that of the latter. In comparing the radiation-induced secondary cancer risks of proton therapy and conventional photon therapy, it is necessary to make neutron measurements using realistic anthropomorphic phantoms. These models are needed to more accurately estimate organ doses and thus estimate risks outside of the radiation field, resulting in more realistic determinations of neutron dose distribution in patients. It is also necessary to include the risks of radiation-induced carcinogenesis in the beam path, by direct comparison of dose distributions from treatment planning. Moreover, comparisons of secondary cancer risk should include an appropriate radiation method. In this study, we compared the secondary radiation dose distribution resulting from proton treatment using a scattering mode and IMRT treatment in patients with prostate and head-and-neck cancers. On the basis of these measurements, Fig. 1. Example of a treatment plan for prostate cancer, with dose distribution. (a) Axial view of intensity-modulated radiotherapy plan, (b) axial view of proton plan, (c) coronal view of intensity-modulated radiotherapy plan, and (d) coronal view of proton plan.

3 Radiation-induced cancers d M. YOON et al Fig. 2. Example of an actual treatment plan for head-and-neck cancer patients, with dose distribution. (a) Axial view of intensity-modulated radiotherapy plan, (b) axial view of proton plan, (c) coronal view of intensity-modulated radiotherapy plan, and (d) coronal view of proton plan. we estimated and compared the secondary cancer risk resulting from these two treatment modalities using the concept of organ equivalent dose (OED) for radiation-induced cancer. METHODS AND MATERIALS Patient data and treatment planning We randomly selected 5 patients with clinically localized prostate cancer and 5 patients with head-and-neck cancer, who were to be treated with proton radiotherapy at our institution. Each prostate cancer patient was instructed to drink 300 ml of water 30 min before treatment to fill the bladder, and a balloon was inserted into the rectum and filled with 100 ml water. For prostate cancer patients, the clinical target volume (CTV) was defined as the whole prostate with involved seminal vesicles, and the planning target volume (PTV) was designed using a uniform 10-mm expansion around the CTV. Although the seminal vesicles may be partially included in the CTV, the dose volume histogram (DVH) of seminal vesicles was for the entire volume. Each patient received a total dose of Gy, using different fractionation schemes, to the isocenter, located at the center of the PTV. The DVH showed that the rectal volume received an average of 20 40% of the prescribed dose. Similar doses were delivered to the bladder. That is, only a small volume of the bladder received the full dose, whereas the bladder volume received an average of 10 35% of the prescribed dose. For head-and-neck cancer patients, the gross tumor volume, CTV, and organs-at-risk (OARs) were contoured on the planning CT scan. Planning volumes for PTV were delineated with circumferential 3-mm margins to the CTV to allow for setup uncertainty. Normal structures defined as OARs included the spinal cord, brain stem, optic nerves and chiasm, eyes, parotid glands, and inner ears. Table 1 lists the clinically relevant patient characteristics, treatment schemes, and size of target volume. An Eclipse proton beam planning system (Varian Medical Systems, Palo Alto, CA) was used for IMRT and proton planning of each patient. Figure 1 shows the actual treatment plan (Patient 2) for each prostate cancer patient, along with the dose distribution for the corresponding coronal and axial views. All treatment plans for prostate cancer used six field beams for IMRT and bilateral beams for proton treatment. Figure 2 shows the actual treatment plan (Patient 6) for head-and-neck cancer patients, with the dose distribution for corresponding coronal and axial views. For head-and-neck cancer patients, six to seven fields were used for IMRT planning and two to three fields for proton treatment planning. Patients 2 and 6 in Table 1 were representative of the prostate and head-and-neck patients, respectively, included in this study. The proximal, distal, and transverse margins were 2 mm, 2 mm, and 10 mm, respectively, and 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.

