Practical Radiation Oncology (2014) 4, 174–180
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Original Report
Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose Anne-Marie Charpentier MD FRCPC a , Tatiana Conrad MD a , Jenna Sykes MMath b , Angela Ng MEd RTT a , Rachel Zhou HBSc RTT a , Amy Parent BSc MRT(T) a , Catherine Coolens PhD a , Richard W. Tsang MD FRCPC a , Mary K. Gospodarowicz MD FRCPC a , Alexander Sun MD FRCPC a , David C. Hodgson MD FRCPC a,⁎ a
Radiation Medicine Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada Department of Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
b
Received 28 May 2013; revised 30 July 2013; accepted 31 July 2013
Abstract Purpose: Active breathing control (ABC) is emerging as a tool to reduce heart and lung dose for lymphoma patients receiving mediastinal radiation therapy (RT). The objective of this study was to report our early institutional experience with this technique, with emphasis on quantifying the changes in normal tissue dose and exploring factors that could be used to select patients with the greatest benefit. Methods and materials: Patients receiving mediastinal involved-field RT (IFRT) for lymphoma were eligible. The ABC was performed using a moderate deep-inspiration breath-hold (mDIBH) technique. All patients were replanned with free-breathing (FB) computed tomographic data sets and comparisons of lung, cardiac, and female breast tissue doses were made between mDIBH and FB plans. Logistic regression models were used to identify factors associated with improvement in mean lung and heart dose with mDIBH. Results: Forty-seven patients were analyzed; the majority (87.2%) had Hodgkin lymphoma. Median prescribed dose was 30 Gy (range, 20-36 Gy), with 78.7% of cases being treated with parallel-opposed beams. The use of mDIBH significantly improved average mean lung dose (FB: 11.0 Gy; mDIBH: 9.5 Gy; P b .0001), lung V20 (28% vs 22%; P b .0001), and mean heart dose (14.3 Gy vs 11.8 Gy; P = .003), but increased the mean breast dose (FB: 3.0 Gy; mDIBH 3.6 Gy; P = .0005). The magnitude of diaphragmatic excursion on the inhale scan was significantly associated with dosimetric improvement in both heart and lung dose with mDIBH. Preliminary results of this study were presented in an oral presentation at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO), Miami Beach, FL, October 2-6, 2011. Sources of support: Dr Charpentier is supported in part by the Princess Margaret Cancer Foundation, Department of Radiation Oncology Academic Enrichment Fund. Dr Hodgson is supported by a Cancer Care Ontario Research Chair. Conflicts of interest: None. ⁎ Corresponding author. Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario, M5G 2M9, Canada. E-mail address: [email protected] (D.C. Hodgson). 1879-8500/$ – see front matter © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2013.07.015
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Conclusions: Mediastinal IFRT for lymphoma delivered with mDIBH can significantly reduce lung and heart dose compared with FB, although not for all patients, and may increase breast dose in females. Its implementation is achievable in both adult and pediatric populations. Further work is necessary to better predict which patients benefit from this technique. © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Patients presenting with early stage Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma have excellent outcomes following treatment with combined modality therapy. 1-4 However, late effects related to normal tissue irradiation remain a significant clinical concern. 5 Consequently, recent clinical efforts have focused on minimizing late effects by reducing normal tissue exposure using a variety of different methods. 1,3,6-13 Early studies using active breathing control (ABC) have shown that the use of moderate deep-inspiration breath-hold (mDIBH) reduces breathing-induced internal organ displacement during treatment 14 and can be used to reduce normal tissue dose for patients receiving adjuvant radiation therapy to left-sided breast cancer. 15 More recently, interest in its use is also gaining for HL patients with mediastinal involvement. 12,13 The objective of our study was to evaluate the changes in normal tissue dose among pediatric and adult patients receiving mediastinal RT for lymphoma using mDIBH, and to identify clinical factors associated with reduced normal tissue dose.
Methods and materials Patient selection Beginning in March 2010, mDIBH technique was employed as standard practice for patients at the Princess Margaret Cancer Centre (PMCC Canada) with a diagnosis of lymphoma and requiring mediastinal radiation therapy. Patients were not eligible for the current retrospective analysis if they were unable to demonstrate consistency of length and depth of breath-hold (n = 1), were treated with palliative intent (n = 2), had concurrent treatment of infradiaphragmatic disease planned on the same computed tomographic (CT) data set (n = 2) or had no free-breathing (FB) planning CT (n = 5). This study was approved by our institutional Research Ethics Board.
Training session and planning visit All patients had a 30-minute individualized training session to assess feasibility of respiratory-gated treatment. The Active Breathing Coordinator device (ABC, Elekta, Stockholm, Sweden) was used to provide controlled
monitoring of breathing and suspended breath-hold position at an inspiration phase during the breathing cycle. If patients could tolerate repeated breath-holds of at least 15 seconds, they were deemed suitable for the technique. Maximal inspiratory capacity was established based on the average of at least 3 breath-hold values during the training appointment. Then, threshold for mDIBH was set at approximately 80% of the maximal inspiratory capacity, and remained the same for the whole planning and radiation delivery process. The planning CT scan was acquired on the same day as the training visit using the mDIBH technique; an additional helical FB CT scan was also obtained in the same position. All patients were immobilized using a Vac-Lok bag (Civco Medical Solutions, Kalona, IA) and neck rest and a leg immobilizer under their knees and were scanned arms by sides.
Contouring guidelines All patients received involved-field radiation therapy, with volumes for targets and organs-at-risk determined by the treating radiation oncologist on the mDIBH CT scan. No systematic registration with the prechemotherapy diagnostic CT scan in FB was performed, but images were available for the radiation oncologist to determine the cranio-caudal extent of the clinical target volume (CTV) to encompass prechemotherapy involvement, with the transverse diameter of the CTV being defined by the postchemotherapy width of the initially involved mediastinal tissue as per published guidelines. 16 Uninvolved hila were treated at physician discretion. Planning target volume (PTV) was maintained as an 8-mm circumferential expansion on CTV, unless a smaller margin was deemed appropriated by the treating physician. The heart was contoured from the level of the root of the aorta and pulmonary trunk down to the apex. Lung volumes were delineated using a threshold technique. Breasts were contoured from the second rib insertion superiorly to the loss of breast tissue inferiorly, excluding the pectoralis muscles and the chest wall, and limited by the mid-axillary line and the sternum-rib junction. Target volumes, heart, lungs and breasts were then recontoured by 2 individuals (T.C., A.N.) on the FB data set, based on anatomic landmarks on the respective CT planning images. Patients were classified as having disease encompassing the whole mediastinum or upper mediastinum, with the former designation being used if the CTV on the mDIBH scan was extending 3 cm or more below the level of the carina. Diaphragmatic excursion was measured in centimeters as the difference between the maximum
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point of the diaphragm on the FB and the mDIBH scans, after image co-registration.
