CTOS 14.11.08 Soft Tissue Sarcoma of the Extremity Comparison of Conformal Post-operative Radiotherapy (CRT) and Intensity Modulated Radiotherapy (IMRT)

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<ul><li><p>CTOS 14.11.08</p><p>Soft Tissue Sarcoma of the ExtremityComparison of Conformal Post-operative Radiotherapy (CRT) and Intensity Modulated Radiotherapy (IMRT)1Joint Department of Physics, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK2St Lukes Cancer Centre, Royal Surrey County Hospital, Guildford, Surrey, UK3Department of Radiotherapy, Royal Marsden NHS Foundation Trust, Sutton, Surrey, UKYoung K Lee1, Alexandra J Stewart2, Frank H Saran3 </p></li><li><p>BackgroundMaterials and MethodsResultsSummaryCRT and IMRT for extremity STS</p></li><li><p>BackgroundMaterials and MethodsResultsSummaryCRT and IMRT for extremity STS</p></li><li><p>BackgroundLimb-sparing surgery in combination with focal radiotherapy - standard of care in patients with intermediate and high grade limb and limb girdle soft tissue sarcomas (STS)Normal tissue toxicity increases with escalating total and integral doseDose prescription limited by organs-at-risk (OAR) surrounding the PTV</p></li><li><p>AimsTo define a reproducible and comparable target volume definition for CT planningTo define reproducible prospective planning dose volume constraintsTo assess the ability of inversely-planned IMRT plans to minimise the dose to surrounding OARTo assess efficacy of simple IMRT compared to complex IMRT planning</p></li><li><p>BackgroundMaterials and MethodsResultsSummaryCRT and IMRT for extremity STS</p></li><li><p>Patient dataT2 and G2/3 STS of the thigh (n=10)No tumours invading boneEntire surgical scar and all drain sites markedPlanning CT scan (GE HiSpeed QX/i, Milwaukee, WI) pelvic brim to below knee customised immobilisation slice thickness = 2.5mm</p></li><li><p>Target volume definitionPhase I volume PTV1 = tumour bed + 5cm SI and 3cm circumferentiallyPhase II volume PTV2 = tumour bed + 2cm isotropicallyOAR defined as whole femur, neurovascular bundle, normal tissue corridor and normal tissue outside PTV1</p></li><li><p>Planning target volumesPTV1PTV2</p></li><li><p>normal tissue outside PTV1Organ definition</p></li><li><p>Radiotherapy planning Primary planning objectivePTV dose femur skin corridor Other planning objectives neurovascular bundle soft tissue outside PTV</p></li><li><p>Dose prescription Pinnacle3 v7.4f (Philips Radiation Oncology Systems, Madison, WI) 2-phase 3D-CRTPh I - 50 Gy/25# (5 weeks)Ph II - 16 Gy/8# (1 weeks)IMRT with simultaneous integrated boost (SIB)Ph I - 50 Gy/25# (5 weeks)Ph II - 62.5 Gy/25# (5 weeks) (/ = 10 Gy)</p></li><li><p>Analysiscumulative dose volume histograms (DVH) Dmean, Dmax, DminConformity Index (CI)Heterogeneity Index (HI)</p></li><li><p>BackgroundMaterials and MethodsResultsSummaryCRT and IMRT for extremity STS</p></li><li><p>Conformal Radiotherapy2-3 field (simple) IMRT 4-5 field IMRT </p></li><li><p>conformal2-3f4-5f IMRTsagittal view</p></li><li><p>conformal2-3f IMRT4-5f IMRTcoronal view</p></li><li><p>Conformity and Heterogeneity</p></li><li><p>DVH summary</p></li><li><p>Simple 2-3f IMRT?Median number of segments26 (range 13-37) for 2-3f IMRT36 (range 34-56) for 4-5f IMRTBoth IMRT plans were more conformal and less heterogeneous than 3D-CRTBoth IMRT delivered significantly lower femur V45 compared to 3D-CRT plansHOWEVER, 4/5f IMRT resulted in significantly lower femur V45 when compared directly to 2/3f IMRT (p=0.04)</p></li><li><p>BackgroundMaterials and MethodsResultsSummaryCRT and IMRT for extremity STS</p></li><li><p>SummaryReproducible, comprehensive planning guidelines and dose-volume constraints for 3D planning for extremity sarcomas devised 4/5f IMRT plan - lowest clinically relevant doses to OAR whilst delivering conformal doses to PTVLarge primary tumour 4/5f preferable to a 2/3f IMRT approachSmall, superficial disease3D-CRT may