High Precision and

High Precision and

Unconventional Fractionation IMRT

Stanley H. Benedict, John Purviance, Danny Song, David E. Wazer

12

Contents

12.1 Introduction . . . 439

12.2 Unique Anatomic Challenges and Target Volume Delineation . . . 439

12.3 Planning Dose Prescription and Optimization . . . . 441

12.4 Clinical Experience and Trials to Define the Role of IMRT . . . 443

12.5 Intracranial: Meningioma . . . 443

12.6 Extracranial: Lung Tumor . . . 449

12.7 Future Directions . . . 449

References . . . 450

12.1 Introduction

Dynamic multileaf collimation and intensity modu- lated radiotherapy (IMRT) produce dose distributions that are superior to conventional radiotherapy planning and may be exploited in a number of anatomic sites and clinical circumstances. In this chapter we report on techniques which combine the spatial accuracy of stereotactic positioning with the dose delivery capabil- ities of IMRT to treat small critically located targets. To date, the majority of studies demonstrating improve- ment in dose distribution with IMRT have been for broad field sizes using relatively large multileaf colli- mation systems, generally with leaves 1.0 cm in width.

The recent introduction of micro-multileaf collimator systems have allowed the advantages of IMRT to be fur- ther extended to small intra- and extra-cranial targets.

The dosimetric advantages seen with IMRT coupled with high precision localization systems have allowed the clinician to explore dose escalation and hypofrac- tionation as a means to improve both tumor control and patient convenience.

12.2 Unique Anatomic Challenges and Target Volume Delineation

The application of small field high precision IMRT requires an extraordinary degree of spatial accuracy.

In fact, for a complete understanding of the potential and limitations of small field IMRT, one must briefly review the concepts that underlie stereotactic radio- surgery and the more recently introduced stereotactic body radiotherapy (SBRT).

Stereotactic radiosurgery (SRS) was a term originally used to describe an approach for radiotherapy of brain tumors using rigid invasive immobilization, precise lo- calization via a stereotactic coordinate system, multiple convergent beams, and single fraction treatments [1].

The spatial precision afforded by the use of an invasive stereotactic immobilization frame practically necessi- tated single fraction irradiation, but in return allowed for treatment with a minimal margin of surrounding tissue. Stereotactic precision coupled with circular col- limator diameters generally less than 2 cm resulted in small volumes of irradiated tissue and the consequent delivery of very high radiation doses. Clinical experience accumulated over the past two decades has validated SRS as achieving a high rate of control with acceptably low rates of complication for a variety of intra-cranial tumors [2–5].

The anatomical characteristics of the skull and sta-

bility of cranial contents made SRS readily feasible for

intra-cranial tumors, but the lack of a similar fixed

bony reference structure as well as target and normal

tissue movement created difficulty for the application

of a similar treatment approach outside of the cra-

nium. Initial progress in addressing this problem was

presented by Lax et al. [6] who described a method

for performing stereotactic body radiotherapy (SBRT)

for abdominal malignancies. In a subsequent report,

Blomgren and Lax [7] reported the clinical appli-

cation of this technique to a series of patients with

tumors of the lung, liver, and abdomen treated to

a mean dose of 30 Gy delivered in one to four frac-

tions.

As a consequence of these studies, there has been in- creasing interest to develop similar approaches of SBRT, that is, spatially precise, hypo-fractionated treatment as applied to several different extra-cranial locations. The general principles that have been used in the selective application of SBRT mirror those of SRS: treatment is limited to a small to moderate volume target with a mini- mal margin of surrounding tissue and dose distributions are chosen that minimize exposure to surrounding normal tissue. Prophylactic coverage of clinically un- involved areas is not performed, thereby maintaining a simple volume and avoiding dose gradients between spatially distinct target structures. A target is generally chosen within or adjacent to anatomic structures with parallel architecture, such that small volumes of nor- mal tissue can receive a high dose of radiation without clinical sequelae due to the functional reserve of the non-irradiated organ.