Treatment planning The planning process was performed on the mDIBH CT, using Pinnacle, version 8 (Philips Radiation Oncology Systems, Milpitas, CA). Patients were treated primarily with a parallel-opposed pair (POP) technique, with an intensity modulated radiation therapy (IMRT) plan allowed based on physician discretion. The multileaf collimator field segmentation was routinely used to achieve dose uniformity within the PTV. Criteria for target coverage were that 100% of the CTV received ≥ 95% of the prescribed dose and ≥ 95% of PTV received ≥ 95% of the prescribed dose. Each of the FB plans was replanned keeping the same beam arrangement as for the breath-hold plan. For POP plans, adjustment of field segmentation and dimensions was permitted to account for the target volume change and achieve the coverage criteria described above. IMRT plans were reoptimized using inverse planning and beam angle changes were permitted if dosimetrically advantageous for target volume coverage or normal tissue sparing. To minimize inconsistency between the mDIBH and FB plans, both were required to meet the CTV and PTV coverage criteria listed above, and in addition the proportion of the CTV receiving ≥ 105% of the prescribed dose was required to be within 5% when comparing mDIBH and FB plans. Figure 1 provides an example of POP fields with mDIBH (A) and FB (B).
Treatment setup verification From March 2010 to October 2011, treatment setup verification was performed with a cone-beam CT (CBCT)
Figure 1
Practical Radiation Oncology: May-June 2014
in FB and portal images with onboard megavoltage imaging in mDIBH prior to delivery of each fraction. These were electronically and visually compared to digitally reconstructed radiographs of the plan prior to treatment based on bony anatomy and an outline of the carina. On treatment, shifts were performed to match the FB CBCT to the planning CT within 1 mm and 5 degrees (bony setup); the carina was matched on the mDIBH megavoltage portal image and digitally reconstructed radiographs to within 3 mm. After October 2011, mDIBH CBCT was implemented for setup verification. A CBCT image was acquired in BH and a registration to the planning CT was performed based on matching of the vertebrae and carina. Maximal acceptable setup tolerance was 1 mm and 5 degrees (bony setup), and 3 mm for the carina. An average of 2-4 BHs were required to complete the CBCT acquisition.
Statistical analysis Comparison between mDIBH and FB plan was made over a range of doses for heart, lung, and female breast tissue. Statistical comparisons for dosimetric variables were performed using a 2-sided paired t test, while a Mann-Whitney test was used to compare the dosimetry between the pediatric versus adult cohort and the IMRT versus POP subgroup. Multivariable logistic regression models were used with a forward selection algorithm to identify factors associated with better than average improvement in mean lung dose (MLD) and mean heart dose with the mDIBH technique. Patients with “better than average” improvement were defined as those who showed a greater decrease in dose from the FB plan to the mDIBH technique than the median decrease in the cohort. A third model was fit to
Treatment field for moderate deep-inspiration breath-hold (A) and free-breathing (B).
Practical Radiation Oncology: May-June 2014
ABC in mediastinal lymphoma radiation therapy
assess which predictors were correlated with patients showing a decrease of any magnitude in both MLD and mean heart dose. Variables explored in the modeling were the following: age (b 18 vs ≥ 18); sex; diaphragmatic excursion (continuous); type of mediastinal involvement (whole vs upper); lung volume on FB scan (continuous); technique (POP vs IMRT); and dose of RT (b 25 vs ≥ 25 Gy). All statistical analysis was performed using R software, version 2.12.1 (The R Foundation for Statistical Computing, Vienna, Austria). A 2-sided P value of less than .05 was used to assess statistical significance.
Results Patient and treatment characteristics Between March 1, 2010 and November 31, 2011, 47 patients were treated with mDIBH and deemed eligible for the current analysis. Table 1 provides the detailed Table 1
Patient characteristics
Characteristic Age Sex Female Male Age category Adult Pediatric Primary diagnosis Hodgkin lymphoma Diffuse large B-cell lymphoma Ann-Arbor stage I II III IV Type of presentation Primary lymphoma Refractory disease Relapse Type of mediastinal involvement Upper mediastinum only Whole mediastinum Technique of radiation Parallel-opposed pair IMRT Dose of radiation b 25 Gy ≥ 25 Gy
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characteristics of the cohort. Most patients had HL (n = 41, 87.2%). Median age at time of treatment was 24.0 years (range, 11.4-67.7), with 15 pediatric cases. Mediastinal disease in most cases extended ≥ 3 cm below the carina (ie, whole mediastinum) (n = 42, 89.4%). POP fields were used for 37 patients (78.7%), while 10 were treated with IMRT. Median dose was 30 Gy (range, 20-36 Gy). The majority of the patients in the lowest dose strata were children treated with 21 Gy in 14 fractions.
Dosimetric comparison for lung irradiation Compared with FB, mDIBH was associated with a reduction in MLD for 45 (95.7%) patients (Fig 2A). Evaluation of lung dosimetry demonstrated a median MLD of 11.0 Gy on FB plans and 9.5 Gy on mDIBH scans, a reduction of 18.0% (P b .0001). Examination of lung V20 revealed a median value of 28% on FB scans that decreased to 22% with the use of mDIBH technique, a relative reduction of 25.4% (P b .0001). Table 2 provides detailed lung dosimetric parameters.
Dosimetric comparison for heart irradiation No. of patients (total = 47)
%
Median, 24.0 y (range, 11.4-67.7) 27 20
57.4% 42.6%
32 15
68.1 31.9
41 6
87.2 12.8
5 30 4 8
10.6 63.8 8.5 17.0
41 3 3
87.2 6.4 6.4
5 42
10.6 89.4
37 10
78.7 21.3
13 34
27.7 72.3
IMRT, intensity modulated radiation therapy.
