Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: Dose-limiting toxicity in apical tumor sites

Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: Dose-limiting toxicity in apical tumor sites

Radiotherapy and Oncology 93 (2009) 408–413 Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjourna...

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Radiotherapy and Oncology 93 (2009) 408–413

Contents lists available at ScienceDirect

Radiotherapy and Oncology journal homepage: www.thegreenjournal.com

Lung cancer SBRT

Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: Dose-limiting toxicity in apical tumor sites Jeffrey A. Forquer a, Achilles J. Fakiris a,*, Robert D. Timmerman b, Simon S. Lo c, Susan M. Perkins d, Ronald C. McGarry e, Peter A.S. Johnstone a a

Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, USA Department of Radiation Oncology, UT Southwestern School of Medicine, Dallas, USA c Department of Radiation Oncology, The Ohio State University, Columbus, USA d Division of Biostatistics, Indiana University School of Medicine, Indianapolis, USA e Department of Radiation Medicine University of Kentucky, Lexington, USA b

a r t i c l e

i n f o

Article history: Received 11 December 2008 Received in revised form 13 April 2009 Accepted 15 April 2009 Available online 18 May 2009 Keywords: Brachial plexopathy Stereotactic body radiotherapy Non-small cell lung cancer Apical Hypofractionation

a b s t r a c t Background and purpose: We report frequency of brachial plexopathy in early-stage non-small cell lung cancer treated with stereotactic body radiotherapy. Materials and methods: 276 T1–T2, N0 or peripheral T3, N0 lesions were treated in 253 patients with stereotactic radiotherapy at Indiana University and Richard L. Roudebush VAMC from 1998 to 2007. Thirtyseven lesions in 36 patients were identified as apical lesions, defined as epicenter of lesion superior to aortic arch. Brachial plexus toxicity was scored for these apical lesions according to CTCAE v. 3.0 for ipsilateral shoulder/arm neuropathic pain, motor weakness, or sensory alteration. Results: The 37 apical lesions (19 Stage IA, 16 IB, and 2 IIB) were treated with stereotactic body radiotherapy to a median total dose of 57 Gy (30–72). The associated brachial plexus of 7/37 apical lesions developed grade 2–4 plexopathy (4 pts – grade 2, 2 pts – grade 3, 1 pt – grade 4). Five patients had ipsilateral shoulder/arm neuropathic pain alone, one had pain and upper extremity weakness, and one had pain progressing to numbness of the upper extremity and paralysis of hand and wrist. The median of the maximum brachial plexus doses of patients developing brachial plexopathy was 30 Gy (18–82). Two-year Kaplan–Meier risk of brachial plexopathy for maximum brachial plexus dose >26 Gy was 46% vs 8% for doses 626 Gy (p = 0.04 for likelihood ratio test). Conclusions: Stereotactic body radiotherapy for apical lesions carries a risk of brachial plexopathy. Brachial plexus maximum dose should be kept <26 Gy in 3 or 4 fractions. Ó 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 93 (2009) 408–413

In 1998, a program investigating stereotactic body radiotherapy (SBRT) was initiated at Indiana University School of Medicine and its associated Veterans Administration Medical Center (VAMC). Since then, 253 non-small cell lung cancer (NSCLC) patients have been treated with SBRT, 130 of these on several prospective protocols. All protocols were performed, and continued, under auspices of the appropriate Institutional Review Board. Members of our team have previously published outcomes of a phase I trial of SBRT for NSCLC [1,2], as well as the need for prudence undertaking thoracic SBRT for central lesions [3]. Correlates of pulmonary function testing with SBRT [4], and the unique clinical opportunities of SBRT to bilateral lesions [5] have also been described. In this review, we discuss the frequency and correlates of brachial plexopathy (BP) after SBRT for NSCLC. * Corresponding author. Address: Department of Radiation Oncology, Indiana University School of Medicine, 535 Barnhill Dr (RT041), Indianapolis, IN 46202, United States. E-mail address: [email protected] (A.J. Fakiris). 0167-8140/$ - see front matter Ó 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.04.018

