Investigation of brachial plexus dose that exceeds RTOG constraints for apical lung tumors treated with four- or five-fraction stereotactic body radiation therapy

Abstract

Purpose/objectives(s)

We sought to determine the rate of brachial plexopathy (BPX) in patients exceeding RTOG dose constraints for treatment of apical lung tumors.

Materials/methods

Patients with apical lung tumors treated with four- or five-fraction SBRT were identified from a prospective registry. Dosimetric data were obtained for ipsilateral subclavian vein (SCV) and anatomic BP (ABP) contours. Cumulative equivalent dose in 2 Gy equivalents (EQD2) was calculated for the SCV contour in patients with a history of prior ipsilateral RT. Five-fraction SBRT RTOG constraints of D0.03cc ≤32.0 Gy and D3cc ≤30.0 Gy were used. BPX was graded according to Common Terminology Criteria for Adverse Events 3.0.

Results

A total of 64 patients met inclusion criteria. Median follow-up was 21 months. Six patients (9.4%) had prior ipsilateral conventional fractionated RT with varying degrees of overlap with subsequent SBRT field. Eleven patients without prior ipsilateral RT exceeded D0.03cc ≤32.0 Gy to SCV (mean 43.8 Gy ± 5.8). No BPX was observed in these patients. Out of the six patients who had prior ipsilateral RT, three patients exceeded D0.03cc ≤32.0 Gy to SCV (44.2 Gy ± 11.3), with two of these patients developing Grade 2 BPX within one year of SBRT. The EQD2 cumulative maximum point dose to BP was 122.6 Gy and 184.7 Gy for the two patients who developed Grade 2 BPX. The D0.03cc was >10 Gy higher to the ABP contour than the SCV contour in 14 patients.

Conclusion

Without a history of prior ipsilateral RT, no BPX was observed at 21 month follow-up in 11 patients who exceeded the RTOG five-fraction BP constraint. This observation is hypothesis generating and more experience with longer follow-up is necessary to validate these findings. For tumors located in close proximity to apical structures, there was substantial variation in dose between the ABP and SCV contours.

Introduction

The safety and efficacy of stereotactic body radiation therapy (SBRT) has been well established for the treatment of Stage I non-small cell lung cancer (NSCLC) in medically inoperable patients. Low rates of toxicity are reported with various SBRT fractionations. ^1-4 However, with the use of ablative, hypofractionated doses, careful attention to the dose to critical, serial structures such as the proximal bronchial tree, esophagus, spinal cord, and brachial plexus (BP) is important in reducing the risk for chronic severe toxicity. Development of brachial plexopathy (BPX), defined as paresthesia along the distribution of the BP, significant discomfort, or muscle weakness/limited movement of the ipsilateral arm or hand, is a concern with the use of SBRT in the treatment of apical lung tumors, specifically when the tumor is in close proximity to the BP. A review of 37 apical lung tumors treated with 3 or 4 fraction SBRT demonstrated that the 2-year risk of BPX when maximum BP dose exceeded 26 Gy was significantly higher (46% vs. 8%; p=0.04), helping establish the RTOG 0236 dose constraint of 24 Gy for 3 fraction SBRT.⁵ Therefore, if there is a concern for meeting these dose constraints, a five-fraction SBRT regimen is often recommended.

RTOG 0813, a phase II protocol assessing the safety of dose-escalated five-fraction SBRT for central lung tumors, provides dose constraints of D0.03cc ≤32 Gy and D3cc ≤30 Gy to the BP.⁶ However, clinical validation of these dose constraints is limited and at times, a clinical decision must be made for tumors close to the plexus, balancing the risk of BPX with SBRT versus the risk of BPX from tumor progression secondary to compromised tumor coverage or the use of conventionally fractionated radiation, which has a lower biologically equivalent dose. Given limited clinical data for 4-5 fraction regimens, we conducted a dosimetric analysis using a large single-institution registry to determine the rate of BPX and clinically validate current BP constraints for four- and five-fraction SBRT targeted to apical lung tumors. Additionally, we sought to investigate potential differences in the RTOG-defined surrogate for the BP, the subclavian vein (SCV), compared to using the anatomic BP (ABP) for apical lung tumors.