The use of mDIBH was associated with a reduction in mean heart dose for 37 (78.7%) patients (Fig 2B). Dosimetric evaluation of the heart showed that the average (median) mean heart dose was 14.3 Gy on FB plans and 11.8 Gy on mDIBH treatment plans (Table 2), a relative reduction of 10.3% (P = .003). All cardiac dosimetric parameters were significantly reduced with the use of mDIBH (Table 2).
Dosimetric comparison for breast irradiation The mean breast dose increased in 20/26 (77%) of female patients with the use of mDIBH, with a median increase in mean breast dose of 0.6 Gy (3.0 Gy with FB to 3.6 Gy with mDIBH; P = .0005). Most of the other breast dosimetric parameters showed similar increase in the range of 10.0% to 16.0%, except breast V30 (Table 2).
Other univariate comparisons There was no significant difference in the dosimetric effects of mDIBH between pediatric versus adult patients, except for a borderline effect of age for MLD (P = .09). Also, there was no significant difference in effect among those treated with IMRT or parallel opposed anteriorposterior opposed beams.
Multivariable model To identify selection criteria for patients who would most benefit from employment of mDIBH in terms of MLD and mean heart dose, a multivariate analysis was
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Figure 2 Waterfall plots of percent change in (A) bilateral mean lung dose, (B) mean heart dose, and (C) both parameters for the whole cohort. Each column represents the percent change with the breath-hold planning as compared with free-breathing, for a single patient. The dashed lines represent the median percent change.
performed to evaluate factors associated with a greater than average reduction in normal tissue dose. For MLD, children were 0.2 times as likely as adults to show a major improvement (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.05-0.91; P = .04), and patients with larger lung volume on FB scan were borderline less likely to have a better than average improvement than patients with smaller lung volume (OR, 0.999 per cc of lung volume; 95% CI, 0.998-1.001; P = .07). For mean heart dose, females were borderline more likely to benefit from mDIBH (OR, 3.85; 95% CI, 1.0005-14.3; P = .05). In exploratory modeling of factors associated with improvement of any magnitude in both lung and heart dose, the only significant predictor found was diaphragmatic excursion (OR, 1.76 per cm of excursion; 95% CI, 1.002-3.09; P = .049). Eighty-eight percent of patients with ≥ 2.3 cm diaphragmatic excursion had improvement in both mean lung and heart doses, whereas 50% of patients with smaller excursions improved in both parameters.
Discussion Reducing the late toxicity of treatment has emerged as a clinical priority in the management of young patients with mediastinal lymphoma. For patients receiving RT, reductions in target volume and improvements in treatment delivery have been shown to diminish normal tissue exposure, with early clinical evidence suggesting that some of these advances will reduce late toxicity compared with conventionally delivered RT. 7,11,13 With doxorubicin commonly integrated in the treatment of most patients with HL and aggressive histology nonHodgkin lymphoma, additional cardiac toxicity from the radiation is a significant concern. 17 In a pediatric population, Tukenova et al 18 found that a mean cardiac dose exceeding 5 Gy increased the estimated relative risk of dying of cardiac disease. Mulrooney et al 19 published on their experience of cardiac outcomes in adult survivors
of childhood and adolescent cancer and found that mean cardiac doses above 15 Gy increased the relative hazard of cardiac toxicity by 2-fold to 6-fold. 19 These studies emphasize the importance of cardiac dose reduction, as was achieved with mDIBH in the present study. Not only did the implementation of mDIBH significantly reduce the mean heart dose from 14.3 to 11.8 Gy, but it also significantly decreased all cardiac dosimetric parameters. When delivering radiation therapy for HL with mediastinal involvement, partial lung volume is inevitably irradiated, raising concerns about the risk of radiation pneumonitis (RP). Fox et al 20 recently published their experience on the risk of RP for HL patients receiving combined modality treatment. Of 75 evaluable patients, 10% developed mild RP. Identified predictive factors were a MLD greater than 13.5 Gy and a bilateral lung V20 exceeding 33.5%. Similar lung parameters were identified by Hua et al 21 in a group of pediatric lymphoma patients. Mean lung dose in the pneumonitis group was 14.4 Gy versus 11.9 Gy in the asymptomatic population. In our cohort, half the patients treated in free-breathing had MLD exceeding 11 Gy, with values as high at 23.1 Gy, thus placing them at an increased risk of mild pneumonitis. Implementation of ABC allowed for a reduction in MLD, with the highest reported value being 15.4 Gy with mDIBH, and based on the dosimetric criteria cited above, the large majority of our patients treated with mDIBH patients would have negligible risk of pneumonitis. The risk of second malignant neoplasms is also a significant concern following mediastinal RT. In a large case-control study, Gilbert et al 22 reported a linear increase in lung cancer risk with an estimated excess relative risk of 0.15 per Gy, consistent with the general principle that normal tissue dose should be kept “as low as reasonably achievable.” In the current study, mDIBH resulted in a 1.5 Gy reduction in MLD. Notably, this dose is equivalent to approximately 67 diagnostic chest CT scans. 23 However, mean breast dose did increase in 77% of females with mDIBH, with the average absolute increase being 0.6 Gy.
