Medical Dosimetry ] (2015) ]]]–]]]

Medical Dosimetry journal homepage: www.meddos.org

Effect of stereotactic dosimetric end points on overall survival for Stage I non–small cell lung cancer: A critical review Kathryn Mulryan, BSc (Hons), Michelle Leech, MSc, and Elizabeth Forde, MSc Applied Radiation Therapy Trinity, Discipline of Radiation Therapy, School of Medicine, Trinity College Dublin, Dublin, Ireland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 23 September 2014 Received in revised form 31 March 2015 Accepted 22 April 2015

Stereotactic body radiation therapy (SBRT) delivers a high biologically effective dose while minimizing toxicities to surrounding tissues. Within the scope of clinical trials and local practice, there are inconsistencies in dosimetrics used to evaluate plan quality. The purpose of this critical review was to determine if dosimetric parameters used in SBRT plans have an effect on local control (LC), overall survival (OS), and toxicities. A database of relevant trials investigating SBRT for patients with early-stage non–small cell lung cancer was compiled, and a table of dosimetric variables used was created. These parameters were compared and contrasted for LC, OS, and toxicities. Dosimetric end points appear to have no effect on OS or LC. Incidences of rib fractures correlate with a lack of dose-volume constraints (DVCs) reported. This review highlights the great disparity present in clinical trials reporting dosimetrics, DVCs, and toxicities for lung SBRT. Further evidence is required before standard DVCs guidelines can be introduced. Dosimetric end points specific to stereotactic treatment planning have been proposed but require further investigation before clinical implementation. & 2015 American Association of Medical Dosimetrists.

Keywords: NSCLC SBRT Dosimetric end points

Background Although stereotactic techniques are an established mode of therapy for cranial tumors, the benefits of stereotactic body radiation therapy (SBRT) are currently being assessed across a number of sites.1 Surgery remains the standard of care for earlystage lung cancers with a 5-year risk of local and distant recurrence of 36%.2 However, for patients with lack of adequate respiratory reserve, cardiac dysfunction, vascular disease, general frailty, or other comorbidities, standard fractionation radiation therapy (RT) is offered, resulting in 5-year survival rates inferior to those of surgery.3 Early results from clinical trials show superior local control (LC) associated with SBRT for lung tumors in comparison with that for standard fractionation.4 The excellent LC and relatively low toxicity associated with SBRT have changed the standard of care for potentially operable patients with T1-T3, N0 non–small cell lung cancer (NSCLC).5 Central to SBRT trials are the planning techniques. Planning and delivery of SBRT generally uses multiple beams spread out over a large angle, hence minimizing entrance dose and volume of

Reprint requests to: Elizabeth Forde, Discipline of Radiation Therapy, School of Medicine, Trinity Centre for Health Sciences, St. James's Hospital Campus, Dublin 8, Ireland. E-mail: [email protected] http://dx.doi.org/10.1016/j.meddos.2015.04.005 0958-3947/Copyright Ó 2015 American Association of Medical Dosimetrists

irradiated tissue and creating steeper dose gradients when compared with conventional RT.6 SBRT is generally prescribed to an isodose line encompassing the target, and recommendations from the International Commission on Radiation Units and Measurements (ICRU) reports 50, 62, and 83 are not commonly used. There are no specific evidence-based guidelines for SBRT treatment planning, and dose-volume constraints (DVCs) have not yet been defined. The National Comprehensive Cancer Network guidelines for DVCS for SBRT planning are based on ongoing trials, which reflects the lack of evidence in defining these guidelines.5 Many trials fail to take into account tissue inhomogeneities when calculating dose7; a potential limitation given the tissue heterogeneity within the thorax. The gross tumor volume is always defined; however, additional margins for clinical, internal, and planning target volumes (PTVs) vary considerably. The biologically equivalent prescribed dose (BED) to that target is higher with hypofractionated SBRT than with conventional radiation.8 The absolute prescribed radiation dose is less, as larger, more biologically efficient dose fractions are used. Onishi et al.9 found a 5-year overall survival (OS) rate of 70.8% in medically operable patients when a BED Z 100 Gy compared with 30.2% among those who received o 100 Gy. DVCs have not been clearly defined for hypofractionated treatments. There is currently no consensus on different dosimetrics in use to assess plans for SBRT. The purpose of this review was to

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compare prospective early-stage NSCLC trial results for the dosimetric parameters used and the effect on OS, LC, and incidence of side effects. If certain quantitative dosimetric parameters do affect plan assessment, this could ultimately aid in the consensus of comparing SBRT lung plans.

