On the possible benefits of a hybrid VMAT technique in the treatment of non–small cell lung cancer

Medical Dosimetry 38 (2013) 460–466

Medical Dosimetry journal homepage: www.meddos.org

On the possible benefits of a hybrid VMAT technique in the treatment of non–small cell lung cancer John Agapito, M.S., C.M.D. Cancer program, Windsor Regional Hospital, Windsor, Ontario

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 December 2012 Accepted 14 August 2013

To assess, using clinical cases, the potential of a hybrid technique for the treatment of non–small cell lung cancer (NSCLC)-blending volumetric-modulated arc therapy (VMAT) and conformal radiation therapy (CRT) fields, and to consider potential issues with implementation of such a technique. Eight clinical cases already treated with CRT were used for a planning study comparing target coverage and organs at risk (OAR) sparing between CRT and hybrid VMAT (VMATh). Quality assurance (QA) implications of the resultant hybrid plans are discussed. The hybrid technique resulted in superior target conformity or improved sparing of OAR or both. The hybrid technique shows promise, but the QA implications of motion at treatment need careful consideration. & 2013 American Association of Medical Dosimetrists.

Keywords: RapidArc Volumetric-modulated arc therapy Planning study Non–small cell lung cancer

Introduction There is increasing evidence for the importance of radiotherapy for curative intent in both small cell lung cancer (SCLC) and non– small cell lung cancer (NSCLC).1 Unfortunately, radiotherapy for lung cancer is hampered by the required dose-volume constraints for the relevant organs at risk (OAR), predominantly, the lung and spinal cord. It can been argued that intensity-modulated radiation therapy (IMRT) has the potential to improve plan quality, reduce toxicity, and improve local control, and thus survival rates, but that wider adoption may be hindered by technical concerns. These concerns might include uncertainty in planning system accuracy for small fields (small area segments) typical in IMRT. Another concern includes motion interplay effects (caused by the dynamic nature of delivery, e.g., multileaf collimator speed during beam on). Effects such as these could affect normal tissue and target dose for mobile tumors, with a potential increase in the volume of lung receiving low doses, with possible implications on rates of radiation pneumonitis. The above considerations have led to the investigation of a hybrid approach, where the majority of dose to the target is delivered with traditional, static conformal radiation therapy (CRT) fields, and the remainder with IMRT fields that are used to finesse the distribution in the desired direction of OAR sparing and

improved target coverage.2 Potentially one could see distributions superior to CRT, while minimizing technical concerns due to the decreased weighting applied to IMRT delivery. The concept being that as one reduces the IMRT component, one consequently reduces the total dosimetric uncertainty to be closer to that of a traditional CRT plan. An IMRT component weighted at zero would obviously not add any dosimetric uncertainty to a hybrid plan above that of a CRT plan. So conceptually, at least, a hybrid with a significant CRT component should offer less dosimetric uncertainty than a full IMRT plan for the same case. The complexity of the planning, delivery, and quality assurance (QA) process, however, increases regardless of the dose contribution from the added modulated fields. So, one must consider whether the potential benefits from the technique justify this increased complexity of process. Recently, volumetric-modulated arc therapy (VMAT) has been added to these investigations.3 Furthermore, the significance of the interplay effect may (especially for longer fractionations) be limited.4 In this work therefore, the potential benefit to our local population from a hybrid VMAT (VMATh) approach is investigated through a planning study of 8 clinical cases, where VMATh plans are compared with the clinically used CRT plans.

Method

Reprint requests to: John Agapito, M.S., C.M.D., Cancer program, Windsor Regional Hospital, 2220 Kildare Road, Windsor, Ontario, N8W 2X3. Tel.: þ1 519 254 5577; fax: þ1 519 255 8679. E-mail: [email protected], [email protected]

The planning computed tomography scans of 8 previously treated patients with NSCLC were used for this planning study. All the patients underwent target contouring by their primary radiation oncologist, and they had completed their treatment with CRT. A new VMATh plan was generated for comparison with the clinical plan.