Methods

Patients treated with four- or five-fraction SBRT for apical lung tumors between 2010 and 2017 were identified from our institution’s IRB-approved prospective SBRT registry of 1,462 patients. An apical lung tumor was defined as having gross tumor volume (GTV) estimated to be within 1 cm of the subclavian vasculature on diagnostic CT scan. All patients were treated with either definitive intent SBRT, or salvage intent SBRT in the setting of recurrence after surgery or conventional radiation therapy (RT). One patient received previous radiation with SBRT to the same location and was excluded. Additionally, patients who did not have available dosimetry archived for analysis were excluded (n=7). All patients received either 48 Gy in 4 fractions, 50 Gy in 5 fractions, or 60 Gy in 5 fractions delivered every day consecutively. Patients were deemed medically inoperable by the multidisciplinary thoracic oncology team due to pulmonary, cardiac, or vascular comorbidities, poor performance status, a multifactorial clinical milieu, a second primary cancer, patient refusal of surgery , or a technically unresectable tumor. Histologic diagnosis of the primary tumor was not required in patients in whom biopsy was medically contraindicated or non-diagnostic. Patient factors analyzed included age, gender, smoking history, smoking status, and tumor factors analyzed included GTV and planning target volume (PTV).

Treatment Planning

All patients underwent Computed Tomography (CT) based simulation with abdominal belt compression or activated breathing control (ABC) to limit tumor motion to ≤ 1.0 cm in all directions. Intravenous (IV) contrast was used as indicated to better delineate tumor from apical structures. When there were motion studies of the GTV, an internal target volume (ITV) was generated, with the addition of a 0.5 cm margin for PTV. Treatment was delivered with image-guided intensity modulated radiation therapy (IMRT) or volumetric arc-based radiation therapy (VMAT). Dose and fractionation schedules were chosen at the discretion of the treating radiation oncologist.

Toxicity

Patients were first evaluated in follow up 6 to 8 weeks after SBRT, and then subsequently followed every 3 months. BPX was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. BPX was defined as regional paresthesia, significant discomfort, or muscle weakness/limited movement of the ipsilateral arm or hand. Symptoms of BPX are included in the standard template for lung SBRT follow-up and therefore data is available for all patients. SBRT-induced BPX was diagnosed by ruling out tumor progression on CT imaging or magnetic resonance imaging (MRI), electromyography (in some instances), and clinical judgment. Grade 1 toxicity was defined as asymptomatic BPX (radiographic evidence), Grade 2 was defined as symptomatic BPX not interfering with activities of daily living, Grade 3 was defined as interfering with activities of daily living, and Grade 4 was defined as disabling BPX.⁷ Imaging was obtained

Dosimetric and Statistical Analysis

The RTOG protocol defined surrogate for the BP, the ipsilateral SCV was contoured in all cases at the time of initial treatment planning. The ABP was retrospectively contoured at the time of analysis to identify if dosimetry was significantly different between the three structures (Figure 1). The ABP contour was reviewed with a thoracic radiologist with reference to the RTOG BP contouring atlas.⁸ The following dosimetric parameters for each plan were obtained for the SCVand ABP: D0.03cc, D0.5cc, and D3cc. The primary endpoint of the study was development of BPX. A p-value ≤ 0.05 was considered statistically significant. SAS version 9.4 software was used for statistical analysis.

Figure 1.

Contouring of anatomic brachial plexus and subclavian vein for apical lung tumor.

Results

We identified a total of 64 apical lung tumors treated with definitive intent SBRT meeting study criteria with available dosimetric data. Patient and tumor characteristics are presented in Table 1. Fifty nine cases (92.2%) were treated with 50 Gy in 5 fractions, 4 cases (6.3%) with 48 Gy in 4 fractions, and 1 case (1.5%) with 60 Gy in 5 fractions. Median follow up for the cohort was 21 months. Of the 64 lesions, 58 (90.6%) were treated with primary definitive intent therapy, while six (9.4%) were treated with SBRT for local recurrence after prior conventionally fractionated RT. There were varying degrees of overlap between the two courses of RT. For the patients who had a prior history of ipsilateral RT (n=6), the time interval between conventional RT and SBRT, the dose of the prior conventional RT, the EQD2 cumulative dose received to the SCV contour from conventional RT and SBRT, and the development of BPX is outlined in Table 2.

