Radiation Therapy in the 21 st Century Competing Technologies

Transcription

1 Radiation Therapy in the 21 st Century Competing Technologies 2 nd Workshop on Hadron Beam Therapy of Cancer Stephen M. Hahn May 21, 2011

2 The Evolution of Radiation Therapy 1960 s The First Clinac Standard Collimator The linac reduced complications compared to Co s Cerrobend Blocking Electron Blocking Blocks were used to reduce the dose to normal tissues 1980 s Mul,leaf Collimator MLC leads to 3D conformal therapy which allows the first dose escalation trials. Computerized 3D CT Treatment Planning 1990 s 2000 s Functional Imaging Dynamic MLC and IMRT Computerized IMRT introduced which allowed escalation of dose and reduced compilations High resolu,on IMRT IMRT Evolution evolves to smaller and smaller subfields and high resolution IMRT along with the introduction of new imaging technologies

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4 Effect of underdosage and overdosage Tumour control Late normal tissue damage Effect Tumour Dose

5 Fractionation Options Conventionally fractionated radiotherapy small daily doses go to very high cumulative doses strategy for IMRT implementation Hypofractionated radiotherapy larger daily doses (3-8 Gy) used mostly for palliation Ablative radiotherapy very high daily doses (8-20 Gy) overwhelm tumor repair causes late effects that may be intolerable

6 Conventional Radiotherapy Now and in the future Recent advances are notable for significant increases in the therapeutic index & have been driven by Increased computing power Improved hardware Improved imaging Application of biology These trends are likely to continue and accelerate.

7 Conventional Radiotherapy Now and in the future We are likely to see the development of new technologies along these same lines Hardware and software developments that will improve the precision and efficiency of therapy as well as improve the relative dose to tumor compared to normal tissue Imaging that will allow for improved identification of the gross & microscopic extent of tumor, predict the biological response of tumors, and identify functional & non-functional normal tissue Biological therapies that will permit improved tumor kill for the same or perhaps lower doses of radiation than are being used now

8 Conventional Radiotherapy Now and in the future Ironically, despite the better physical properties of particle therapy, our approaches with protons lag behind conventional radiotherapy in many key ways On board imaging Incorporation of biological therapies Hardware and software advances that improve the precision and efficiency of delivery

9 IMRT Intensity Modulated Radiotherapy

10 Dose Distribution: Conventional Radiation Therapy vs. IMRT vs. Proton Therapy

11 Intensity Modulated Radiation Therapy Driven by improved computing Multiple beams from different angles, divided into even more small beamlets Constantly changing beam shapes Changing shapes = intensity modulation Made possible by invention of multileaf collimator Inverse treatment planning: MD enters desired doses & limits, and computer attempts to achieve them Image Courtesy of Varian Medical Systems

12 Week 1 Post- Chemoradiotherapy: complete clinical response noted in the right base of tongue and involved vallecula and pharyngoepiglokc fold with resolving confluent fibrinous mucosi,s.

13 The Price of IMRT IMRT because it is delivered in real time has problems coping with organ motion. Also. with IMRT there is spread of low to moderate doses to many normal tissues. Also, the long treatment times needed for IMRT increase total body exposure. This may be critical for children and young adults, but also could be important for older patients.

14 IMRT Cumulative Adoption Mell et al, Cancer 2005

15 IMRT vs. conventional RT 61 studies have been reported 6 RCTs 3 HNC & 3 breast cancer All RCTs powered for toxicity endpoints All RCTs showed IMRT significantly better than conventional RT Early results suggest that there is no decrease in tumor control HNC xerostomia Breast cancer - cosmesis Non-randomized studies consistently show sparing of acute and late radiation induced side effects across multiple tumor sites These data support considered sufficient to implement IMRT across the UK Radiotherapy Development Board Staffurth J et al Clinical Oncology Oct 2010

16 Bowel Complications Requiring an Invasive Procedure Composite Bowel Complica/ons Proc//s, Hemorrhage Bekelman et. al. ASTRO, 2010

17 Conclusions IMRT associated with moderate reduction in composite measure of bowel complications, and specific complications of proctitis/hemorrhage IMRT not significantly associated with reduction in urinary complications Erectile complications involving invasive procedures rare in both treatment groups IMRT associated with a moderate increase in new diagnoses of impotence compared to CRT Bekelman et. al. ASTRO, 2010

18 IGRT Image guided radiotherapy

19 The irradiated volumes ICRU 62 report GTV = Gross Tumour Volume = Macroscopic tumour CTV = Clinical Target Volume = Microscopic tumour PTV = Planning target Volume = IM + SM PTV

20 Image Guidance in Radiation Targeting therapy Targeting of cancer cells is a theme that runs throughout oncology Biological targeting e.g. EGFR Physical targeting IGRT as currently practiced facilitates our physical targeting of cancers. The goal is to improve the therapeutic index through improved identification of tumor & assessment with daily on-board imaging

21 MIV: Composite GTV Chen, G & colleagues

22 IGRT Technologies Cumulative Adoption Simpson et al, Cancer 2010

23 SBRT Stereotactic Radiotherapy

24 Medically Inoperable Early Stage: Stereotactic Body Radiotherapy Nyman et al Lung Cancer 2006

25 Early Stage Disease: Stereotactic Body Radiation Therapy Pretreatment 6- weeks Post- treatment

26 RTOG 0236: Stereotactic Body Radiation Therapy (SBRT) to Treat Medically Inoperable Early Stage Lung Cancer Patients R. Timmerman 1, R. Paulus 2, J. Galvin 3, J. Michalski 4, W. Straube 4,5, J. Bradley 4, A. Fakiris 6, A. Bezjak 7, G. Vide,c 8, and H. Choy 1 1 Univ. of Texas Southwestern, 2 RTOG Headquarters, 3 Thomas Jefferson Univ., 4 Washington Univ., 5 Advanced Technology Consor,um (ATC), 6 Indiana Univ., 7 Princess Margaret Hosp., 8 Cleveland Clinic Founda,on