0958-3947/$ – see front matter Copyright Ó 2013 American Association of Medical Dosimetrists http://dx.doi.org/10.1016/j.meddos.2013.08.004

J. Agapito / Medical Dosimetry 38 (2013) 460–466 The primary intent of the hybrid plan was to lower dose to the lung or improve target coverage and conformation or both, while respecting maximum dose limits of the spinal cord. Sometimes, therefore, the dose for the spinal cord was allowed to increase in the VMATh plan, if still within dose constraints. Beams in these plans were 6, 10 MV, or a mixture of both. No particular limitation was set on arcs (number, total degrees), but arc location was considered in terms of reducing dose to the contralateral lung. Only one plan had a full arc. Two plans had 1 partial arc, the others had 2 partial arcs. The typical CRT plan used clinically was a 3-field plan. The CRT base plan for the hybrid usually kept 2 of these 3, but did not necessarily adopt beam geometry found in the clinical CRT plan. The CRT beams in the hybrid saw the entire planning target volume (PTV) and typically contributed the majority of dose (mean ¼ 54.2%, s ¼ 11.2% as defined by the contribution to the International Commission on Radiation Units and Measurements [ICRU] reference point). All hybrid plans were generated by the author, using Eclipse, version 10 (Varian Medical Systems, Palo Alto, CA), with the anisotropic analytical algorithm, version 10.0.28 and heterogeneity corrections on. The VMATh plans are thus based on Varian's RapidArc approach. In Eclipse, it is possible to use a previously calculated dose distribution as a “base” for an inverse plan to be built on. The result of this optimization (i.e., a new VMAT field) can then be copied into the original plan and dose recalculated to produce a hybrid plan. The general intent of our clinical protocol for these patients is to deliver at least 95% of the prescribed dose (66 Gy) to 95% of the PTV, in 2 Gy fractions. The expansion from clinical target volume to PTV was generally 1 cm. However, not unusually for these patients, 2 of the cases had a compromise dose of 60 Gy (cases 3 and 4) to meet dose-volume constraints with the CRT plans. Furthermore, in case 3, the PTV expansion was reduced to 0.5 cm for the same reason. Composite lung V20 was to be kept below 30% wherever possible, and V30 for heart should be below 50%. Spinal cord maximum point dose values were to be o 45 Gy. Assessing differences between techniques was accomplished via dose-volume histogram analysis, target conformity, and dose maximums to OARs and target. Although there is some consensus on the spinal cord maximum dose criteria, there is less when it comes to the appropriate dose-volume limit for the lung. Although much

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still remains to be answered in this regard, various Vd (volume of combined lung receiving dose d or higher) have been shown to reflect risk of radiation pneumonitis,5,6 and in this work, values of V20, V10 and V5 are reported for plan comparison in this regard, as well as mean total lung dose and mean ipsilateral lung dose. The conformity measure (CN) used was that of van't Riet7: CN ¼

TVRI TVRI TV VRI

where CN is the conformity number, TV is the target volume (in this case the PTV), RI is the reference isodose (in this case 95%), and VRI is the volume of the reference isodose and TVRI is the volume of the target covered by the reference isodose. The significance of differences between techniques was assessed via the paired, 2-tailed Student t-test. Differences were considered statistically significant if p o 0.05. QA consisted of preliminary secondary monitor unit calculations (RadCalc, Lifelines Software Inc., Austin, TX), and measurement using ArcCHECK (Sun Nuclear Corporation, Melbourne, FL). When performing ArcCHECK QA, only the VMAT fields were measured. The exact IGRT couch top was modeled in all plans, including verification plans. The time required for plan delivery was recorded, for both the clinical CRT plan and the VMATh plan.

Results Figures 1 to 3 show iso-dose distributions (CRT and VMATh) for cases 2, 4, and 8, respectively. Tables 1 to 5 summarize some of the plan comparison results and case characteristics.

