A Low-Dose Ipsilateral Lung Restriction Improves 3-D Conformal Planning for Partial Breast Radiation Therapy
Article Outline
Abstract
In trials of 3D conformal external beam partial breast radiotherapy (PBRT), the dosimetrist must balance the priorities of achieving high conformity to the target versus minimizing low-dose exposure to the normal structures. This study highlights the caveat that in the absence of a low-dose lung restriction, the use of relatively en-face fields may meet trial-defined requirements but expose the ipsilateral lung to unnecessary low-dose radiation. Adding a low-dose restriction that ≤20% of the ipsilateral lung should receive 10% of the prescribed dose resulted in successful plans in 88% of cases. This low-dose lung limit should be used in PBRT planning.
Key Words: Partial breast irradiation, Treatment planning, Dose restriction, Lung exposure, Secondary malignancies
Introduction
Accelerated partial breast radiation therapy (PBRT) is currently undergoing prospective comparison with standard whole-breast radiation therapy (WBRT) for selected women with early-stage breast cancer treated with breast-conserving surgery.1, 2, 3 In the Canadian Randomized Trial of Accelerated Partial Breast Irradiation (RAPID) study comparing external beam 3D conformal PBRT with standard WBRT, a noncoplanar arrangement of 4 or 5 beams is used to encompass the planning target volume (PTV), consisting of the postoperative tumor bed with margins.2 In PBRT planning, beam directions must avoid normal structures such as the ipsilateral lung, heart, and contralateral breast to meet trial-defined criteria for limiting dose to normal tissues. Similar to other ongoing randomized trials of PBRT, the RAPID trial used a single ipsilateral lung maximum dose restriction that ≤10% of the lung volume should receive 30% of the prescribed dose.2, 3 Patients randomized to PBRT on the RAPID trial were successfully planned to meet this and all other trial-defined dose volume criteria. However, without a low-dose lung restriction, a “low-dose hump” was observed on the dose-volume histogram (DVH) curves of the ipsilateral lung in a number of PBRT plans (Fig. 1). For some patients meeting trial-defined dose restrictions, >20% of the lung received >10% of the prescribed dose.
Fig. 1.
Left-sided, 4-beam PBRT plan meeting trial-defined dose restrictions but with a “low-dose hump” in the ipsilateral lung DVH (right panel). The volume receiving 10% or more of the prescribed dose is shown in colorwash (left panel).
Although secondary malignancies are a well-documented long-term risk of therapeutic radiation, the risk of radiation therapy (RT)–induced carcinogenesis as a function of RT dose remains poorly understood. Dose-response relationships for RT-induced carcinogenesis in the modern era of 3D conformal external beam RT are a concern, because the use of an increased number of beams and monitor units can expose larger volumes of normal tissue to lower doses of radiation.
The current study aims to determine whether adding a low-dose lung restriction can improve PBRT planning by removing the low-dose hump and reducing the volume of ipsilateral lung exposed to low-dose radiation.
Methods
Study subjects were the first 30 PBRT and first 34 WBRT patients accrued to the RAPID trial at the British Columbia Cancer Agency between April 2006 and January 2007.
3D conformal PBRT planning
All patients underwent planning computed tomography (CT) in the supine position with the ipsilateral arm abducted. A breast board was used for immobilization. CT images (GE Medical Systems, Milwaukee, WI) were obtained using 3-mm interslice thickness, extending from 5 cm above the suprasternal notch to 5 cm below the inframammary fold. The CT images were transferred to the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA) for PBRT planning.
The tumor bed, ipsilateral and contralateral breasts, ipsilateral and contralateral lungs, and heart were contoured. The ipsilateral breast and chest wall were delineated as all the tissue within the standard WBRT tangential fields excluding the lung. The tumor bed was the postoperative surgical cavity seen on CT. The contouring of the target volumes was performed according to previously published defined guidelines.4 The tumor bed was expanded by 1 cm, excluding the chest wall and pectoralis muscles and trimmed to 5 mm from skin to form the clinical target volume (CTV). The CTV was expanded by a further 1 cm to form the PTV.
Dose-volume restrictions
Each plan was manually optimized to ensure coverage of the PTV by at least the 90% isodose posteriorly while not exceeding a maximum dose of 107% to an area of 2 cc within the PTV. The plans were also optimized to limit the dose to the normal tissues. Doses to the ipsilateral and contralateral lungs, contralateral breast, and heart were minimized below those experienced with WBRT for both right-sided and left-sided lesions.2 Dose limits for the ipsilateral breast were that <25% of the breast should receive 95% of the dose and <50% of the breast should receive 50% of the dose.2 For right-sided breast cancers, dose volume restriction for the heart stipulated that <5% of the heart should receive 5% of the prescribed dose. For left-sided lesions excluding lower inner quadrant tumors, <5% should receive 10% of the prescribed dose, and for left-sided lesions located in the lower inner quadrant, <5% should receive 15% of the prescribed dose.2
Beam arrangements
Guidelines for 3D conformal PBRT planning in the RAPID study recommended a 4-beam noncoplanar technique for right-sided breast treatment, and either a 4-beam or 5-beam noncoplanar technique for left-sided breast treatment.2 The 4-beam arrangement usually consisted of lateral, medial, inferior-posterior, and superior-anterior oblique beams. A left-sided 5-beam arrangement would be chosen if the 4-beam arrangement could not meet the trial's DVH restrictions for the heart. The photon beams were modulated by dynamic wedges.