Practical Radiation Oncology: May-June 2014 Table 2
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Dosimetric parameters with the free breathing (FB) and the moderate deep-inspiration breath-hold (mDIBH) techniques
Dosimetric parameter Lungs V5 (%) V10 (%) V15 (%) V20 (%) V25 (%) V30 (%) Mean dose (Gy) Heart V5 (%) V10 (%) V15 (%) V20 (%) V25 (%) V30 (%) Mean dose (Gy) Breasts V5 (%) V10 (%) V15 (%) V20 (%) V25 (%) V30 (%) Mean dose (Gy)
FB Median value (range)
mDIBH Median value (range)
Relative % change with mDIBH technique (range)
P value
52 (19 to 97) 41 (11 to 93) 35 (3 to 87) 28 (1 to 82) 20 (0 to 58) 6 (0 to 40) 11.0 (2.5 to 23.1)
44 34 29 22 14 4.37 9.5
(16 to 86) (10 to 64) (3 to 53) (1 to 41) (0 to 32) (0 to 27) (2.5 to 15.4)
−15.0 (−47.9 to −18.5 (−52.6 to −22.1 (−55.3 to −25.4 (−69.8 to −26.4 (−78.8 to −32.8 (−68.7 to −18.0 (−49.0 to
b .0001 b .0001 b .0001 b .0001 b .0001 b .0001 b .0001
55 (0 to 100) 48 (0 to 100) 43 (0 to 100) 38 (0 to 100) 20 (0 to 95) 5 (0 to 73) 14.3 (0.6 to 28.6)
45 42 35 29 13 2 11.8
(0 to 100) (0 to 100) (0 to 100) (0 to 100) (0 to 80) (0 to 75) (0.6 to 29.9)
−9.2 (−71.6 to 96.8) −9.9 (−78.8 to 71.3) −11.3 (−84.2 to 68.0) −13.5 (−94.0 to 73.5) −17.3 (−100.0 to 123.6) −9.4 (−99.5 to 128.6) −10.3 (−76.3 to 61.8)
12 (1 to 72) 10 (0 to 48) 8 (0 to 40) 6 (0 to 37) 2 (0 to 33) 1 (0 to 21) 3.0 (0.3 to 13.1)
13 11 9 6 3 1 3.6
(4 to 75) (2 to 49) (1 to 44) (0 to 41) (0 to 35) (0 to 21) (0.9 to 14.3)
10.3 (−15.0 to 663.5) 11.5 (−12.4 to 48.3) 10.0 (−20. 8 to 66.3) 13.1 (−30.2 to 110.0) 16.0 (−39.0 to 100.0) 39.3 (−42.9 to 2300.0) 12.8 (−14.2 to 195.5)
This highlights the need to better understand the relative tradeoff of doses to different tissues, and for better methods of sparing breast tissue for females receiving mediastinal RT. Measuring diaphragmatic excursion may be 1 way to increase the chance that a patient will benefit from mDIBH. When the diaphragmatic excursion on the mDIBH planning scan was ≥ 2.3 cm greater than the FB scan, the probability that the patient had improvement in both heart and lung dose was 88%. To our knowledge, this is the largest study to evaluate the feasibility and dosimetric effects of ABC for the management of mediastinal lymphoma. Stromberg et al 24 initially described the use of ABC for 5 patients treated for HL with mantle RT fields, and reported that planning with deep inspiration, as opposed to FB, allowed a 12% reduction in the lung volume irradiated. They concluded that the treatment was both well tolerated and reproducible and further postulated that this technique could be implemented as a means to reduce normal tissue toxicity. Claude et al 12 reported a small series of children (n = 7) treated for HL with ABC (median age of 15 years; range, 13-18 years). The mean reduction in the lung V20 was of 25% when using ABC, and mean heart dose decreased from 15 Gy to 12 Gy. For girls without axillary irradiation, mean breast dose was less than 2 Gy, for both techniques. More recently, Paumier et al 13 published their experience of the dosimetric benefits of IMRT combined with DIBH,
10.9) 9.3) 11.9) 19.6) 681.8) 48.5) 11.3)
.004 .007 .003 .001 .004 .04 .003 .0005 .0005 .01 .003 .004 .005 .0005
for 28 patients. Involved-node RT volumes were smaller on the DIBH scans, by a significant 7% for the CTV, and a nonsignificant 4% for the PTV, although not all patients were treated with mDIBH. They found a 15% to 20% significant reduction in the mean doses to the coronary arteries, the heart and the lungs, and a 28% decrease in lung V20 with the use of DIBH compared with FB. The dose reduction benefit was greater for patients having disease confined only to their upper mediastinum. In comparison, all 47 patients of our study were planned and completed radiation treatment with mDIBH. Our experience is thus not purely dosimetric, but confirms that this technique can be implemented clinically for most of lymphoma patients requiring mediastinal irradiation. Our study has some inherent limitations. First, the benefits seen are currently purely dosimetric and longer follow-up and many more patients would need to be assessed and followed to see if this translates into clinically meaningful reductions in long-term side effects. The dosimetric improvement described here is attributable only to more favorable displacement of lung and cardiac tissue with mDIBH, and does not include that which might be attained by reducing PTV margins because the same expansion was maintained for both planning processes, and generally kept at 8 mm. Future work focusing on reduction of PTV margins when using mDIBH might further limit irradiation of normal tissue. Finally, a minority of cases had a higher lung and heart dose on
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the mDIBH plan than the FB plan (Fig 2C). A better identification of patients who benefit from the technique would facilitate optimal patient selection and efficiency in treatment planning as it increases the workload with the necessity of a training visit, and adds an average of 10 minutes for each daily fraction in our experience. In conclusion, the use of mDIBH to treat lymphoma patients with mediastinal involvement decreased mean lung and heart doses for most patients. However, the procedure should not be assumed to be beneficial for female patients. Measuring the difference in diaphragmatic excursion between mDIBH and FB scans may identify patients with the greatest chance of benefitting. Further steps are, however, needed to elucidate which patients should be treated with mDIBH routinely.