4 1480 I. J. Radiation Oncology d Biology d Physics Volume 77, Number 5, 2010 Fig. 3. (a) Experimental setup for dosimetric measurement of secondary photon dose due to intensity-modulated radiotherapy. (b) Experimental setup for dosimetric measurement of secondary neutron dose due to proton treatment. Calibration of the CR-39 neutron detector A CR-39 detector was used to measure the secondary neutron dose, because it is relatively insensitive to photon irradiation and can accurately measure neutron doses at various sites simultaneously. The CR-39 and 3 He neutron detectors were calibrated as H*(10) dose equivalents using 252 Cf from the Korea Atomic Energy Research Institute. Before the experiment, we compared the doses measured by the CR-39 detectors with the neutron dose measured with the 3 He Swendi-2 neutron detector, using a 22-cm range with a 5-cm spread-out Bragg peak. We found that the maximum measurements obtained using the CR-39 detectors were within 14% of those measured with the 3 He Swendi-2 neutron detector, indicating that the CR-39 detectors are useful for measuring neutron doses. Measurement of secondary dose during IMRT and proton treatment Secondary radiation during IMRT treatment was assessed by measuring the ionization of the photon beam as a function of distance from the isocenter, because the contribution of secondary neutron dose is negligible in 6-MV photon beams. These measurements were performed using a 0.6-cm 3 ionization chamber with buildup cap for a 6-MV photon beam (Farmer-type chamber, PTW30013, 0.6 cm 3 ; PTW, Freiburg, Germany) at distances cm from the beam isocenter on a humanoid phantom (RANDO; The Phantom Laboratory, Salem, NY). Figure 3a shows the experimental setup for dosimetric measurements of secondary doses due to IMRT treatment. To measure the secondary dose during proton treatment, CR-39 detectors were attached at the same sites on the humanoid phantom as secondary doses were measured for IMRT. Figure 3b shows the experimental setup for dosimetric measurements of secondary doses due to proton treatment. Figure 4 shows the locations for measurements of prostate cancer patients on the humanoid phantom, which were 20, 30, 40, 50, and 60 cm from the beam isocenter. In all treatments, a photon energy of 6 MV (Clinac 21EX; Varian Medical Systems) was used for IMRT, and the passive scattering mode was used for proton treatment (IBA, Louvain-la-Neuve, Belgium). The relative biologic effectiveness or quality factor was set at 10 for all calculations of equivalent dose from neutron dose. Because measurements of secondary photon dose during IMRT were performed using an ionization chamber with buildup cap, the secondary doses measured at various distances from the isocenter

5 Radiation-induced cancers d M. YOON et al Fig. 4. Humanoid phantom sites for measuring secondary doses during prostate cancer treatment, located 20, 30, 40, 50, and 60 cm from the beam isocenter. were the maximum possible doses at those distances, decreasing relative to depth in the body. This suggests that the actual dose at certain body depths at each distance from the isocenter will be smaller than the calculated doses. As with photon secondary doses, neutron doses were measured by attaching the CR-39 detectors to the surface of the humanoid phantom. Therefore, using both treatment methods, the actual secondary dose inside the body will be smaller than the measured dose. Cancer risk estimation due to secondary dose Information about radiation-induced carcinogenesis comes from the statistical data of atomic bomb survivors and medically exposed patients. The probability of cancer is linearly related to absorbed dose, up to approximately 2.5 Sv, but is no longer linear at higher doses, indicating great uncertainty concerning radiation-induced carcinogenesis (24 26). Relative cancer risk may decrease at high radiation doses, because of cell-killing or a plateau effect. This has led to the concept of OED, expressed as linear exponential, plateau, and linear dose response curves to estimate the secondary cancer risks of individuals treated with various radiotherapy modalities (25, 26). The OED, a dose response weighted dose variable, is a useful concept for cancer risk in populations because the relationship between dose distributions and radiation-induced cancers in radiotherapy patients can be compared on the basis of DVH analysis. The OED can be calculated according to (1) a linear dose-response model: OED ¼ 1 X V i D i (1) V (2) a linear exponential (bell-shaped) model: OED ¼ 1 X V i D i expð ad i Þ (2) V and (3) a plateau model: OED ¼ 1 X 1 expð ddi Þ V i V d i i where V is the total body volume, and V i and D i are the volume and dose elements, respectively. Although all three models above are virtually identical at doses up to approximately 4 Gy in a fractionated protocol, the three dose response relationships differ widely at high dose, depending on the assumptions made concerning cell killing. The previous data show that the incidence of leukemia in mice after total-body irradiation with various doses of X-rays increases with dose initially and then decreases in some points owing to the killing of cells as the doses increased (27). The balance between these two factors results in a bell-shaped model. Although the bell-shaped model is appropriate to the leukemia data from total-body radiation in animals, it cannot be applied to solid tumors in humans because the majority of secondary tumors occur in or close to the high-dose region (6). Therefore, to estimate secondary cancer risk, we used a plateau dose response curve, which is located approximately in the middle of the two extreme curves. In a plateau model, the value of d, which is a model parameter, concerns the dose response curve for a specific organ. This model parameter was taken from Schneider et al. (25, 26) and was acquired on the basis of data from A-bomb survivors and patients receiving radiotherapy for Hodgkin s disease. In the present study all analyses of radiation-induced carcinogenesis risk factors were based on the OED ratio between IMRT and proton treatments. RESULTS Table 2 shows the secondary photon doses at various distances from the isocenter during the IMRT treatment of prostate and head-and-neck cancer patients. The normalized dose i (3) Table 2. Secondary doses [H/D (msv/gy)] due to IMRT treatment at various distances from the beam isocenter Patient 0 cm (msv/gy) 20 cm (msv/gy) 30 cm (msv/gy) 40 cm (msv/gy) 50 cm (msv/gy) 60 cm (msv/gy) Abbreviation: IMRT = intensity-modulated radiotherapy.

