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Dosimetric Comparison of Three Different Involved Nodal Irradiation Techniques for Stage II Hodgkin's Lymphoma Patients: Conventional Radiotherapy, Intensity-Modulated Radiotherapy, and Three-Dimensional Proton Radiotherapy
Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 4, pp. 1173–1180, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.12.048
CLINICAL INVESTIGATION
Lymphoma
DOSIMETRIC COMPARISON OF THREE DIFFERENT INVOLVED NODAL IRRADIATION TECHNIQUES FOR STAGE II HODGKIN’S LYMPHOMA PATIENTS: CONVENTIONAL RADIOTHERAPY, INTENSITY-MODULATED RADIOTHERAPY, AND THREE-DIMENSIONAL PROTON RADIOTHERAPY BHISHAMJIT S. CHERA, M.D.,* CHRISTINA RODRIGUEZ, B.S.,* CHRISTOPHER G. MORRIS, M.S.,* DEBBIE LOUIS, C.M.D.,y DANIEL YEUNG, PH.D,y ZUOFENG LI, D.SC.,y AND NANCY P. MENDENHALL, M.D.y * Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL; and y University of Florida Proton Therapy Institute, Jacksonville, FL Purpose: To compare the dose distribution to targeted and nontargeted tissues in Hodgkin’s lymphoma patients using conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and three-dimensional proton RT (3D-PRT). Methods and Materials: CRT, IMRT, and 3D-PRT treatment plans delivering 30 cobalt Gray equivalent (CGE)/ Gy to an involved nodal field were created for 9 Stage II Hodgkin’s lymphoma patients (n = 27 plans). The dosimetric endpoints were compared. Results: The planning target volume was adequately treated using all three techniques. The IMRT plan produced the most conformal high-dose distribution; however, the 3D-PRT plan delivered the lowest mean dose to nontarget tissues, including the breast, lung, and total body. The relative reduction in the absolute lung volume receiving doses of 4–16 CGE/Gy for 3D-PRT compared with CRT ranged from 26% to 37% (p < .05), and the relative reduction in the absolute lung volume receiving doses of 4–10 CGE/Gy for 3D-PRT compared with IMRT was 48–65% (p < .05). The relative reduction in absolute total body volume receiving 4–30 CGE/Gy for 3D-PRT compared with CRT was 47% (p < .05). The relative reduction in absolute total body volume receiving a dose of 4 CGE/ Gy for 3D-PRT compared with IMRT was 63% (p = .03). The mean dose to the breast was significantly less for 3DPRT than for either IMRT or CRT (p = .03) The mean dose and absolute volume receiving 4–30 CGE/Gy for the heart, thyroid, and salivary glands were similar for the three modalities. Conclusion: In this favorable subset of Hodgkin’s lymphoma patients without disease in or below the hila, 3D-PRT significantly reduced the dose to the breast, lung, and total body. These observed dosimetric advantages might improve the clinical outcomes of Hodgkin’s lymphoma patients by reducing the risk of late radiation effects related to low-to-moderate doses in nontargeted tissues. Ó 2009 Elsevier Inc. Intensity-modulated radiotherapy, IMRT, Protons, Hodgkin’s lymphoma.
INTRODUCTION
Hodgkin’s lymphoma patients who had received mediastinal irradiation (4–6). RT has also been associated with second malignancies in Hodgkin’s lymphoma patients, particularly solid tumors such as lung, breast, and thyroid carcinomas. The 15–25-year actuarial risk of developing a second malignancy after treatment has been reported to be as great as 18–28% (7–10). These late effects of therapy have been correlated with the radiation dose and volume of tissue irradiated (11–16). With time, the combined mortality from the late effects of therapy can exceed the deaths from Hodgkin’s lymphoma (2, 17). The reality of late radiation effects in Hodgkin’s lymphoma survivors has driven cooperative research groups to develop treatment strategies that have reduced the radiation dose and field size by increasing the
Combined modality therapy for early-stage Hodgkin’s lymphoma has resulted in a 10-year freedom from relapse rate of 84% and a 15–20-year actuarial overall survival rate of 84–78% (1, 2). Most relapses occur within the first 3 years after treatment, and death from Hodgkin’s lymphoma occurs within the first 5–10 years after treatment. Because of the high survival rate and young age at diagnosis for most Hodgkin’s lymphoma patients, the late treatment effects of radiotherapy (RT), such as hypothyroidism, cardiovascular disease, and second malignancies, have been observed in #30–50% of Hodgkin’s lymphoma patients followed for 20 years after treatment (3). Specifically, premature coronary artery disease and valve disease have been documented in Reprint requests to: Nancy Price Mendenhall, M.D., University of Florida Proton Therapy Institute, 2015 N. Jefferson St., Jacksonville, FL 32206. Tel: (904) 588-1800; Fax: (904) 588-1300; E-mail: [email protected]
Conflict of interest: none. Received Aug 29, 2008, and in revised form Dec 15, 2008. Accepted for publication Dec 15, 2008. 1173
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chemotherapy dose, dose density, or dose intensity; thus far, disease control has been comparable to that with treatment strategies using more extensive radiation volumes and higher radiation doses (18–22). Computer models have estimated that the rate of second malignancies is likely to be lower with contemporary RT regimens (23, 24) than with historical RT regimens with larger treatment volumes and higher doses. Most of the complications observed in late follow-up have occurred in tissues not at risk of Hodgkin’s lymphoma and therefore not necessarily included in the target volume of modern treatment regimens. Thus far, efforts to reduce the radiation-related late effects have focused on reducing the volume of tissue targeted to receive RT and the dose prescribed to targeted tissues. A potentially more important strategy might be in developing RT techniques that reduce the volume of nontargeted tissue exposed to RT and the dose of radiation inadvertently delivered to nontargeted tissues. Treatment techniques such as intensity-modulated RT (IMRT) and three-dimensional conformal proton RT (3D-PRT) might substantially reduce the dose to nontargeted tissues and/or the volume of nontargeted tissue exposed to radiation. IMRT provides a very conformal high-dose distribution through the overlapping of many X-ray beams over the targeted tissue. Rather than minimizing the overall dose that must be given to nontargeted tissues, it spreads the dose out over a large volume of nontargeted tissue, thereby minimizing the dose to particular nontargeted tissues. Protons are charged particles that deposit most of their energy at a proportional depth, resulting in the characteristic dose distribution known as the Bragg peak. Through the addition of multiple energies, a spread-out Bragg peak can be created that provides target coverage with only a few treatment fields. The spread-out Bragg peak has steep lateral and deep dose gradients, thereby reducing the dose to nontargeted tissues. To explore the possible dosimetric advantages of IMRT and 3D-PRT, we created conventional radiotherapy (CRT), IMRT, and 3D-PRT involved-nodal RT plans for Hodgkin’s lymphoma patients and compared the dose distribution to the volumes of targeted and nontargeted tissues. METHODS AND MATERIALS Nine patients with Stage IIA-IIB Hodgkin’s lymphoma of the neck and/or mediastinum treated at the University of Florida between 2005 and 2007 were included in the present study. The nodal sites were the neck and anterosuperior mediastinum in 5 patients; the anterosuperior mediastinum alone in 3 patients; and the neck in 1 patient. None of the patients with mediastinal disease had involvement of the hilar, subcarinal, internal mammary, pericardial, or diaphragmatic nodes. All patients were treated with four to six cycles of multiagent chemotherapy, most often Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine, followed by involved-field RT.