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Practical Radiation Oncology: May-June 2014 10. Cella L, Liuzzi R, Magliulo M, et al. Radiotherapy of large target volumes in Hodgkin's lymphoma: normal tissue sparing capability of forward IMRT versus conventional techniques. Radiat Oncol. 2010;5:33. 11. Hoppe BS, Flampouri S, Su Z, et al. Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012;84:449-455. 12. Claude L, Malet C, Pommier P, Thiesse P, Chabaud S, Carrie C. 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. 13. Paumier A, Ghalibafian M, Gilmore J, et al. Dosimetric benefits of intensity-modulated radiotherapy combined with the deep-inspiration breath-hold technique in patients with mediastinal Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys. 2012;82:1522-1527. 14. Wong JW, Sharpe MB, Jaffray DA, et al. The use of active breathing control (ABC) to reduce margin for breathing motion. Int J Radiat Oncol Biol Phys. 1999;44:911-919. 15. Remouchamps VM, Letts N, Vicini FA, et al. Initial clinical experience with moderate deep-inspiration breath hold using an active breathing control device in the treatment of patients with leftsided breast cancer using external beam radiation therapy. Int J Radiat Oncol Biol Phys. 2003;56:704-715. 16. Yahalom J, Mauch P. The involved field is back: issues in delineating the radiation field in Hodgkin's disease. Ann Oncol. 2002;13(Suppl 1):79-83. 17. Schellong G, Riepenhausen M, Bruch C, et al. Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DALHD studies. Pediatr Blood Cancer. 2010;55:1145-1152. 18. Tukenova M, Guibout C, Oberlin O, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol. 2010;28:1308-1315. 19. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606. 20. Fox AM, Dosoretz AP, Mauch PM, et al. Predictive factors for radiation pneumonitis in Hodgkin lymphoma patients receiving combinedmodality therapy. Int J Radiat Oncol Biol Phys. 2012;83:277-283. 21. Hua C, Hoth KA, Wu S, et al. Incidence and correlates of radiation pneumonitis in pediatric patients with partial lung irradiation. Int J Radiat Oncol Biol Phys. 2010;78:143-149. 22. Gilbert ES, Stovall M, Gospodarowicz M, et al. Lung cancer after treatment for Hodgkin's disease: focus on radiation effects. Radiat Res. 2003;159:161-173. 23. Berrington de González A, Darby S. Risk of cancer from diagnostic x-rays: estimates for the UK and 14 other countries. Lancet. 2004;363:345-351. 24. 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.
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Original Report
Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose Anne-Marie Charpentier MD FRCPC a , Tatiana Conrad MD a , Jenna Sykes MMath b , Angela Ng MEd RTT a , Rachel Zhou HBSc RTT a , Amy Parent BSc MRT(T) a , Catherine Coolens PhD a , Richard W. Tsang MD FRCPC a , Mary K. Gospodarowicz MD FRCPC a , Alexander Sun MD FRCPC a , David C. Hodgson MD FRCPC a,⁎ a
Radiation Medicine Program, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada Department of Biostatistics, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
b
Received 28 May 2013; revised 30 July 2013; accepted 31 July 2013
Abstract Purpose: Active breathing control (ABC) is emerging as a tool to reduce heart and lung dose for lymphoma patients receiving mediastinal radiation therapy (RT). The objective of this study was to report our early institutional experience with this technique, with emphasis on quantifying the changes in normal tissue dose and exploring factors that could be used to select patients with the greatest benefit. Methods and materials: Patients receiving mediastinal involved-field RT (IFRT) for lymphoma were eligible. The ABC was performed using a moderate deep-inspiration breath-hold (mDIBH) technique. All patients were replanned with free-breathing (FB) computed tomographic data sets and comparisons of lung, cardiac, and female breast tissue doses were made between mDIBH and FB plans. Logistic regression models were used to identify factors associated with improvement in mean lung and heart dose with mDIBH. Results: Forty-seven patients were analyzed; the majority (87.2%) had Hodgkin lymphoma. Median prescribed dose was 30 Gy (range, 20-36 Gy), with 78.7% of cases being treated with parallel-opposed beams. The use of mDIBH significantly improved average mean lung dose (FB: 11.0 Gy; mDIBH: 9.5 Gy; P b .0001), lung V20 (28% vs 22%; P b .0001), and mean heart dose (14.3 Gy vs 11.8 Gy; P = .003), but increased the mean breast dose (FB: 3.0 Gy; mDIBH 3.6 Gy; P = .0005). The magnitude of diaphragmatic excursion on the inhale scan was significantly associated with dosimetric improvement in both heart and lung dose with mDIBH. Preliminary results of this study were presented in an oral presentation at the 53rd Annual Meeting of the American Society for Radiation Oncology (ASTRO), Miami Beach, FL, October 2-6, 2011. Sources of support: Dr Charpentier is supported in part by the Princess Margaret Cancer Foundation, Department of Radiation Oncology Academic Enrichment Fund. Dr Hodgson is supported by a Cancer Care Ontario Research Chair. Conflicts of interest: None. ⁎ Corresponding author. Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario, M5G 2M9, Canada. E-mail address: [email protected] (D.C. Hodgson). 1879-8500/$ – see front matter © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2013.07.015
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Conclusions: Mediastinal IFRT for lymphoma delivered with mDIBH can significantly reduce lung and heart dose compared with FB, although not for all patients, and may increase breast dose in females. Its implementation is achievable in both adult and pediatric populations. Further work is necessary to better predict which patients benefit from this technique. © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction Patients presenting with early stage Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma have excellent outcomes following treatment with combined modality therapy. 1-4 However, late effects related to normal tissue irradiation remain a significant clinical concern. 5 Consequently, recent clinical efforts have focused on minimizing late effects by reducing normal tissue exposure using a variety of different methods. 1,3,6-13 Early studies using active breathing control (ABC) have shown that the use of moderate deep-inspiration breath-hold (mDIBH) reduces breathing-induced internal organ displacement during treatment 14 and can be used to reduce normal tissue dose for patients receiving adjuvant radiation therapy to left-sided breast cancer. 15 More recently, interest in its use is also gaining for HL patients with mediastinal involvement. 12,13 The objective of our study was to evaluate the changes in normal tissue dose among pediatric and adult patients receiving mediastinal RT for lymphoma using mDIBH, and to identify clinical factors associated with reduced normal tissue dose.
Methods and materials Patient selection Beginning in March 2010, mDIBH technique was employed as standard practice for patients at the Princess Margaret Cancer Centre (PMCC Canada) with a diagnosis of lymphoma and requiring mediastinal radiation therapy. Patients were not eligible for the current retrospective analysis if they were unable to demonstrate consistency of length and depth of breath-hold (n = 1), were treated with palliative intent (n = 2), had concurrent treatment of infradiaphragmatic disease planned on the same computed tomographic (CT) data set (n = 2) or had no free-breathing (FB) planning CT (n = 5). This study was approved by our institutional Research Ethics Board.