provide adequate treatment without added cost and complexity</p></li><li><p>Results from this study may not be directly translated to all other primary locations of STS of the extremityIMRT approach should be assessed prospectively with respect to late toxicity within the confines of a prospective clinical trialFurther work</p></li><li><p>Radiotherapy DepartmentRoyal Marsden NHS Foundation TrustAcknowledgment</p><p>282828In the UK, post-operative RT remains the standard of care in large or intermediate-high grade extremity STS, benefiting from the ability to histopathologically assess the entire tumor specimen including appropriateness of surgical margins and a decreased risk of post-operative wound healing complications 5. Modern imaging has allowed improved pre-operative definition of the extent of tumor, allowing the surgeon and radiation oncologist greater knowledge to plan the primary surgical approach and target volume definitions for the adjuvant radical RT. Primary STS of the thigh are often difficult to plan for radiotherapy with long treatment fields curving around the femur. Large areas of irradiated normal soft tissue increase the risk of severe late morbidity such as fibrosis, atrophy, decreased range of movement, increased risk of fracture, peripheral nerve injury and dependant edema 7, 8. The total dose received has been shown to be an independent predictor of local control in post-operative extremity STS radiotherapy with significantly better local control at doses over 60-62.5Gy 6, 9. These doses regularly exceed some of the ideal dose constraints of adjacent organs at risk (OAR) e.g. pathological fracture of the femur is more frequent in patients receiving high-dose radiotherapy (60-66Gy) than patients receiving 50Gy (10% vs. 2%) 10. Intensity modulated radiotherapy (IMRT) is a RT technique which offers the opportunity to better conform the RT field to the target volume whilst sparing critical normal tissue. Whilst planning studies for extremity STS have been previously been published suggesting a technical benefit for IMRT, IMRT planning parameters were only limitedly defined, not allowing independent assessment of the conclusions drawn 11, 12. We have defined a comprehensive set of reproducible planning parameters and dose-volume constraints for adjuvant post-operative RT. We then compared the ability of three conformal radiotherapy (CRT) techniques, 3D-CRT and simple and more complex IMRT using a simultaneous integrated boost (SIB) to deliver a homogeneous dose to the target volume whilst minimizing the integral dose to surrounding OAR. </p><p>282828Immobilization of the leg was performed on an individual patient basis using ankle casts or customized immobilization devices to provide reproducible daily set-up. The images were imported to the planning system (Pinnacle3, v7.4f, Philips Radiation Oncology Systems, Madison, WI) for target volume definition and radiotherapy planning.</p><p>28The tumor bed was defined using pre-operative imaging, surgical notes, pathology results and, in some patients, surgical clips placed in the tumor bed at the time of surgery. </p><p>The scar was marked at the skin surface as wired using a 0.4cm circle. </p><p>The 3D clinical target volume (CTV) was defined as the tumor bed up to the bone surface; this was drawn on each individual planning CT slice. </p><p>The margins were chosen as they form part of the control arm of the international randomized sarcoma trial, Vortex 14. Modifications were then made to PTV1 and PTV2 to lie 0.5cm within the bone cortex and for IMRT planning 0.5cm within the skin surface for IMRT planning.</p><p>The neurovascular bundle was contoured manually from pelvic brim to mid knee joint. </p><p>The whole femur was contoured using an auto contour setting and then checked and modified manually if necessary.