Sophisticated three-dimensional conformal treat- ment planning and IMRT has improved dose sculpting such that normal tissue avoidance is both more practical and achievable. However, aggressive dose escalation or hypofractionated treatment regimens have seen limited application in extra-cranial sites due primarily to the complexity of ensuring precise and reproducible target- ing of small and often mobile tumors. A long appreciated limitation of conventional external beam radiotherapy derives from the inherent difficulty of reproducibility for both inter- and intra-fractional set-up. Specifically, clinicians must recognize that, at many anatomic sites,

Stereotactic body radiotherapy immobilization techniques

Author Site Immobilization

|

Lax-1994 [6] Abdomen Woodframe | stereotactic coordinates on box to skin marks

3.7 mm lat 5.7 mm long

Hamilton-1995 [43] Spine Screw fixation of spinous processes to box 2 mm Tokuuye-1997 [44] Liver Prone position | jaw and arm straps 5 mm Murphy-1997 [45] Spine Frameless | implanted fiducial markers with

real time imaging and tracking

1.6 mm radial

Sato-1998 [46] Abdomen Frameless | combination CT, X-ray, and linac

N | ^A

Lohr-1999 [47] Body cast with stereo- tactic ≤ 3.6 mm coordinates

mean vector

Wulf-2000 [48] Lung, liver Elekta

3.3 mm lat 4.4 mm long

Nakagawa-2000 [49] Thoracic Megavoltage CT on linac N | ^A

Herfarth-2001 [50] Liver Leibinger body frame 1.8 – 4.4 mm

Nagata-2002 [51] Lung Elekta body frame 2 mm

Fukumoto-2002 [52] Lung Elekta

N | ^A

Hara-2002 [53] Lung Custom bed transferred to treatment unit after confirmatory scan

2 mm

Hof-2003 [54] Leibinger body frame 1.8– 4 mm

Timmerman-2003 [55] Lung Elektabody frame Approx 5 mm

there is a relative independence of target tumor posi- tion from bony anatomy. Further, intra-fractional target movements may occur due to patient movement on the treatment couch or normal physiologic processes such as respiration and peristalsis. Traditional radiation therapy planning methods have compensated for these factors with the use of generous margins around clin- ical target volumes. However, due to the constraint of normal tissue toxicity, such an approach severely limits the extent to which dose escalation or hypofractionation can be explored.

Therefore, a basic requirement of small field high precision IMRT is a high degree of confidence in tumor targeting throughout treatment delivery. For tumors of the cranium and upper neck, stereotactic localization can be readily applied and immobilization can be ac- complished with both invasive [8] and non-invasive [9–12] techniques. Invasive immobilization with rigid fixation to the treatment couch can achieve sub- mil- limeter positional accuracy [8,13] but severely limits the number of treatment fractions that can be practically employed. Non-invasive immobilization will result in positional reproducibility within approximately 2 mm [14, 15] but has the advantage of less discomfort for the patient and is readily amenable to more extended fractionation.

For extra-cranial tumors, a number of positional

verification and immobilization systems are under de-

velopment. The initial report by Lax et al. [6] described

a body cast within a rigid box frame with radio-opaque

scale markers for imaging data acquisition. The scales mounted on the frame corresponded with fiducial points and were used to set up the isocenter co-ordinates in the treatment room. Diaphragmatic movement was limited by using a plate to apply pressure to the anterior ab- dominal musculature. A number of similar systems have been subsequently described that have relied upon some method of body stereotaxis, rigid immobilization, res- piratory gating, or some combination thereof (Table 1).

Overall, the reported positional accuracy is within 5 mm for the various methods utilized.

An alternative method for achieving precise tumor localization and to guide correction for organ move- ment is to implant radio-opaque markers. This allows for setup verification on a daily basis, correction of both translational and rotational errors [16], and the poten- tial for tracking organ motion in real time. For example, the Cyberknife system (Accuray, Sunnyvale CA) employs a combination of implanted fiducials and skeletal land- marks for real-time beam positioning via fluoroscopic monitors. The use of this method has been described for targets in multiple organs including the spine [17], pancreas [18], brain [19], and lung [20].

Positional verification of tumors within mobile organ structures has also been described at Kyoto Univer- sity where 2.0-mm gold spheres were placed through a bronchoscope into the airways of patients with lung tumors [21]. A real-time tumor tracking system consist- ing of dual fluoroscopic detectors was used to activate the treatment beam when the markers were within pre-defined coordinates.

Radio-opaque markers may also be implanted into the prostate to correct for inter-fractional positional variability due to differences in rectal and bladder vol- ume [22, 23]. Although current electronic imaging technology does not allow for intra-fractional real- time tracking, portal images may be taken immediately prior to treatment and guide positional corrections [24, 25].

Techniques to place radio-opaque markers in the liver have employed intravascular as well as intra- parenchymal approaches. Dawson et al. described the use of intra-arterial hepatic microcoils (5 × 0.46 mm platinum) placed through a hepatic artery catheter for liver localization [26]. Kitamura et al. used an inter- stitial technique to implant 2.0-mm gold markers into patients with liver tumors and found minimal migration with follow-up CT scans [27].

