Clinical Concept and History of Protons. Relevance and Limitations of Conformality. Gudrun Goitein

Transcription

1 Clinical Concept and History of Protons Relevance and Limitations of Conformality Gudrun Goitein PSI Winter School January 2010 Bad Zurzach and PSI, Villigen Switzerland

2 P + Who came first: The Clinical Concept or Protons?

3 Clinical Concept and History of Protons Clinical concepts developed in simple forms shortly after the discovery of x-rays, when effects of radiation on human tissues were observed. Stopping uncontrolled cellular and tissue activities was the goal treatment of a hairy nevus; 1897 irradiation for trigeminal neuralgia, rheumatic pain; 1899 irradiation of a SCC of the skin;. Irradiation until the desired effect occurred was the logical approach; the term tolerance dose was introduced as late as 1925 The understanding of the underlying biology developed during decades until to date Observation of toxicities (1896 skin toxicity) led to the introduction of shielding blocks very early on; this was the first, important step to conformation (first individually shaped blocks as late as 1973) Technical innovations and increasingly sophisticated tools (treatment devices) allowed to translate the growing understanding and knowledge into medical praxis

4 1895: Röntgen R discovers x-rays 1896: Emil Grubbe, a Chicago electrician and metallurgist, first treated the recurrent breast cancer of a 55-year-old woman in the last days of January only weeks after the announcement of Roentgen's discovery. 1897: Note that the eyes are shielded for protection.

5 Clinical Concept and History of Protons Clinical concepts for radiation treatments of malignancies (and non-malignant conditions) has been growing on the grounds of understanding of diseases, pathophysiology, biochemistry, pathology,... knowledge about spread and dynamics of diseases the idea of defined target volumes radio-biological knowledge about target- and normal tissues developments and improvements of other than radiation treatments and their interaction with radiation therapy physical knowledge about different kinds of radiation technical progress - not to forget imaging The clinical concepts for the use of therapeutic radiation were (and still are) strongly based on limitations through normal tissue tolerance Where combination of radiotherapy with other modalities (local/ systemic) did/do not increase local tumor control and cure rates, outcomes are to date unsatisfactory for many diseases and conditions

6 Clinical Concept and History of Protons The desire and necessity to focus radiation to target volumes and the physical knowledge about particle beams led Prof. Robert Wilson to write his landmark paper Radiological Use of Fast Protons in 1946 These properties (of( of protons, as described before) ) make it possible to irradiate intensily a strictly localized region within the body,, with but little skin dose. One naturally asks what are the advantages of fast protons over high-energy electrons such as those from a betatron.. This question can be answered only by medical workers, and the answers will probably be different for different kinds and sizes of tumors. Robert Wilson, 1946 Robert Wilson, years prior to the introduction of individually shaped blocks

7 narrow peak (few mm) DOSE low entrance dose depth of penetration depends on the proton s energy no exit dose DEPTH (CM)

8 Clinical Concept and History of Protons Robert Wilson had understood one main principle of radiation therapy: Put the dose where the target is. This means the right = necessary amount of dose in optimized = most efficient and best tolerable fractionation to the correct = medically appropriate, large enough, but as small and conformal as possible volume The clinical concept of delivering sufficiently high radiation dose to the target was and still is supported by the fact that protons offer a geometrical advantage in dose deposition as compared to photons and electrons dose conformation Dose conformation can allow for increased target doses which are resulting in different biological effects, supposedly in better local tumor control without increase in, or even with reduction of, normal tissue toxicities

9 Clinical Concept and History of Protons (1954 ongoing) HCL-MGH pioneers of proton radiation therapy The first large field treatment with protons at the Harvard Cyclotron in 1976, for a pediatric pelvic rhabdo-myosarcoma. The patient died several years later from probably a marginal tumor progression or relapse Slides courtesy of M. Goitein The second large field treatment, for a chondrosarcoma of the base of skull. The patient is alive and active, though diagnosed with local relapse more than 30 years after proton radiation therapy

