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Medical Radiology Radiation Oncology Series Editors Luther W. Brady Hans-Peter Heilmann Michael Molls Carsten Nieder For furthervolumes: http://www.springer.com/series/4353 Simon S. Lo Bin S. Teh • Jiade J. Lu Tracey E. Schefter • Editors Stereotactic Body Radiation Therapy 123 Editors SimonS. Lo JiadeJ. Lu Department of RadiationOncology Department ofRadiation Oncology UniversityHospitals Seidman Cancer NationalUniversity CancerInstituteof Center Singapore(NCIS) Case ComprehensiveCancer Center NationalUniversity ofSingapore Case WesternReserve University Singapore Cleveland, OH USA Tracey E.Schefter Department ofRadiation Oncology Bin S.Teh UniversityofColorado Department of RadiationOncology Aurora,CO Weill Cornell Medical College USA The MethodistHospital Cancer Center and Research Institute Houston, TX USA ISSN 0942-5373 ISBN 978-3-642-25604-2 ISBN 978-3-642-25605-9 (eBook) DOI 10.1007/978-3-642-25605-9 SpringerHeidelbergNewYorkDordrechtLondon LibraryofCongressControlNumber:2012947064 (cid:2)Springer-VerlagBerlinHeidelberg2012 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting, reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationofthispublication orpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLawofSeptember9, 1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Violationsare liabletoprosecutionundertheGermanCopyrightLaw. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protectivelawsandregulationsandthereforefreeforgeneraluse. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consultingtherelevantliterature. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) To my parents, my wife, and my children for their support and encouragement in this project Simon S. Lo, M.D. Dedicated to the support and love from my mother, wife, daughter, and siblings. The chapter on renal cell carcinoma is a special dedication to my late father who passed away from renal cell carcinoma. He had great impact on my life and career and motivated both my brother and I to pursue research and contribute to the advances in the field of renal cell carcinoma Bin S. Teh, M.D. To my family for their support and encouragement in this project and many others Jiade J. Lu, M.D. In loving memory of my mother who lost her short battle with breast cancer in 1986. Her spirit lives within me Tracey E. Schefter, M.D. Foreword Stereotactic Radiosurgery In 1980, the National Cancer Institute on the advice of the Committee for Radiation Oncology Studies proposed an investigation into the feasibility for the dynamic treatment planning and dynamic treatment delivery which would allowforthetumortobeinthefieldoftreatmentthroughouttheentirecourse of the treatment program accommodating for motion of the tumor with res- pirationormotionofthepatientduringtreatment.Anumberofinstitutionsin theUnitedStateswereinvolvedinthisprojectbuttheultimateresultindicated thatthetechnologyandcomputerprogramswerenotadequatetodealwiththe issue. As a consequence of the work being done by Professor Mort Kligerman at the Los Alamos Pi-Meson project, various devices for immobilization were developed allowing a much more sophisticated technology for immobilization than had existed before and these were rapidly incorporated into clinical practice. This allowed for the development of three-dimensional conformal treatment programs, leading ultimately to the development of the intensity modulated radiation therapy in the early 1990s to image guided radiation therapy in the later 1990s, and ultimately to linear accelerator-based stereotactic radiation therapy technologies, and then to the CyberKnife. The stereotactic body radiosurgery procedures allowed for focusing on the tumor throughout the entire course of treatment accommodating for motion andbreathingwiththemachineoperatinginsynchronywiththetable.Without question, this represented a dramatic advance in terms of the potential for improvement in control rates for tumors based on the evolution of technology and imaging studies, and the ability to fuse these imaging studies to more precisely define the tumor but also with the reduction in side effects relative to the treatment program itself. The results from the stereotactic body radiosurgery programs are now becoming more widely available, clearly indicating that this is a dramatic step forwardintermsofallowingformaximumcontrolofthetumorwithminimum in the way of complication. vii viii Foreword The present volume deals in a most effective fashion with all the issues that aremandatedbystereotacticbodyradiosurgery.Itisadocumentthatneedsto beontheshelfofeveryradiationoncologistintheworldbecauseoftheclarity, the comprehensive character, and the significance of the data being presented. 7 June 2012 Luther W. Brady Hans-Peter Heilmann Michael Molls Carsten Nieder Foreword The Desperate Role of Clinical Science in the Implementation of Stereotactic Body Radiation Therapy/Stereotactic Ablative Radiotherapy Mostphysicianshaveextensiveundergraduatetraininginscienceandspecifically thescientificmethod.Theyalsohavetraininginart,history,languages,andother liberal arts intended to give them balance and social conscience. Subsequent medicaltrainingisalmostpurelyintherealmofscienceasidefromtheoccasional classinhumanitieslikecoursesfordevelopinginterviewingskills.Successinthe sciencecoursesinmedicalschoolallowsfuturephysicianstochoosefromthebest residenciesandfellowshipstotrainfortheirlife’scraft.Aftermorethanadecade ofmedicaltrainingandhardwork,theyreachthepointwheretheyarecompetent to care for patients...and then, oddly, they abruptly abandon the scientific method. Instead, they champion non-scientific attributes like strong will, emo- tional fervor, and parochial (even religious) zeal relating to their specialty. Indeed,thephysicianproductsofthemostcompetitiveresidencyprogramsare frequentlytheworstoftheanti-sciencecontingency.Theycontinuetoworkhard andhonetheirskills,butunbiasedscientificgrowthisstifled. The science of clinical practice that too many physicians abandon is called clinical science or the science of determining the best management options for our patients. It is a well developed, serious, and critically important science in that it is the best pathway to prudent change. Ongoing patient suffering is the obvious motivation for this change. How could the medical community not be motivated to change? Patients suffer from their commonly poor health status, and they will potentially suffer from the course of diseases that they will develop. Clinical science allows us to make a valid comparison between the statusquoandthevariousprospectsforachangingevaluationormanagement. What a shame it is that clinical science and the scientific method play such a small role in day-to-day clinical operations where so few patients will ever be offered a clinical trial as a diagnostic or therapeutic option. Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiationtherapy(SBRT),wasfirstintroducedinthemid-1990sandconstituted a dramatic change in the way radiation had been previously delivered in both conductandbiology.Itprimarilyexploitedmoderntechnologicalinnovationsto achievegeometricavoidanceofhighdosetonormaltissues.Importantly,though, wastheuseofoligofractionated(i.e.,fewfractions)radiationdeliverythatwould ix x Foreword undoubtedly result in biological effects very different from conventionally fractionated radiation. This different biology constituted a potential for a dramatic change in outcome. While change in therapy outcome for deadly cancers, like lung cancer, should have been welcomed, it also put a veil of uncertaintyovertheuseofstereotacticradiationinregardtoinformingpatients about risks and benefits. Whenthereispotentialforapositivechangeintheoutcomeofapreviously dismal disease with simultaneous uncertainty about toxicity, the only rational courseistoapplyalegitimateclinicalscienceapproach.Thisinvolvesforminga hypothesis, defining a clinical model, devising an experiment (i.e., a clinical trial), testing the hypothesis under controlled circumstances, collecting data, andreportingtheresults.TheearliestimplementationofSABRintheclinicwas mostlyuncontrolled,similartotheimplementationoftoomanyinnovationsin radiation oncology. These early reports were both compelling and, frankly, frightening. More historical use of such large dose per fraction radiotherapy brought disaster than promise for patients. Early investigators recognized two important caveats surrounding stereotactic radiotherapy: (1) Patients deserved the utmost protection from risk and (2) The potentially paradigm changing therapywasatriskofbeingmarginalizedifthelevelofevidencewaslow.Both of these caveats are best addressed with legitimate clinical testing using vali- dated clinical science. Early investigators of SABR from across the world met at any chance to share ideas. A series of clinical trials were developed and performed using variations of the technology, dosing, and patient selection. Despite the differ- ences, the biology was strikingly similar such that outcomes could be system- atically assessed. Phase I and II trials were performed selecting patients who were properly consented to understand the uncertainties associated with the therapy. Fortunately, the outcomes have been overall positive. Hence, the impetus for new textbooks on the subject. As a case in point, the Indiana University experience in early lung cancer demonstratesthestrengthofthescientific approach.Theclinicalmodelchosen for investigation by the researchers was early lung cancer in patients too frail forstandardsurgicalresection.Thetechniqueforradiationdeliverywasdefined and used consistently. A logistically attractive 3-fraction regimen was chosen for comprehensive study. Initially, a phase I dose escalation study was per- formedtryingtohoneinontheoptimaldose.Patientswereconsentedwithfull disclosurethatsuchtreatmentscouldleadtopreviouslyunobservedtoxicity.To the surprise of all associated with the experiment, dose was escalated to strik- inglyhighdoselevels(24Gyperfraction times3fractions,total72Gy)before doselimitingtoxicitywasfinallyobserved.Thisdosedramaticallyexceededthe ‘‘expectations’’ of the researcher via any logical predictions. Patients enjoyed very high levels of tumor control at the tolerable high dose levels. In reality, withouttheframeworkofascientificallyvalidclinicalapproach,patientswould not have been treated at the dose levels affording such impressive tumor eradication.Clinicalscienceliterallysavedpatientsbothinthistrialandfuture trials from dying of lung cancer via treatment with inadequate dose. ThelessonsofclinicalsciencefromtheIndianaexperiencegoesfarther.The phase I study described above was underpowered with regard to patient subgroups.Itenrolled any medically inoperable patientwith early lung cancer Foreword xi irrespectiveofthelocationofthetumorinthelung.Bydesign,asmallnumber of patients were enrolled to each level of a broad range of dose levels. In the subsequent phase II study, a larger (more statistically powered) group of patientswasenrolledtothehighesttolerabledoselevel.InthephaseIIstudy,a subtle but important reality was observed that patients with centrally located tumors had higher risk of severe toxicity as compared to patients with peripheral tumors. This distinction was critical in both selecting appropriate patients for the most potent form of the therapy as well as protecting those at high risk of harm. Again, this important distinction was afforded by an appreciation of valid clinical science. The value of legitimate clinical science does not go unnoticed. The best journals now require that key elements to the scientific method of discovery, like statistical power and data safety monitoring, be conveyed in order to publish. Retrospective reports, so flawed in their approach to reaching valid conclusions, will increasingly be rejected for publication by good journals. Ideally,astechnologiesusedinstereotacticradiotherapydeliveryareimproved or initially introduced, investigators will perform valid testing in patients to draw conclusions about the value of the new therapy. The same goes for using chemical and biological modulators in conjunction with potent stereotactic radiation. Morethanmostradiotherapyinnovations,theimplementationofSABRhas followed a clinically scientific approach. Even only 15 years after the first extracranial stereotactic radiation treatments, it is clear that the impact will be paradigm changing. Phase III trials possibly changing the standard of care are underway. Unfortunately, they are in danger of failing from problems of accrual. Why? Recall the first two paragraphs of this preface describing the ‘‘anti-science’’perspectiveoftoomanyclinicians.Nonetheless,wehopethatthe success of the therapy will continue as it is implemented in new organ systems andbodysites.Yethope,asanyclinicalscientistwilltellyou,mustgivewayto prudent evaluations, evidence gathering, and, ultimately, appreciation of reality. Dallas, TX, USA Robert D. Timmerman