12.3 Planning Dose Prescription and Optimization

In general, the sequence of events for patients undergo- ing small field high precision IMRT include:

1. Immobilization

2. CT simulation 3. Planning 4. Repositioning 5. Re-localization 6. Treatment delivery

To ensure a reproducible set-up, immobilization typ- ically includes a custom-fit device to minimize motion.

The CT simulation is used to assess the size, location, and range of motion of the tumor as well as to determine if the patient can tolerate the planned immobilization.

The measurement of motion of the tumor provides the necessary data to determine the PTV and to assess if respiratory gating should be incorporated in the treat- ment delivery. The treatment planning must address the complexity of small field dosimetry [28] and, when appropriate, inhomogeneity corrections (e.g., the lung) [29]. A critical parameter in treatment planning is the volume of normal tissue exposed to threshold doses that will vary according to the organ that either sur- rounds or is adjacent to the target. The normal tissue complication probabilities are intimately related to these dose-volume relationships [30–32]. Repositioning ad- dresses the accurate set up of the patient in the planned treatment position while re- localization addresses the specific identification of the tumor and planned isocen- ter in the treatment field. Finally, treatment delivery is performed using an assortment of high precision beam delivery techniques, including micro-multileaf collima- tion (MLC), gantry mounted linear accelerators, and combined imaging and treatment units.

The accepted limit for accurate dose delivery for an SRS linear accelerator is < 1 mm for the gantry, couch, collimator angles, and the mechanical isocenter. This degree of tolerance places a very strict accuracy require- ment on the design of any multileaf collimator system that may be used for small field high precision IMRT.

While most commercially available multi-leaf collima- tors have a leaf positioning accuracy of approximately 1 mm and are acceptable for standard fractionated large

Fig. 1.

Geometric advantage of the beak intensity modulated se-

quential tomotherapy (BIMST) vs 1- cm MIMiC for irradiation of

irregularly shaped small lesions. The identical black region rep-

resents the clinical target volume for comparison between both

modalities. Reproduced with permission from Elsevier [38]

Fig. 2a–f.

The influence of 0.39 cm vs 0.85 cm leaf width on dose distribution for a small intracranial irregularly shaped target:

(a)

beak intensity modulated sequential tomotherapy (BIMST) axial view;

1-cm MIMiC axial view;

BIMST sagittal view;

(d)

1-cm MIMiC sagittal view. The purple isodose line corresponds

to the prescription line (84%), and the 90, 70, and 50% isodose lines

are red, yellow, and green, respectively;

BIMST and 1-cm

MIMiC DVHs for various clinical target volumes. Reproduced with

permission from Elsevier [38]

field radiotherapy, they do not meet the general clin- ical accuracy standard for SRS. Therefore, in order to provide small field high precision IMRT, substan- tial hardware development was required to develop the

“mini and micro” multi-leaf (mMLC) collimator tech- nology.

High precision and a steep dose gradient (rapid dose fall-off) are the two requirements that must be met by any conformal SRS or SBRT system. These critical criteria can now be achieved with mMLC collimators.

Standard MLC devices that are components of commer- cial linear accelerators have leaf widths that range from 0.5 to 1.0 cm. In contrast, the leaf width of an mMLC is narrower which greatly influences the beam penum- bra and is the determinant parameter for how sharply the dose gradient extends beyond a target boundary.

The physical characteristics of the mMLC leaf tips have been specifically designed to satisfy the rigorous re- quirements for SRS and SBRT. A conventional MLC has a penumbra width between 6 and 8 mm (meas- ured from the 80 to −20% isodose line), whereas the penumbra width of an mMLC ranges between 2.5 and 3.5 mm.

The relevance of leaf width for small field high pre- cision IMRT is illustrated in Fig. 1 and Fig. 2 [33].

In this example, a geometrically complex target sits in immediate proximity to several radiosensitive crit- ical normal structures. One can readily appreciate that the mMLC with the leaf width of 0.39 cm results in a significant enhancement of dose conformity as com- pared to the MLC with a leaf width of 0.85 cm. This is associated with an improvement in the normal tis- sue dose-volume relationships. These seemingly modest changes in dose distribution may be of particular clin- ical importance when treatment is delivered by a high dose hypofractionated treatment scheme.

Several mMLC systems are now commercially avail- able that can deliver highly conformal treatment using fixed static fields, dynamic conformal arcing, and IMRT.