</p><p>The minimum skin corridor was defined as volume of a 2cm thick band that covered 30% of the limb circumference at 180 degrees from the centre of the PTV1 over the length of PTV1, </p><p>Normal tissue was defined as the volume of ipsilateral limb lying outside PTV1 extending 1cm superior and inferior to the longest cranio-caudal field size. Where the disease or PTV involved the insertion of the muscle group, pelvic organs were contoured; rectum, bowel, bladder and reproductive organs.</p><p>All tumor bed and OAR contouring was performed by the same practitioner (AJS) and independently reviewed by a second clinician (FHS). Figure 1 demonstrates PTV1 and PTV2 and their relationship to OAR for all patients.</p><p>The neurovascular bundle was contoured manually from pelvic brim to mid knee joint. </p><p>The whole femur was contoured using an auto contour setting and then checked and modified manually if necessary.</p><p>The minimum skin corridor was defined as volume of a 2cm thick band that covered 30% of the limb circumference at 180 degrees from the centre of the PTV1 over the length of PTV1, </p><p>Normal tissue was defined as the volume of ipsilateral limb lying outside PTV1 extending 1cm superior and inferior to the longest cranio-caudal field size. Where the disease or PTV involved the insertion of the muscle group, pelvic organs were contoured; rectum, bowel, bladder and reproductive organs.</p><p>All tumor bed and OAR contouring was performed by the same practitioner (AJS) and independently reviewed by a second clinician (FHS). Figure 1 demonstrates PTV1 and PTV2 and their relationship to OAR for all patients.</p><p>28For each patient, the 3D-CRT plans were designed using two or three coplanar fields oriented to achieve 95 to 107% of the prescription dose to PTV1 and PTV2 with maximal avoidance of the contralateral leg and the ipsilateral femur. </p><p>Collapsed cone convolution algorithm was used to calculate the final dose. The volume of tissue irradiated for the cPTV1 conventional plans was compared to the conformal PTV1 3D-CRT plans. </p><p>Two 6MV step-and-shoot IMRT plans were created. A simple IMRT plan was created using the same beam angles that were used in the 3D-CRT planning (2/3f IMRT). </p><p>A more standard IMRT plan was calculated using 4 to 5 fields (4/5f IMRT). The individualized beam angles for 4/5f IMRT were chosen to maximally avoid the OAR with no beams entering through the contralateral leg. Beam angles and collimator twists were used for 4/5f IMRT on an individual basis where appropriate.</p><p>Dose prescription and normalizationThe dose was prescribed to deliver the equivalent of 50Gy in 25 fractions for phase 1 and 16Gy in 8 fractions for phase 2.For 3D-CRT plans the dose was prescribed to a normalization point chosen to treat with adequate dose to PTV1.For the IMRT plans, the dose was prescribed to the mean of PTV2. The IMRT was planned over a 25 fraction treatment course using a SIB technique. </p><p>The linear quadratic concept was used to provide a radiobiological comparison of doses when using an SIB. Dose compensation was calculated using the biological equivalent dose (BED), overall treatment time was not considered in the calculation as there are no accurate estimates of how this may affect STS radiotherapy, especially in the post-operative setting. </p><p>The phase 2 dose was calculated to be 62.5Gy in 25 fractions, using an / ratio of 10Gy for high grade sarcoma, though this may be a conservative estimate. To provide a biologically similar dose comparison, the 3D-CRT plans used a concomitant boost technique, administering a dose of 2Gy per fraction to PTV1 with a boost dose of 0.5Gy to PTV2. 