Volume definition and prescription dose The historical RT volumes have included not only disease grossly apparent on clinical or radiographic evaluation, but also the tissues in the entire region of involvement judged to be at risk of moderate
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to high volumes of subclinical disease and grossly uninvolved regions at risk of small volumes of subclinical disease. With increasing confidence in the efficacy of chemotherapy regimens to control subclinical disease, RT to adjacent clinically uninvolved fields at risk of subclinical disease has been abandoned in the de novo setting in favor of treatment of the ‘‘involved field‘‘ only. With the availability of three-dimensional imaging and treatment planning programs, the question has arisen as to whether the entire ‘‘involved field’’ requires radiation or only the areas of gross involvement (i.e., should the gross target volume [GTV] be defined solely on the basis of imaged radiographic and nuclear abnormalities?). In some cooperative group settings, the question has also been raised as to whether it is only the postchemotherapy, residual radiographic abnormality that is positive on positron emission tomography after varying amounts of chemotherapy that requires RT. Although the actual definition of ‘‘involved field’’ for RT purposes is evolving, the movement is clearly toward treatment of only grossly apparent involvement, with reliance on chemotherapy to manage all but immediately adjacent subclinical disease. Therefore, in the present study, the GTV, determined from radiographically apparent disease, was defined as the target volume for comparisons of the various techniques to reduce the volume of nontargeted tissue irradiated and the radiation dose to the nontargeted tissue. The data set for the present study consisted of the postchemotherapy computed tomography (CT) simulations of these 9 patients. CT images were obtained within 1 month of completing chemotherapy using a Philips ‘‘Brilliance’’ wide-bore, 16-slice CT scanner (Amsterdam, The Netherlands). The image slice thickness was 3 mm, and patients underwent scanning from the vertex to below the diaphragm. The CT images were imported into the Pinnacle treatment planning system (Milpitas, CA) for the definition of target and nontarget tissues. The postchemotherapy residual disease volume, as seen on the CT simulation, was contoured and constituted the GTV. The GTV was nonuniformly (i.e., lung tissue was excluded) expanded by 5 mm to create the clinical target volume. Subsequently, the CTV was uniformly expanded by 3 mm to create the planning target volume (PTV). Historical simulation CT scans were used; thus, respiratory motion was not accounted for because none of the CT simulations were four-dimensional. Nontargeted normal tissues were defined as the body, lung, breast, thyroid, heart, and major salivary glands (parotid and submandibular). The CRT, IMRT, and 3D-PRT plans were created for each patient (n = 27 plans). The prescription dose was 30 cobalt Gray equivalent (CGE)/Gy, and all plans were normalized such that 100% of the prescription dose covered $95% of the PTV. The same target and nontarget structure sets were used for all three treatment plans.
Treatment planning Conventional RT planning was performed with the Pinnacle, version 7.6, software package (ADAC, Milpitas, CA). Traditional CRT plans were designed with a pair of parallel-opposed (anteroposterior and posteroanterior) 6- or 18-megavoltage photon beams centered on the PTV. Each beam was optimized (i.e., with weighting and dynamic wedges) to minimize the dose to nontargeted tissues while achieving the desired PTV dose. Multileaf collimation was used and was accounted for in the treatment planning and dose calculations. The Pinnacle, version 7.6, software package was also used for IMRT planning. The IMRT plans were designed with five, equally spaced (every 72 ), beams centered on the PTV. For optimization purposes, dose objectives were created for the PTV and nontarget tissues. The CT images and structures were transferred to the Eclipse software (Varian Medical Systems, Palo Alto, CA) for
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Fig. 1. Computed tomography images demonstrating dose distribution for conventional radiotherapy (RT), intensity-modulated RT, and three-dimensional proton RT plans for 1 patient in present study. (A–C) Axial slices through middle of planning target volume for conventional RT, intensity-modulated RT, and three-dimensional proton RT plans for this patient. Planning target volume shaded blue; blue line indicates 105% isodose line; red, 100%; green, 95%; brown, 80%; orange, 50%; and yellow, 10% isodose line. forward-planned, double-scattered 3D-PRT treatment planning. Dose calculations were performed with beam data commissioned and individualized at the University of Florida Proton Therapy Institute. For simplicity, a single anteroposterior-oriented beam was centered on the PTV. The brass aperture margin was uniformly 1 cm around the PTV. The proximal and distal margins of the spreadout Bragg peak were 5 mm. The treatment planning software designed Lucite compensators and brass apertures for each field in the 3D-PRT plan for field shaping and for conformity of the distal proton range to the distal target contour in the beam’s eye view.
Statistical analysis Various dosimetric comparisons were made among the 27 CRT, IMRT, and 3D-PRT plans. The mean, maximal, and minimal doses to the PTV, as well as the relative volume receiving 26, 28, 30, 32, and 34 CGE/Gy, were used to evaluate the quality of target coverage. The mean, maximal, and minimal doses and relative volumes of the lung, breast, thyroid, heart, and major salivary glands, in addition to the absolute volume of the body receiving 4–30 CGE/Gy (V4–V30) were evaluated to determine the doses to the surrounding nontarget, normal structures. The maximal and minimal doses were
defined as the maximal and minimal dose to 1 cm3. Both breasts were combined, and the total breast volume was evaluated. Similarly, the parotid and submandibular glands were consolidated as one volume (i.e., major salivary glands) for evaluation. All statistical analyses were performed with Statistical Analysis Systems and JMP software (SAS Institute, Cary, NC). For each volume, the prognostic factor was a three-level stratification-of-treatment technique: proton alone vs. proton-IMRT vs. IMRT alone. As each treatment plan was performed for each patient, a repeated-measures analysis of variance using PROC MIXED was performed. Because of the large number of required tests, the likelihood of a Type I error (incorrectly concluding that one group was significantly different statistically than another) was high; the Bonferroni adjustment was considered critical to minimize the likelihood of false-positive conclusions. In rare situations in which one or more of the comparative groups had volume percentages that were identical across the 9 patients (either all 0% or all 100%), the PROC MIXED procedure was unable to function properly owing to a complete lack of variance in one or more of the groups. In these situations, we performed paired t tests for each of the three possible group pairings. To maximize consistency with the repeated
Table 1. Target coverage for CRT, IMRT, and 3D-PRT plans (n = 27 plans) prescribing 30 CGE/Gy to PTV PTV
CRT
IMRT
3D-PRT
Adjusted p
V30 (%) Mean dose (CGE/Gy) Maximal dose (CGE/Gy) Minimal dose (CGE/Gy)
96.49 (1.54) 31.92 (0.44) 34.15 (0.82) 28.10 (1.52)
97.52 (1.92) 31.37 (0.13) 32.67 (0.52) 29.14 (1.02)
95.00 (0.0006) 31.30 (0.84) 33.41 (1.69) 28.50 (0.98)
.003* .09 .002* .03*
Abbreviations: CRT = conventional radiotherapy; IMRT = intensity-modulated RT; 3D-PRT = three-dimensional proton RT; PTV = planning target volume; V30 = relative volume receiving 30 CGE/Gy; CGE = cobalt Gray equivalent. Data in parentheses are standard deviation.
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Table 2. Mean dose and V4, V10, V16, V24, and V30 for body (n = 27 plans) Pairwise comparison p Body Mean dose (CGE/Gy) V4 (cm3) Body V10 (cm3) Body V16 (cm3) Body V24 (cm3) Body V30 (cm3)
CRT
IMRT
3D-PRT
2.47 (1.05) 2.66 (1.21) 1.12 (0.75) 2,525 (1,227) 3,731 (2,381) 1,360 (904) 2,073 (1,029) 2,013 (1,725) 1,189 (819) 1,812 (919) 1,141 (969) 1,050 (775) 1,535 (821) 624 (525) 888 (697) 1,158 (712) 358 (338) 608 (497)
Adjusted p CRT vs. IMRT CRT vs. 3D-PRT IMRT vs. 3D-PRT < .0001 .0009 .0009 < .0001 < .0001 .002
.10 .27 .99 .07 .005 .006
< .0001 .0003 .0003 < .0001 < .0001 .0007
.0002 .03 .26 .99 .41 .15
Abbreviations: V4–V30 = absolute volume receiving doses of 4–30 CGE/Gy; other abbreviations as in Table 1. Data in parentheses are standard deviations.
measures analysis of variance results, we also subjected each paired t test to a Bonferroni adjustment. The reported results for these situations will therefore be missing an overall adjusted p value, because this was only available by repeated-measures analysis of variance.
