dose calculations using the monte carlo ( mc ) method have the potential for the most accurate predictions of dose distributions for clinical radiotherapy .
accurate predictions of dose distributions and associated ranges are of particular importance for radiation therapy with proton and ion beams due to the conformity of the treatment .
this is specifically challenging for complex treatment situations , involving large heterogeneities or metal implants [ 2 , 3 ] .
a novel mc - based treatment - planning ( mctp ) tool was presented and validated for protons using scanned pencil beams for realistic patient treatment conditions in a previous paper .
mctp can support tp by helping to understand and improve inaccuracies due to approximations made by analytical dose and fluence algorithms , and allows provision of a 
furthermore , the developed mctp tool seeks to enable tp and research studies for state - of - the - art ion beam therapy .
an asset for such usage is the versatility of the mctp tool , which is to some extent due to the usage of the mc method and the flexible interface to external relative biological effectiveness ( rbe ) models via ion charge and energy - specific tabulations of the linear - quadratic ( lq ) model parameters , as predicted by the external model . in this work ,
an extension of this mctp tool to perform tp with carbon ions is presented for realistic patient treatment conditions .
this will enable future tp studies to be carried out using and comparing different ions and optimization techniques .
the mctp tool is composed of various program components that require a range of treatment- and facility - specific input information .
a description of the workflow and details of the mctp tool can be found in mairani et al .
, including in particular information about its general structure , the pre - optimization and pencil beam selection procedure , and the configuration of the mc code fluka [ 5 , 6 ] , that is used for dose and fluence computations in phantom and patient geometries .
the tool allows the user to perform inverse optimization of single fields , and simultaneous multiple - fields optimization ( often referred to as intensity - modulated particle therapy ( impt ) ) of absorbed and rbe - weighted doses using gradient - based methods . for the present work
, the tool was extended to be able to perform tp for ion beams for treatment conditions at the hit facility ( heidelberg ion - beam therapy , germany ) .
this was achieved by merging the mctp tool with parts of the fluka - based mc framework fiction ( fluka integrated framework for ct - based calculations in ion therapy ) , developed at hit   within the framework of partner ( http://partner.web.cern.ch ) and using the corresponding visualization tool .
the fiction tool was validated and carefully fine - tuned to reproduce dosimetric measurements for hit treatment conditions [ 8 , 10 ] .
fiction previously allowed only a recalculation of a given proton or carbon ion treatment plan and not for the mc - based optimization of treatment plans using protons , carbon ions or other light ions .
differences in the biological effectiveness of ions were taken into account via tabulations of the linear and quadratic parameters of the lq model , specific to the ion charge and its energy , which can be generated from external rbe models .
for this work , such input tables were obtained using a hit re - implementation of the local effect model ( lem ) in flavours of the lem versions i and iv [ 4 , 12 , 13 ] .
further details about the calculation of absorbed and rbe - weighted dose with the mctp tool can be found in [ 4 , 8 ] .
calculation and optimization of absorbed and rbe - weighted doses performed by the certified analytical treatment planning system ( tps ) , presented as comparison for the test carbon ion patient , are largely based on the work of krmer et al . .
the mctp tool was used to compute and optimize a treatment field for a cube - shaped target volume in water .
the pencil beams were optimized to yield a constant absorbed dose of 1 gy in the target volume .
1.carbon ion field computed and optimized by the mctp tool for a cube - shaped target volume in water .
the pencil beams were optimized to yield a constant absorbed dose of 1 gy in the target volume .
carbon ion field computed and optimized by the mctp tool for a cube - shaped target volume in water .
the pencil beams were optimized to yield a constant absorbed dose of 1 gy in the target volume . as a further example
, a test patient plan for a carbon ion treatment of a brain tumour for hit treatment conditions was created using the mctp tool .
a biological optimization was performed to obtain an rbe - weighted dose of 3 gy ( rbe ) in the target volume using rbe values predicted by the lem - i for chordoma .
figures 2 and 3 show a comparison of the example treatment plan created by the certified analytical tps used at hit ( siemens syngo rt planning ) and an mc recalculation of the same treatment plan using the fluka - based fiction tool together with a treatment plan computed with the mctp tool . for this test patient plan
only minor differences between the treatment plan created using the analytical tps , the mc recalculation of the same plan , and the treatment plan created with the mctp tool are observable for the treated homogeneous tissue region .
the mc recalculation of the plan created by the analytical tps predicts a slight over - dosage in the clinical target volume of about 2% , which is , however , not clinically relevant .
doses to the brain stem are very small . observed differences in the dvh of the brain stem between the tps and mc recalculation are therefore not addressed in the mctp optimization . 