The MIMiC, manufactured by NOMOS Corporation, is a multileaf collimator driven by the CORVUS in- verse treatment planning software component of the PEACOCK System. The MIMiC provides a 40-leaf bi- nary temporal modulator specifically with a leaf width of 0.85 cm designed for the delivery of sequential to- motherapy and was the first MLC developed to deliver IMRT. The device directs thousands of pencil-thin ra- diation beams at a tumor target, each of which may be varied in intensity as the linear accelerator gantry ro- tates about the patient. For small field IMRT, NOMOS developed the mMLC BEAK collimator with a leaf width of 0.39 cm. The BrainLAB m3 mMLC (BrainLAB AG, Heimstetten, Germany) was designed specifically for radiosurgery with 3-mm center leaves for an effective penumbra of < 3.0 mm for all SRS field sizes. In a field size dimension of 10 × 10 cm, the m3 leaves are of vari- able width, including 14 pairs of 0.3 cm, 6 pairs of

0.45 cm, and 6 pairs of 0.55 cm leaves [34, 35]. The Ra- dionics (Radionics – Tyco Healthcare, Burlington, MA) MMLC has 31 pairs of 4-mm leaves, with a total field size of 10 × 12 cm and a leaf height of 7 cm of tungsten.

The leaf geometry of the MMLC is a divergent lock and key design in order to minimize radiation leakage and transmission. Planning for the MMLC is with the XKnife software [36]. The mMLC manufactured by 3DLINE (3DLINE USA Inc., Reston, VA) is called DMLC (Dy- namic Multi Leaf Collimator) and is an auto-controlled dual focused system. This mMLC is designed as an ac- cessory for all models of liner accelerator and consists of 24 tungsten leaf pairs providing a maximum field size of 10. 8 × 12 cm. The dual focused characteristic of the DMLC is a unique feature and provides a penumbra that is field size independent.

12.4 Clinical Experience and Trials to Define the Role of IMRT

Small field high precision IMRT has been applied to a number of anatomic sites. In general, the studies reported to date have represented small institutional experiences that have focused on innovations in pa- tient immobilization, target definition and tracking, treatment planning, and mMLC applications. Table 2 presents a summary of trials that have specifically em- ployed small field high precision and unconventionally fractionated IMRT techniques. Many of the relevant related technologies of patient immobilization, tumor localization, and physiological gating have been re- ported in detail in studies of SBRT which are beyond the scope of this chapter but have been extensively reviewed elsewhere [37].

The interpretation of existing clinical literature is made complicated by the small number of treated pa- tients, the different anatomic sites addressed, and the variety of fractionation schemes that were used. As such, it is difficult to draw definitive conclusions or to make ex- plicit treatment recommendations for the application of small field high precision IMRT. Therefore, to assist the reader better in understanding the concepts explored in this chapter as applied to actual patient treatment, two case examples are presented.

12.5 Intracranial: Meningioma

This case is presented to demonstrate the issues re-

lated to the application of small field high precision

IMRT to a highly irregular target volume in proximity

to radiosensitive critical normal structures. In this case

a patient received a partial resection for a left cavernous

sinus meningioma that extended into the suprasellar

Table2.ClinicaltrialsforhighprecisionandunconventionallyfractionatedIMRT

A n at o m ic si te Immob iliza tio n | L o calica ti o n Col lima tio n | Planning Dose(G y ) F rac ti o n Si ze (G y ) P at ien t # M edian F ield S ize (r ange) Clinical E nd po in ts Glio blast o ma Flo yd NS, et al. [56]

A q uaplast mas k Co o rd in at ic sy st em

Pe ac o ck IM R T sy st em (NOMOS) 60 3 Gy 20 N o t re p o rt ed M edian time to disease p rog re ssio n six mo n th s. M edian su rv iv al sev en mo n th s Minimal g rade 0–1 acu te neur to xicit y. B rain necr osis in thr ee p at ien ts. Glio blast o ma Su lt an em , K et al. [57]

Ther mo plast ic mas k C o o rdina te sy st em ML C “st ep -and- sh o o t” w it h m u lt iple co - | no n-c o planar be am s

60 3 Gy 25 P o st-o p tumo r vo lu m e ≤ 110 cc Di se as e p rog re ssio n in 21 pa ti en ts ,1 6 d ea th s at 8.8 mo n th s. N o im p ro vemen t in O ve ral l Sur v iv al o r T ime to D is ea se P ro g re ss ion . Hi g h Gr ad e Glio ma Chang , IL et al. [58]

Ther mo plast ic mas k C o o rdina te sy st em (CT | MRI fu sio n) Seg m en tal IMR T v ia n o n -c o p lan ar be am s

90 2 Gy 34 N o t re p o rt ed 67.6% dev elo ped radiog raphic recur re nc e. 91% o f recur re n ce s p redo min an tl y w ithin hi g h dose field (PT V ). M eningo ma Pi rz k al l, A et al. [59]

Cu st o m h ea d m as k C o o rdina te Sy st em Sta tic ML C Ko n R ad o r C o rv u s