6 1482 I. J. Radiation Oncology d Biology d Physics Volume 77, Number 5, 2010 Table 3. Secondary doses [H(10)/D (msv/gy)] based on neutron due to proton treatment at various distances from the beam isocenter Patient 0cm (msv/gy) 20 cm (msv/gy) 30 cm (msv/gy) 40 cm (msv/gy) 50 cm (msv/gy) 60 cm (msv/gy) equivalent to the photon absorbed dose measured cm from the isocenter ranged from 3.97 to 0.72 msv/gy for prostate cancer and from 4.13 to 0.21 msv/gy for head-and-neck cancer. Fluctuations in secondary dose were patient dependent, owing to the differences in field size, monitor units, and other factors. In IMRT, the average secondary dose was generally higher in prostate than in head-and-neck cancer treatment. The secondary dose for Patient 10 was much smaller than for the other patients, perhaps because the target or field size of this patient was much smaller. The maximum field size for Patient 10 was cm, two- to threefold Fig. 5. Comparison of secondary doses resulting from proton and intensity-modulated radiotherapy (IMRT) treatment of patients with (a) prostate cancer and (b) head-and-neck cancers. smaller than that of the other head-and-neck cancer patients (Table 1). The relatively low secondary doses for Patients 6 and 8, compared with those of Patients 7 and 9, confirm that secondary dose is dependent on field or target size, because the field sizes of Patients 6 and 8 were each smaller than those of Patients 7 and 9. Although there was a slight variation in secondary dose during IMRT, secondary dose was dependent on the distance from the isocenter and was roughly of the same order of magnitude at the same distance, regardless of patient or treatment site. Secondary doses during photon treatment are due primarily to leakage and scattering radiation, which are not dependent on individual treatment plan. We found that the secondary dose cm from the isocenter during IMRT treatment of prostate and head-and-neck cancer patients ranged from approximately 4 msv/gy to approximately 0.2 msv/gy. Table 3 shows the secondary dose due to neutrons during proton treatment at various distances from the isocenter. The neutron dose equivalent to the proton absorbed dose [H(10)/ D] cm from the isocenter ranged from 0.55 to 0.01 msv/gy during treatment of prostate cancer patients and from 1.70 to 0.15 msv/gy during treatment of head-andneck cancer patients. The secondary doses due to neutrons during proton treatment were generally smaller than those observed during IMRT treatment. In prostate cancer patients, the average secondary dose 20 cm from the isocenter was 0.39 msv/gy, much smaller than the 3.11 msv/gy observed during IMRT. Figure 5a shows that, for prostate cancer patients, the secondary dose was an order of magnitude lower for proton treatment than for IMRT. Although there were small fluctuations, this trend held at various distances from the isocenter. Although the difference was not significant in head-and-neck cancer patients, the average secondary doses were lower for proton therapy than for IMRT (Fig. 5b). For example, the average secondary dose for proton treatment 20 cm from the isocenter was 1.27 msv/gy, approximately twofold lower than the 2.62 msv/gy observed during IMRT. DISCUSSION The findings presented here indicate that the secondary radiation dose using the scattering mode in proton therapy

7 Radiation-induced cancers d M. YOON et al Fig. 6. Relative organ equivalent dose (OED) of the stomach, lungs, and thyroid due to proton treatment of patients with (a) prostate cancer and (b) head-and-neck cancer, normalized relative to that resulting from intensity-modulated radiotherapy (IMRT) treatment, using three calculation models. was either significantly lower than that observed using IMRT treatment or, at least, did not exceed the secondary dose induced by conventional IMRT treatment. We used OED to estimate organ-specific radiation-induced cancer risk, based on the measured secondary doses for these two treatment modalities. In OED calculations of the out-of field regions, we used directly measured values, or the maximum value at that distance, because it was measured on the skin during treatment. This approximation may be reasonable for two reasons. First, it may be considered a conservative estimate of organ-specific secondary dose because the actual values were slightly lower than the measured values if the percentage depth dose was applied. Second, it did not alter the relative cancer risks of IMRT and proton treatment because maximum secondary doses are applied in both modalities. For prostate cancer treatment, the relative OEDs for the stomach, lungs, and thyroid were normalized relative to those of IMRT treatment to determine the changes that may occur when introducing proton treatment (Fig. 6a). Organ equivalent doses were calculated according to a plateau model. The secondary cancer risks to the stomach, lungs, and thyroid were much higher after prostate radiotherapy using IMRT than using scattered proton treatment (Fig. 6a). Although there were small fluctuations, the OEDs from IMRT treatment were at least 5 times higher than those from proton treatment. When we plotted the OED ratios for head-and-neck cancer patients, we found that although the average OEDs from proton treatment were generally lower than from IMRT, there were no distinct differences between treatment modalities (Fig. 6b). Our results also indicate that the low doses due to the number of neutrons produced by the scattering components of passively scattered proton beams did not exceed that produced by conventional photons in patients being treated for prostate and head-and-neck cancers. Accurate comparisons of radiation-induced carcinogenesis between treatment modalities should also include comparisons of DVH data in in-field regions. Figure 7a and b shows the DVHs of the target and OAR for prostate and head-andneck cancer patients, respectively; the DVH of the original plan was normalized so that 95% of the PTV received the prescribed dose. For prostate cancer treatment, the volume of the rectum and the external body receiving the same dose was Fig. 7. (a) Sample dose volume histogram (DVH) for Patient 2, undergoing treatment of prostate cancer by intensity-modulated radiotherapy (IMRT) and a proton treatment planning system. (b) Sample DVH for Patient 6, undergoing treatment of head-and-neck cancer by IMRT and a proton treatment planning system. PTV = planning target volume.