dvhs of the clinical target volume ( ctv ) and the brain stem of a treatment plan created with an analytical treatment planning tool , the mc recalculation of the same plan , and a treatment plan created with the mctp tool . 

sagittal ( left ) , coronal ( middle ) and axial ( right ) view are shown for ( a ) a treatment plan created with a tps using an analytical dose engine , ( b ) the mc recalculation of the same plan , and ( c ) a treatment plan created with the mctp tool .
dvhs of the clinical target volume ( ctv ) and the brain stem of a treatment plan created with an analytical treatment planning tool , the mc recalculation of the same plan , and a treatment plan created with the mctp tool .
sagittal ( left ) , coronal ( middle ) and axial ( right ) view are shown for ( a ) a treatment plan created with a tps using an analytical dose engine , ( b ) the mc recalculation of the same plan , and ( c ) a treatment plan created with the mctp tool .
this test patient plan serves as a show - case and it is also a direct test of the mctp implementation at hit .
larger discrepancies between plans obtained using an mc recalculation of an analytical tps and mctp can be expected in the presence of tissue regions in the beam , with large heterogeneities and patient cases involving metallic implants [ 2 , 3 ] . coupled with an adequate rbe model ,
the mctp tool is able to compute treatment plans not only for proton and carbon ion beams but also using other light ions , such as helium and oxygen , as well as treatment plans with several ion beams of different charges .
the mc code fluka was shown to be able to simulate bragg curves and fragmentation of ions beams such as oxygen beams with a satisfactory accuracy for investigative tp studies [ 15 , 16 ] .
tp involving ions other than protons and carbon ions , or even the usage of mixed - ion fields , could yield an improved therapeutic outcome for certain cases .
for instance , ion beams with linear energy transfers ( let ) higher than those of carbon ions , such as oxygen beams , are proposed for use to target radio - resistant tumours and to treat hypoxic tumour regions more efficiently [ 15 , 17 ] .
the simultaneous use of ions with different charges for patient treatment has been suggested : ( i ) to perform dose- and let - painting ; ( ii ) to decrease the fragmentation dose tail beyond the distal part of the spread - out bragg peak ( sobp ) , while compromising to a lesser degree the high - let component in the target , as well as to obtain benefit from the steeper lateral dose gradients achievable with ions heavier than protons ; ( iii ) to avoid microscopic cold spots ; and ( iv ) to reduce relative uncertainties of rbe for a given treatment protocol [ 1820 ] . in the following , treatment plans using ion beams of two different charges for a cubic - shaped target in a water phantom are presented .
points ( iii ) and ( iv ) can be addressed by delivering a more homogeneous radiation quality in the target volume , which in turn can be achieved by plans using two ion species , even for mono - directional beams .
4 , where a combination of mono - directional proton and carbon ion pencil beams were optimized to obtain a constant rbe , as a measure for homogeneity of radiation quality , throughout the sobp .
similarly , dual ion fields of protons and carbon ions can be optimized to obtain a sobp with a constant rbe - weighted dose in the target region , while delivering a 
high - let boost to a central hypoxic area with carbon ions , associated with a higher rbe , and delivering the dose around the boost region preferably by low - let protons .
the plans were optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells . 
 fig .