RESULTS The isodose distributions of the CRT, IMRT, and 3D-PRT plans for a representative patient in the present study are shown in Fig. 1. PTV coverage As shown in Table 1, the PTV coverage was excellent with CRT, IMRT, and 3D-PRT. The mean dose to the target volume was similar among the three techniques. The IMRT plans created more dose inhomogeneity in the PTV. For all three treatment modalities, 100% of the prescription dose covered 95% of the PTV (Table 1). Dose to body The absolute total body volumes receiving 4, 10, 16, 24, and 30 CGE/Gy are listed in Table 2, as is the mean total body dose using CRT, IMRT, and 3D-PRT. In a three-way comparison, 3D-PRT produced a significantly lower total body dose than did CRT or IMRT (p < .0001); specifically, the mean total body dose of 1.12 CGE with 3D-PRT was significantly lower than either the dose of 2.47 Gy with CRT (p < .0001) or 2.66 Gy with IMRT (p = .0002). Figure 2 shows the mean dose as a function of absolute total body volume for the three techniques. The shapes of the curves for 3D-PRT and CRT were similar; however, at all dose levels, 3D-PRT resulted in smaller volumes of nontargeted tissues receiving varying radiation dose levels. As listed in Table 2, the differences in the absolute volume receiving doses of 4–30 CGE/Gy (V4–V30) between 3D-PRT and CRT were all significant (p < .0001 to p < .0007), with a relative reduction in the volume of nontargeted tissue with 3D-PRT of 42% at V24 to 46% at V4. The absolute reduction in volume with 3D-PRT compared with CRT ranged from 1165 cm3 for V4 to 550 cm3 for V30. Comparing IMRT and CRT, the shapes of the curves in Fig. 2 were different. The volume of nontargeted tissue receiving doses of #10 Gy were greater with IMRT than with CRT, but less for doses >10 Gy. The abso-
lute increase in V4 with IMRT compared with CRT was 1,206 cm3 (Table 2). In contrast, the absolute decrease in V30 with IMRT compared with CRT was 800 cm3. The only statistically significant difference between IMRT and CRT was in the V24 and V30. In comparing 3D-PRT and IMRT, the V4 was significantly less with 3D-PRT (p = .03).
Dose to lung The mean dose and relative volumes of lung receiving 4– 30 CGE/Gy are listed in Table 3. Figure 4 depicts the dose to the relative lung volumes. The mean dose to the lung was similar for CRT and IMRT (p = .31) and lowest for 3DPRT (p = .005). The lung V4–V16 were lower for 3D-PRT than for CRT (p = .02 to p = .004), with an absolute and relative reduction of 3–8% and 26–37%, respectively. The lung V4–V10 was lower for 3D-PRT than for IMRT, with an absolute and relative reduction of 10–25% and 48–65%, respectively (p = .02 to p = .004). For V20–V30, none of the differences between CRT and IMRT, CRT and 3D-PRT, or IMRT and 3D-PRT were significant. However, in the three-way comparison, the lung V20–V30 were larger for CRT and 3D-PRT compared with IMRT (p = .05 to p = .07).
Fig. 2. Irradiated planning target volume (PTV) for conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and threedimensional proton RT (3D-PRT) for varying dose levels.
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Table 3. Mean dose and V4, V10, V16, V20, V24, and V30 for lung (n = 27 plans) Pairwise comparison p Lung Mean dose (CGE/Gy) V4 (%) V10 (%) V16 (%) V20 (%) V24 (%) V30 (%)
CRT
IMRT
3D-PRT
4.83 (3.67) 5.38 (3.85) 3.04 (2.88) 20.70 (15.99) 37.54 (23.78) 12.99 (11.82) 15.33 (12.19) 21.07 (18.97) 10.89 (10.22) 12.67 (10.28) 11.26 (12.04) 9.39 (9.03) 11.20 (9.26) 6.80 (6.94) 8.44 (8.25) 9.77 (8.28) 4.16 (4.31) 7.40 (7.38) 6.23 (5.86) 0.76 (0.90) 4.57 (4.80)
Adjusted p CRT vs. IMRT CRT vs. 3D-PRT IMRT vs. 3D-PRT .005 .01 .03 .02 .07 .05 .07
.31 .005 .19 .99 NS NS NS
.004 .01 .02 .02 NS NS NS
.002 .004 .02 .48 NS NS NS
Abbreviations: V4–V30 = relative volume receiving doses of 4–30 CGE/Gy; NS = not significant (p > .05); other abbreviations as in Table 1. Data in parentheses are standard deviations.
Dose to breasts The mean dose and relative volumes of breast receiving 4– 30 CGE/Gy are listed in Table 4. Figure 5 depicts the mean relative volume as a function of the mean dose. 3D-PRT resulted in a lower mean breast dose than either CRT (p = .02) or IMRT (p = .02). The mean dose to the breast was lower for CRT than for IMRT (p = .03). Although the mean dose to the breast was different, the breast V2–V30 was similar among the three plans. Dose to thyroid The mean dose and relative volumes of the thyroid receiving 4–30 CGE/Gy are listed in Table 5. Although the mean thyroid dose was lowest for 3D-PRT, statistical analysis showed no difference in the mean thyroid dose among the three modalities. The thyroid V2–V30 was also similar for the three plans. Dose to heart and major salivary glands Although the mean heart dose was lowest for 3D-PRT (1.96 CGE), it was not significantly different statistically from the mean dose delivered by CRT (2.97 Gy) or IMRT (2.74 Gy; p > .05). It is important to note that none of these
Fig. 3. Irradiated absolute volume of body for conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and three-dimensional proton RT (3D-PRT) for varying dose levels.
patients had disease in or below the hila. No significant differences were found among the three plans in the coverage of the nontargeted major salivary glands. DISCUSSION The present study was a treatment planning comparison of CRT, IMRT, and 3D-PRT for Stage II Hodgkin’s lymphoma patients. We observed a reduction in the radiation dose to nontargeted tissues with the 3D-PRT plans. Reductions in the mean dose and/or dose to the absolute or relative volumes of the nontargeted tissues were observed for the nontargeted body, lung, and breast tissue. The relative reduction (3D-PRT vs. CRT or IMRT) in mean body, lung, and breast doses was 20–60% (Tables 2–4). The total body V4–V30 was lower with 3D-PRT than with CRT, and the total body V4 was lower for 3D-PRT than for IMRT. Compared with CRT, IMRT reduced the absolute volume of the body receiving 24–30 Gy. 3D-PRT reduced the V4–V16 in the lungs. The body and lung dose–volume histogram curves for the IMRT and 3D-PRT plans intersected at approximately 16 Gy/CGE (Figs. 3 and 4). At <16 Gy/CGE, 3D-PRT significantly
Fig. 4. Irradiated relative volumes of lung for conventional radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and three-dimensional proton radiotherapy (3D-PRT) for varying dose levels.
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Table 4. Mean dose and V4, V10, V16, V24, and V30 for breast (n = 27 plans) Pairwise comparison p Breast
CRT
IMRT
3D-PRT
Adjusted p
CRT vs. IMRT
CRT vs. 3D-PRT
IMRT vs. 3D-PRT
Mean dose (CGE/Gy) V4 (%) V10 (%) V16 (%) V24 (%) V30 (%)
1.94 (1.95) 7.89 (8.12) 6.46 (6.82) 5.35 (5.66) 3.58 (4.20) 0.76 (1.19)
3.74 (3.43) 25.29 (24.71) 16.79 (18.94) 5.17 (7.92) 1.55 (3.57) 0.31 (0.81)
1.59 (1.73) 6.25 (6.45) 5.71 (6.02) 5.31 (5.72) 4.61 (5.35) 1.66 (2.19)
.03 .12 .24 .99 .27 .35
.03 NS NS NS NS NS
.02 NS NS NS NS NS
.02 NS NS NS NS NS
Abbreviations as in Tables 1 and 3. Data in parentheses are standard deviations.
