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Imaging e Radioterapia: presente e futuro Umberto Ricardi Università di Torino Radiation therapy is targeted therapy • Technological advances in treatment planning and delivery provide unique opportunities for improving the precision and, potentially, also the locoregional effectiveness of RT • Radiation treatment “failure” occurs if and only if… – the biologically equivalent dose is not sufficiently high OR … – there is disease outside the high-dose volume – excessive dose to normal healthy tissues Role of imaging in radiotherapy How to improve radiotherapy results? Treatment simulation: all relevant informations on target definition are incorporated Treatment planning: involves selection of delivery technique and approach for optimizing target coverage and normal tissue avoidance Radiation delivery and treatment verification Summary of abbreviations and terms commonly used in modern thoracic radiation oncology 4D-CT Four-dimensional CT scan: respiration-correlated CT can used to visualize and account for tumor motion. The fourth dimension is time 4D-RT Four-dimensional RT is the explicit inclusion of the temporal changes in anatomy during the imaging, planning and delivery of radiotherapy CBCT Cone-beam CT refers to the use of a cone shaped Kilovoltage X-ray beam and a flat panel imaging device integrated into a linear accelerator to generate CT images. CBCT permits visualization of the tumor position durignt reatment Coaching Audio-coaching is used to optimize breathing regularity during RGRT. Video-coaching provides visual feedback of the breathing pattern to the patient to optimize breathing depth during RGRT IGRT Image-guided RT: modern linear accelerators have integrated X-ray imaging devices and conebeam CT scanners, making it possible to verify tumor position before and during treatment. The ability to check the tumor position during treatment allows for smaller safety margins and better sparing of normal tissues MVCT See cone-beam CT: megavoltage CT is a cone-beam CT scanner integrated in a linear accelerator using the megavoltage treatment beam instead of a separate Kilovoltage source RGRT Respiration gated radiation therapy: also known as Gating. Advanced treatment technique that switches the radiation beams on and off according to respiration, allowing for smaller radiation fields in moving tumor SRT Stereotactic radiation therapy is a high precision technique used to deliver high-dose fractions of radiation in only 3-8 sessions Clinical proof of malignancy Histology is missing in: Nyman (2006) 9/45 pts (20%) Wulf (2004) 4/20 pts (20%) Beitler (2006) 17/75 pts (23%) diameter 8 mm diameter 12 mm 24/72 pts (33%) SUVmax 1.8 SUVmax 4.8 Role of imaging in radiotherapy How to improve radiotherapy results? Treatment simulation: all relevant informations on target definition are incorporated Treatment planning: involves selection of delivery technique and approach for optimizing target coverage and normal tissue avoidance Radiation delivery and treatment verification Terminology used for defining target volumes in radiotherapy Gross tumor volume (GTV): the volume encompassing all recognized tumor volume Irradiated Volume Clinical target volume (CTV): the GTV volume + an extra margin for potential microscopic tumor extension and inaccuracies in target definition; this margin can be symmetrical around the tumor (typically 5 mm), or asymmetrical, for example lesser margins in the direction of an adjacent bony structure Internal target volume (ITV) : the CTV volume + an extra margin to account for intra-fractional movement of lung tumors and pathological nodes (organ motion) Planning target volume (PTV): the CTV or ITV plus an extra margin for planning and patient setup inaccuracy. The PTV is the volume used for treatment planning. Treated Volume GTV ICRU EORTC recommendations • patient positioning • CT scanning • tumor mobility • generating target volumes • treatment planning • treatment delivery • scoring response and toxicity Target Contouring recommendations (EORTC Radiotherapy Group) • The optimal CT window settings for contouring tumors in lung parenchyma or mediastinum should ideally be preset at the planning workstation • The Naruke scheme should be referred in Rt planning, and nodes with a short-axis diameter of > 1 cm should be included in the GTV •PET