Table 1.

Patient and tumor characteristics.

Variable	n=64
Median age (y) (range)	72 (42-88)
Sex (M:F)	28:36
Median KPS (range)	80 (70-100)
Median body mass index (range)	26 (15-47)
Smoking during treatment (%)	18 (28.1)
Etiology of inoperability
Pulmonary (%)	21 (33)
Cardiac (%)	4 (6)
Refusal (%)	6 (9)
Others/Multifactorial (%)	33 (52)
Dose/fractions
48 Gy/4 fractions (%)	4 (6)
50 Gy/5 fractions (%)	59 (92)
60 Gy/5 fractions (%)	1 (2)
Treatment Intent
Definitive (%)	46 (72)
Salvage after Radiation Therapy (%)	6 (9)
Salvage after Surgery (%)	4 (6)
Oligometastatic Disease (%)	9 (14)
Prior ipsilateral RT (%)	6 (9)
Median months of follow up (range)	21.2 (6.5-80.4)

Table 2.

Characteristics of prior ipsilateral radiation therapy.

Patient	Months between prior ipsilateral RT and salvage SBRT	Dose/fx for prior ipsilateral RT	EQD2 cumulative maximum point dose to SCV BP from prior ipsilateral RT and salvage SBRT (Gy)	Brachial plexopathy
A	28	63 Gy/35 fx	26.2	No
B	14	60 Gy/30 fx	32.0	No
C	19	59.4 Gy/33 fx	55.8	No
D	10	60 Gy/30 fx	122.6	Yes
E	4	60 Gy/30 fx	162.2	No
F	19	63 Gy/35 fx	184.7	Yes

We found no clinically significant BPX in patients who did not receive prior ipsilateral RT (n=58) at median follow-up of 21 months (range, 6.1-77.5 months). Figure 2 illustrates that there were 11 of these patients (19%) who had doses to the SCV contour that exceeded the RTOG constraint of D0.03cc ≤32.0 Gy. The D0.03cc to the SCV ranged from 35.9 to 53.8 Gy, with no clinically significant BPX observed at median follow-up of 21 months. We observed no patients who exceeded the RTOG constraint of D3cc ≤30 Gy to the SCV. Table 3 demonstrates the estimated EQD2 to the SCV surrogate BP for all patients who exceeded RTOG 0813 constraints.

Figure 2.

Brachial plexopathy by D0.03 cc to subclavian vein contour.

Table 3.

Characteristics of dose to SCV BP for those exceeding RTOG 0813 BP constraints.

Patient	Maximum point dose to SCV BP with 5 fx SBRT (Gy)	History of prior ipsilateral RT	EQD2 maximum point dos SCV BP (Gy)	Brachial plexopathy
1 (D)*	32.4	Yes	122.6***	Yes
2	35.9	No	73.1	No
3	38.1	No	80.9	No
4	40.9	No	91.5	No
5	41.1	No	92.2	No
6	41.3	No	93.0	No
7	41.9	No	95.4	No
8	42.9	No	99.4	No
9	43.9	No	103.4	No
10 (F)**	45.1	Yes	184.7***	Yes
11	51.1	No	135.1	No
12	51.4	No	136.5	No
13	53.8	No	148.1	No
14 (E)**	55.0	Yes	162.2***	No

^*Patient (D) from Table 2;

^**Patient (F) from Table 2;

^**Patient (E) from Table 2;

^***cumulative EQD2 maximum point dose including prior ipsilateral RT and salvage SBRT

In comparison, when assessing dose to the ABP contour, Figure 3 illustrates that 17 patients exceeded the RTOG constraint of D0.03cc ≤32.0 Gy, compared to only 11 patients seen in Figure 2,suggesting that some patients were not captured as exceeding protocol constraints by using only the SCV as a surrogate for the BP. Figure 4 plots the difference in D0.03cc to the ABP contour and the SCV contour. We identified 14 patients who had at least a 10 Gy higher maximum point dose to the ABP contour compared to the SCV contour. This discrepancy was most apparent for doses that were above the RTOG 0813 constraint of 32 Gy. The median difference in dose to the ABP contour was 23.0 Gy higher than the SCV contour (range, 14.6-43.8 Gy) for these 14 patients. The overall median difference in dose between the ABP and SCV contour was 7.4 Gy (range, 0.4-43.8 Gy). Of note, for the entire cohort, the dose to the ABP contour was not always higher than the SCV contour.