55.8–58.2 1.8 Gy 20 108 cc 60 % imp rove m ent o f n eu ro lo g ic sy mp to m s. 40% tumo r shr ink age. Tr ig em in al Ne u ra lg ia R o manel li, P et al. [60]

Cu st o m h ea d mas k w ith C T cist er nog raph y fo r lo caliza tio n

C y b er k nif e X X X 10 X X X P ain re lief achi ved in 7 p at ien ts. Pa ra sp in al Bi lsk y, M H et al. [17]

Me m o ri al B o d y Crad le | El ec tr o n ic P o rtal Im ag e Dev ic e w it h metal lic im plan ts or M em or ia l S ter eo tac tic Bo d y Fr am e w it h C T b ased lo caliza tio n Cy b er k n if e P ri m ar y T u - mo rs : m edian dose 70 Gy in 33–37 frac ti o n s. Me ta st at ic tumo rs: 20 Gy in 4–5 frac tio n s af te r co n ve n- ti o n al E B R T to to le ra n ce of no rm al ti ss ue.

16 M edian tumo r vo lu m e 7. 8 cc (8.1–385.3)

N oi n te rv al g ro w th fo r1 3o f1 5p at ie n ts . Im p ro vemen t in p ain fo r al l 11 sy m p to ma ti c p at ien ts. Im p ro ve d radiculo p at h y in 4 o f 4 p at ien ts.

Table2.(continued)

A n at o m ic si te Immob iliza tio n | L o calica ti o n Col lima tio n | Planning Dose(G y ) F rac ti o n Si ze (G y ) P at ien t # M edian F ield S ize (r ange) Clinical E nd po in ts Sp in e Ger szt en, PC et al. [61]

A q uaplast F ac e Ma sk (c er v ic al ) Tr ac k in g o f Im - plan te d F id ucial s (tho racic, lum b ar , sacral) Cy b er k n if e w it h Dy namic T rack ing Sy st em 3. 0

Sing le F rac ti o n of 12 – 20 Gy to the 80% is o dose line (median 14 Gy ) 115 M ean tumo r vo lu me 27.8 cc (0.3–232)

N o new acu te radia tio n to xicit y o r n eur o log ical sy m p to m s.P ai ni m p ro ve di n7 4o f7 9s y m p to m at ic pa ti en ts . Sp in e Mi lk er -Z ab el et al. [62]

Cu st o m m ad e b o d y cast | head mas k C o o rdina te sy st em ML C “st ep -and- sh o o t” Ko n R ad

Al l p at ien ts u n- de rw en t E BTR (median dose 38 Gy ) Me d ia n to - tal dose fo r re -ir radia tio n 39.6 Gy in 2 Gy fr ac ti o n s 14 M edian target vo lu me 111.2 cc (20.8–734.9)

94% lo cal co n tr ol at 12 mo n th s- 81.2% re ciev ed p ain re lief. T u mo r size un chang ed in 84.2%. Lu n g T immer man, RD et al. [55]

S ter eo tac tic Bo d y Fr am e (E le k ta Onc olo g y) w it h Ab d o m in al C o m - pr es si o n C o o rdina te Sy st em 7 n o n -c o p lan ar , no n-o p p osing be am s w it h m il le d at te nu at io n co m - pen sa to rs Re n d er P la n 3D planning sy st em 24 – 60 Gy in 3f ra ct io n s. Dose escala ti o n per fo rmed wi th co h o rt s re ce iv in g 3 fr ac ti o n s o f 8,10,12,16,18 o r 20 Gy

37 22.5 cc 27 % com pl et e tu m or re sp o n se .6 0% p ar ti al tu m or re sp ons e. A ll 6 p at ie n ts w it h lo ca l fa il ur e rec ei ved

18 Gy | fr ac ti o n . Lu n g W h y te, RI et al. [20]

Al pha Crad le Im plan te d m etal Fi d u ci als T u m or tr ac k in g w it h li g h t-emitt ing dio des | diag nost ic x-ra y Cy b er k n if e 15 Gy Sing le fr ac ti o n of 15 Gy

23 T u mo r d iamet er 1–5 cm Radiog raphic tumo r re spo n se: co m p let e in 2 p at ien ts, p ar tial in 15 p at ien ts, sta ble in 4, pr o g res siv e in 2. N o g rade 3–5 radia tio n rela ted co m plica tio n s. M es o thelio ma Mu n te r, M W et al. [63]

Cu st o m b o d y cask | fa ce m ask (Sc o tchcast) C o o rdina te sy st em

ML C “st ep -and- sh o o t” Ko n R ad o r COR VUS

Me d ia n tu m o r dose 40 Gy for 3 pa ti en ts , 48 Gy fo r1a n d 50 Gy for 3 p at ie n ts Fr ac ti on si ze no t re p o rt ed

7 2,314 cc (1006– 3981) 28% ac tuar ial o veral l sur v iv al at 1 ye ar . N o si g n ifican t acu te sid e eff ec ts ac co rding to RT O G cr it er ia .