scans are superior to CT scans for staging mediastinal nodes, and incorporating PET findings into CT-based planning scan results in changes to Rt plans in a significant proportion of patients Senan, Radiotherapy and Oncoogy, 2004 Imaging for RT planning Challenges for RT planning: - Atelectasis - Effusion - Nodal involvement - Movements (respiration, cardiac) Imaging for RT planning Challenges for RT planning: - Atelectasis - Effusion - Nodal involvement - Movements (respiration, cardiac) CT for RT planning PET: Why? “Delineation, differentiation” - Combination of high sensitivity and high spatial resolution - Exact measure of regional tracer concentration: higher glucose metabolism in tumour cells - Combination with anatomic detail (PET/CT) Imaging for RT planning Challenges for RT planning: - Atelectasis - Effusion - Nodal involvement - Movements (respiration, cardiac) Impact of PET scan on RT planning Improved accuracy on nodal target volume Æ need for redefining the GTV PTV is expanded to encompass PET positive mediastinal node PET-CT information for nodal volume (GTV) Defining the Target Imprecision in clinical target volume definition remains an obstacle for high-precision RT Functional imaging may reduce the GTV definition’s inter-clinician variability Interobserver variability in target volume delineation CT: large interobserver variability PET-CT: reduction in interobserver variability Steenbakkers et al., 2006 FDG-PET: methodological aspects and pitfalls 4D CT-PET imaging Introduction of systematic error: mismatches in position between two imaging modalities From GTV to CTV “ The Clinical Target Volume (CTV) is a tissue volume that contains the GTV(s) and/or subclinical malignant disease at a certain probability level” The relevant data to consider are the probability of microscopic extension at different distances around the GTV, and the probability of subclinical invasion of regional lymph nodes or other tissues From GTV to CTV NSCLC: In specifying the CTV…. International consensus (Choi, 2001) • CTV for involved nodes consists of a 1 cm margin of normal tissue around the involved hilar nodes, a 2 cm circumferential and a 2.5 cm craniocaudal margin for the coverage of one sentinel node station beyond the involved mediastinal lymph nodes • CTV-N for involved nodes at stations 7 and 4R should include stations 4L, 5, 6, 2R and 2L 1 2 A B NSCLC: In specifying the CTV…. Evaluation of microscopic tumor extension in NSCLC for 3D-CRT… ..The microscopic extension between ADC and SCC… was different ..The mean value of microscopic extension was 2.69 mm for ADC and 1.48 mm for SCC (p=0.01) ..A margin of 8 mm and 6 mm must be chosen for ADC and SCC respectively…. Giraud, 2000 10 radiation oncologists, particularly expert in thoracic oncology, contoured the postoperative CTV in 2 representative resected NSCLC patients (pT2pN2) Even among experts, significant interclinician variations are observed in PORT fields!!! Literature-based recommendations for treatment planning and execution for highprecision radiotherapy in lung cancer. S. Senan, D. DeRuysscher et al., Radiother Oncol ‘04 High-precision radiotherapy is a multi-step process, which is only as good as the weakest component How to improve radiotherapy results? Treatment simulation: all relevant informations on target definition are incorporated Treatment planning: involves selection of delivery technique and approach for optimizing target coverage and normal tissue avoidance Radiation delivery and treatment verification New Potentials of Radiotherapy in NSCLC: IMRT Complex dose distribution with steep dose gradients 3D‐CRT IMRT Mean dose to critical organ according to different treatment technique NN+ Intensity-modulated radiotherapy and motion IMRT fluence maps for one out of five beams used for a treatment of lung tumor and the resulting dose distributions in an axial plane. Theoretical fluence map (a,d); Fluence map obtained in motion (b, e) Fluence map in motion but acquired in respiration-gated mode (c,f) Breathing motion and tumor position Jiang, Semin Radiat Oncol 2006 Lung tumor mobility - 100 lymph-nodes from 14 patients (Stage I) and 27 patients (Stage III) were manually contoured in all 4D CT respiratory phases. - Motion was derived from changes in the nodal center-of-mass position. - Primary tumors were also delineated in all phases for 16 patients