Fig. 1. Case 2. CRT (above) vs VMATh (below).

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Fig. 2. Case 4. CRT (above) vs VMATh (below).

The mean PTV in this sample was 195.6 cm3 (s ¼ 79.7 cm3). There was a predominance of right-sided (n ¼ 6) vs left-sided (n ¼ 2) disease. As can be seen from Table 2, there are too few cases to draw any conclusions from the OAR optimization parameters. The need for certain parameter values and priorities being too dependent on PTV size and location relative to OARs. Cognizance of the CRT contribution to OARs in the base plan allowed for setting of appropriate parameters in the VMAT component for the purpose of limiting dose to OARs as much as possible. However, there were some consistent settings in terms of the normal tissue objective and target objectives. The normal tissue objective was always set to automatic, with a priority between 75 and 150. The priorities in general being only meaningful in relation to the PTV priorities, it should be noted that these were always 100 to 110. The PTV parameters were always set so as to force the greatest homogeneity of dose: e.g., 100% volume to receive 65.99 Gy, 0.0% volume to receive 66.01 Gy. In terms of plan results, lung sparing from VMATh was significantly superior for mean total lung dose (p ¼ 0.001) and mean ipsilateral lung dose (p ¼ 0.003), total lung V20 (p ¼ 0.018) and V10 (p ¼ 0.011), but not for V5 (Table 3). For the opposite lung, VMATh sparing was significantly better for V10 (p ¼ 0.015). There was no significant difference at V20 and V5. Spinal cord sparing was not significantly different (Table 4). Only the maximum dose was of concern here, and this criterion was met for all cases, both in CRT and VMATh. Heart criteria were met for all cases, although only marginally with CRT in case 2 (Table 4). As one would expect, the

dose-volume constraint for the heart was more easily met for right-sided disease. The VMATh plans for left-sided cases showed superior sparing of the heart, but this improvement was not statistically significant, presumably because of the limited number of cases. Table 6 shows information regarding QA results and time for delivery of beams. As expected, time required to deliver the VMATh plans was elevated relative to CRT only. The time required to deliver all beams went from a mean of 2.5 to 3.6 minutes. This value represents the time from first beam on to last beam off. It accounts for beam time and gantry and collimator adjustment time between beams. It does not account for imaging, or other necessary delays due to treatment process such as verbal parameter checks between therapists, e.g., as these are very patient dependent. RadCalc secondary monitor unit checks included all fields and showed a mean difference in calculated dose to the ICRU reference point of 2% (s ¼ 1.1%) for VMATh vs 1.4% (s ¼ 1.0%) for CRT plans. ArcCHECK pass rates (Table 6) are for VMAT fields only, with RadCalc being considered adequate for CRT fields. All measurements were acceptable according to our institutional standard, which is based on pass rates at 3%/3 mm. As can be seen, even at 2%/2 mm, all measurements had better than 95% pass rates. All gamma pass rates are for absolute dose and a 10% threshold. Where plans included CRT fields of the same energy as the VMAT field, a second ArcCHECK measurement was made to include these. There were only 4 such plans. One would expect that including the simpler CRT deliveries would lower dosimetric uncertainty and thus improve measurement pass rates. Indeed,

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Fig. 3. Case 8. CRT (above) vs VMATh (below).