Low-dose lung exposure
The RT plans and DVH curves of study subjects were reviewed retrospectively. Ipsilateral lung DVH analysis revealed that all 30 PBRT and 18/34 (53%) of the WBRT cases met the trial's maximum lung limit of <10% of the ipsilateral lung volume receiving 30% of the dose (Fig. 1). Among the WBRT cases, 27/34 (79%) had 20% or less of the ipsilateral lung receiving 10% of the prescribed dose. However, 24/30 (80%) of the PBRT patients had >20% of the ipsilateral lung volume receiving 10% of the prescribed dose. Beam arrangements were reviewed for the 24 PBRT patients with a “low-dose hump” to assess whether any beam was more en-face than necessary (Fig. 1).
Retrospective PBRT replanning
Retrospective replanning was undertaken with a priority to reduce the low-dose lung exposure while maintaining PTV coverage and DVH restrictions for all other structures defined in the RAPID protocol.2 Replanning involved individualized adjustments of the original treatment beams to direct any relatively en-face beam away from the ipsilateral lung while avoiding the other critical structures. Evaluation of each critical structure's DVH was performed throughout the planning process until a plan was achieved meeting all PTV coverage and critical structure dose-volume limits, and the added low-dose restriction that ≤20% of the ipsilateral lung should receive 10% of the prescribed dose (Fig. 2).
Fig. 2.
Replan of the same case to meet the low-dose ipsilateral lung restriction resulted in reduced low-dose lung exposure (right panel). The volume receiving 10% or more of the prescribed dose is shown in colorwash (left panel).
The clinical characteristics of PBRT cases examined included breast laterality, seroma location, seroma volume, PTV, dose-evaluation volume (DEV), ipsilateral breast volume, and the ratio of DEV to ipsilateral breast volume. The DEV is a reference volume used in the RAPID trial to confirm that the target is adequately covered in the DVH.2 The DEV is defined as the PTV excluding the chest wall, pectoralis major muscle, and 5 mm of skin.
Results
The median age of the subjects treated with PBRT was 64 years (range 41–84). All patients had unicentric tumors ≤3 cm, node-negative disease, and were treated with breast-conserving surgery with clear margins. In the 30 patients treated with PBRT, 11 patients had right-sided and 19 patients had left-sided breast cancer. The location of the seroma was central in 17, lateral in 9, and medial in 7 cases. The median time from breast-conserving surgery to planning CT was 8 weeks (range 4.5–14). The median seroma volume was 11.8 cc (range 1.3–54.2). The median PTV was 167.6 cc (range 86.8–513.8). The median DEV was 111.5 cc (range 54.0–368.7). Twenty-five (83%) cases had PTV <250 cc and corresponding DEV <175 cc, and 5 (17%) cases had PTV >250 cc and corresponding DEV >175 cc. The median ipsilateral breast volume was 1182.4 cc (range 617.1–2142.5). The DEV to ipsilateral breast volume ratio was <5% in 2 patients, 5–10% in 13 patients, and >10% in 15 patients.
In total, 21/24 (88%) of PBRT replans achieved reduced ipsilateral lung exposure, with ≤20% of the lung volume receiving 10% of the prescribed dose, while meeting all other dose restrictions. The analysis of ipsilateral lung DVHs showed that the successful replans had lower lung volume receiving 10% of the dose than with WBRT. There was an associated mean increase of 2.8% in the ipsilateral breast volume that received 95% of the dose compared with the original plans; however, these replans still met the RAPID protocol's stipulation that no more than 25% of the breast volume should receive 95% of the prescribed dose. All patients met protocol-stipulated cardiac dose-volume limits before and after the addition of the low-dose lung limit. The DVHs for the heart and ipsilateral breast before and after the addition of the low-dose lung restriction are shown in an illustrative example in Figs. 1 and 2.
Three patients (12%) did not have a successful replan because of failure to meet one or more of the RAPID protocol's constraints when the low-dose lung restriction was added. The seroma was located centrally in 2 cases and laterally in 1 case. All cases had a PTV >250 cc and a DEV >175 cc. The ratios of the DEV to the ipsilateral breast volume in the 3 cases were 10.6, 12.3, and 25.7.