Materials and methods The records of 253 patients with 276 T1–T2, N0 or peripheral T3, N0 NSCLC lesions treated at Indiana University and the Richard L. Roudebush VAMC with SBRT from 1998 to 2007 were reviewed. Thirty-seven lesions in 36 patients were retrospectively identified as apical tumor sites, defined as such because the epicenter of the lesion was superior to the aortic arch. Symptoms referable to BP were scored for these apical lesions (AL) according to CTCAE v. 3.0 [6] for brachial plexopathy including ipsilateral shoulder/arm neuropathic pain, motor weakness, or sensory alteration. Grade 1 indicates an asymptomatic brachial plexopathy; grade 2 indicates a symptomatic brachial plexopathy but not interfering with activity of daily living; grade 3 indicates a symptomatic brachial plexopathy and interferes with activity of daily living; grade 4 indicates a disabling brachial plexopathy. One patient had bilateral synchronous AL; these were treated as separate and independent in our analysis.

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Briefly, eligible patients were treated with SBRT using strictly defined criteria, which we have previously described [1,2]. Patients received 3–4 fractions using noncoplanar field arrangements. In general, 6–12 fields were designed to treat the CT-defined gross tumor volume with an axial expansion of 0.5 cm and superior expansion of 1 cm to form the planning target volume. All patients were immobilized in the Stereotactic Body Frame (Elekta Oncology, Norcross, GA) including a rigid three-sided frame with vacuum pillow as well as abdominal compression for limitation of respiratory motion of the target [1,2]. Complete dose–volume histogram (DVH) data were available for 29 AL (including 6 of 7 with grade 2–4 toxicity). In these cases, the ipsilateral brachial plexus was retrospectively contoured using the subclavian/axillary vessels as a surrogate for the major trunks of the brachial plexus per directions described in RTOG protocol 0236 [7]. See Fig. 1 for example of brachial plexus contour. The maximum dose to the brachial plexus was recorded for these patients. A brachial plexus maximum dose was obtained by visual inspection of isodose curves in the chart for the remaining 8 patients for whom the treatment plan files could not be accessed. We retrospectively analyzed the follow-up notes of the patients with AL, specifically for evidence of BP symptoms. Follow-up visits

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were performed every 3 months for the first 2 years after treatment completion and then every 6 months during years three and four. Dates on which the patients first experienced BP were recorded and were used for Kaplan–Meier analysis. A cutoff dose point for Kaplan–Meier BP risk analysis was set at 26 Gy as this represented the median of the maximum brachial plexus doses for all 37 AL. Absolute risk of BP was also analyzed for patients with a maximum brachial plexus dose of greater than or lesser than 26 Gy. Local lesion control and overall survival were also analyzed for this cohort of patients. For the subject with bilateral synchronous AL, we also performed the Kaplan–Meier analyses excluding the AL occurring second in time; the results did not substantially change. Brachial plexus maximum doses were also converted to a brachial plexus maximum Biologically Effective Dose (BED) based on the linear quadratic model to standardize dose analysis between patients receiving different number of fractions, using the equation:

  ðDoseÞ=# fractionsÞ BED ¼ Dose  1 þ 3 where # fractions represent the number of total treatment fractions of SBRT delivered which in our study was 3 or 4 fractions. The denominator of 3 represents the a/b ratio. The label Gy3 indicates a BED with a/b ratio of 3. This value is used because of our emphasis on late tissue effects (in this case, peripheral nerve), and is standard for chronic toxicity calculations [8]. A brachial plexus maximum BED of 100 Gy3 was chosen as a cutoff point for risk analysis for BP as this corresponds to the accepted toxicity threshold for peripheral nerves of 60 Gy treated at 2 Gy per fraction [9]. The linear quadratic formalism behind this BED calculation is appropriate for lower fraction dose levels (i.e., <6–7 Gy per fraction); for higher fraction dose levels (i.e., >7 Gy), use of the BED may be inappropriate. Instead, for higher dose levels, it has been suggested to use the Single Fraction Equivalent Dose (SFED) model [10]. With SBRT, the distribution of daily dose within a given patient’s plan is very heterogeneous such that either of these models might be necessary depending on the planned dose distribution. The SFED is given by the following equation [10]:

SFED ¼ Dose  ð# fractions  1Þ  4 For Dq (point of extrapolation of the exponential portion of a multi-target survival curve to the level of zero survival) we used a value of 4 Gy for normal tissue [8]. An SFED-4 of 15 Gy was used as the cutoff point for risk analysis of BP from intraoperative radiation therapy peripheral nerve toxicity data [11]. Results

Fig. 1. Brachial plexus contour (yellow) in axial plane (A) using axillary/subclavian vessels as surrogate. Brachial plexus contour on coronal digitally reconstructed radiograph (B).