mean pass rates (for the same case) improved with the inclusion of the CRT fields in the measurement—the 2%/2 mm mean pass rate rising to 99.5% from 98.1%, the 3%/3 mm rising from 99.9% to 100%. However, there were too few cases for statistical significance. Figure 4 shows a mean dose-volume histogram curve comparison for total lung between the 2 techniques, if all patients had received the desired dose prescription of 66 Gy in 33 fractions. Note patients 3 and 4 had not, instead receiving 60 Gy in the clinical plan. As can be seen, the hybrid technique is generally superior, with the curves crossing at the 470-cGy dose level. Given the usual compromise required in CRT techniques, particularly with beam orientations to minimize lung and cord dose, it is not surprising that PTV conformity was significantly improved by VMATh (p ¼ 0.000). Although PTV mean dose was generally better for VMATh (102% vs 100.9% for CRT), differences did not reach statistical significance (p ¼ 0.088). Neither was there a significant difference between the approaches in the percentage volume of PTV receiving 95% dose or more (97.5% for VMATh vs 97.9% for CRT, p ¼ 0.432). The maximum dose to 2 cm3 of PTV was higher for VMATh (mean of 106.6% vs 105.4%) but this was not statistically significant (p ¼ 0.245). Discussion This work, being predominantly a planning study, has sought to compare a potential VMATh technique with CRT in the treatment of 8 NSCLC cases at our institution. The results of this work suggest

that such a VMATh approach might indeed benefit patients in our population. In general, hybrid plans could be expected to improve sparing of OAR, while better conforming to the target. This might allow for treatment in cases that might otherwise be abandoned owing to normal tissue complication concerns, or prevent compromise in target dose applied or PTV expansion used to guard against setup uncertainty—examples of which were seen in this clinical sample. This could be achieved without resorting to VMATonly plans. Indeed, 2 patients who received reduced doses owing to lung-sparing concerns could have been treated to the desired dose prescription, given the hybrid approach. This is potentially significant, if in fact doses above 64 Gy result in superior local control as reported by Rengan et al.8

Table 1 Case characteristics Case

PTV (cm3)

Location

TNM

1 2 3 4 5 6 7 8

100.0 273.4 187.4 301.5 208.6 76.4 168.3 248.8

Right upper lobe Left lower lobe Left upper lobe Right upper lobe Right upper lobe Right lower lobe Right upper lobe Right upper lobe

T1bN2M0 T2N0M0 T1N2M0 T3N2M0 T3N2M0 T2N1M0 T2bN0M0 T2N2M0

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Table 2 OAR optimization parameters for VMAT component. Cells show percentage volume requested to receive a dose value, and the priority (p) assigned NTO

Case 1 Auto, p75

Combined lung

4.9%, 19.9 Gy, p50

Case 2 Auto, p150

Case 3 Auto, p65

Case 4 Auto, p75

Case 5 Auto, p100

Case 6 Auto, p150

Case 7 Auto, p150

Case 8 Auto, p150

17.7%, 10.5 Gy, p40

19.4%, 19.2 Gy, p50 21.2%, 14.6 Gy, p50 24.1%, 10.1 Gy, p50 27.1%, 5.5 Gy, p50 35.2%, 2.91 Gy, p50 0.4%, 3.3 Gy, p100

10.8%, 32.1 Gy, p35 17.7%, 20.9 Gy, p40 20.7%, 12.1 Gy, p55 23.0%, 8.0 Gy, p60 27.7%, 3.2 Gy, p65

4.1%, 24.7 Gy, p50 4.9%, 17.3 Gy, p50 8.6%, 10.3 Gy, p50 14.9%, 6.5 Gy, p75 20.0%, 24.8 Gy, p75 4.4%, 6.5 Gy, p70 14.3%, 4.7 Gy, p75

1.2%, 21.4 Gy, p50 2.2%, 16.3 Gy, p50 3.3%, 10.2 Gy, p50 7.9%, 6.6 Gy, p50 14.7%, 4.5 Gy, p50 0.0%, 0.6 Gy, p75

6.8%, 15.9 Gy, p50 8.6%, 10.9 Gy, p50 10.4%, 6.3 Gy, p50 12.4%, 2.3 Gy, p50 16.9%, 1.2 Gy, p50

9.4%, 20 Gy, p100 13.4%, 12.7 Gy, p100 16.8%, 8.8 Gy, p100

9.7%, 30.0 Gy, p50 10.9%,22.7 Gy, p50 12.4%, 16.8 Gy, p50 17.7%, 10.0 Gy, p50 0.0%, 40.0 Gy, p5 0.0%, 38.0 Gy, p5