27 100 Local Control 1 failure within PTV, 0 within 1 cm of PTV / / / / / / / / // / / // / / / // / // / / Local Control (%) month local control = 98% (CI: %) Fail: 1 Total: Patients Months after Start of SBRT at Risk

28 100 Overall Survival Median survival is 48.1 months Overall Survival (%) month overall survival = 56% (CI: 42-68%) Dead: Total: 55 MST: 48.1 (95% CI): (29.6, not reached) Patients Months after Start of SBRT at Risk / / / / /

29 Biological Approaches

30 The Promise of Molecularly Targeted Therapy and Radiation Bonner JA et al. Lancet Oncol 2010; 11: 21 28

31 HPIs are in vitro and in vivo radiosensi/zers and downregulate P- Akt - + P-Ser 473 Akt Total Akt

32 Nelfinavir can increase blood flow in xenograis SQ20B Pre- nelfinavir Day 10 A549

33 Nelfinavir can increase tumor oxygena,on A. B. EF5 binding (fluorescence intensity) control NFV EF5 Hoechst 200 p = control NFV

34 Hypoxia Imaging with 18F EF5 Post-GAD 3 hr 18F EF5

35 Imaging Correlates b % % c % % (a) HASTE image showing por,on of metasta,c NSCLC in pre- aor,c trans lymph node. Color maps for tumor Ktrans before treatment(b), aier Bar graph showing median pixel tumor K values prior to (blue) and post (burgundy) administra,on 7 days of Nelfinavir(c). Note vascular hot spot at periphery of of Nelfinavir for ini,al four pa,ents tumor inferiorly at baseline(b) is diminished aier seven days of Nfv

36 IMRT vs. Proton therapy

37 Value Value includes patient preferences, quality, equity, efficiency, and product acceptability among a wide range of stakeholders. The European Observatory on Health Systems and Policies JE Bekelman

38 Value An intervention s value resides in its ability to reduce mortality, morbidity, or save money, not in its unique mechanism of action. Technology evaluations in health care can provoke controversy, anger, and hostility... But, novelty [or theory] cannot be equated with benefit. Ezekiel Emanuel, JAMA, 2007 JE Bekelman

39 When Should We Use Protons? Serious AE with x-rays Importance of surrounding normal tissue Improvements in local control are needed Late morbidity is an important issue Complex geometry Target volume large relative to normal tissue compartment Zietman, Goiten, Tepper JCO 2010

40 An Example: Prostate Cancer Despite the theoretical advantages of PBT, investigators have yet to demonstrate prospectively a clinical benefit to PBT compared to IMRT A 2008 AHRQ-sponsored systematic review of found little high-quality evidence of either IMRT or PBT Interpreting the sparse evidence available is problematic because of the absence of rigorous, prospective, randomized trials of sufficient size and statistical power to assess key clinical outcomes, failure to control for known confounders, and substantial selection effects Wilt TJ et al Ann Int Med 2008

41 Efficacy & Toxicity of IMRT and PBT Outcome IMRT PBT FU (yrs) Evidence OS >80-90% >80-90% 5 Limited DSS8 >95% >95% 5 Limited FFBF 74-95% 69-95% Toxicity Acute vs. Late IMRT (Pooled Rate 95 CI) GI Acute 18.4 (8.3, 28.5) 0* PBT (Pooled Rate 95 CI) Late 6.6 (3.9, 9.4) 16.7 (1.6, 31.8) GU Acute 30.0 (13.2, 46.7) 40.1* Late 13.4 (7.5, 19.2) 5.5 (4.6, 6.5) ED 48-49** Not reported ** 2 studies * 1 study

42 Rationale for PBT in Prostate Cancer

43 Study Schema

44 Clinical Data-the Rationale For Protons Non-small cell lung cancer (NSCLC) ~ 200K cases per year ~35-40% treated with a combination chemotherapy & radiation 3-D radiation therapy or IMRT is used Substantial morbidity and some mortality result from the concurrent use of chemotherapy and radiation in this patient population We achieve 80% complete response rates with radiation and chemotherapy

45 Protons MD Anderson All pts had inoperable lung CA, enrolled from >2008 for proton treatment ITV derived from 4D CT simulation, pts treated with 2 CGE fractions with concurrent platinum-based doublet. Historical controls for 3D conformal/imrt were used. Median dose of 74 CGE vs 63 Gy Grade 3 esophagitis (requiring placement of a PEG tube) was seen in 16%, 40%, and 6% (3D conformal, IMRT, and protons) Grade 3 pneumonitis (some of which was lethal) was seen in 32%, 9% and 0% Cox J, ASTRO Advances in Technology Mee,ng 2008

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47 Conclusions There has been a substantial increase in the technological complexity of radiotherapy over the last 20 years Driven by advances in computing power, imaging and more efficient methods for delivering radiation IMRT leads to a reduction in acute and late toxicities compared to conventional radiotherapy SBRT for early stage lung cancer is ablative therapy that has control rates similar to surgery

48 Conclusions Image guidance IGRT is widely adopted and considered standard. Improvements in imaging will drive future clinical advances in radiotherapy Biological approaches are likely to make the biggest impact Rapid adoption of new radiation technologies & attention from payers will force us to carefully evaluate value incorporating efficacy, toxicity, patient preference, and cost effectiveness Proton therapy may provide theoretical benefit over conventional radiotherapy peds, lung cancer, prostate cancer; however, improvements are needed in hardware, software, and imaging

49 Thank You Roberts Proton Therapy Center