Table 1 demonstrates patient characteristics and specifics of treatment. The median age of the 36 patients was 73 (range 57– 81). Of the 37 lesions, 19 were Stage IA, 16 IB, and 2 IIB. SBRT was delivered to a median total dose of 57 Gy (30–72). 28 AL were treated in 3 fractions and 9 AL treated in 4 fractions with median duration of treatment of 8 days (6–14). Thirty-five AL had dose prescribed to the 80% isodose line, one was dosed to 75% and one to 90%. With a median follow-up of 13 months (1–71), 2-yr Kaplan– Meier local control for AL was 89%. One of the three patients with local failure was treated with a total dose of 30 Gy in 3 fractions on the phase I dose escalation trial, far below current standard SBRT dose schemes. Two-year Kaplan–Meier overall survival for the 36 patients with AL was 64%.

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SBRT brachial plexopathy

Table 1 Apical lesions: patient and treatment characteristics. All apical lesions treated with SBRT (n = 37)

Apical lesions without brachial plexopathy (n = 30)

Apical lesions with grade 2–4 brachial plexopathy (n = 7)

Stage IA IB IIB

19 16 2

IA IB IIB

16 12 2

IA IB IIB

3 4 0

Gender Female Male

16 21

Female Male

14 16

Female Male

2 5

Histology Squamous Adenocarcinoma NSCLC/other

10 12 15

Squamous Adenocarcinoma NSCLC/other

7 11 12

Squamous Adenocarcinoma NSCLC/other

3 1 3

Laterality of lesion Right Left

21 16

Right Left

17 13

Right Left

4 3

History of smoking Yes No

35 2

Yes No

28 2

Yes No

7 0

Quit smoking at time of treatment Yes 25 No 9 Unknown 3

Yes No Unknown

18 9 3

Yes No

7 0

Oxygen dependent Yes

4

Yes

4

Yes

0

Treated on/off study Phase I Phase II RTOG 0236 Off-study

7 10 1 19

Phase I Phase II RTOG 0236 Off-study

7 7 1 15

Phase I Phase II RTOG 0236 Off-study

0 3 0 4

GTV size (cc) Median Range

13 1–113

Median Range

9 1–113

Median Range

15 9–53

Total treatment dose (Gy) Median Range

57 30–72

Median Range

57 30–72

Median Range

54 48–66

Treatment dose per fraction (Gy) Median 19 Range 10–24

Median Range

19 10–24

Median Range

18 12–22

Maximum brachial plexus dose (Gy) Median 26 Range 6–83

Median Range

25 6–83

Median Range

30 18–82

Max brachial plexus dose per fraction (Gy) Median 8 Range 2–28

Median Range

8 2–28

Median Range

9 4–27

Max brachial plexus BED (Gy3) Median 103 Range 10–851

Median Range

84 10–851

Median Range

123 45–839

Max brachial plexus SFED-4 (Gy) Median 18 Range 2 to 75

Median Range

15 2 to 75

Median Range

21 6–74

SBRT of 7 of 37 lesions resulted in grade 2–4 BP. None of these patients developed local failure as a potential contributor to their BP symptoms. Four patients had grade 2 BP, characterized as ipsilateral shoulder/arm neuropathic pain alone. All grade 2 BP were controlled by over-the-counter medications and pain resolved in 3, 7, and 9 months after developing in three cases. The remaining patient had experienced pain for 3 months at the time of last follow-up 10 months post-treatment. Two patients had grade 3 BP. One developed ipsilateral shoulder/arm neuropathic pain requiring Oxycodone and Neurontin after referral to pain clinic and upper extremity weakness particularly with abduction. This patient had symptoms lasting for 6 months until the time of last follow-up, but at that time, pain

was improving slightly with complete resolution of motor weakness. The other patient with grade 3 BP had neuropathic pain requiring Oxycodone. His pain was also present at last follow-up, but after 3 months he had begun to improve somewhat after adding Neurontin to his opiate regiment. One patient had grade 4 BP after receiving a brachial plexus maximum dose of 76 Gy. Nine months after treatment, the patient experienced shoulder ache progressing to warm tingling pain in skin of axilla and inner arm. Later, the patient had shoulder weakness and then developed numbness of entire arm and difficulty with hand manipulation. Oxycodone helped relieve pain and 19 months after completion of treatment, pain had started to improve significantly. However, at last follow-up 42 months after completion, the patient had arm/hand muscle wasting with resid-