Methods Several databases were systematically searched: Cochrane Central, Excerpta Medica Database (EMBASE), and PubMed. Medical subject headings (MeSH) and subject headings were used to search the variables “radiation therapy,” “stereotactic,” “treatment planning,” and “non–small cell lung cancer.” The search was limited to English-language articles and trials from January 2005 to October 2013. Series including prospective clinical trials were identified, and the references were manually searched. Trials of participants with Stage I NSCLC were included in this review. For inclusion trials must have








been prospective, corrected for tissue heterogeneity in dose calculation, included no other modalities (chemotherapy), reported on survival and LC, and reported on treatment planning end points.

The comparison of dosimetric end points with clinical outcomes was the primary purpose for this review. OS, LC, and toxicity outcomes were reported. The second purpose was to compare DVCs with toxicity end points. Planning end points identified included the following:










BED, conformity index (CI), homogeneity index (HI), prescription point, margin expansion, target coverage, and immobilization/motion management.

Results A total of 9 clinical trials published between 2006 and 2012 met the inclusion criteria for this review, with a patient population of 669 patients (Table 1).10-18 We excluded 3 trials from this review owing to late-stage disease (n ¼ 1) or not reporting on OS or LC (n ¼ 2).

Dosimetric end points and their LC or OS Each trial was assessed for LC and OS at 1, 2, and 3 years. After analysis of data, there is no apparent connection between different dosimetric end points on LC or OS (Tables 2 and 3). Favorable OS is seen in the potentially operable patient population, as reported by Lagerwaard et al., with an OS of 84.7%13 at 3 years. Reported 3-year OS for inoperable patient populations range from 55% to 61%.10,14,19 Olsen et al.16 report a 2-year OS of 85% and 61% for operable and inoperable patients, respectively. DVCs used and their effect on toxicities Of the 9 trials, 6 report DVCs11-14,16,18 including heart, trachea, lung, spinal cord, brachial plexus, and esophagus (Table 4). There are discrepancies in the use and reporting of constraints. The use of toxicity scoring systems is heterogeneous (Table 5). No trials reported dose constraints to the rib/chest wall, and an incidence of rib fractures and thoracic pain is evident in 7 trials that report toxicities.11-13,15-18 Radiation pneumonitis, ranging from 12% early grade I to 8% late grade III, is evident in 7 trials.11-13,15-18

Discussion Different dosimetric end points did not affect OS or LC in this review. CI, HI, PTV expansion, prescription point, and target coverage were the end points reviewed, as well as DVCs. Prescription normalization methods were variable, and typically, the dose prescribed to the periphery achieved better target coverage, but with increased heterogeneity.20 However, prescribing to the isocenter reduces dose to the PTV and, in aiming for a more homogeneous PTV via use of a penumbra margin, the dose to surrounding critical structures is increased.20 PTV expansions were inconsistent; however, expansion should vary and should be based on knowledge of immobilization, tumor motion, and steep dose gradients.21,22 Dosimetrics associated with target coverage were similar with 3 of 9 trials using PTVmin 4 95%14,16,18; more commonly associated with ICRU 50 and 62.23,24 The only factor affecting OS was surgical status. Lagerwaard et al. investigated SBRT in a population retrospectively described

Table 1 Characteristics of trials that met inclusion criteria Trials

Accrual period

Median follow-up (mo)

Baumann et al.10

2003 to 2005

35

Chang et al.11

Surgical status

Biologically equivalent dose

Tumor location

Tumor category

57 (3)

Inoperable

112 Gy

–

17

27 (none)

Inoperable

112.5 Gy

Central

2005 to 2008

12.5

40 (none)

Inoperable

150 Gy

Peripheral

Lagerwaard et al.13

2003 to 2010

31.5

177 (none)