Discussion
Despite growing interest in shorter, more convenient RT regimens, accelerated external beam 3-D conformal PBRT remains an experimental treatment that requires prospective data to confirm equivalent tumor control and normal tissue toxicities compared with standard WBRT. This study highlights the caveat that in the absence of a low-dose lung restriction, some planners' thought processes may be more in favor of higher conformity because this is the standard goal in 3D conformal planning than in reducing low-dose exposure to the lung, especially in the absence of a low-dose lung limit. The use of relatively en-face fields may appear to meet all protocol-stipulated restrictions, but they can expose larger volumes of the ipsilateral lung to low-dose radiation and should be avoided. This study also demonstrated that the low-dose ipsilateral lung restriction was feasible to implement while maintaining PTV coverage and DVH requirements for other structures for the majority of PBRT candidates.
Ionizing radiation can increase the risk of long-term normal tissue toxicities including fibrosis and secondary malignancies.5, 6, 7, 8, 9, 10 In a population-based analysis of Surveillance, Epidemiology, and End Results (SEER) data, Zablotska et al. reported an association between postmastectomy RT and increased risk of ipsilateral lung cancer, with an estimated risk ratio (RR) of 2.09 for ipsilateral lung cancer 15 years or more after RT.7 Similarly, Darby et al. reported that the RR of lung cancer mortality for women diagnosed and treated with radiation during 1973–1982 increased from 1.17 at <10 years to 2.00 at 10–14 years, to 2.71 at 15 or more years after RT.8
The risk of RT-induced carcinogenesis as a function of RT dose is unclear. In a case-control study using registry data of 8976 women diagnosed with breast cancer between 1935 and 1971, Inskip et al. identified 61 cases of lung cancer that developed 10–20 years after treatment. RT doses to different segments of the lung were estimated using treatment simulations, yielding estimates of an excess RR of lung cancer development of 0.08 per Gy, based on average dose to both lungs, and RR 0.20 per Gy to the ipsilateral lung.9 In the current era of 3D conformal external beam RT and intensity-modulated RT using an increased number of beams and monitor units, larger volumes of normal tissue can be exposed to lower doses of radiation. Hall et al. have estimated that intensity-modulated RT may double the incidence of secondary cancers compared with conventional RT in patients surviving 10 years.10
Compared with conventional RT schedules using 1.8–2 Gy per fraction delivered once daily, most PBRT regimens being tested in randomized trials use accelerated hypofractionation, with larger doses per fraction ranging from 3–4 Gy, delivered twice per day over one week.1, 2, 3 Although the risk of cardiopulmonary injury and secondary malignancies associated with accelerated hypofractionated PBRT remains unknown, caution and efforts to minimize this risk are warranted, especially because PBRT trial candidates are women with favorable-risk disease expected to be long-term survivors.
Among the 3 patients who did not have successful replans, the PTV and corresponding DEV volumes were generally larger (PTV >250 cc and DEV >175 cc) compared with those with successful replans, and the DEVs to ispilateral breast ratio were >10%. However, successful replans were achieved in other subjects with similar parameters, supporting the current practice of customized PBRT planning of each subject to ensure that all PBRT dose-volume restrictions can be met before randomization.
In conclusion, the current planning study has demonstrated that adding a low-dose ipsilateral lung restriction was achievable and resulted in ipsilateral lung exposure to levels equal to or lower than with tangential WBRT for the vast majority of PBRT trial candidates, while meeting all other trial-stipulated limits to other normal tissues. With this knowledge, and in compliance with the “as low as reasonably achievable” principle, the RAPID trial protocol has been amended to incorporate a low-dose restriction specifying that ≤20% of the ipsilateral lung should receive 10% of the prescribed dose.
References
- Accelerated partial breast irradiation in early-stage breast cancer. J. Clin. Oncol. 2007;25:996–1002
- . RAPID: Randomized trial of accelerated partial breast irradiation. http://www.clinicaltrials.gov/ct/show/NCT00282035Accessed October 25, 2008
- National Surgical Adjuvant, Breast and Bowel Project (NSABP B-39/RTOG 0413) (A randomized Phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with Stage 0, I, or II breast cancer). http://www.nsabp.pitt.edu/B-39.aspAccessed December 12, 2008
- Consistency in seroma contouring for partial breast radiotherapy: Impact of guidelines. Int. J. Radiat. Oncol. Biol. Phys. 2006;66:372–376
- A little to a lot or a lot to a little? (An analysis of pneumonitis risk from dose-volume histogram parameters of the lung in patients with lung cancer treated with 3D-conformal radiotherapy). Strahlenther. Onkol. 2003;179:548–556
- . Normal tissue complication probability modelling of tissue fibrosis following breast radiotherapy. Phys. Med. Biol. 2007;52:1831–1843
- . Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma. Cancer. 2003;97:1404–1411
- Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: Prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet. Oncol. 2005;6:557–565
- . Lung cancer risk and radiation dose among women treated for breast cancer. J. Natl. Cancer. Inst. 1994;86:983–988
- . Radiation-induced second cancers: The impact of 3D-CRT and IMRT. Int. J. Radiat. Oncol. Biol. Phys. 2003;56:83–88
PII: S0958-3947(09)00122-8
doi:10.1016/j.meddos.2009.10.003
© 2011 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.