8 1484 I. J. Radiation Oncology d Biology d Physics Volume 77, Number 5, 2010 Fig. 8. The organ equivalent dose (OED) vs. dose using a plateau model for (a) d = 5.0 and (b) d = 0.5. It is assumed that the total body volume (V) receives the homogeneous dose (D). much lower during proton therapy than during IMRT, indicating that proton treatment was associated with a much lower integral dose to the rectum and whole body (Fig. 7a). The other important OAR in the treatment of prostate cancer is the bladder, which showed complicated DVH curves (Fig. 7a). Whereas the volume receiving a low dose is higher in IMRT, the volume receiving a high dose is higher in proton treatment. In contrast, during treatment of head-and-neck cancers, the DVHs for all OARs showed lower doses for proton treatment than for IMRT. Although a plateau model is a reasonable choice to estimate the risk, the problem still remains for high-dose exposure because there are many possibilities for the dose at which the plateau occurs. In general, it is difficult to choose the most realistic dose response relationship for carcinogenesis. In the case of the induction of carcinoma of the bladder by radiation, previous data imply comparatively little differences in the relative risk over the dose range from 2 to 80 Gy (28 30). This means that the secondary cancer risk approaches saturation value rapidly as the radiation dose approaches approximately 2 Gy. In OED calculation, we used the value of approximately 5 as the constant of d for bladder in a plateau model. The OED vs. dose using this value is shown in Fig. 8a, where OED approaches the saturation value rapidly at approximately 1 Gy. This result indicates that the shape of OED vs. dose is relatively well matched with previously published data. However, there is still a possibility that the value of the parameter deviates much from the value proposed by Schneider et al. Figure 8a and b shows that both the absolute value of OED and the dose at which the plateau occurs are significantly dependent on the value of the model parameter (d in a plateau model). To check whether relative OED is also significantly dependent on the model parameter, we calculated relative OED for various d values in a plateau model. Figure 9 shows examples of calculated organ-specific OEDs in in-field regions for prostate treatment. The relative OEDs of the rectum and bladder were calculated according to DVHs from the treatment planning system using 0.5, 5, and 20 for d values in a plateau model. Whereas the absolute value of OED is significantly dependent on the value of d (Fig. 8), the relative OED or relative secondary cancer risk depending on treatment modality does not seriously depend on the value of d. In other words, the relative risk of secondary cancer remains virtually the same, independent of the dose at which the plateau occurs. The results show that the relative OED of the rectum during IMRT was approximately 2 times higher than during proton treatment for various d values. Organ-specific OED for the in-field region was higher for IMRT than for proton treatment, both for prostate and head-and-neck cancer Fig. 9. Calculated organ-specific relative organ equivalent doses (OEDs) for the (a) rectum and (b) bladder during prostate cancer treatment using various values of d.

9 Radiation-induced cancers d M. YOON et al patients, because all organ doses in the beam path were lower during proton treatment than during IMRT. Compared with the OED ratio outside the radiation field region, the difference in OED was lower in in-field regions. CONCLUSION We compared secondary neutron doses produced by proton radiotherapy using the scattering mode with the secondary photon dose from IMRT for prostate and head-and-neck cancer patients. Secondary doses for prostate treatment were approximately 10 4 Sv/Gy 50 cm from the beam isocenter, an order of magnitude lower than for conventional IMRT. Although the difference in secondary dose between these two modalities was lower for head-and-neck cancer patients, the average secondary doses were generally lower for proton therapy than for IMRT. 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