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J.A. Forquer et al. / Radiotherapy and Oncology 93 (2009) 408–413

ual physical exam motor strength grades of 3/5 for biceps/triceps and of 1/5 for wrist flexion/extension [12]. The maximum brachial plexus dose median for all AL was 26 Gy (range 6–83). The maximum brachial plexus dose median for patients with BP was 30 Gy (range 18–82). Two-year Kaplan–Meier risk of BP for maximum brachial plexus dose >26 Gy was 46% vs 8% for doses 626 Gy (p = 0.04 for likelihood ratio test). Fig. 2 shows these data. BP developed a median of 7 months after treatment. The onset of BP symptoms occurred between 6 and 23 months after the completion of treatment. All but 7 AL had follow-up of at least 6 months. Kaplan–Meier toxicity analysis was re-run excluding the 7 AL (n = 30) that did not have 6 months of follow-up. Results were similar to those of primary analysis (n = 37) as 2-yr Kaplan– Meier risk of BP for maximum brachial plexus dose >26 Gy was 47% vs 8% for doses 626 Gy (p = 0.04 for likelihood ratio test). Absolute risk of brachial plexopathy for patients with a maximum brachial plexus dose >26 Gy was 6/19 (32%) vs 1/18 (6%) for AL treated to 626 Gy (p = 0.09). See Fig. 3 for dot plot distribution of maximum brachial plexus doses. The maximum brachial plexus BED median for all AL was 103 Gy3 (10–851). The maximum brachial plexus BED median for patients with BP was 123 Gy3 (45–839). Two-year Kaplan–Meier risk of plexopathy symptoms for a brachial plexus maximum BED >100 Gy3 was 46% vs 8% for BED 6100 Gy3 (p = 0.04 for likelihood ratio test). The maximum brachial plexus SFED-4 median for all AL was 18 Gy (2 to 75) while the maximum brachial plexus SFED-4 for patients with BP was 21 Gy (6–74). Two-year Kaplan–Meier risk of plexopathy symptoms for a brachial plexus maximum SFED >15 Gy was 42% vs 8% for SFED-4 615 Gy (p = 0.06 for likelihood ratio test).

team [1–3], and others using SBRT [13–23], argue that a prudent respect for toxicity co-exist with a reasoned understanding of benefits of the procedure. We recently discussed the construct of increased toxicity of thoracic SBRT in central lesions [3]; in this case hilar/pericentral tumor location showed a strong prediction of grade 3–5 toxicity when compared to peripheral tumor location. Radiation-induced brachial plexopathy is uncommon when using conventional fractionation for breast or axillary lesions. In the breast cancer literature, doses to the supraclavicular field of 45–60 Gy result in a brachial plexopathy rate of 1–6% in the setting of axillary dissection and previous chemotherapy [24–28]. In a series of patients with brachial plexopathy from various conventional regimens, doses exceeding 60 Gy were associated with toxicity [29]. Ballo and colleagues reported on hypofractionated radiation to the axilla/supraclavicular fossa for melanoma with a dose of 30 Gy at 6 Gy/fraction delivered twice per week. In their 89 patient series, no brachial plexopathy was seen [30]. Zero of 82 patients in the START B trial treated to the supraclavicular fossa with 40 Gy in 15 fractions (2.67 Gy/fraction) developed brachial plexopathy [31]. Peripheral nerve damage has also been described using both large fraction sizes after intraoperative radiotherapy [11,32] and twice-daily fractionation with inadequate repair time between

Discussion

6000 4000

•• • •

•• •• •• ••

0

It is of little surprise that SBRT using large fraction sizes may contribute to increased toxicity in some areas over conventionally fractionated radiotherapy. It has been long understood that fraction size is the single most important aspect of chronic normal tissue toxicity [8]. Our results must be interpreted carefully, as further late toxicity may develop after the extent of our current follow-up. Nevertheless, the promising control rates reported by our

• •

• • •• •

2000

Brachial Plexus Max Dose

8000



No Yes Brachial Plexus Toxicity Fig. 3. Dot plot demonstrates distribution of maximum brachial plexus doses for those patients who did and did not experience grade 2–4 brachial plexopathy.