Potentially operable

4 100 Gy

–

Mirri et al.14

2003 to 2007

25

15 (none)

Inoperable

72 Gy

1998 to 2003

43

45 (none)

Inoperable

112.5 Gy

Central (n ¼ 2) Peripheral (n ¼ 13) Peripheral

T1, n ¼ 40 T2, n ¼ 17 T1, n ¼ 22 T2, n ¼ 5 T1, n ¼ 27 T2, n ¼ 13 T1, n ¼ 106 T2, n ¼ 71 –

2004 to 2007

Olsen et al.16

2004 to 2009

Peripheral (n ¼ 115)

2004 to 2008

Potentially operable (n ¼ 13) Inoperable (n ¼ 117) Inoperable

142.8 Gy

Taremi et al.17

11, 16, and 13 for 45 Gy/5#, 50 Gy/5#, and 54 Gy/3#, respectively 19.1

–

Central (n ¼ 15) –

van der Voort van Zyp et al.18

2005 to 2007

15

Inoperable

–

Peripheral

Dunlap et al.

Nyman et al.

12

15

# ¼ Fraction. – Denotes an unreported value.

Patient population (exclusions)

130 (none)

108 (none) 70 (none)

T1, n ¼ 18 T2, n ¼ 27 T1, n ¼ 100 T2, n ¼ 29 T3, n ¼ 1 T1, n ¼ 86 T2, n ¼ 36 T1, n ¼ 39 T2, n ¼ 31

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Table 2 Reported dosimetrics used to assess plans Trials

Homogeneity index

Conformity index

Prescription point

GTV expansion

PTV expansion Immobilization/motion management

Baumann et al.10

–

–

67% Isodose line

Chang et al.11

–

–

75% To 90% PTV

Dunlap et al.12

1.06

1.17

95% Isodose line

GTV þ 0.2 cm GTV þ CTV GTV ¼

Lagerwaard et al.13 Mirri et al.14

–

–

80% Isodose line

–

–

–

PTV

ITV

Nyman et al.15

–

–

GTV ¼ CTV

–

–

–

–

Periphery of PTV (100% isodose line) 60% To 90% (median 84%) isodose line 95% Isodose line

van der Voort van – Zyp et al.18

–

70% To 85% isodose line 0.5 cm

0.5 To 1 cm anisotropic 0.3 cm Isotropic 0.5 To 1 cm anisotropic Individual margins 0.5 cm Isotropic 0.5 To 1 cm anisotropic 0.5 To 1 cm anisotropic 0.5 cm Isotropic –

Olsen et al.

16

Taremi et al.

17

0.1 To ¼ CTV 0.8 cm ¼ CTV

GTV ¼ CTV ITV

Body frame ⫾ abdominal compression Free breathing

Target coverage

–

Free breathing

GTV þ 0.3 cm 4 95% GTV 4 100% PTV 4 95% 95% PTV ¼ 100% prescribed dose –

Free breathing

PTV 4 95%

Body frame ⫾ abdominal compression Body frame ⫾ abdominal compression Free breathing

–

99% PTV 4 90% dose

Synchrony

PTV 4 95%

Vac-Lok

PTV 4 95%

CTV ¼ clinical target volume; GTV ¼ gross tumor volume; ITV ¼ internal target volume. – Denotes an unreported dosimetric or value.

as potentially operable. The 3-year OS rates are higher than those in an inoperable population, 84.7%13 vs 60%,10 61%,14 and 55%.15 However, similar 1-year LC rates are seen in the trial by Lagerwaard et al. and other trials, 98%13 vs 100%11 and 92%.17 This suggests that comorbidities rendering patients inoperable are the contributing factors that affect OS. Olsen et al.16 reported on both operable and inoperable patients and reported rates of 85% and 61% for OS at 2 years. OS for operable patients was to be investigated in the Study of Anastrozole and Radiotherapy Sequencing (STARS) and the Radiotherapy for Early-Stage (IA) Lung Cancer (ROSEL) trials, which would have compared surgery with SBRT, but these have closed owing to suboptimal accrual.25,26 Larger tumor volumes correspond with lower LC; van der Voort van Zyp et al. and Dunlap et al. reported 2-year LC of 100% and 89%18 and 90% and 70%12 for categories T1 and T2, respectively. Olsen et al. also reported a correlation between larger tumor volumes and local failure using univariate analysis (p ¼ 0.009).16 This has been supported by other single-institution trials, though none have reached statistical significance.27,28 This may have implications in treatment planning regarding dose escalation, larger planning margins, or possibly multimodality treatments.