Figure 3.

Brachial plexopathy by D0.03 cc to anatomic brachial plexus contour.

Figure 4.

Maximum point dose difference between anatomic brachial plexus and supraclavicular vein contour.

Six patients in this cohort received prior ipsilateral RT. The median time between completion of prior ipsilateral RT and start of salvage SBRT was 16.5 months (range, 4.0-28.0 months). The median prior ipsilateral RT dose was 60 Gy (range, 59.4-63 Gy) (Table 2). Three of these patients exceeded the RTOG maximum point dose constraint of D0.03cc ≤32.0 Gy to the SCV and ABP, two of whom developed Grade 2 BPX within 1 year after SBRT (Figure 2&3). The time to development of BPX after completion of SBRT was 9.0 months and 5.6 months for these two patients. The cumulative maximum EQD2 point dose to the SCV contour for the two patients who developed BPX was 122.6 Gy and 184.7 Gy. One of the two patients who developed BPX, also exceeded the RTOG dose constraint of D3cc ≤30.0 Gy to the ABP.

Discussion

We observed no evidence of clinically significant BPX after 4- or 5-fraction SBRT for apical lung tumors in those patients without a history of prior ipsilateral RT at median follow-up of 21 months, despite 19% of patients (n=11) exceeding the RTOG maximum point dose constraint to the SCV contour as a surrogate for the BP. This observation is hypothesis generating and more experience and longer follow-up is necessary to validate these findings. The risk of treatment related toxicity and toxicity due to tumor progression must be carefully weighed. Further study in this area is warranted to determine whether the dose threshold for BPX can be adjusted given very limited data investigating the relationship of BP dose and plexopathy for 4-5 fraction SBRT regimens. While RTOG constraints are based on dose to the SCV, as a surrogate for the BP, we identified more patients who exceeded constraints when evaluating dose to the ABP contour compared to the SCV contour. We observed 14 patients who had a D0.03cc greater than 10 Gy to the ABP contour compared to the SCV contour. Therefore, it may be prudent to evaluate dose to the ABP, particularly when tumors are in close proximity to the subclavian structures.

With regards to brachial plexus constraints, there are several publications which suggest that the BP may tolerate higher doses than the current maximum point dose constraint of 66 Gy recommended for conventional fractionated RT. ^9-12 Most recently, Chen et al. evaluated 43 patients who received re-irradiation for recurrent head and neck cancer with overlapping dose to the BP. They identified cumulative maximum point doses ranging between 20.2 Gy to 111.5 Gy (median 63.8 Gy) with an elapsed time between the two courses of RT ranging between 3 to 144 months (median 24 months). The 1-year freedom from BPX for cumulative maximum dose greater than and less than 95.0 Gy was 67% and 76% (p=0.05), respectively.¹¹ Amini et al. analyzed 90 patients with non-small cell lung cancer treated with definitive chemoradiation therapy and determined that a median maximum point dose of >69.0 Gy to the BP (OR 10.09; p=0.038) and D2cc >75 Gy (OR 4.91; p=0.04) were significant independent predictors for BPX on multivariate analysis.¹² It is important to recognize that in patients with a poor prognosis and limited survival, the late toxicity of BP injury may not clinically manifest, and exceeding these constraints should be approached extremely cautiously in patients with an extended life expectancy. Still, taken together, this data suggests that the tolerance of the BP to RT may be higher than current dose constraints specify in the conventionally fractionated setting. We must certainly be very careful to extrapolate data to lung SBRT from conventional fractionation, given that the effect of extreme hypofractionation on late responding, serial structures, is not completely understood.