with Stage III disease. - Average 3D nodal motion during quiet breathing was 0.68 cm (range, 0.17–1.64 cm) Motion was greatest in the lower mediastinum (p = 0.002), and bulky nodes showed motion similar to that in smaller nodes - In 11/16 patients studied, at least one node moved more than the corresponding primary tumor - No association between 3D primary tumor motion and nodal motion was observed Respiratory motion results in imaging artifacts - One CT scan is not sufficient to delineate the GTV - Motion should be taken into account: - 4D CT How can we use 4D-CT informations in RT planning? Individualized margins based on motion of tumor and nodes Respiration correlated (4-D) CT During 4D-CT image acquisition, the respitatory waveform is recorded and ‘time-stamped’ on each of the many images that are acquired at each couch position, for the duration of at least one full respiratory cycle Respiration correlated (4D) CT All acquired images are resorted in order to derive multiple 3DCT sets which represent the patient’s anatomy during each specific phase of the respiratory cycle The 4D-CT is reconstructed in 8 or 10 phases, yelding 8 or 10 3D CT datasets Respiration correlated (4D) CT The 4D-CT is reconstructed in 8 or 10 phases, yelding 8 or 10 3D CT datasets 4D-CT: University of Turin Geometrical differences in target volumes between conventional CT and 4D CT imaging in stereotactic body radiotherapy for lung tumours The mean target volumes of conventional CT and 4D-CT were 19.40 cm3 and 13.14 cm3 , respectively Conventional CT (with 10 mm in CC Conventional CT (with 2. 5 mm in all and 5 mm in all directions of margin) directions of margin) Respiration correlated (4D) CT MIPs can help to individualize the RT treatment for lung cancer patients How to improve radiotherapy results? Treatment simulation: all relevant informations on target definition are incorporated Treatment planning: involves selection of delivery technique and approach for optimizing target coverage and normal tissue avoidance Radiation delivery and treatment verification Role of imaging in radiotherapy Improving Radiation Therapy in Lung Cancer Highly Conformal RT Multimodality Imaging IGRT Image Guided Radiation Therapy Modern linear accelerators have integrated X-ray imaging devices and cone-beam CT scanners, making it possible to verify tumor position before and during treatment • Cone-beam CT refers to the use of a cone shaped Kilovoltage X-ray beam and a flat panel imaging device integrated into a linear accelerator to generate CT images (MV-CBCT: using megavoltage treatment beam) • CBCT permits visualization of the tumor position before each fraction, allowing on-line repositioning and daily assessment of changes in tumour volume and patient’s anatomy • Image Guided Radiation Therapy (IGRT) Image-guided radiotherapy (IGRT) is defined as frequent imaging in the treatment room (treatment position) that allows treatment decisions to be made on the basis of these images IGRT aims at decreasing CTV-to-PTV margins (allowing for smaller safety margins around the tumor) V25, V20, V30 and Pneumonitis (Volume receiving d or higher doses) Author (year) Armstrong (1995) Graham (1999) Hernando (2001) Pt# 31 99 201 Grade ≥III ≥II Any Vd % V25 ≤30% 4 >30% 38 V20 <22 22-31 32-40 >40 0 7 13 36 V30 ≤18 6 V30 >18 24 Advanced-Technology RT Intra-cranial SRS Conformance Extra-cranial SRS/SRT IGRT IMRT 3D-CRT Conventional Radiotherapy Accuracy What CBCT Guidance RT can do for you - Check tumor motion shortly before treatment - Reduce interfraction patient set-up errors - Discover tumor baseline shifts - Detect anatomical changes within the thorax - Quantify intrafraction patient stability Image Guided Adaptive Radiotherapy (IGART) Interactive adaptation of the treatment on the basis of daily assessment of changes in tumour volume and response to therapy Megavolt Computed Tomography imaging (blue) superimposed on the reference CT data set (grey) showing a large deformation in the patient’s anatomy Adaptive IGRT - 22 pts underwent RT for Stage I-III NSCLC with conventional fractionation; 15 received concurrent chemotherapy - Two repeat CT scans were performed at a nominal dose of 30 Gy and 50 Gy - Respiration-correlated 4D-CT scans were used for evaluation of respiratory effects in 17 pts - The gross tumor volume (GTV) was delineated on simulation and all individual