Total dose, dose/fraction, volume of normal tissue exposed to higher doses of radiation, and geographic location of the tumor are critical in predicting late toxicity. Organs at risk (OARs) are protected from damage with steep dose gradients, but conformality to the target is imperative. Only 6 of the trials reviewed reported DVCs,11-14,16,18 and none reported DVCs for all organs at risk under investigation. This lack of consensus can be seen for heart dose, trachea/main stem bronchus, brachial plexus, spinal cord, and esophagus with maximum dose throughout treatment of 30 to 44 Gy, 30 to 44 Gy, 24 to 36 Gy, 18 to 28 Gy, and 21 to 40 Gy, respectively. Only 2 trials report toxicities relating to the esophagus; Taremi et al.17 reported grade I dyspepsia/dysphagia (11%) and Nyman et al.15 reported grade I esophagitis (9%). However, owing to disparate toxicity reporting in all trials, no connections can be made. Complicating this, Taremi et al.17 and Nyman et al.15 did not report DVCs. There are no reported rib dose limits that are reflected in the high incidence of rib fractures and chest pain. The high correlation with thoracic pain after SBRT is documented extensively.29-32 Creach et al.33 estimated the risk of chest wall pain at 2 years at 20.1%. Rib toxicity is recognized in Radiation Therapy Oncology

Table 3 Reported overall survival and local control for Stage I NSCLC Trials

LC at 1 y

LC at 2 y

LC at 3y

OS at 1 y

OS at 2 y

OS at 3y

Baumann et al.10 Chang et al.11 Dunlap et al.12

– 100% –

– – 83% T1 ¼ 90% T2 ¼ 70% – – – 50% 45 Gy/5#, 100% 50 Gy/5#, and 91%54 Gy/3# – 96% To 60 Gy (T1, n ¼ 100%) (T2, n ¼ 89%) 78% To 45 Gy

92% – –

86% – 85%

65% – 45%

60% – –

93% – – –

94.7% 81% 80% Operable—92%, inoperable—81% 84% 83%

– – 71% Operable—85%, inoperable—61% – 62%

84.7% 61% 55% –

Lagerwaard et al.13 Mirri et al.14 Nyman et al.15 Olsen et al.16

98% – – 75% 45 Gy/5#, 100% for 50 Gy/5#, and 99% 54 Gy/3# Taremi et al.17 92% van der Voort van Zyp – et al.18

# ¼ Fraction. – Denotes unreported outcome.

– –

– –

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Table 4 Reported dose-volume constraints used in treatment planning Trials