13.3%, 29.7 Gy, p1 15.1%, 23.8 Gy, p1 17.1%, 18.1 Gy, p1 22.3%, 12.1 Gy, p1 0.0%, 45.0 Gy, p50

20.0%, 6.2 Gy, p55 23.3%, 4.0 Gy, p65

Contralateral lung Ipsilateral lung

4.1%, 9.7 Gy, p50

Heart

23.7%, 12.9 Gy, p50 0.0%, 42 Gy, p100 0.0%, 41.0 Gy, p100

0.0%, 20.0 Gy, p100

2.8%, 2.5 Gy, p50 0.0%, 40.0 Gy, p100

0.0%, 38.0 Gy, p50

NTO ¼ normal tissue objective; PRV ¼ planning organ at risk volume.

Table 3 Lung dose-volume comparisons. Total lung ¼ combined lung volume  GTV Case

CRT V20 (%)

VMATh V20 (%)

CRT V10 (%)

VMATh V10 (%)

CRT V5 (%)

VMATh V5 (%)

CRT MTLD (Gy)

VMATh MTLD (Gy)

CRT MILD (Gy)

VMATh MILD (Gy)

1 2 3 4 5 6 7 8

15.6 23.6 30.0 32.9 24.8 9.5 13.9 27.2

9.6 24.0 26.1 29.3 18.5 10.4 12.3 24.1

21.4 45.5 46.0 44.7 30.7 13.9 15.9 46.7

16.4 31.6 31.4 36.0 26.5 14.9 15.0 38.6

26.5 55.9 52.7 51.3 36.4 23.2 18.4 54.8

27.3 50.0 43.3 47.7 44.7 20.0 21.8 53.5

8.99 16.00 18.14 18.55 14.35 6.69 8.20 18.01

6.78 14.52 14.63 16.74 12.32 5.76 7.44 15.33

13.90 30.25 37.76 30.50 25.67 10.60 14.70 29.52

10.75 28.49 28.89 27.18 21.89 9.34 12.34 25.18

GTV ¼ gross tumor volume; MILD ¼ mean ipsilateral lung dose; MTLD ¼ mean total lung dose.

J. Agapito / Medical Dosimetry 38 (2013) 460–466

Cord PRV Spinal cord

29.9%, 2.7 Gy, p100

J. Agapito / Medical Dosimetry 38 (2013) 460–466 Table 4 Comparison of heart volume receiving 30 Gy, spinal cord (SC) maximum dose (Dmax) Case SC Dmax CRT (cGy)

SC Dmax VMATh (cGy)

Heart V30 CRT (%)

Heart V30 VMATh (%)