Table2.(continued)

A n at o m ic si te Immob iliza tio n | L o calica ti o n Col lima tio n | Planning Dose(G y ) F rac ti o n Si ze (G y ) P at ien t # M edian F ield S ize (r ange) Clinical E nd po in ts Pa n cr ea s Ko o n g , AC et al. [64]

Al pha Crad le Im pl an te d G old Fi d u ci al s

C y b er k nif e Sing le F rac ti o n : 15 Gy (3 p a- ti en ts ) 20 Gy (5 p a- ti en ts ) 25 Gy (7 pa ti en ts )

15 M edian GT V 29.0 cc (19.2–71.9) No g ra d e ≥ 3G It o x ic it yo b se rv ed . L o ca l co n tr ol ac hiev ed in al l p at ien ts w ho rec ei ved 25 Gy . Pa n cr ea s | Bi le D u ct M il an o ,M Te t al. [65]

Al pha Crad le C o o rdina te sy st em

Dy namic ML C 50.4 – 59.4 Gy 1.8 Gy 25 N o t re p o rt ed M edian sur v iv al was 13.4 mo n th s. N o re se ct ed p at ie n ts h ad lo ca l fa il u re an d 1 u n re se ct ab le p at ien t h ad disease p ro g ressio n at 10 m o n th s. 1 P at ien t sur v iv ing

5 year s had g rade 4 li ver to xicit y. Pr o st ate K u pelian, PA et al. [66]

Minimal immo b i- liza tio n Dail y tran sa b do m- in al ul tr as o u nd (B A T ) p rosta te lo calica tio n 5s ta ti cfi el d su si n g dy n am ic M L C in - te ns it y m o d u la ti o n C o rv us planning sys te m

70 Gy 2.5 Gy 166 N o t re p o rt ed B io chemical re lapse-f re e sur v iv al at 30 m o n th s 94%. L at e re ct al to xicit y (g rade 2-3) was 5%. L at e ur in ar y to x icit y in 4 p at ien ts. Pr o st ate Ze le fs k y, M J et al. [67]

Minimal immo b i- liza tio n L o caliza tio n ba se d o n C T sim ula tio n | sk in fid ucial s 5 fi eld sliding w in- do w techniq ue In ve rs e p lanning sys te m

81.0 Gy (698 pa ti en ts ) 86.4 Gy (74 pa ti en ts )

1.8 Gy 722 N o t re p o rt ed 3-y ear PSA relapse-f ree sur v iv al fo r fa vo ra b le, in ter - media te, and un fa vo ra ble ris k g ro u p s wer e 92%, 86%, 81% re spec ti ve ly . 4% ri sk o f la te ≥ g rade 2 rec tal to xicit y at 3 year s. 15% ri sk ≥ la te g rade 2 ur inar y to xicit y at 3 year s. Or o p har y nx Chao , K SC et al. [68]

Ther mo plast ic mas k C o o rdina te sy st em MIMiC P eac o ck p lanning sy st em (NOMOS)

70 Gy (a ve rag e dose p re- scr ib et to GT V in pr im ar y cases) 66 Gy (dose to GT V in post-o p cases)

1.9 – 2.0 Gy Dail y 74 M ean GT V 30.5 cc ± 22. 3 87 % lo core g ion al con tr o l at 4 ye ars . 81 % D is ea se fre e su rv iva l at 4 ye ar s. 87% o veral l sur v iv al at 4 ye ar s 32 pa ti en ts w it h gr ad e 1 xe ro st o m ia .9 pa ti en ts w it h gr ad e 2 xe ro st o m ia .