Number of fractions

Baumann et al.10

Chang et al.11

Dunlap et al.12

Lagerwaard et al.13

Mirri et al.14

Nyman et al.15

Olsen et al.16

Taremi et al.17

van der Voort van Zyp et al.18

Heart

3

–

–

Dmax ¼ 30 Gy

10 Gy/#

–

–

–

–

4

–

–

–

–

–

–

5 8

– –

r 1 mL, 10 Gy/# r 10 mL, 8.8 Gy/# – –

o 30 Gy –

7.5 Gy/# 5.5 Gy/#

V16 o 50% –

– –

–

– –

– –

3

–

–

10 Gy/#

–

–

–

10 Gy/#

4

–

–

–

–

–

–

5 8

– –

r 1 mL, 8.8 Gy/# r 10 mL, 7.5 Gy/# – –

o 30 Gy –

7.5 Gy/# 5.5 Gy/#

– –

– –

–

– –

– –

3

–

–

8 Gy/#

–

–

–

8 Gy/#

4 5 8

– – –

– – –

– 6 Gy/# 4.5 Gy/#

– – –

– – –

– – –

– – –

3

–

–

6 Gy/#

–

–

–

8 Gy/#

4

–

–

–

–

–

–

5 8

– –

r 1 mL, 5 Gy/# r 10 mL, 3.8 Gy/# – –

o 18 Gy –

4.5 Gy/# 3.5 Gy/#

Dmax ¼ 19 Gy –

– –

–

– –

– –

Trachea/main stem bronchus

Brachial plexus

Spinal cord

Esophagus

Dmax ¼ 24 Gy

Dmax ¼ 18 Gy

o 24 Gy – –

–

–

–

–

–

–

–

–

–

3 4

– –

V10 o 20%

– –

– –

– –

– –

– –

V4.5/# o 31% –

5 8

– –

– V2 Gy o 20% V10 Gy o 30% V5 Gy o 40% – –

–

V9 o 25% –

– –

–

– –

– –

3 4

– –

Dmax ¼ 27 Gy

9 Gy/# –

– –

– –

–

– –

7 Gy/# –

5 8

– –

– r 1 mL, 8.8 Gy/# r 10 mL, 7.5 Gy/# – –

6.5 Gy/# 5 Gy/#

V22 o 55% –

– –

–

– –

– –

Rib Lung

Dmax ¼ 30 Gy

Dmax ¼ maximum dose; # ¼ fraction. – Denotes an unreported constraint.

Group (RTOG) 0913 where it will be prospectively evaluated throughout the trial. There is a well-documented dose-volume relationship between the volume of lung treated and the incidence of acute radiation pneumonitis.34,35 This acute pneumonitis can increase the incidence of lung fibrosis, as consequential late damage can lead to pulmonary function loss or morbidity. Marks et al.36 describe radiation pneumonitis as the clinical end point for standard fractionation; however, with hypofractionated treatments, large volumes of irradiated lung are not common. With higher doses, Matsuo et al.37 reported that SBRT with PTV Z 37.7 mL and lung V25 Z 4.2% indicated a 50% risk of Z grade II radiation pneumonitis. There are inherent difficulties in advising DVCs for use with SBRT owing to the difficulties in applying the linear-quadratic model to hypofractionated schedules and because current guidelines are only in place for conventional fractionation. The National Comprehensive Cancer Network guidelines for DVCs to be used in SBRT planning are based on recent and ongoing trials (RTOG 0618, 0813, and 0915).5 When the results of these trials mature, conclusions can be drawn on optimal DVCs. Establishing evidencebased DVCs is complicated by the lack of consistent reporting of DVCs and grading toxicities.38-40 Toxicity scoring is notoriously

underreported in RT trials,41,42 which is detrimental when establishing the therapeutic window. The testing of a radiobiological rationale that investigates the difference between tumor and normal tissue response is adversely affected by underreporting. There are many methods to assess plan quality, but consensus in these metrics has not been reached; this is reflected in the disparity of end points in the trials. Fairchild et al.43 made several recommendations in the evaluation of advanced techniques. Although basing its recommendations on ICRU 83,44 its guidelines on reporting and using DVCs should be considered in SBRT protocols. Different practices of dose specification may cause a 5% to 10%41 difference in the mean target dose. CI and HI were reported in just 1 trial,45 and although recommendations are made,6 it must be appreciated that these indices do not take into account spatial intersection of volumes.46 Brock et al.20 defined dose conformality as the ratio of the volume irradiated to 50% of the prescribed dose to the volume of the PTV (R50) and the maximum dose 2 cm from the PTV in all directions (D2 cm). Miften et al.47 proposed an uncomplicated CI for evaluating intensity-modulated RT plans that considers both target conformity and normal tissue sparing; allowing for faster plan evaluation. Despite the evidence-based nature of these DVCs, they are yet to be established for SBRT. Other dosimetric parameters

Table 5 Toxicities reported Trials

Grade II

Grade III

Grade IV

Baumann et al.10 CTC v2/pulmonary fibrosis graded according to RTOG/EORTC late radiation morbidity scoring scheme Chang et al.11 CTCAEv.3

26% Unspecified location

35% Unspecified location

22% Unspecified location

2% – Dyspnea

–

–

Dunlap et al.12

CTCAEv.3

12% Pneumonitis

11.1% Grade II to III dermatitis and chest wall pain and 28.6% grade II pneumonitis 2% Pneumonitis 2% Pneumonitis