reduced the volume of tissue exposed to radiation. At >16 Gy/CGE, IMRT was more conformal, but not significantly different from that of 3D-PRT. The mean dose to the breast was significantly lower with 3D-PRT than with the other two techniques. No statistically significant difference was found in the amount of breast or heart receiving 2–30 Gy/ CGE among the techniques, likely because this population of patients had no targeted tissue below the hila. Similarly, because of the close proximity of the targeted involved nodes relative to the thyroid, no significant difference was found in the dose parameter for thyroid or salivary gland exposure among the techniques. Generally, proton therapy reduces the low-to-intermediate dose exposure (<70% of the target dose) to nontargeted tissues (25). The use of proton therapy for Hodgkin’s lymphoma, in particular, has not been well studied. To our knowledge, the present study is the only published dosimetric comparison of 3D-PRT to IMRT and CRT for Hodgkin’s lymphoma. Others have compared IMRT and three-dimensional conformal RT and/or CRT for the potential treatment of Hodgkin’s lymphoma (26–28). Compared with three-dimensional conformal RT or CRT, IMRT reduced the mean lung dose, improve the PTV coverage, and reduced the dose to the heart, coronary arteries, esophagus, and spinal cord (26–28) but at the expense of significantly increasing the volume of nontargeted tissues receiving low-dose radiation. The present study has shown that 3D-PRT can further minimize the radiation dose to nontargeted tissues beyond what is achievable with IMRT or CRT. The observed reduction in dose to the nontargeted tissues should decrease the acute and late effects of RT, especially the incidence of second malignancies. Schneider et al. (29) has estimated that proton therapy might reduce the incidence of treatment-related secondary cancer in Hodgkin’s lymphoma patients by 50% compared with photon treatment plans. Our conclusions, as well as those of Schneider et al. (29), were determined from the physical dose distribution and did not account for the effect of incidental neutron dose to the patient. The total body neutron dose produced by proton therapy has been an issue of contention (30–32). Proton therapy centers in the United States use passively scanned proton beams for treatment: the narrow proton beam (pencil beam) emerging from the cyclotron or synchrotron passes
through a scattering foil to obtain a practical treatment field size, thereby producing incident neutrons that could contribute to the formation of second malignancies. It has been reported that the out-of-field dose (scattered primary radiation and neutron dose) is 10 times greater for passively modulated proton therapy than for IMRT (30). Some disagree, contending that the neutron dose with today’s passively modulated proton beam technology is much lower, that the calculations were incorrect, that a conservative estimation was used, and that the integral dose contributed by the primary radiation is more important (31, 32). Clinical studies of second malignancies in cancer survivors treated with proton therapy have not, to date, shown an increased incidence of secondary cancers, despite the use of first-generation proton therapy delivery systems (33), suggesting that the potential production of secondary neutrons in proton therapy might not be clinically relevant. An involved nodal technique was used in the present treatment comparison study. To date, the efficacy of an involved nodal field design has not been tested, and the standard of care is involved-field RT. The currently available maximal
Fig. 5. Irradiated relative volumes of breast for conventional radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and three-dimensional proton radiotherapy (3D-PRT) for varying dose levels.
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Table 5. Mean dose and V4, V10, V16, V24, and V30 for thyroid (n = 27 plans) Pairwise comparison p Thyroid
CRT
IMRT
3D-PRT
Mean dose (CGE/Gy) V4 (%) V10 (%) V16 (%) V24 (%) V30 (%)
7.09 (6.80) 28.15 (29.33) 20.96 (21.88) 18.05 (18.94) 14.04 (15.30) 5.33 (7.18)
9.07 (8.61) 44.62 (44.61) 34.41 (38.95) 25.54 (30.24) 15.89 (22.06) 4.64 (7.50)
4.65 (4.94) 20.76 (20.81) 17.42 (18.28) 15.07 (16.61) 10.66 (13.03) 4.28 (7.37)
Adjusted p CRT vs. IMRT CRT vs. 3D-PRT IMRT vs. 3D-PRT .07 .23 .29 .15 .64 .99
NS NS NS NS NS NS
NS NS NS NS NS NS
NS NS NS NS NS NS
Abbreviations as in Tables 1 and 3.
field size with passive scattered proton therapy systems is approximately 24 cm. Treatment fields >24 cm would require field-matching techniques, such as those used in proton therapy to the cranial–spinal axis. The development of uniform scanning and, ultimately, pencil beam or spot scanning will increase the maximal field size to 30 40 cm, eliminating the need for field matching techniques in most ‘‘involved fields’’ for Hodgkin’s lymphoma. Several other issues should be considered when interpreting our data. The in vivo dose distribution of the proton beam depends significantly on the tissue densities. A greater proton dose distribution uncertainty might exist around mediastinal masses because of the tissue–air–tissue interfaces and how these interfaces react to movement. Active breathing control devices might help to minimize the motion of mediastinal masses. Active breathing control devices have been studied in Hodgkin’s lymphoma patients and shown to be tolerable, reproducible, and help in reducing the dose to the lung and heart (34, 35). Currently, at the University of Florida Proton
Therapy Institute, we account for respiratory motion when treating tumors in the chest by performing four-dimensional CT scan. Next, the PTV margin, distal and proximal extent of the proton beam, and other treatment planning parameters were adjusted to account for tumor motion. Finally, it is likely that patients with disease in or below the hila would benefit significantly from a reduced radiation dose to the heart with proton therapy; however, none of the patients in the present study had involvement in or below the hila.
CONCLUSION Compared with CRT or IMRT, 3D-PRT significantly reduced the dose to nontargeted normal tissues, particularly to the body, lung, and breast in patients with Stage II Hodgkin’s lymphoma. The observed dosimetric advantages of 3D-PRT might improve the therapeutic ratio for Hodgkin’s lymphoma patients.
REFERENCES 1. Specht L, Gray RG, Clarke MJ, et al., for the International Hodgkin’s Disease Collaborative Group. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin’s disease: A meta-analysis of 23 randomized trials involving 3,888 patients. J Clin Oncol 1998;16:830–843. 2. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol 2002; 20:2101–2108. 3. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of Hodgkin’s disease: Data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 2000;85: 3227–3232. 4. Hull MC, Morris CG, Pepine CJ, et al. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin’s lymphoma treated with radiation therapy. JAMA 2003;290:2831–2837. 5. Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA 1993;270:1949–1955. 6. Boivin JF. Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer 1992;69:1241–1247. 7. Tucker MA, Coleman CN, Cox RS, et al. Risk of second cancers after treatment for Hodgkin’s disease. N Engl J Med 1988;318:76–81.
8. Van Leeuwen FE, Klokman WJ, Hagenbeek A, et al. Second cancer risk following Hodgkin’s disease: A 20-year follow-up study. J Clin Oncol 1994;12:312–325. 9. Dores GM, Metayer C, Curtis RE, et al. Second malignant neoplasms among long-term survivors of Hodgkin’s disease: A population-based evaluation over 25 years. J Clin Oncol 2002;20:3484–3494. 10. Van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol 2000;18: 487–497. 11. Ng AK, Bernardo MV, Weller E, et al. Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: Long-term risks and risk factors. Blood 2002; 100:1989–1996. 12. Alterio D, Jereczek-Fossa BA, Franchi B, et al. Thyroid disorders in patients treated with radiotherapy for head-and-neck cancer: A retrospective analysis of seventy-three patients. Int J Radiat Oncol Biol Phys 2007;67:144–150. 13. Guerin S, Guibout C, Shamsaldin A, et al. Concomitant chemoradiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: A case-control study. Int J Cancer 2007;120:96–102. 14. Chronowski GM, Wilder RB, Tucker SL, et al. Analysis of in-field control and late toxicity for adults with early-stage Hodgkin’s disease treated with chemotherapy followed by
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radiotherapy. Int J Radiat Oncol Biol Phys 2003;55: 36–43. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003;290:465–475. Acharya S, Sarafoglou K, LaQuaglia M, et al. Thyroid neoplasms after therapeutic radiation for malignancies during childhood or adolescence. Cancer 2003;97:2397–2403. Mauch PM, Kalish LA, Marcus KC, et al. Long-term survival in Hodgkin’s disease relative impact of mortality, second tumors, infection, and cardiovascular disease. Cancer J Sci Am 1995;1: 33–42. Ferme C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 2007;357:1916–1927. Bonadonna G, Bonfante V, Viviani S, et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: Long-term results. J Clin Oncol 2004;22: 2835–2841. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extendedfield radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: Results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 2003;21:3601–3608. Noordijk EM, Carde P, Dupouy N, et al. Combined-modality therapy for clinical stage I or II Hodgkin’s lymphoma: Longterm results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol 2006;24:3128–3135. Duhmke E, Franklin J, Pfreundschuh M, et al. Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin’s disease: Long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 2001; 19:2905–2914. Hodgson DC, Koh ES, Tran TH, et al. Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma. Cancer 2007;110:2576–2586. Koh ES, Tran TH, Heydarian M, et al. A comparison of mantle versus involved-field radiotherapy for Hodgkin’s lymphoma: Reduction in normal tissue dose and second cancer risk. Radiat Oncol 2007;2:13.