Though data with historical techniques suggested an increased risk for BPX with doses greater than 3 Gy per fraction, the safety of moderate hypofractionation to the BP has been well studied in the modern era in the breast cancer and melanoma literature.^13-16 Moderate hypofractionation of 40 Gy in 15 fractions to the supraclavicular fossa on the START B trial for early stage breast cancer demonstrated no BPX.¹⁵ Similarly, Ballo et al. demonstrated no BPX with a more hypofractionated regimen of 30 Gy in five-fractions twice a week to the axilla and supraclavicular fossa with adjuvant RT for melanoma.¹⁶ It is worth noting that the 3D conformal nature of this treatment delivery likely resulted in doses in excess of 30 Gy in 5 fractions to the ABP in many cases.

The rate of BPX with SBRT for apical lung tumors and clinical validation of protocol-specified dose constraints is limited, but does demonstrate a dose-response relationship. Forquer et al. analyzed 37 apical lung tumors, defined as the tumor epicenter superior to the aortic arch, treated with 3- or 4-fraction SBRT. The group contoured the axillary and SCV as the BP surrogate. They identified 7 out of 37 patients who developed Grade 2-4 BPX, with 3 Grade 3 & 4 toxicities, and the median maximum BP dose was 30.0 Gy for those who developed BPX (range 18-82). Of note, they determined that the 2-year risk of BPX was significantly higher (46% vs. 8%; p=0.04) for maximum BP dose >26 Gy and ≤ 26 Gy, respectively.⁵ This study provided clinical validation for the RTOG 0236 3-fraction BP maximum point dose constraint of 24 Gy and informs the decision for when to consider transitioning to a four or five-fraction SBRT regimen. In a study of central tumors treated to 50 Gy in 4 fractions, Chang et al. reported that BP Dmax > 35,0 Gy was associated with the development of BPX, with toxicity in 3 out of 9 patients above this threshold, compared to no BPX in 73 patients with Dmax <35.0 Gy (p=0001).¹⁷

It is challenging to reconcile why the Forquer et al. and Chang et al. data suggest that 8.67 Gy and 8.75 Gy per fraction, respectively, to the BP was associated with a higher rate of toxicity, while we found no evidence of BPX in 11 patients who received max point doses ranging between 7.2 Gy-10.8 Gy per fraction. The Forquer study studied predominately 3 fraction patients treated with 3D-non-coplanar or volumetric arc beams. Given that late toxicity is associated with not only dose, but also volume and fractionation we would hypothesize that the tolerance to the BP is likely higher for 5 fraction regimens, and likewise that the more contemporary use of IMRT and VMAT delivery optimized to rapid fall-off at the brachial plexus may add an extra element of safety given rapid dose fall-off, as evidenced by the fact that our 3 cc doses were comparatively quite low, and never exceeded RTOG constraints. In addition for patients with tumors near the BP, IGRT strategy at the time of treatment delivery now can focus on not only tumor coverage, but also not moving closer to the BP during CBCT alignment review. Comparing out data to the observations of Chang et al is more difficult, as the only clear difference is the use of 4 fraction SBRT in Chang et al., compared to primarily (94%) 5 fraction SBRT in our study. Given that Chang et al. was primarily a report on central tumors it is possible that dose to central structures had to weigh heavily on the optimization algorithm, allowing less flexibility for optimizing the BP than in our study of predominately small peripheral apical tumors, however this is only a hypothesis. As such we do not mean to suggest that it is safe to routinely exceed the RTOG 5-fraction BP constraint, but rather that it would be worthwhile to gather more data on BPX with 5 fraction SBRT regimens in order to investigate whether there might be additional room for treatment of patients with apical tumors.

RTOG protocols also offer a second BP dose constraint of D3 cc ≤ 30 Gy.¹⁸ No patients in our dataset exceeded the RTOG constraint of D3.0cc ≤30 Gy, indicating that this constraint may be a good predictor for the absence of toxicity. However, with the rapid dose gradients observed with IMRT/VMAT, it may be less common to observe larger volumes receiving these higher doses, and it is possible that a secondary constraint to a smaller volume than 3 cc should be established. Given the lack of clinically significant BPX in our data-set we are unable to hypothesize what an appropriate volume would be.