Lagerwaard et al.13

–

–

–

2% Radiation pneumonitis

–

Mirri et al.14 Nyman et al.15

CTCAEv.3 RTOG/EORTC

– 9% Esophagitis

13% Unspecified location (late) –

– –

– –

RTOG/EORTC

–

–

–

–

– –

– 11% Dyspepsia/dysphasia, 40% fatigue, 1% pneumonitis, 24% cough/shortness of breath, 8% skin, 3% anorexia, and 7% chest wall pain

3% Radiation pneumonitis 1% Dyspepsia/dysphasia, 9% fatigue, 10% cough/shortness of breath, 3% skin, and 3% chest wall pain

–

28% Fatigue, 26% cough/shortness of breath, 12% 7% Fatigue, 12% cough/shortness of breath, 9% pneumonitis, 10% chest wall pain, 7% rib fracture, 1% pneumonitis, 5% chest wall pain, 15% rib pleural effusion, 4% hemoptysis, and 1% skin toxicity fracture, 1% pleural effusion, and 1% hemoptysis 46% Fatigue/dyspnea/cough –

– – 1% Fatigue, 4% pneumonitis, – 2% cough/shortness of breath, and 1% chest wall pain 2% Cough/shortness of – breath, 2% pneumonitis, and 8% rib fracture

15

Olsen et al.16 Taremi et al.17

Taremi (late)

17

CTCAEv.3 van der Voort van Zyp et al.18

4% Thoracic pain, 4% radiation pneumonitis, and 6% (late) thoracic pain

–

–

Note

6% Brachial plexus neuropathy 23% Chest wall pain and 5% rib fracture 25% Fatigue, 14% cough,11% chest wall pain, 10% dyspnea, and 3% rib fractures – 20% Skin reactions and 9% infections/bronchitis/ pneumonias 4% Rib fractures and 7% atelectasis 16% Chest wall pain –

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Grade I

Nyman (late)

Scoring system

–

1% Rib fracture

CTCAEv.3 ¼ Common Terminology Criteria for Adverse Effects-3; RTOG/EORTC ¼ Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer; CTC v2 ¼ Common Toxicity Criteria version 2. – Denotes an unreported toxicity.

5

6

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that have been suggested include high and intermediate dose spillage.6 The American Association of Physicists in Medicine task group recommended the use of equivalent uniform dose, as it is ideal when assessing plans with inhomogeneous distributions.48 ICRU 83 recommend that biologically based planning metrics be used in evaluation to provide additional quantitative data.49 There are several limitations associated with this research. Different fractionation schedules and doses are used in each of the trials, thus making comparison difficult. The BED provides a means of comparing dose, but there are doubts on the applicability of the linear-quadratic model for doses greater than 10 Gy/fraction.48,50 Trial-specific limitations include that few studies report the pretreatment lung function status and some do not report whether the cancer diagnosis was verified by biopsy. Furthermore, most studies have inadequate follow-up, ranging from 11 to 43 months. Another potential limitation is the exclusion of several trials that do not use a heterogeneity correction or do not explicitly state the use of same, as this decreased the number of included trials in adherence with the stated inclusion criteria. RTOG 0236, the first North American multicenter, cooperative group study testing SBRT in medically inoperable patients with early-stage NSCLC, did not mandate the use of heterogeneity corrections, and significant differences were reported between the calculated doses and the actual heterogeneity-corrected doses.51,52 There is a paucity of quality data for dosimetric end points in these trials, and comparisons were difficult to make between evidence in the included trials. Heterogeneity of techniques between centers and trials does not allow for correlation with outcome for patients,20 and this is another limiting factor of this research.

Conclusions No connections were found between different dosimetric end points, OS, and toxicities. However, this review highlighted the lack of consensus on dosimetric parameters or DVCs in use to assess stereotactic lung treatment plans. Many dosimetric end points exist, but without clinical application and evaluation, they remain confined to the literature. Future clinical trial protocols should mandate correct reporting of end points, DVCs, and toxicities, so that treatment planning can be comparable between trials.

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