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25. Lomax AJ, Bortfeld T, Goitein G, et al. A treatment planning inter-comparison of proton and intensity modulated photon radiotherapy. Radiother Oncol 1999;51:257–271. 26. Goodman KA, Toner S, Hunt M, et al. Intensity-modulated radiotherapy for lymphoma involving the mediastinum. Int J Radiat Oncol Biol Phys 2005;62:198–206. 27. Girinsky T, Pichenot C, Beaudre A, et al. Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin’s disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes? Int J Radiat Oncol Biol Phys 2006;64:218–226. 28. Ghalibafian M, Beaudre A, Girinsky T. Heart and coronary artery protection in patients with mediastinal Hodgkin lymphoma treated with intensity-modulated radiotherapy: Dose constraints to virtual volumes or to organs at risk? Radiother Oncol 2007; 25:5523–5524. 29. Schneider U, Lomax A, Lombriser N. Comparative risk assessment of secondary cancer incidence after treatment of Hodgkin’s disease with photon and proton radiation. Radiat Res 2000;154:382–388. 30. Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006;65: 1–7. 31. Paganetti H, Bortfeld T, Delaney TF. Neutron dose in proton radiation therapy: In regard to Eric J. Hall (Int J Radiat Oncol Biol Phys 2006;65:1–7). Int J Radiat Oncol Biol Phys 2006;66: 1594–1595. 32. Gottschalk B. Neutron dose in scattered and scanned proton beams: In regard to Eric J. Hall (Int J Radiat Oncol Biol Phys 2006;65:1–7). Int J Radiat Oncol Biol Phys 2006;66:1594. 33. Chung CS, Yock T, Johnson J, et al. Proton radiation therapy and the incidence of secondary malignancies [Abstract]. Int J Radiat Oncol Biol Phys 2007;69:S178–S179. 34. Claude L, Malet C, Pommier P, et al. Active breathing control for Hodgkin’s disease in childhood and adolescence: Feasibility, advantages, and limits. Int J Radiat Oncol Biol Phys 2007;67:1470–1475. 35. Stromberg JS, Sharpe MB, Kim LH, et al. Active breathing control (ABC) for Hodgkin’s disease: Reduction in normal tissue irradiation with deep inspiration and implications for treatment. Int J Radiat Oncol Biol Phys 2000;48:797–806.
doi:10.1016/j.ijrobp.2008.12.048
CLINICAL INVESTIGATION
Lymphoma
DOSIMETRIC COMPARISON OF THREE DIFFERENT INVOLVED NODAL IRRADIATION TECHNIQUES FOR STAGE II HODGKIN’S LYMPHOMA PATIENTS: CONVENTIONAL RADIOTHERAPY, INTENSITY-MODULATED RADIOTHERAPY, AND THREE-DIMENSIONAL PROTON RADIOTHERAPY BHISHAMJIT S. CHERA, M.D.,* CHRISTINA RODRIGUEZ, B.S.,* CHRISTOPHER G. MORRIS, M.S.,* DEBBIE LOUIS, C.M.D.,y DANIEL YEUNG, PH.D,y ZUOFENG LI, D.SC.,y AND NANCY P. MENDENHALL, M.D.y * Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL; and y University of Florida Proton Therapy Institute, Jacksonville, FL Purpose: To compare the dose distribution to targeted and nontargeted tissues in Hodgkin’s lymphoma patients using conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and three-dimensional proton RT (3D-PRT). Methods and Materials: CRT, IMRT, and 3D-PRT treatment plans delivering 30 cobalt Gray equivalent (CGE)/ Gy to an involved nodal field were created for 9 Stage II Hodgkin’s lymphoma patients (n = 27 plans). The dosimetric endpoints were compared. Results: The planning target volume was adequately treated using all three techniques. The IMRT plan produced the most conformal high-dose distribution; however, the 3D-PRT plan delivered the lowest mean dose to nontarget tissues, including the breast, lung, and total body. The relative reduction in the absolute lung volume receiving doses of 4–16 CGE/Gy for 3D-PRT compared with CRT ranged from 26% to 37% (p < .05), and the relative reduction in the absolute lung volume receiving doses of 4–10 CGE/Gy for 3D-PRT compared with IMRT was 48–65% (p < .05). The relative reduction in absolute total body volume receiving 4–30 CGE/Gy for 3D-PRT compared with CRT was 47% (p < .05). The relative reduction in absolute total body volume receiving a dose of 4 CGE/ Gy for 3D-PRT compared with IMRT was 63% (p = .03). The mean dose to the breast was significantly less for 3DPRT than for either IMRT or CRT (p = .03) The mean dose and absolute volume receiving 4–30 CGE/Gy for the heart, thyroid, and salivary glands were similar for the three modalities. Conclusion: In this favorable subset of Hodgkin’s lymphoma patients without disease in or below the hila, 3D-PRT significantly reduced the dose to the breast, lung, and total body. These observed dosimetric advantages might improve the clinical outcomes of Hodgkin’s lymphoma patients by reducing the risk of late radiation effects related to low-to-moderate doses in nontargeted tissues. Ó 2009 Elsevier Inc. Intensity-modulated radiotherapy, IMRT, Protons, Hodgkin’s lymphoma.
INTRODUCTION
Hodgkin’s lymphoma patients who had received mediastinal irradiation (4–6). RT has also been associated with second malignancies in Hodgkin’s lymphoma patients, particularly solid tumors such as lung, breast, and thyroid carcinomas. The 15–25-year actuarial risk of developing a second malignancy after treatment has been reported to be as great as 18–28% (7–10). These late effects of therapy have been correlated with the radiation dose and volume of tissue irradiated (11–16). With time, the combined mortality from the late effects of therapy can exceed the deaths from Hodgkin’s lymphoma (2, 17). The reality of late radiation effects in Hodgkin’s lymphoma survivors has driven cooperative research groups to develop treatment strategies that have reduced the radiation dose and field size by increasing the
Combined modality therapy for early-stage Hodgkin’s lymphoma has resulted in a 10-year freedom from relapse rate of 84% and a 15–20-year actuarial overall survival rate of 84–78% (1, 2). Most relapses occur within the first 3 years after treatment, and death from Hodgkin’s lymphoma occurs within the first 5–10 years after treatment. Because of the high survival rate and young age at diagnosis for most Hodgkin’s lymphoma patients, the late treatment effects of radiotherapy (RT), such as hypothyroidism, cardiovascular disease, and second malignancies, have been observed in #30–50% of Hodgkin’s lymphoma patients followed for 20 years after treatment (3). Specifically, premature coronary artery disease and valve disease have been documented in Reprint requests to: Nancy Price Mendenhall, M.D., University of Florida Proton Therapy Institute, 2015 N. Jefferson St., Jacksonville, FL 32206. Tel: (904) 588-1800; Fax: (904) 588-1300; E-mail: [email protected]
Conflict of interest: none. Received Aug 29, 2008, and in revised form Dec 15, 2008. Accepted for publication Dec 15, 2008. 1173
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chemotherapy dose, dose density, or dose intensity; thus far, disease control has been comparable to that with treatment strategies using more extensive radiation volumes and higher radiation doses (18–22). Computer models have estimated that the rate of second malignancies is likely to be lower with contemporary RT regimens (23, 24) than with historical RT regimens with larger treatment volumes and higher doses. Most of the complications observed in late follow-up have occurred in tissues not at risk of Hodgkin’s lymphoma and therefore not necessarily included in the target volume of modern treatment regimens. Thus far, efforts to reduce the radiation-related late effects have focused on reducing the volume of tissue targeted to receive RT and the dose prescribed to targeted tissues. A potentially more important strategy might be in developing RT techniques that reduce the volume of nontargeted tissue exposed to RT and the dose of radiation inadvertently delivered to nontargeted tissues. Treatment techniques such as intensity-modulated RT (IMRT) and three-dimensional conformal proton RT (3D-PRT) might substantially reduce the dose to nontargeted tissues and/or the volume of nontargeted tissue exposed to radiation. IMRT provides a very conformal high-dose distribution through the overlapping of many X-ray beams over the targeted tissue. Rather than minimizing the overall dose that must be given to nontargeted tissues, it spreads the dose out over a large volume of nontargeted tissue, thereby minimizing the dose to particular nontargeted tissues. Protons are charged particles that deposit most of their energy at a proportional depth, resulting in the characteristic dose distribution known as the Bragg peak. Through the addition of multiple energies, a spread-out Bragg peak can be created that provides target coverage with only a few treatment fields. The spread-out Bragg peak has steep lateral and deep dose gradients, thereby reducing the dose to nontargeted tissues. To explore the possible dosimetric advantages of IMRT and 3D-PRT, we created conventional radiotherapy (CRT), IMRT, and 3D-PRT involved-nodal RT plans for Hodgkin’s lymphoma patients and compared the dose distribution to the volumes of targeted and nontargeted tissues. METHODS AND MATERIALS Nine patients with Stage IIA-IIB Hodgkin’s lymphoma of the neck and/or mediastinum treated at the University of Florida between 2005 and 2007 were included in the present study. The nodal sites were the neck and anterosuperior mediastinum in 5 patients; the anterosuperior mediastinum alone in 3 patients; and the neck in 1 patient. None of the patients with mediastinal disease had involvement of the hilar, subcarinal, internal mammary, pericardial, or diaphragmatic nodes. All patients were treated with four to six cycles of multiagent chemotherapy, most often Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine, followed by involved-field RT.