Training session and planning visit All patients had a 30-minute individualized training session to assess feasibility of respiratory-gated treatment. The Active Breathing Coordinator device (ABC, Elekta, Stockholm, Sweden) was used to provide controlled
monitoring of breathing and suspended breath-hold position at an inspiration phase during the breathing cycle. If patients could tolerate repeated breath-holds of at least 15 seconds, they were deemed suitable for the technique. Maximal inspiratory capacity was established based on the average of at least 3 breath-hold values during the training appointment. Then, threshold for mDIBH was set at approximately 80% of the maximal inspiratory capacity, and remained the same for the whole planning and radiation delivery process. The planning CT scan was acquired on the same day as the training visit using the mDIBH technique; an additional helical FB CT scan was also obtained in the same position. All patients were immobilized using a Vac-Lok bag (Civco Medical Solutions, Kalona, IA) and neck rest and a leg immobilizer under their knees and were scanned arms by sides.
Contouring guidelines All patients received involved-field radiation therapy, with volumes for targets and organs-at-risk determined by the treating radiation oncologist on the mDIBH CT scan. No systematic registration with the prechemotherapy diagnostic CT scan in FB was performed, but images were available for the radiation oncologist to determine the cranio-caudal extent of the clinical target volume (CTV) to encompass prechemotherapy involvement, with the transverse diameter of the CTV being defined by the postchemotherapy width of the initially involved mediastinal tissue as per published guidelines. 16 Uninvolved hila were treated at physician discretion. Planning target volume (PTV) was maintained as an 8-mm circumferential expansion on CTV, unless a smaller margin was deemed appropriated by the treating physician. The heart was contoured from the level of the root of the aorta and pulmonary trunk down to the apex. Lung volumes were delineated using a threshold technique. Breasts were contoured from the second rib insertion superiorly to the loss of breast tissue inferiorly, excluding the pectoralis muscles and the chest wall, and limited by the mid-axillary line and the sternum-rib junction. Target volumes, heart, lungs and breasts were then recontoured by 2 individuals (T.C., A.N.) on the FB data set, based on anatomic landmarks on the respective CT planning images. Patients were classified as having disease encompassing the whole mediastinum or upper mediastinum, with the former designation being used if the CTV on the mDIBH scan was extending 3 cm or more below the level of the carina. Diaphragmatic excursion was measured in centimeters as the difference between the maximum
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point of the diaphragm on the FB and the mDIBH scans, after image co-registration.
Treatment planning The planning process was performed on the mDIBH CT, using Pinnacle, version 8 (Philips Radiation Oncology Systems, Milpitas, CA). Patients were treated primarily with a parallel-opposed pair (POP) technique, with an intensity modulated radiation therapy (IMRT) plan allowed based on physician discretion. The multileaf collimator field segmentation was routinely used to achieve dose uniformity within the PTV. Criteria for target coverage were that 100% of the CTV received ≥ 95% of the prescribed dose and ≥ 95% of PTV received ≥ 95% of the prescribed dose. Each of the FB plans was replanned keeping the same beam arrangement as for the breath-hold plan. For POP plans, adjustment of field segmentation and dimensions was permitted to account for the target volume change and achieve the coverage criteria described above. IMRT plans were reoptimized using inverse planning and beam angle changes were permitted if dosimetrically advantageous for target volume coverage or normal tissue sparing. To minimize inconsistency between the mDIBH and FB plans, both were required to meet the CTV and PTV coverage criteria listed above, and in addition the proportion of the CTV receiving ≥ 105% of the prescribed dose was required to be within 5% when comparing mDIBH and FB plans. Figure 1 provides an example of POP fields with mDIBH (A) and FB (B).
Treatment setup verification From March 2010 to October 2011, treatment setup verification was performed with a cone-beam CT (CBCT)
Figure 1
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in FB and portal images with onboard megavoltage imaging in mDIBH prior to delivery of each fraction. These were electronically and visually compared to digitally reconstructed radiographs of the plan prior to treatment based on bony anatomy and an outline of the carina. On treatment, shifts were performed to match the FB CBCT to the planning CT within 1 mm and 5 degrees (bony setup); the carina was matched on the mDIBH megavoltage portal image and digitally reconstructed radiographs to within 3 mm. After October 2011, mDIBH CBCT was implemented for setup verification. A CBCT image was acquired in BH and a registration to the planning CT was performed based on matching of the vertebrae and carina. Maximal acceptable setup tolerance was 1 mm and 5 degrees (bony setup), and 3 mm for the carina. An average of 2-4 BHs were required to complete the CBCT acquisition.
Statistical analysis Comparison between mDIBH and FB plan was made over a range of doses for heart, lung, and female breast tissue. Statistical comparisons for dosimetric variables were performed using a 2-sided paired t test, while a Mann-Whitney test was used to compare the dosimetry between the pediatric versus adult cohort and the IMRT versus POP subgroup. Multivariable logistic regression models were used with a forward selection algorithm to identify factors associated with better than average improvement in mean lung dose (MLD) and mean heart dose with the mDIBH technique. Patients with “better than average” improvement were defined as those who showed a greater decrease in dose from the FB plan to the mDIBH technique than the median decrease in the cohort. A third model was fit to
Treatment field for moderate deep-inspiration breath-hold (A) and free-breathing (B).
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assess which predictors were correlated with patients showing a decrease of any magnitude in both MLD and mean heart dose. Variables explored in the modeling were the following: age (b 18 vs ≥ 18); sex; diaphragmatic excursion (continuous); type of mediastinal involvement (whole vs upper); lung volume on FB scan (continuous); technique (POP vs IMRT); and dose of RT (b 25 vs ≥ 25 Gy). All statistical analysis was performed using R software, version 2.12.1 (The R Foundation for Statistical Computing, Vienna, Austria). A 2-sided P value of less than .05 was used to assess statistical significance.
Results Patient and treatment characteristics Between March 1, 2010 and November 31, 2011, 47 patients were treated with mDIBH and deemed eligible for the current analysis. Table 1 provides the detailed Table 1
Patient characteristics
Characteristic Age Sex Female Male Age category Adult Pediatric Primary diagnosis Hodgkin lymphoma Diffuse large B-cell lymphoma Ann-Arbor stage I II III IV Type of presentation Primary lymphoma Refractory disease Relapse Type of mediastinal involvement Upper mediastinum only Whole mediastinum Technique of radiation Parallel-opposed pair IMRT Dose of radiation b 25 Gy ≥ 25 Gy
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characteristics of the cohort. Most patients had HL (n = 41, 87.2%). Median age at time of treatment was 24.0 years (range, 11.4-67.7), with 15 pediatric cases. Mediastinal disease in most cases extended ≥ 3 cm below the carina (ie, whole mediastinum) (n = 42, 89.4%). POP fields were used for 37 patients (78.7%), while 10 were treated with IMRT. Median dose was 30 Gy (range, 20-36 Gy). The majority of the patients in the lowest dose strata were children treated with 21 Gy in 14 fractions.