Our analysis included 6 patients who had prior ipsilateral RT, 3 of whom exceeded the RTOG maximum point dose constraint. Grade 2 BPX was observed in two out of these three patients (mean D0.03 cc of 38.8 Gy or 7.8 Gy per fraction). One of the two patients who developed BPX had the highest EQD2 cumulative maximum point dose of the entire cohort (184.7 Gy). Certainly, the risk of developing BPX and the risk of tumor progression causing BPX must be carefully balanced.

RTOG lung SBRT protocols specify contouring the route of the subclavian vein from the bifurcation of the brachiocephalic trunk proximally, to the axillary vein distally, as a surrogate for the major trunks of the BP.¹⁸ We observed, for some patients, contouring the actual roots and trunks of the BP (ABP) led to higher maximum point doses, and this is reflected in our data in which 17 patients exceeded constraints to the ABP, as opposed to only 11 to the SCV. Additionally, of the 17 patients who exceeded constraints to the ABP contour, 14 patients (82%) were found to have a maximum point dose greater than 10 Gy to the ABP contour compared to the SCV contour. For the entire cohort of 64 patients, the overall median dose discrepancy was 7.4 Gy between the two contours (Figure 4). ^6,8 For apical lung tumors at risk of exceeding RTOG dose constraints, we recommend the use of IV contrast for better delineation of the supraclavicular structures and detailed contouring of the ABP, in addition to the RTOG surrogate SCV for lung SBRT. With more data and longer follow up, delineation of the ABP could be used for optimization of dose to this structure during planning, in addition to the SCV, for tumors in close proximity to the apex.

While it is clear that a dosimetric relationship exists with the development of BPX, other factors may also contribute and should be taken into consideration for risk stratification. The presence of BPX symptoms prior to irradiation has been identified as a significant predictor (OR 4.22; p=0.04) in the setting of definitive chemotherapy and RT for superior sulcus non-small cell lung carcinoma.¹² Prior neck dissection (OR 9.55; p=0.01) and concurrent chemotherapy (OR 2.10; p=0.01) have also been shown to be significantly associated with BPX in the postoperative RT setting for head and neck cancer.¹⁰ Alternatively, a significant association has not been definitively demonstrated with gender, diabetes, and active smoking.¹²

We have presented a cohort of patients prospectively followed and recorded in our lung SBRT database. Our study is limited by the diagnosis and work up of BPX being at the discretion of the treating physician and may not have been standardized. Additionally, while medically inoperable Stage I NSCLC patients have a limited life expectancy due to competing risk factors for death, the median survival still approaches 3 years, and therefore, our median follow up of only 21 months should be approached with caution given the latency of BPX that can be well beyond this time frame.⁶ The current outcomes data for both tumor control and toxicity is based upon the SCV surrogate BP and therefore, there is limited evidence to support optimization of dose to the ABP contour at this time, which could potentially compromise tumor coverage and more study is needed in this space. Given the low number of toxicity events in our study, our analysis is more descriptive and only accounts for dosimetric factors. Despite these limitations, we have presented a robust cohort of patients undergoing SBRT for apical lung tumors with detailed dosimetric analysis. While our intent is not to conclude that BP doses above RTOG 0813 constraints are safe, we do believe it is important to note that clinical data demonstrating BPX for lung SBRT have been predominately in the setting of 3-4 fraction SBRT. Additional data investigating and validating the 5 fraction SBRT constraint would be worthwhile in considering which patients might be eligible for SBRT as opposed to more conventionally fractionated regimens when tumors are in close proximity to the apex.

Conclusion

For tumors located in close proximity to apical structures, we observed dosimetric discrepancies between the ABP and the SCV, the RTOG specified brachial plexus surrogate contour. Contouring the ABP should be considered. Of the 11 patients (without prior ipsilateral RT) who exceeded the RTOG dose constraints for 5-fraction SBRT, none developed BPX. The present analysis may provide a basis for further investigation of modification of BP constraints for five-fraction lung SBRT. External validation of these findings is critical.