Volume definition and prescription dose The historical RT volumes have included not only disease grossly apparent on clinical or radiographic evaluation, but also the tissues in the entire region of involvement judged to be at risk of moderate
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to high volumes of subclinical disease and grossly uninvolved regions at risk of small volumes of subclinical disease. With increasing confidence in the efficacy of chemotherapy regimens to control subclinical disease, RT to adjacent clinically uninvolved fields at risk of subclinical disease has been abandoned in the de novo setting in favor of treatment of the ‘‘involved field‘‘ only. With the availability of three-dimensional imaging and treatment planning programs, the question has arisen as to whether the entire ‘‘involved field’’ requires radiation or only the areas of gross involvement (i.e., should the gross target volume [GTV] be defined solely on the basis of imaged radiographic and nuclear abnormalities?). In some cooperative group settings, the question has also been raised as to whether it is only the postchemotherapy, residual radiographic abnormality that is positive on positron emission tomography after varying amounts of chemotherapy that requires RT. Although the actual definition of ‘‘involved field’’ for RT purposes is evolving, the movement is clearly toward treatment of only grossly apparent involvement, with reliance on chemotherapy to manage all but immediately adjacent subclinical disease. Therefore, in the present study, the GTV, determined from radiographically apparent disease, was defined as the target volume for comparisons of the various techniques to reduce the volume of nontargeted tissue irradiated and the radiation dose to the nontargeted tissue. The data set for the present study consisted of the postchemotherapy computed tomography (CT) simulations of these 9 patients. CT images were obtained within 1 month of completing chemotherapy using a Philips ‘‘Brilliance’’ wide-bore, 16-slice CT scanner (Amsterdam, The Netherlands). The image slice thickness was 3 mm, and patients underwent scanning from the vertex to below the diaphragm. The CT images were imported into the Pinnacle treatment planning system (Milpitas, CA) for the definition of target and nontarget tissues. The postchemotherapy residual disease volume, as seen on the CT simulation, was contoured and constituted the GTV. The GTV was nonuniformly (i.e., lung tissue was excluded) expanded by 5 mm to create the clinical target volume. Subsequently, the CTV was uniformly expanded by 3 mm to create the planning target volume (PTV). Historical simulation CT scans were used; thus, respiratory motion was not accounted for because none of the CT simulations were four-dimensional. Nontargeted normal tissues were defined as the body, lung, breast, thyroid, heart, and major salivary glands (parotid and submandibular). The CRT, IMRT, and 3D-PRT plans were created for each patient (n = 27 plans). The prescription dose was 30 cobalt Gray equivalent (CGE)/Gy, and all plans were normalized such that 100% of the prescription dose covered $95% of the PTV. The same target and nontarget structure sets were used for all three treatment plans.
Treatment planning Conventional RT planning was performed with the Pinnacle, version 7.6, software package (ADAC, Milpitas, CA). Traditional CRT plans were designed with a pair of parallel-opposed (anteroposterior and posteroanterior) 6- or 18-megavoltage photon beams centered on the PTV. Each beam was optimized (i.e., with weighting and dynamic wedges) to minimize the dose to nontargeted tissues while achieving the desired PTV dose. Multileaf collimation was used and was accounted for in the treatment planning and dose calculations. The Pinnacle, version 7.6, software package was also used for IMRT planning. The IMRT plans were designed with five, equally spaced (every 72 ), beams centered on the PTV. For optimization purposes, dose objectives were created for the PTV and nontarget tissues. The CT images and structures were transferred to the Eclipse software (Varian Medical Systems, Palo Alto, CA) for
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Fig. 1. Computed tomography images demonstrating dose distribution for conventional radiotherapy (RT), intensity-modulated RT, and three-dimensional proton RT plans for 1 patient in present study. (A–C) Axial slices through middle of planning target volume for conventional RT, intensity-modulated RT, and three-dimensional proton RT plans for this patient. Planning target volume shaded blue; blue line indicates 105% isodose line; red, 100%; green, 95%; brown, 80%; orange, 50%; and yellow, 10% isodose line. forward-planned, double-scattered 3D-PRT treatment planning. Dose calculations were performed with beam data commissioned and individualized at the University of Florida Proton Therapy Institute. For simplicity, a single anteroposterior-oriented beam was centered on the PTV. The brass aperture margin was uniformly 1 cm around the PTV. The proximal and distal margins of the spreadout Bragg peak were 5 mm. The treatment planning software designed Lucite compensators and brass apertures for each field in the 3D-PRT plan for field shaping and for conformity of the distal proton range to the distal target contour in the beam’s eye view.
Statistical analysis Various dosimetric comparisons were made among the 27 CRT, IMRT, and 3D-PRT plans. The mean, maximal, and minimal doses to the PTV, as well as the relative volume receiving 26, 28, 30, 32, and 34 CGE/Gy, were used to evaluate the quality of target coverage. The mean, maximal, and minimal doses and relative volumes of the lung, breast, thyroid, heart, and major salivary glands, in addition to the absolute volume of the body receiving 4–30 CGE/Gy (V4–V30) were evaluated to determine the doses to the surrounding nontarget, normal structures. The maximal and minimal doses were
defined as the maximal and minimal dose to 1 cm3. Both breasts were combined, and the total breast volume was evaluated. Similarly, the parotid and submandibular glands were consolidated as one volume (i.e., major salivary glands) for evaluation. All statistical analyses were performed with Statistical Analysis Systems and JMP software (SAS Institute, Cary, NC). For each volume, the prognostic factor was a three-level stratification-of-treatment technique: proton alone vs. proton-IMRT vs. IMRT alone. As each treatment plan was performed for each patient, a repeated-measures analysis of variance using PROC MIXED was performed. Because of the large number of required tests, the likelihood of a Type I error (incorrectly concluding that one group was significantly different statistically than another) was high; the Bonferroni adjustment was considered critical to minimize the likelihood of false-positive conclusions. In rare situations in which one or more of the comparative groups had volume percentages that were identical across the 9 patients (either all 0% or all 100%), the PROC MIXED procedure was unable to function properly owing to a complete lack of variance in one or more of the groups. In these situations, we performed paired t tests for each of the three possible group pairings. To maximize consistency with the repeated
Table 1. Target coverage for CRT, IMRT, and 3D-PRT plans (n = 27 plans) prescribing 30 CGE/Gy to PTV PTV
CRT
IMRT
3D-PRT
Adjusted p
V30 (%) Mean dose (CGE/Gy) Maximal dose (CGE/Gy) Minimal dose (CGE/Gy)
96.49 (1.54) 31.92 (0.44) 34.15 (0.82) 28.10 (1.52)
97.52 (1.92) 31.37 (0.13) 32.67 (0.52) 29.14 (1.02)
95.00 (0.0006) 31.30 (0.84) 33.41 (1.69) 28.50 (0.98)
.003* .09 .002* .03*
Abbreviations: CRT = conventional radiotherapy; IMRT = intensity-modulated RT; 3D-PRT = three-dimensional proton RT; PTV = planning target volume; V30 = relative volume receiving 30 CGE/Gy; CGE = cobalt Gray equivalent. Data in parentheses are standard deviation.