4.a 4-cm sobp obtained using a combination of mono - directional proton and carbon ion pencil beams while optimizing for a constant rbe in the target volume .
the left and right panels show rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
5.a 4-cm sobp obtained using a combination of opposed fields of proton and carbon ion pencil beams .
a constant rbe - weighted dose in the target volume is achieved while delivering a 
high - let boost to a central hypoxic area with carbon ions , associated with a higher rbe , and delivering the dose around the boost region preferably by low - let protons .
the left and right panels show the rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
the area with the fine stripes marks the target volume including the boost volume . a 4-cm sobp obtained using a combination of mono - directional proton and carbon ion pencil beams while optimizing for a constant rbe in the target volume .
the left and right panels show rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
the area with the fine stripes marks the target volume . a 4-cm sobp obtained using a combination of opposed fields of proton and carbon ion pencil beams .
a constant rbe - weighted dose in the target volume is achieved while delivering a 
high - let boost to a central hypoxic area with carbon ions , associated with a higher rbe , and delivering the dose around the boost region preferably by low - let protons .
the left and right panels show the rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
the mctp tool was used to compute and optimize a treatment field for a cube - shaped target volume in water .
the pencil beams were optimized to yield a constant absorbed dose of 1 gy in the target volume .
1.carbon ion field computed and optimized by the mctp tool for a cube - shaped target volume in water .
the pencil beams were optimized to yield a constant absorbed dose of 1 gy in the target volume .
carbon ion field computed and optimized by the mctp tool for a cube - shaped target volume in water .
the pencil beams were optimized to yield a constant absorbed dose of 1 gy in the target volume . as a further example
, a test patient plan for a carbon ion treatment of a brain tumour for hit treatment conditions was created using the mctp tool .
a biological optimization was performed to obtain an rbe - weighted dose of 3 gy ( rbe ) in the target volume using rbe values predicted by the lem - i for chordoma .
figures 2 and 3 show a comparison of the example treatment plan created by the certified analytical tps used at hit ( siemens syngo rt planning ) and an mc recalculation of the same treatment plan using the fluka - based fiction tool together with a treatment plan computed with the mctp tool . for this test patient plan
only minor differences between the treatment plan created using the analytical tps , the mc recalculation of the same plan , and the treatment plan created with the mctp tool are observable for the treated homogeneous tissue region .
the mc recalculation of the plan created by the analytical tps predicts a slight over - dosage in the clinical target volume of about 2% , which is , however , not clinically relevant .
doses to the brain stem are very small . observed differences in the dvh of the brain stem between the tps and mc recalculation are therefore not addressed in the mctp optimization . 

dvhs of the clinical target volume ( ctv ) and the brain stem of a treatment plan created with an analytical treatment planning tool , the mc recalculation of the same plan , and a treatment plan created with the mctp tool . 

sagittal ( left ) , coronal ( middle ) and axial ( right ) view are shown for ( a ) a treatment plan created with a tps using an analytical dose engine , ( b ) the mc recalculation of the same plan , and ( c ) a treatment plan created with the mctp tool .
dvhs of the clinical target volume ( ctv ) and the brain stem of a treatment plan created with an analytical treatment planning tool , the mc recalculation of the same plan , and a treatment plan created with the mctp tool .
sagittal ( left ) , coronal ( middle ) and axial ( right ) view are shown for ( a ) a treatment plan created with a tps using an analytical dose engine , ( b ) the mc recalculation of the same plan , and ( c ) a treatment plan created with the mctp tool .
this test patient plan serves as a show - case and it is also a direct test of the mctp implementation at hit .
larger discrepancies between plans obtained using an mc recalculation of an analytical tps and mctp can be expected in the presence of tissue regions in the beam , with large heterogeneities and patient cases involving metallic implants [ 2 , 3 ] .
coupled with an adequate rbe model , the mctp tool is able to compute treatment plans not only for proton and carbon ion beams but also using other light ions , such as helium and oxygen , as well as treatment plans with several ion beams of different charges .
the mc code fluka was shown to be able to simulate bragg curves and fragmentation of ions beams such as oxygen beams with a satisfactory accuracy for investigative tp studies [ 15 , 16 ] .
tp involving ions other than protons and carbon ions , or even the usage of mixed - ion fields , could yield an improved therapeutic outcome for certain cases .
for instance , ion beams with linear energy transfers ( let ) higher than those of carbon ions , such as oxygen beams , are proposed for use to target radio - resistant tumours and to treat hypoxic tumour regions more efficiently [ 15 , 17 ] .
the simultaneous use of ions with different charges for patient treatment has been suggested : ( i ) to perform dose- and let - painting ; ( ii ) to decrease the fragmentation dose tail beyond the distal part of the spread - out bragg peak ( sobp ) , while compromising to a lesser degree the high - let component in the target , as well as to obtain benefit from the steeper lateral dose gradients achievable with ions heavier than protons ; ( iii ) to avoid microscopic cold spots ; and ( iv ) to reduce relative uncertainties of rbe for a given treatment protocol [ 1820 ] . in the following , treatment plans using ion beams of two different charges for a cubic - shaped target in a water phantom are presented .
points ( iii ) and ( iv ) can be addressed by delivering a more homogeneous radiation quality in the target volume , which in turn can be achieved by plans using two ion species , even for mono - directional beams .