Dosimetric comparison for lung irradiation Compared with FB, mDIBH was associated with a reduction in MLD for 45 (95.7%) patients (Fig 2A). Evaluation of lung dosimetry demonstrated a median MLD of 11.0 Gy on FB plans and 9.5 Gy on mDIBH scans, a reduction of 18.0% (P b .0001). Examination of lung V20 revealed a median value of 28% on FB scans that decreased to 22% with the use of mDIBH technique, a relative reduction of 25.4% (P b .0001). Table 2 provides detailed lung dosimetric parameters.
Dosimetric comparison for heart irradiation No. of patients (total = 47)
%
Median, 24.0 y (range, 11.4-67.7) 27 20
57.4% 42.6%
32 15
68.1 31.9
41 6
87.2 12.8
5 30 4 8
10.6 63.8 8.5 17.0
41 3 3
87.2 6.4 6.4
5 42
10.6 89.4
37 10
78.7 21.3
13 34
27.7 72.3
IMRT, intensity modulated radiation therapy.
The use of mDIBH was associated with a reduction in mean heart dose for 37 (78.7%) patients (Fig 2B). Dosimetric evaluation of the heart showed that the average (median) mean heart dose was 14.3 Gy on FB plans and 11.8 Gy on mDIBH treatment plans (Table 2), a relative reduction of 10.3% (P = .003). All cardiac dosimetric parameters were significantly reduced with the use of mDIBH (Table 2).
Dosimetric comparison for breast irradiation The mean breast dose increased in 20/26 (77%) of female patients with the use of mDIBH, with a median increase in mean breast dose of 0.6 Gy (3.0 Gy with FB to 3.6 Gy with mDIBH; P = .0005). Most of the other breast dosimetric parameters showed similar increase in the range of 10.0% to 16.0%, except breast V30 (Table 2).
Other univariate comparisons There was no significant difference in the dosimetric effects of mDIBH between pediatric versus adult patients, except for a borderline effect of age for MLD (P = .09). Also, there was no significant difference in effect among those treated with IMRT or parallel opposed anteriorposterior opposed beams.
Multivariable model To identify selection criteria for patients who would most benefit from employment of mDIBH in terms of MLD and mean heart dose, a multivariate analysis was
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Figure 2 Waterfall plots of percent change in (A) bilateral mean lung dose, (B) mean heart dose, and (C) both parameters for the whole cohort. Each column represents the percent change with the breath-hold planning as compared with free-breathing, for a single patient. The dashed lines represent the median percent change.
performed to evaluate factors associated with a greater than average reduction in normal tissue dose. For MLD, children were 0.2 times as likely as adults to show a major improvement (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.05-0.91; P = .04), and patients with larger lung volume on FB scan were borderline less likely to have a better than average improvement than patients with smaller lung volume (OR, 0.999 per cc of lung volume; 95% CI, 0.998-1.001; P = .07). For mean heart dose, females were borderline more likely to benefit from mDIBH (OR, 3.85; 95% CI, 1.0005-14.3; P = .05). In exploratory modeling of factors associated with improvement of any magnitude in both lung and heart dose, the only significant predictor found was diaphragmatic excursion (OR, 1.76 per cm of excursion; 95% CI, 1.002-3.09; P = .049). Eighty-eight percent of patients with ≥ 2.3 cm diaphragmatic excursion had improvement in both mean lung and heart doses, whereas 50% of patients with smaller excursions improved in both parameters.
Discussion Reducing the late toxicity of treatment has emerged as a clinical priority in the management of young patients with mediastinal lymphoma. For patients receiving RT, reductions in target volume and improvements in treatment delivery have been shown to diminish normal tissue exposure, with early clinical evidence suggesting that some of these advances will reduce late toxicity compared with conventionally delivered RT. 7,11,13 With doxorubicin commonly integrated in the treatment of most patients with HL and aggressive histology nonHodgkin lymphoma, additional cardiac toxicity from the radiation is a significant concern. 17 In a pediatric population, Tukenova et al 18 found that a mean cardiac dose exceeding 5 Gy increased the estimated relative risk of dying of cardiac disease. Mulrooney et al 19 published on their experience of cardiac outcomes in adult survivors
of childhood and adolescent cancer and found that mean cardiac doses above 15 Gy increased the relative hazard of cardiac toxicity by 2-fold to 6-fold. 19 These studies emphasize the importance of cardiac dose reduction, as was achieved with mDIBH in the present study. Not only did the implementation of mDIBH significantly reduce the mean heart dose from 14.3 to 11.8 Gy, but it also significantly decreased all cardiac dosimetric parameters. When delivering radiation therapy for HL with mediastinal involvement, partial lung volume is inevitably irradiated, raising concerns about the risk of radiation pneumonitis (RP). Fox et al 20 recently published their experience on the risk of RP for HL patients receiving combined modality treatment. Of 75 evaluable patients, 10% developed mild RP. Identified predictive factors were a MLD greater than 13.5 Gy and a bilateral lung V20 exceeding 33.5%. Similar lung parameters were identified by Hua et al 21 in a group of pediatric lymphoma patients. Mean lung dose in the pneumonitis group was 14.4 Gy versus 11.9 Gy in the asymptomatic population. In our cohort, half the patients treated in free-breathing had MLD exceeding 11 Gy, with values as high at 23.1 Gy, thus placing them at an increased risk of mild pneumonitis. Implementation of ABC allowed for a reduction in MLD, with the highest reported value being 15.4 Gy with mDIBH, and based on the dosimetric criteria cited above, the large majority of our patients treated with mDIBH patients would have negligible risk of pneumonitis. The risk of second malignant neoplasms is also a significant concern following mediastinal RT. In a large case-control study, Gilbert et al 22 reported a linear increase in lung cancer risk with an estimated excess relative risk of 0.15 per Gy, consistent with the general principle that normal tissue dose should be kept “as low as reasonably achievable.” In the current study, mDIBH resulted in a 1.5 Gy reduction in MLD. Notably, this dose is equivalent to approximately 67 diagnostic chest CT scans. 23 However, mean breast dose did increase in 77% of females with mDIBH, with the average absolute increase being 0.6 Gy.