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Table 2. Mean dose and V4, V10, V16, V24, and V30 for body (n = 27 plans) Pairwise comparison p Body Mean dose (CGE/Gy) V4 (cm3) Body V10 (cm3) Body V16 (cm3) Body V24 (cm3) Body V30 (cm3)
CRT
IMRT
3D-PRT
2.47 (1.05) 2.66 (1.21) 1.12 (0.75) 2,525 (1,227) 3,731 (2,381) 1,360 (904) 2,073 (1,029) 2,013 (1,725) 1,189 (819) 1,812 (919) 1,141 (969) 1,050 (775) 1,535 (821) 624 (525) 888 (697) 1,158 (712) 358 (338) 608 (497)
Adjusted p CRT vs. IMRT CRT vs. 3D-PRT IMRT vs. 3D-PRT < .0001 .0009 .0009 < .0001 < .0001 .002
.10 .27 .99 .07 .005 .006
< .0001 .0003 .0003 < .0001 < .0001 .0007
.0002 .03 .26 .99 .41 .15
Abbreviations: V4–V30 = absolute volume receiving doses of 4–30 CGE/Gy; other abbreviations as in Table 1. Data in parentheses are standard deviations.
measures analysis of variance results, we also subjected each paired t test to a Bonferroni adjustment. The reported results for these situations will therefore be missing an overall adjusted p value, because this was only available by repeated-measures analysis of variance.
RESULTS The isodose distributions of the CRT, IMRT, and 3D-PRT plans for a representative patient in the present study are shown in Fig. 1. PTV coverage As shown in Table 1, the PTV coverage was excellent with CRT, IMRT, and 3D-PRT. The mean dose to the target volume was similar among the three techniques. The IMRT plans created more dose inhomogeneity in the PTV. For all three treatment modalities, 100% of the prescription dose covered 95% of the PTV (Table 1). Dose to body The absolute total body volumes receiving 4, 10, 16, 24, and 30 CGE/Gy are listed in Table 2, as is the mean total body dose using CRT, IMRT, and 3D-PRT. In a three-way comparison, 3D-PRT produced a significantly lower total body dose than did CRT or IMRT (p < .0001); specifically, the mean total body dose of 1.12 CGE with 3D-PRT was significantly lower than either the dose of 2.47 Gy with CRT (p < .0001) or 2.66 Gy with IMRT (p = .0002). Figure 2 shows the mean dose as a function of absolute total body volume for the three techniques. The shapes of the curves for 3D-PRT and CRT were similar; however, at all dose levels, 3D-PRT resulted in smaller volumes of nontargeted tissues receiving varying radiation dose levels. As listed in Table 2, the differences in the absolute volume receiving doses of 4–30 CGE/Gy (V4–V30) between 3D-PRT and CRT were all significant (p < .0001 to p < .0007), with a relative reduction in the volume of nontargeted tissue with 3D-PRT of 42% at V24 to 46% at V4. The absolute reduction in volume with 3D-PRT compared with CRT ranged from 1165 cm3 for V4 to 550 cm3 for V30. Comparing IMRT and CRT, the shapes of the curves in Fig. 2 were different. The volume of nontargeted tissue receiving doses of #10 Gy were greater with IMRT than with CRT, but less for doses >10 Gy. The abso-
lute increase in V4 with IMRT compared with CRT was 1,206 cm3 (Table 2). In contrast, the absolute decrease in V30 with IMRT compared with CRT was 800 cm3. The only statistically significant difference between IMRT and CRT was in the V24 and V30. In comparing 3D-PRT and IMRT, the V4 was significantly less with 3D-PRT (p = .03).
Dose to lung The mean dose and relative volumes of lung receiving 4– 30 CGE/Gy are listed in Table 3. Figure 4 depicts the dose to the relative lung volumes. The mean dose to the lung was similar for CRT and IMRT (p = .31) and lowest for 3DPRT (p = .005). The lung V4–V16 were lower for 3D-PRT than for CRT (p = .02 to p = .004), with an absolute and relative reduction of 3–8% and 26–37%, respectively. The lung V4–V10 was lower for 3D-PRT than for IMRT, with an absolute and relative reduction of 10–25% and 48–65%, respectively (p = .02 to p = .004). For V20–V30, none of the differences between CRT and IMRT, CRT and 3D-PRT, or IMRT and 3D-PRT were significant. However, in the three-way comparison, the lung V20–V30 were larger for CRT and 3D-PRT compared with IMRT (p = .05 to p = .07).
Fig. 2. Irradiated planning target volume (PTV) for conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and threedimensional proton RT (3D-PRT) for varying dose levels.
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Table 3. Mean dose and V4, V10, V16, V20, V24, and V30 for lung (n = 27 plans) Pairwise comparison p Lung Mean dose (CGE/Gy) V4 (%) V10 (%) V16 (%) V20 (%) V24 (%) V30 (%)
CRT
IMRT
3D-PRT
4.83 (3.67) 5.38 (3.85) 3.04 (2.88) 20.70 (15.99) 37.54 (23.78) 12.99 (11.82) 15.33 (12.19) 21.07 (18.97) 10.89 (10.22) 12.67 (10.28) 11.26 (12.04) 9.39 (9.03) 11.20 (9.26) 6.80 (6.94) 8.44 (8.25) 9.77 (8.28) 4.16 (4.31) 7.40 (7.38) 6.23 (5.86) 0.76 (0.90) 4.57 (4.80)
Adjusted p CRT vs. IMRT CRT vs. 3D-PRT IMRT vs. 3D-PRT .005 .01 .03 .02 .07 .05 .07
.31 .005 .19 .99 NS NS NS
.004 .01 .02 .02 NS NS NS
.002 .004 .02 .48 NS NS NS
Abbreviations: V4–V30 = relative volume receiving doses of 4–30 CGE/Gy; NS = not significant (p > .05); other abbreviations as in Table 1. Data in parentheses are standard deviations.
Dose to breasts The mean dose and relative volumes of breast receiving 4– 30 CGE/Gy are listed in Table 4. Figure 5 depicts the mean relative volume as a function of the mean dose. 3D-PRT resulted in a lower mean breast dose than either CRT (p = .02) or IMRT (p = .02). The mean dose to the breast was lower for CRT than for IMRT (p = .03). Although the mean dose to the breast was different, the breast V2–V30 was similar among the three plans. Dose to thyroid The mean dose and relative volumes of the thyroid receiving 4–30 CGE/Gy are listed in Table 5. Although the mean thyroid dose was lowest for 3D-PRT, statistical analysis showed no difference in the mean thyroid dose among the three modalities. The thyroid V2–V30 was also similar for the three plans. Dose to heart and major salivary glands Although the mean heart dose was lowest for 3D-PRT (1.96 CGE), it was not significantly different statistically from the mean dose delivered by CRT (2.97 Gy) or IMRT (2.74 Gy; p > .05). It is important to note that none of these
Fig. 3. Irradiated absolute volume of body for conventional radiotherapy (CRT), intensity-modulated RT (IMRT), and three-dimensional proton RT (3D-PRT) for varying dose levels.
patients had disease in or below the hila. No significant differences were found among the three plans in the coverage of the nontargeted major salivary glands. DISCUSSION The present study was a treatment planning comparison of CRT, IMRT, and 3D-PRT for Stage II Hodgkin’s lymphoma patients. We observed a reduction in the radiation dose to nontargeted tissues with the 3D-PRT plans. Reductions in the mean dose and/or dose to the absolute or relative volumes of the nontargeted tissues were observed for the nontargeted body, lung, and breast tissue. The relative reduction (3D-PRT vs. CRT or IMRT) in mean body, lung, and breast doses was 20–60% (Tables 2–4). The total body V4–V30 was lower with 3D-PRT than with CRT, and the total body V4 was lower for 3D-PRT than for IMRT. Compared with CRT, IMRT reduced the absolute volume of the body receiving 24–30 Gy. 3D-PRT reduced the V4–V16 in the lungs. The body and lung dose–volume histogram curves for the IMRT and 3D-PRT plans intersected at approximately 16 Gy/CGE (Figs. 3 and 4). At <16 Gy/CGE, 3D-PRT significantly
Fig. 4. Irradiated relative volumes of lung for conventional radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and three-dimensional proton radiotherapy (3D-PRT) for varying dose levels.