1 2 3 4 5 6 7 8

4448.8 2538.5 2813.7 4426.2 4201.1 489.8 2605.3 2095.2

0.0 49.8 23.3 0.8 1.9 0.0 0.0 4.6

0.0 26.7 19.5 0.3 0.1 0.0 0.0 3.2

4497.7 2134.4 4182.5 4218.2 4144.7 159.3 2438.4 3843.1

One of the potential concerns of using VMAT in the lung is the potential for larger volumes of normal tissue, particularly the lung, receiving low dose. This follows intuitively from the technique's delivery method, which can be thought of essentially as composed of single-segment deliveries but from many gantry angles. In this review, this was found not to be the case, except for doses below the 470-cGy (7.1% of prescription) dose level. For discreet dose levels tested, the only significant differences found point to better sparing of total lung at V10 and V20, and also V10 for the opposite lung, with a VMATh approach. These results may have implications for potential dose escalation. Figure 4 is interesting in this regard. Depending on which dose level one considers to best represent normal tissue complication risk, one might be able to deliver higher target doses while maintaining an acceptable lung dose-volume criterion. However, according to this sample and technique, if it is the case that extremely low dose to lung (o 470 cGy over 30 to 33 fractions) proves significant to radiation pneumonitis risk, then this approach is unlikely to be helpful. There are problems with this review. It is a small sample from 1 institution. The hybrid plans were designed by the author, but the clinical plans by other (albeit experienced) planners. So, it is not possible to eliminate the possibility that superior CRT or VMATh plans were achievable. Nevertheless, given the ease with which the hybrid plans were achieved, and the significant differences seen between the 2 methods, it is easy to conclude that the hybrid approach has potential merit. Although there was no attempt to select for PTV size, the largest PTV seen here was 301.5 cm3. Larger volumes are not uncommon in this disease,10 and therefore bias may be present in this regard. Although the concept of a hybrid plan is introduced partly for the purpose of reducing dosimetric uncertainty resulting from highly modulated fields, the approach remains complex. Planning is not straightforward in the current version of treatment planning system used. Also, the introduction of VMAT fields introduces the need for QA measurements in these patients—an added burden. That being said, all QA measurements in these cases passed our institutional criteria, and time increase for plan delivery was modest.

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Table 6 Case-by-case beam on times and QA results Case Time Time for RadCalc for CRT VMATh difference (min) (min) CRT (%)

RadCalc difference VMATh (%)

ArcCHECK ArcCHECK pass rate (3%/ pass rate 3 mm) (%) (2%/2 mm) (%)

1 2 3 4 5 6 7 8

0.0 2.3 2.8 3.2 0.9 2.9 2.6 1.3

100.0 100.0 100.0 100.0 100.0 99.7 100.0 100.0

2.7 1.9 2.6 3.0 2.7 2.5 2.2 2.7

3.4 2.3 3.7 3.7 3.6 4.0 3.7 4.5

1.9 2.7 2.1 1.7 1.0 0.5 1.3 1.2

How much weight should be given to the arc fields in a hybrid plan? And how should this be defined? Using the ICRU reference point (as in this work) may not have as much meaning as one would like. A modulated arc field might easily deposit significantly more fluence at the edges of a target compared with the ICRU point. One more significant issue is that of the validity of the hybrid plans if delivered, when one considers breathing motion. Neither the CRT plans nor VMATh plans shown here consider motion, except to the extent of using 4-dimensional computed tomography to generate an internal target volume. Experimental validation to consider dose blurring and interplay effects is beyond the scope of this work. Indeed, it is a nontrivial problem to experimentally address the effect of a nonregular breathing cycle with heterogeneous distributions that are clinically meaningful yet consider interplay, as well as interface and small-field effects. It is important to remember that even static CRT field distributions are not immune to the effects of motion, which results in a blurring or widening of the effective penumbra around a target. The problem is exacerbated in the presence of a dynamic wedge, which results in the simplest example of the interplay effect. In dynamic IMRT, the increasing complexity of delivery increases the potential for extreme dose discrepancies, being particularly dependent on multileaf collimator speed and minimal leaf gap. An excellent review of these effects has been presented by Bortfeld et al.9 Although that review does not explicitly address VMAT deliveries, the observation that discrepancies will have a

Table 5 Comparison of PTV conformity. CN to 1 as conformity approaches perfection Case

CN CRT

CN VMATh

1 2 3 4 5 6 7 8

0.372 0.506 0.245 0.427 0.427 0.436 0.453 0.527

0.812 0.936 0.716 0.641 0.873 0.842 0.795 0.757

97.5 99.1 98.3 99.7 100.0 96.2 100.0 98.1

Fig. 4. Comparison of mean total lung DVH.