Practical Radiation Oncology: May-June 2014 Table 2
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Dosimetric parameters with the free breathing (FB) and the moderate deep-inspiration breath-hold (mDIBH) techniques
Dosimetric parameter Lungs V5 (%) V10 (%) V15 (%) V20 (%) V25 (%) V30 (%) Mean dose (Gy) Heart V5 (%) V10 (%) V15 (%) V20 (%) V25 (%) V30 (%) Mean dose (Gy) Breasts V5 (%) V10 (%) V15 (%) V20 (%) V25 (%) V30 (%) Mean dose (Gy)
FB Median value (range)
mDIBH Median value (range)
Relative % change with mDIBH technique (range)
P value
52 (19 to 97) 41 (11 to 93) 35 (3 to 87) 28 (1 to 82) 20 (0 to 58) 6 (0 to 40) 11.0 (2.5 to 23.1)
44 34 29 22 14 4.37 9.5
(16 to 86) (10 to 64) (3 to 53) (1 to 41) (0 to 32) (0 to 27) (2.5 to 15.4)
−15.0 (−47.9 to −18.5 (−52.6 to −22.1 (−55.3 to −25.4 (−69.8 to −26.4 (−78.8 to −32.8 (−68.7 to −18.0 (−49.0 to
b .0001 b .0001 b .0001 b .0001 b .0001 b .0001 b .0001
55 (0 to 100) 48 (0 to 100) 43 (0 to 100) 38 (0 to 100) 20 (0 to 95) 5 (0 to 73) 14.3 (0.6 to 28.6)
45 42 35 29 13 2 11.8
(0 to 100) (0 to 100) (0 to 100) (0 to 100) (0 to 80) (0 to 75) (0.6 to 29.9)
−9.2 (−71.6 to 96.8) −9.9 (−78.8 to 71.3) −11.3 (−84.2 to 68.0) −13.5 (−94.0 to 73.5) −17.3 (−100.0 to 123.6) −9.4 (−99.5 to 128.6) −10.3 (−76.3 to 61.8)
12 (1 to 72) 10 (0 to 48) 8 (0 to 40) 6 (0 to 37) 2 (0 to 33) 1 (0 to 21) 3.0 (0.3 to 13.1)
13 11 9 6 3 1 3.6
(4 to 75) (2 to 49) (1 to 44) (0 to 41) (0 to 35) (0 to 21) (0.9 to 14.3)
10.3 (−15.0 to 663.5) 11.5 (−12.4 to 48.3) 10.0 (−20. 8 to 66.3) 13.1 (−30.2 to 110.0) 16.0 (−39.0 to 100.0) 39.3 (−42.9 to 2300.0) 12.8 (−14.2 to 195.5)
This highlights the need to better understand the relative tradeoff of doses to different tissues, and for better methods of sparing breast tissue for females receiving mediastinal RT. Measuring diaphragmatic excursion may be 1 way to increase the chance that a patient will benefit from mDIBH. When the diaphragmatic excursion on the mDIBH planning scan was ≥ 2.3 cm greater than the FB scan, the probability that the patient had improvement in both heart and lung dose was 88%. To our knowledge, this is the largest study to evaluate the feasibility and dosimetric effects of ABC for the management of mediastinal lymphoma. Stromberg et al 24 initially described the use of ABC for 5 patients treated for HL with mantle RT fields, and reported that planning with deep inspiration, as opposed to FB, allowed a 12% reduction in the lung volume irradiated. They concluded that the treatment was both well tolerated and reproducible and further postulated that this technique could be implemented as a means to reduce normal tissue toxicity. Claude et al 12 reported a small series of children (n = 7) treated for HL with ABC (median age of 15 years; range, 13-18 years). The mean reduction in the lung V20 was of 25% when using ABC, and mean heart dose decreased from 15 Gy to 12 Gy. For girls without axillary irradiation, mean breast dose was less than 2 Gy, for both techniques. More recently, Paumier et al 13 published their experience of the dosimetric benefits of IMRT combined with DIBH,
10.9) 9.3) 11.9) 19.6) 681.8) 48.5) 11.3)
.004 .007 .003 .001 .004 .04 .003 .0005 .0005 .01 .003 .004 .005 .0005
for 28 patients. Involved-node RT volumes were smaller on the DIBH scans, by a significant 7% for the CTV, and a nonsignificant 4% for the PTV, although not all patients were treated with mDIBH. They found a 15% to 20% significant reduction in the mean doses to the coronary arteries, the heart and the lungs, and a 28% decrease in lung V20 with the use of DIBH compared with FB. The dose reduction benefit was greater for patients having disease confined only to their upper mediastinum. In comparison, all 47 patients of our study were planned and completed radiation treatment with mDIBH. Our experience is thus not purely dosimetric, but confirms that this technique can be implemented clinically for most of lymphoma patients requiring mediastinal irradiation. Our study has some inherent limitations. First, the benefits seen are currently purely dosimetric and longer follow-up and many more patients would need to be assessed and followed to see if this translates into clinically meaningful reductions in long-term side effects. The dosimetric improvement described here is attributable only to more favorable displacement of lung and cardiac tissue with mDIBH, and does not include that which might be attained by reducing PTV margins because the same expansion was maintained for both planning processes, and generally kept at 8 mm. Future work focusing on reduction of PTV margins when using mDIBH might further limit irradiation of normal tissue. Finally, a minority of cases had a higher lung and heart dose on
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the mDIBH plan than the FB plan (Fig 2C). A better identification of patients who benefit from the technique would facilitate optimal patient selection and efficiency in treatment planning as it increases the workload with the necessity of a training visit, and adds an average of 10 minutes for each daily fraction in our experience. In conclusion, the use of mDIBH to treat lymphoma patients with mediastinal involvement decreased mean lung and heart doses for most patients. However, the procedure should not be assumed to be beneficial for female patients. Measuring the difference in diaphragmatic excursion between mDIBH and FB scans may identify patients with the greatest chance of benefitting. Further steps are, however, needed to elucidate which patients should be treated with mDIBH routinely.
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