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Table 4. Mean dose and V4, V10, V16, V24, and V30 for breast (n = 27 plans) Pairwise comparison p Breast
CRT
IMRT
3D-PRT
Adjusted p
CRT vs. IMRT
CRT vs. 3D-PRT
IMRT vs. 3D-PRT
Mean dose (CGE/Gy) V4 (%) V10 (%) V16 (%) V24 (%) V30 (%)
1.94 (1.95) 7.89 (8.12) 6.46 (6.82) 5.35 (5.66) 3.58 (4.20) 0.76 (1.19)
3.74 (3.43) 25.29 (24.71) 16.79 (18.94) 5.17 (7.92) 1.55 (3.57) 0.31 (0.81)
1.59 (1.73) 6.25 (6.45) 5.71 (6.02) 5.31 (5.72) 4.61 (5.35) 1.66 (2.19)
.03 .12 .24 .99 .27 .35
.03 NS NS NS NS NS
.02 NS NS NS NS NS
.02 NS NS NS NS NS
Abbreviations as in Tables 1 and 3. Data in parentheses are standard deviations.
reduced the volume of tissue exposed to radiation. At >16 Gy/CGE, IMRT was more conformal, but not significantly different from that of 3D-PRT. The mean dose to the breast was significantly lower with 3D-PRT than with the other two techniques. No statistically significant difference was found in the amount of breast or heart receiving 2–30 Gy/ CGE among the techniques, likely because this population of patients had no targeted tissue below the hila. Similarly, because of the close proximity of the targeted involved nodes relative to the thyroid, no significant difference was found in the dose parameter for thyroid or salivary gland exposure among the techniques. Generally, proton therapy reduces the low-to-intermediate dose exposure (<70% of the target dose) to nontargeted tissues (25). The use of proton therapy for Hodgkin’s lymphoma, in particular, has not been well studied. To our knowledge, the present study is the only published dosimetric comparison of 3D-PRT to IMRT and CRT for Hodgkin’s lymphoma. Others have compared IMRT and three-dimensional conformal RT and/or CRT for the potential treatment of Hodgkin’s lymphoma (26–28). Compared with three-dimensional conformal RT or CRT, IMRT reduced the mean lung dose, improve the PTV coverage, and reduced the dose to the heart, coronary arteries, esophagus, and spinal cord (26–28) but at the expense of significantly increasing the volume of nontargeted tissues receiving low-dose radiation. The present study has shown that 3D-PRT can further minimize the radiation dose to nontargeted tissues beyond what is achievable with IMRT or CRT. The observed reduction in dose to the nontargeted tissues should decrease the acute and late effects of RT, especially the incidence of second malignancies. Schneider et al. (29) has estimated that proton therapy might reduce the incidence of treatment-related secondary cancer in Hodgkin’s lymphoma patients by 50% compared with photon treatment plans. Our conclusions, as well as those of Schneider et al. (29), were determined from the physical dose distribution and did not account for the effect of incidental neutron dose to the patient. The total body neutron dose produced by proton therapy has been an issue of contention (30–32). Proton therapy centers in the United States use passively scanned proton beams for treatment: the narrow proton beam (pencil beam) emerging from the cyclotron or synchrotron passes
through a scattering foil to obtain a practical treatment field size, thereby producing incident neutrons that could contribute to the formation of second malignancies. It has been reported that the out-of-field dose (scattered primary radiation and neutron dose) is 10 times greater for passively modulated proton therapy than for IMRT (30). Some disagree, contending that the neutron dose with today’s passively modulated proton beam technology is much lower, that the calculations were incorrect, that a conservative estimation was used, and that the integral dose contributed by the primary radiation is more important (31, 32). Clinical studies of second malignancies in cancer survivors treated with proton therapy have not, to date, shown an increased incidence of secondary cancers, despite the use of first-generation proton therapy delivery systems (33), suggesting that the potential production of secondary neutrons in proton therapy might not be clinically relevant. An involved nodal technique was used in the present treatment comparison study. To date, the efficacy of an involved nodal field design has not been tested, and the standard of care is involved-field RT. The currently available maximal
Fig. 5. Irradiated relative volumes of breast for conventional radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and three-dimensional proton radiotherapy (3D-PRT) for varying dose levels.
Involved nodal PRT for stage I-II Hodgkin’s lymphoma d B. S. CHERA et al.
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Table 5. Mean dose and V4, V10, V16, V24, and V30 for thyroid (n = 27 plans) Pairwise comparison p Thyroid
CRT
IMRT
3D-PRT
Mean dose (CGE/Gy) V4 (%) V10 (%) V16 (%) V24 (%) V30 (%)
7.09 (6.80) 28.15 (29.33) 20.96 (21.88) 18.05 (18.94) 14.04 (15.30) 5.33 (7.18)
9.07 (8.61) 44.62 (44.61) 34.41 (38.95) 25.54 (30.24) 15.89 (22.06) 4.64 (7.50)
4.65 (4.94) 20.76 (20.81) 17.42 (18.28) 15.07 (16.61) 10.66 (13.03) 4.28 (7.37)
Adjusted p CRT vs. IMRT CRT vs. 3D-PRT IMRT vs. 3D-PRT .07 .23 .29 .15 .64 .99
NS NS NS NS NS NS
NS NS NS NS NS NS
NS NS NS NS NS NS
Abbreviations as in Tables 1 and 3.
field size with passive scattered proton therapy systems is approximately 24 cm. Treatment fields >24 cm would require field-matching techniques, such as those used in proton therapy to the cranial–spinal axis. The development of uniform scanning and, ultimately, pencil beam or spot scanning will increase the maximal field size to 30 40 cm, eliminating the need for field matching techniques in most ‘‘involved fields’’ for Hodgkin’s lymphoma. Several other issues should be considered when interpreting our data. The in vivo dose distribution of the proton beam depends significantly on the tissue densities. A greater proton dose distribution uncertainty might exist around mediastinal masses because of the tissue–air–tissue interfaces and how these interfaces react to movement. Active breathing control devices might help to minimize the motion of mediastinal masses. Active breathing control devices have been studied in Hodgkin’s lymphoma patients and shown to be tolerable, reproducible, and help in reducing the dose to the lung and heart (34, 35). Currently, at the University of Florida Proton
Therapy Institute, we account for respiratory motion when treating tumors in the chest by performing four-dimensional CT scan. Next, the PTV margin, distal and proximal extent of the proton beam, and other treatment planning parameters were adjusted to account for tumor motion. Finally, it is likely that patients with disease in or below the hila would benefit significantly from a reduced radiation dose to the heart with proton therapy; however, none of the patients in the present study had involvement in or below the hila.
CONCLUSION Compared with CRT or IMRT, 3D-PRT significantly reduced the dose to nontargeted normal tissues, particularly to the body, lung, and breast in patients with Stage II Hodgkin’s lymphoma. The observed dosimetric advantages of 3D-PRT might improve the therapeutic ratio for Hodgkin’s lymphoma patients.
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