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tendency to be much diminished over a number of fractions should hold. Despite the experimental difficulties, there is a growing body of work focused on the particular problem of VMAT delivery in the presence of significant heterogeneities and motion, and considering small-field apertures typical in such plans.4,10–13 These works largely support the considerations of Bortfeld et al. Nevertheless, the inability to measure the dose delivered in the presence of inconsistent breathing patterns both intrafraction and over a treatment course (i.e., patient-like) remains. Planning studies such as presented here hopefully will help to clarify the potential gains from a hybrid approach. Undoubtedly, for any given fraction, the complexity of a VMAT treatment will lead to greater dose delivery uncertainty than in a static beam, unmodulated case. As more data become available to better quantify this level of uncertainty, and considering the hybrid nature of the technique in question (which should lower the relative uncertainty further), the clearer it will become as to whether the benefit/harm ratio is warranted given the potential for dose escalation or normal tissue sparing or both.

Conclusions A VMATh technique as described could be beneficial for our local patient population. It should produce superior dose distributions compared with conformal techniques alone, potentially allowing for the treatment of some patients who would otherwise be denied owing to normal tissue complication concerns. The reduced contribution of the VMAT component could help to lower the overall effect of uncertainties in delivery due to motion and heterogeneity effects.

References 1. Ruysscher, D.; Elmpt, W.; Lambin, P. Radiotherapy with curative intent for lung cancer: a continuing success story. Radiother. Oncol. 101:237–9; 2011. 2. Verbakel, W.; Reij, E.; Ladenius-Lischer, I.; et al. Clinical application of a novel hybrid intensity-modulated radiotherapy technique for stage III lung cancer and dosimetric comparison with four other techniques. Int. J. Radiat. Oncol. Biol. Phys. 83:e297–303; 2012. 3. Chan, O.; Lee, M.; Hung, A.; et al. The superiority of hybrid-volumetric arc therapy (VMAT) technique over double arcs VMAT and 3D-conformal technique in the treatment of locally advanced non-small cell lung cancer—a planning study. Radiother. Oncol. 101:298–302; 2011. 4. Rao, M.; Wu, J.; Cao, D.; et al. Dosimetric impact of breathing motion in lung stereotactic body radiotherapy treatment using image-modulated radiotherapy and volumetric modulated arc therapy. Int. J. Radiat. Oncol. Biol. Phys. 83: e251–e256; 2012. 5. Schallenkamp, J.; Miller, R.; Brinkmann, D.; et al. Incidence of radiation pneumonitis after thoracic irradiation: dose-volume correlates. Int. J. Radiat. Oncol. Biol. Phys. 67:410–6; 2007. 6. Yorke, E.; Jackson, A.; Rosenzweig, K.; et al. Correlation of dosimetric factors and radiation pneumonitis for non-small-cell lung cancer patients in a recently completed dose escalation study. Int. J. Radiat. Oncol. Biol. Phys. 63:672–82; 2005. 7. Feuvret, L.; Noël, G.; Mazeron, J.; et al. Conformity index: a review. Int. J. Radiat. Oncol. Biol. Phys. 64:333–42; 2006. 8. Rengan, R.; Rosenzweig, K.; Venkatraman, E.; et al. Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 60:741–7; 2004. 9. Bortfeld, T.; Jiang, S.; Rietzel, E. Effects of motion on the total dose distribution. Semin. Radiat. Oncol. 14:41–51; 2004. 10. Ong, C.; Verbakel, W.; Cuijpers, J.; et al. Dosimetric impact of interplay effect on RapidArc lung stereotactic treatment delivery. Int. J. Radiat. Oncol. Biol. Phys. 79:305–11; 2011. 11. Ong, C.; Cuijpers, J.; Senan, S.; et al. Impact of the calculation resolution of AAA for small fields and RapidArc treatment plans. Med. Phys. 38:4471–9; 2011. 12. Court, L.; Wagar, M.; Berbeco, R.; et al. Evaluation of the interplay effect when using RapidArc to treat targets moving in the craniocaudal or right-left direction. Med. Phys. 37:4–11; 2010. 13. Fakir, H.; Gaede, S.; Mulligan, M.; et al. Development of a novel ArcCHECKs insert for routine quality assurance of VMAT delivery including dose calculation with inhomogeneities. Med. Phys. 39:4203–8; 2012.