28For each patient, the 3D-CRT plans were designed using two or three coplanar fields oriented to achieve 95 to 107% of the prescription dose to PTV1 and PTV2 with maximal avoidance of the contralateral leg and the ipsilateral femur. </p><p>Collapsed cone convolution algorithm was used to calculate the final dose. The volume of tissue irradiated for the cPTV1 conventional plans was compared to the conformal PTV1 3D-CRT plans. </p><p>Two 6MV step-and-shoot IMRT plans were created. A simple IMRT plan was created using the same beam angles that were used in the 3D-CRT planning (2/3f IMRT). </p><p>A more standard IMRT plan was calculated using 4 to 5 fields (4/5f IMRT). The individualized beam angles for 4/5f IMRT were chosen to maximally avoid the OAR with no beams entering through the contralateral leg. Beam angles and collimator twists were used for 4/5f IMRT on an individual basis where appropriate.</p><p>Dose prescription and normalizationThe dose was prescribed to deliver the equivalent of 50Gy in 25 fractions for phase 1 and 16Gy in 8 fractions for phase 2.For 3D-CRT plans the dose was prescribed to a normalization point chosen to treat with adequate dose to PTV1.For the IMRT plans, the dose was prescribed to the mean of PTV2. The IMRT was planned over a 25 fraction treatment course using a SIB technique. </p><p>The linear quadratic concept was used to provide a radiobiological comparison of doses when using an SIB. Dose compensation was calculated using the biological equivalent dose (BED), overall treatment time was not considered in the calculation as there are no accurate estimates of how this may affect STS radiotherapy, especially in the post-operative setting. </p><p>The phase 2 dose was calculated to be 62.5Gy in 25 fractions, using an / ratio of 10Gy for high grade sarcoma, though this may be a conservative estimate. To provide a biologically similar dose comparison, the 3D-CRT plans used a concomitant boost technique, administering a dose of 2Gy per fraction to PTV1 with a boost dose of 0.5Gy to PTV2. 28Planning comparison and analysis</p><p>These dose-volume constraints were chosen because the volume of normal tissue irradiated to greater than 55Gy has been associated with poorer long-term function in patients with trunk or extremity sarcoma (Karasek K, Constine LS, Rosier R. Sarcoma therapy: functional outcome and relationship to treatment parameters. Int J Rad Oncol Biol Phys 1992;24:651-656). </p><p>Where OAR dose constraints for sarcoma have not been defined and associated with a risk of late normal tissue complications, OAR dose constraints have been defined using data from series of other cancer patients, modeling data and radiobiological data 8, 10, 23-25. These data are generally obtained using fraction sizes of 1.8-2Gy per fraction and the biological effect of a greater dose per fraction for the smaller volumes affected by the PTV2 field should be borne in mind.</p><p>PTV conformity was compared using the conformity index (CI), the ratio of volume of 95% isodose to PTV2. </p><p>PTV heterogeneity was compared using the heterogeneity index (HI), which is defined as the ratio of maximum point dose and the prescription dose.</p><p>28282845%D = 28 Gy54%D = 34 Gy20%D = 12.5Gy10%D = 6.3 Gy</p><p>28Subjectively it appeared that a greater decrease in dose to femur was seen in patients with a large PTV1 (volume of the central PTV1 slice greater than 50% of the central thigh slice) and/or whose PTV covered greater than 50% of the transverse diameter of the femur. </p><p>However there was not a correlation between PTV1 and 2/3f or 4/5f IMRT femur V45 or Dmean. As would be expected, there was a positive correlation between PTV1 and 2/3f IMRT normal tissue V55 (p=0.0009) and between PTV1 and 4/5f IMRT normal tissue V55 (p=0.002). There was no correlation between PTV1 and normal tissue V55 for 2/3f or 4/5f IMRT.</p><p>2828The risk of late toxicity following RT for extremity sarcoma has been shown to increase as the radiotherapy field size increases 27, 28. Therefore options which allow a decrease in the radiotherapy field size are sought. Traditionally in extremity sarcoma the entire affected compartment was treated with radiotherapy with superior and inferior margin expansions of up t...</p></li></ul>