phases of the repeat CT scans The median GTV reduction was 24.7% (p<0.001) at the first repeat scan and 44.3% (p<0.001) at the second repeat scan Tumor evolution during radiotherapy Pre-RT 4th week of RT Atelectasis resolved Dose distribution before and after re-planning What CBCT Guidance RT can NOT (yet) do for you - Monitor tumor motion variability during a treatment fraction Lung Tumour Baseline Shift Managing tumor motion Encompass motion: increased risk of normal tissue toxicity Breath‐hold: freeze movement John R. van Sörnsen de Koste, PhD Tumor tracking: implanted marker Gating: respiratory cycle as surrogate of tumor position Viscoil Gold seed Although marker geometry can be affected by tumor shrinkage, implanted markers are stable within tumors throughout the treatment duration Planning Concepts For Breathing Conventional free breathing Maximum exhale Geometrical average position Maximum inhale Internal target volume CTV GTV PTV ITV Gating or breath holding Respiration-gated radiation therapy (RGRT) Breathing synchronized irradiation requires a technology to monitor the breathing motion and its relationship with the actual tumor position (infrared reflective markers placed on the patients’surface) This information is then used to trigger the treatment beam When the patient’s respiratory signal coincides with the treatment window or “gate”, triggers the beam for treatment (on) Gating Challenges Breathing cycle Gating Challenges Breathing cycle Gating Challenges Breathing cycle Planning Concepts For Breathing Conventional free breathing Maximum Timeexhale weighted Geometrical average average position position Maximum inhale Internal target volume CTV GTV PTV ITV Gating or breath holding Mid-position Lung Tumour Baseline Shift 4D VolumeView Imaging Breathing cycle 4D VolumeView Imaging Breathing cycle 4D Image Registration 4D Image Registration Patient Shift And Delivery Treatment Process Planning 4D planning CT 4D Volume View Mid-ventilation 4D image reg. Treatment plan Patient shift Treatment Delivery - Retrospective study compares disease outcomes and toxicity in pts treated with concomitant CT and either 4DCT/IMRT or 3DCRT - A total of 496 NSCLC were enrolled (318 treated with CT/3DCRT and 91 with 4DCT/IMRT) - Median dose of 63 Gy - Disease end points were LRP, distant metastasis, and OS - Disease covariates were GTV, nodal status, and histology - The toxicity end point was Grade3 radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors Role of imaging in radiotherapy FDG-PET as a predictor of response FDG-PET as a predictor of response • Because glucose uptake, which is directly related to tissue metabolic activity, can be affected before changes in tumour size, there is potential for detection or prediction of early response • However, difficulties arise when comparing studies because of the variable quantification methods used and post-therapy imaging delays Æ EORTC PETstudy Recommendations Weber et al. J Clin Oncol, 2003 Monitoring Response … The Past • By using tumor skrinkage as a standard endpoint of response, current conventional imaging follow-up is based on morphological criteria Æ RECIST (Response Evaluation Criteria In Solid Tumors) criteria RECIST Criteria Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Limitations of RECIST - Line lengths can fail to account for: – complex shapes – changes in non-transaxial extent of disease – total tumor burden - Assumes uniform contraction or expansion - Inter-rater reliability decreases as disease becomes more complex - Inter-observer variability - Assumes spheroid growth of tumors - Arbitrary number of measurable lesions Radiation pulmonary injury Pre-SBRT 6-12 months after SBRT No evidence of tumor recurrence on PET at 24 months Hi-Tech Radiotherapy in thoracic oncology • • • An armada of advanced technology is becoming clinically available: PET-CT imaging, IMRT treatment, respirationgated beam delivery, Image Guided Radiotherapy Advanced radiotherapy technology has the potential to lead to significant improvement in the local control (to be proven) Radiation Oncology family should be aware of the new technical developments and to critically assess their potential impact upon clinical outcome Thoracic Oncology Unit Radiation Oncology University of Turin Andrea Filippi, M.D. Alessia Guarneri, M.D. Cristina Mantovani, M.D. Riccardo Ragona, Ph.D.