Table2.(continued)

A n at o m ic si te Immob iliza tio n | L o calica ti o n Col lima tio n | Planning Dose(G y ) F rac ti o n Si ze (G y ) P at ien t # M edian F ield S ize (r ange) Clinical E nd po in ts He ad an d N ec k Le e, N et al . [69]

Ther maplast ic mas k C o o rdina te sy st em M an ual ly cu t p ar - ti al tr an sm is si o n blo cks, seg m en tal M L Co rM IM iC C o rv us planning sys te m

70 Gy (a ve rag e dose p re- scr ib et to GT V in pr im ar y cases) 66 Gy (dose to GT V in post-o p cases)

2.12 Gy Dail y 15 0 N ot rep or te d L o ca l fr ee d om fr om pr o g re ss io n ra te for pr im ar y tr ea te d g ro u p 95% at 3 year s. L o ca l fr ee d om fr om pr o g re ss io n ra te for p o st -o p g ro u p 82% at 2 year s. A ve ra ge o f 3% o f d efi n iti ve tr ea tm en t g ro u p re ce iv ed ≤ 95% o f p rescr ib ed dose to GT V and CT V . A verag e o f 6% o f p ost-o p tr ea tmen t rec ei ved 95% o f p rescr ib ed dose to GT V and CT V . Na so p h ar y n x Le e, N et al . [70]

Ther maplast ic mas k C o o rdina te sy st em M an ual ly cu t p ar - ti al tr an sm is si o n blo cks, seg m en tal M L Co rM IM iC C o rv us planning sys te m

65 – 70 Gy pr e- scr ib ed to G T V 60 Gy to CT V 50 – 60 Gy to clin- ical ly nega ti ve neck

2.12– 2.25 Gy to G T V 1.8 Gy to CT V

67 M ean GT V vol ume 104 (10–669.2) Me an C T V vo lu m e 301 cc (82–1248)

Lo co re g ion al pr o g re ss io n -f re e su rv iva l 98 % at 4 ye ars . D istan t m etastases-f ree sur v iv al 66% w ith gr ad e 0 xe ro st o m ia . Na so p h ar y n x (r ecur re n t) Lu , T X et al . [71]

Immo b iliza tio n no t re p o rt ed C o o rdina te sy st em MIMiC C o rv us planning sy st em (NOMOS)

M edian dose fo r init ial co n- ve nt io n al E B R T 70 Gy to th e n a- so p h ar y n x . R e-ir radia tio n p rescr ib ed dose to n as o p h ar - yn x 68 – 70 Gy in 2.2 – 2.3 Gy dail y frac tio n s.

49 M ean GT V 47.2 cc (7.0–158.9) 10 0 % Lo co re g io n al con tr o l at 9 m on th s. X er o st o m ia :5 3% wi th g ra d e 1, 47 % wi th g ra d e 2.

Table 3.

Sphenoid wing meningioma. A comparison of doses delivered with fixed field uniform intensity to intensity-modulated plans.

All plans prescribed to 10 Gy to 99% of PTV

Plan type PITV Volume Volume Volume Brainstem Brainstem

9.0 Gy 8.0 Gy 5.0 Gy 9.0 Gy 5.0 Gy

IMRT 2.86 14.32 18.48 38.31 0.19 1.13

FIXED FLDS 3.05 13.88 17.87 37.73 0.25 1.37

Fig. 3.

Dose distributions for treatment of a sphenoid wing menin- gioma. Transverse CT of isodose lines through the PTV, comparing a plan with 15 fixed- gantry uniform intensity fields (left) and the same fixed-field arrangement with intensity modulation (right).

Both plans were normalized to deliver 10 Gy to 99% of the PTV.

The lesion and brainstem are the dark contours and the dose lines surrounding the lesion are 11, 10, 9, 8, and 5 Gy respectively

region. The patient was referred for radiotherapy to in- clude a hypofractionated boost dose of radiation as gross residual disease remained within the left cavernous si- nus and sella turcica. Clinically, the patient presented with post-operative cranial nerve deficits on the ipsilat- eral side. A treatment planning goal was to minimize the dose of radiation to the intact and functioning right op- tic apparatus. The patient was immobilized with the BrainLab invasive stereotactic cranial frame system.

This consists of a rigid fixation frame with four pins inserted into the outer table of the skull. The frame was mounted to the treatment couch resulting in repo- sitioning and reproducibility accuracy < 1 mm. A plan was generated with 15 beams (3 fixed fields equidistant along 5 conventional SRS arcs) and optimized for open static fields. This was followed by an alternate plan using the same fixed beams but with IMRT.

Figure 3 shows a transverse CT slice for comparison of the open static field and IMRT techniques. Each plan was normalized to deliver the prescription dose of10 Gy per fraction to 99% of the target volume. The IMRT plan provided a modest improvement as compared to the open static field plan as reflected in higher dose con- formity. This is quantified in Table 3, which shows the dose-volume data for the total brain, including the PITV, and volume enclosed in the 9.0, 8.0, and 5.0-Gy isodose surfaces. These data demonstrate that the optimization available with IMRT applied to the fixed beam configura-

tion provides additional tumor conformity and sparing of the adjacent brainstem.