Cumulative Incidence

0.4

0.3 Brachial Plexus Max Dose <= 26 Gy Brachial Plexus Max Dose > 26 Gy

0.2

0.1

0.0 0 No. at Risk Max Dose <= 26 Gy Max Dose > 26 Gy

10

20

30

40

50

60

70

Months Since Final Stereotactic Body Radiotherapy 18 19

9 10

6 7

3 2

2 2

2 1

1

1

Fig. 2. Kaplan–Meier curves describing cumulative incidence of developing brachial plexopathy in 36 patients with 37 apical lesions of non-small cell lung cancer treated with stereotactic body radiotherapy. Curves are divided by the brachial plexus maximum doses greater than or 626 Gy.

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SBRT brachial plexopathy

Table 2 Maximum point dose constraints for various dose fractionation schemes used for conventional radiotherapy (30 fractions) and SBRT (1–6 fractions). Daily dose (Gy)

No. of fractions

Total dose (Gy)

BED-3 (Gy3)

SFED-4 (Gy)

15 9.5 7.65 6.75 6.2 5.55 2

1 2 3 4 5 6 30

15 19 22.95 27 31 33.3 60

NA NA NA NA 95 95 100

15.0 15.0 15.0 15.0 15.0 NA NA

NA, not applicable.

daily treatments [33]. Intraoperative doses of greater than 15 Gy were associated with neurotoxicity in 14/28 patients when treating pelvic malignancies [11]. Modifications of clinical standards have contributed to these being infrequently observed in modern RT practices. For apical tumors, contrast given through the arm ipsilateral to the tumor can be helpful for delineating a brachial plexus contour using the subclavian/axillary vessels as a surrogate. More extensive contouring of the roots of the brachial plexus may be warranted for head and neck cases, but was not utilized in our study of apical tumors [34]. Maximum brachial plexus doses from apical tumors are located along the subclavian/axillary neurovascular bundle, not in the more proximal roots in the neck. The maximum dose to the brachial plexus was a point dose as characteristic of a maximum dose received for serial organs such as peripheral nerve. However, maximum dose to a volume such as 1 cc may affect dose tolerance thresholds. Since 8 patients did not have a contoured brachial plexus, estimations from axial, coronal, and sagittal isodose line maps from charts were scrutinized to establish a brachial plexus maximum dose used in the analysis. Certainly, this is a limitation of the study, but estimated brachial plexus maximum doses as well as all maximum dose data from retrospectively contoured brachial plexuses were recorded prior to reviewing the charts for toxicity. Excluding the 8 AL with estimated maximum brachial plexus doses (data obtained from chart isodose curves) from the analysis, the 2yr Kaplan–Meier risk of BP for maximum brachial plexus dose >26 Gy was 36% vs 11% for doses 626 Gy (p = 0.14). Traditionally, the construct of Biologically Effective Dose (BED) has been used to allow translation of different dose fractionation schemes between studies [8]. More recently, the Single Fraction Equivalent Dose (SFED) has emerged as a potentially more functional metric for doses per fraction over 6–7 Gy – typical of SBRT [10]. Interestingly, the RTOG currently uses a brachial plexus maximum dose constraint of 24 Gy in 3 fractions [7] which falls fairly close to the tolerance values determined herein. Using the SFED-4 = 15 Gy dose potency as the cutoff for toxicity analysis, Table 2 shows isoeffect dose levels for SBRT fractionation schemes using 1–6 fractions. Comparison is made in Table 2 to the 2 Gy  30 = 60 Gy total dose limit given as the brachial plexus tolerance for conventional radiotherapy given by Emami et al. [9]. This table, then, gives values for each fractionation scheme used for SBRT that may be considered the upper limit for brachial plexus tolerance based on the analysis from this paper. Conclusion Use of SBRT for apical lesions of NSCLC may be accomplished with excellent local control. Attention must be paid to the brachial plexus dose distribution. Longer follow-up and additional data are needed to corroborate our data as patients with longer expected survival than in our series may show a lower tolerance of the brachial plexus to hypofractionated treatment. Despite these uncertainties, we currently recommend a fractionation regimen

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