4 , where a combination of mono - directional proton and carbon ion pencil beams were optimized to obtain a constant rbe , as a measure for homogeneity of radiation quality , throughout the sobp .
similarly , dual ion fields of protons and carbon ions can be optimized to obtain a sobp with a constant rbe - weighted dose in the target region , while delivering a 
high - let boost to a central hypoxic area with carbon ions , associated with a higher rbe , and delivering the dose around the boost region preferably by low - let protons .
the plans were optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells . 

4.a 4-cm sobp obtained using a combination of mono - directional proton and carbon ion pencil beams while optimizing for a constant rbe in the target volume .
the left and right panels show rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
5.a 4-cm sobp obtained using a combination of opposed fields of proton and carbon ion pencil beams .
a constant rbe - weighted dose in the target volume is achieved while delivering a 
high - let boost to a central hypoxic area with carbon ions , associated with a higher rbe , and delivering the dose around the boost region preferably by low - let protons .
the left and right panels show the rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
the area with the fine stripes marks the target volume including the boost volume . a 4-cm sobp obtained using a combination of mono - directional proton and carbon ion pencil beams while optimizing for a constant rbe in the target volume .
the left and right panels show rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
a 4-cm sobp obtained using a combination of opposed fields of proton and carbon ion pencil beams .
a constant rbe - weighted dose in the target volume is achieved while delivering a 
high - let boost to a central hypoxic area with carbon ions , associated with a higher rbe , and delivering the dose around the boost region preferably by low - let protons .
the left and right panels show the rbe - weighted dose and rbe along the central axis of the field .
the plan was optimized using the lem - iv model for the proton and carbon ion beams with parameters for human salivary gland cells .
it enables the user to perform tp with protons and carbon ions using realistic treatment conditions at hit as well as with other light ions .
example treatment plans using carbon ions and mixed - ion treatments consisting of protons and carbon ions have been presented here .
this versatile tool is useful for research applications and to support tp studies at state - of - the - art ion beam therapy facilities . in particular ,
this research project was supported by a marie curie initial training network fellowship of the european community 's seventh framework programme under contract no .
pitnga-2008 - 215840-partner , by envision , which is co - funded by the european commission under fp7 grant agreement no .
241851 and by the bundesministerium fr bildung , wissenschaft , forschung und technologie of germany ( dotmobi project , grant 01ib08002f ) .
 ion beam therapy , as an emerging radiation therapy modality , requires continuous efforts to develop and improve tools for patient treatment planning ( tp ) and research applications . 
 dose and fluence computation algorithms using the monte carlo ( mc ) technique have served for decades as reference tools for accurate dose computations for radiotherapy . in this work , a novel mc - based treatment - planning ( mctp ) tool for ion beam therapy using the pencil beam scanning technique is presented . 
 it allows single - field and simultaneous multiple - fields optimization for realistic patient treatment conditions and for dosimetric quality assurance for irradiation conditions at state - of - the - art ion beam therapy facilities . 
 it employs iterative procedures that allow for the optimization of absorbed dose and relative biological effectiveness ( rbe)-weighted dose using radiobiological input tables generated by external rbe models . using a re - implementation of the local effect model ( lem ) , 
 the mctp tool is able to perform tp studies using ions with atomic numbers z  8 . 
 example treatment plans created with the mctp tool are presented for carbon ions in comparison with a certified analytical treatment - planning system . 
 furthermore , the usage of the tool to compute and optimize mixed - ion treatment plans , i.e. plans including pencil beams of ions with different atomic numbers , is demonstrated . 
 the tool is aimed for future use in research applications and to support treatment planning at ion beam facilities . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
Examples of carbon ion treatment plans
Treatment plans using new ions and combined ion beams of different charges
CONCLUSION AND PERSPECTIVE
FUNDING