The maximum to minimum dose ratios for the tumor were 1.48 (13.0 | 8.8 Gy) for the open static fields and 1.41 (12.7 | 9.0) for the IMRT plan. The open static field plan and IMRT plan resulted in similar dose homogeneity.

Fig. 4.

CT transverse slice of an NSC RLL lung lesion treated with

a small field IMRT plan with the gross tumor volume (GTV-blue),

and the expanded planning target volume (PTV-red) (see text for

details)

Fig. 5.

A 3D animation of the multiple fixed field coplanar beam arrangement for the RLL lung lesion treated with a small field IMRT plan (see text for details)

12.6 Extracranial: Lung Tumor

This case is presented to demonstrate the issues rel- evant to the application of small field high precision IMRT in an extracranial location where target move- ment presents a particular challenge. An 81-year-old male presented with a history of heavy tobacco abuse and long-standing severe emphysema. A routine chest X-ray revealed multiple right-sided pulmonary nodules. After a work-up that included a CT scan, PET imaging, and biopsy, the patient was diagnosed with a TxN0M1 Non- Small Cell Lung Carcinoma. The patient was initially managed with carboplatin and taxol chemotherapy. He was followed with CT scans of the chest every three months and had no evidence of disease progression for two years. After 26 months of follow- up, he was found to have a new site of metastasis manifesting as a right lower lobe pulmonary nodule that measured

Fig. 6.

Transverse, saggital and coronal views of the NSC RLL lung lesion with overlay of resultant isodose curves from small field

IMRT plan: the prescription was to the 80% isodose line 1. 7 × 1.2 cm (Fig. 4). This lesion was clearly defined on CT scan and was noted in immediate proximity to the anterior chest wall and right ventricle. Serial CT scans demonstrated that this mass was enlarging and threat- ened to cause imminent symptoms. The patient was referred for SBRT.

The patient underwent a CT simulation and was im- mobilized with the BrainLab ExacTrac system. As the target was subject to significant movement with each breathing cycle, expiratory respiratory gating was em- ployed. The treatment plan was developed with forward planned IMRT that resulted in an eight beam configu- ration. In accordance with an institutional protocol, the dose was prescribed to the 80% isodose line at 10 Gy per fraction for a total of 30 Gy (Fig. 4,Fig. 5,Fig. 6,Fig. 7).

The patient tolerated the treatment well, and on subse- quent follow-up the lesion decreased in size.

12.7 Future Directions

The central future clinical application of small field high precision IMRT is dose escalation achievable through increased target conformity, improved target coverage, and decreased dose to adjacent organs-at- risk. These same characteristics may also allow hypofractionated treatment schemes to replace the standard six to seven week course of radiation therapy. Progress in imaging (e.g., spectroscopic magnetic resonance,

1C-choline or -acetate positron emission tomography) may help to im- prove further the definition of tumor extent and allow for radiation delivery tailored to specific three-dimensional metabolic tumor maps based on regions of hypoxia, proliferation, and distribution of clonogens. This extent of functional and physiological data would support the application of small field IMRT to intentionally inhomo- geneous dose distributions to high density or high risk tumor- bearing areas.

Small field high precision IMRT has been currently

established to be particularly advantageous for small,

Fig. 7.

The dose volume histogram of the NSC RLL lung lesion treated with a small field IMRT plan: GTV (blue-right), PTV (red),

heart (blue-left), spinal cord (green), and ipsilateral lung (dark

irregularly shaped lesions of the brain particularly when compared to complex, multi-isocenter linac-based stereotactic arc or uniform-intensity fixed static field techniques [38–41]. Its application to extracranial tu- mor locations is still in development and will require further advancement in techniques that allow for patient immobilization, target localization, target tracking, and physiological gating. Recent linear accelerator designs provide technological solutions to each of these issues by incorporating stereotactic head and body localization, cone beam tomographic imaging, high-resolution real- time portal imaging, tracking software, and mMLCs into a fully integrated system.

The potential for further improvements in small field shaping with the application of IMRT is possi- ble using dynamic mMLC collimation. In addition to enhanced dose conformity, small field high precision IMRT allows for the selective prioritization of dose to adjacent critical areas. Small field high precision IMRT has the potential to achieve superior dose distributions as compared to uniform-intensity fixed-field, arc-based methods with circular collimators, and even gamma knife radiosurgery [33]. Future research challenges in this field are related to the fact that while IMRT has been demonstrated to produce significant dosimetric improvements for large tumors, its application and util-

ity for small tumors may be limited due to the lateral transport of radiation [42]. Further investigation of the dosimetry inherent to small leaf collimation must in- clude automated beam configurations, automated beam weight optimization, and the use of conformal arcs with dynamic collimation.

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