10 Clinical Concept and History of Protons (1954 ongoing) Pioneers of proton radiation therapy PSI 2005 HCL 1976 The preparation for proton treatment of a skullbase tumor has changed over the decades; however, the goal has remained the same: local tumor control and minimal treatement related toxicity The patient has explicitely agreed to be recognized on instructive photographs

11 Clinical Concept and History of Protons (1954 ongoing) Pioneers of proton radiation therapy The first compact gantry and the first gantry providing spot scanning technology, a PSI-product, designed by E. Pedroni; ; : >500 patients treated α rotation for treatments in the trunk α+β rotation for cranial/intracranial and c-spine treatments β rotation

12 Clinical Concept and History of Protons (1954 ongoing) Pioneers of proton radiation therapy The first 3-d 3 d treatment planning program, including DRR and BEV, by M. Goitein in Patients position Number of treatments Slides courtesy of M. Goitein Motion (mm)

13 Clinical Concept and History of Protons (1954 ongoing) Pioneers of proton radiation therapy Dynamic beam application, 3-d 3 d dose calculation; discrete spot scanning, IMPT at PSI + Treatment planning for spot scanning protons and IMPT + + IMPT IMPT IMPT IMPT

14 Clinical Concept and History of Protons (1954 ongoing) MEEI-MGH MGH-HCLPioneersHCLPioneers of proton radiation therapy for ocular melanomas The first proton irradiation of a choroidal melanoma took place at the Harvard Cyclotron in 1976 a collaboration between MEEI, MGH, HCL The first collimator not yet computer fabricated, with a tiny shield for the macula

15 Clinical Concept and History of Protons (1954 ongoing) PSI introduced proton radiation therapy for ocular melanomas to Europe in 1984; ~4700 pts, ~ pts./y, largest number of patients worldwide OPTIS E. Egger J. Verwey H. Staeuble, proband OPTIS installation at the beam line of the injector 1 cyclotron at PSI Robotic chair for patient positioning in the OPTIS2 facility, to open in late spring 2008

16 Clinical Concept and History of Protons (1954 ongoing) Pioneers of proton radiation therapy for ocular melanomas EyePlan (by M. Goitein), first used in 1976, meanwhile modernized, and still in use for many hundred patients every year If the clinical concept and, in this case, the model are correct and performance is standardized at a high level, treatment outcomes can be as excellent as for ocular melanomas: 98% LC@10ys; OMs are the by far largest tumor entity treated with protons about worldwide GG03/07

17 Clinical Concept and History of Protons (1954 ongoing) The clinical concept from the very beginning was proton irradiation ion for localized and well defined lesions in radiation sensitive environments (e.g. skull base, brain), and histologies which require relatively ly high radiation doses for local tumor control (e.g. sarcomas) The users of medical proton facilities were wise to restrict the indications according to the available technologies: limited energies; fixed horizontal beam lines; collimated and, where necessary, compensated = range-modulated broad beams; devices for stereotactic irradiation; equipment for large field treatments Main indications since the early times of proton radiation therapy were therefore intra-cranial lesions (benign and malignant); choroidal melanomas; skull base, spinal and para-spinal tumors (mostly sarcomas); and later prostate cancer The local control rates of proton radiotherapy for sarcomas of the skullbase and for ocular melanomas were a proof of principle that dose conformation with the consequence of target dose escalation can improve outcomes significantly

18 Clinical Concept and History of Protons (1954 ongoing) Combination treatment with surgery and proton irradiation for sarcomas was one of the important foci of the medical program at the HCL/MGH Learning about normal tissue tolerance in case of partial or non-uniform dose load to organs at risk (OARs) has allowed to modify clinical concepts to including higher than traditional target doses and special fractionation schemes (e.g. for ocular melanoma, since recent years for NSC lung cancer) The impact of local control rates on survival has been shown mainly with the excellent outcomes of proton radiation therapy for choriodal melanoma and sarcomas of the base of skull both diseases for which the results of conventional irradiation and brachytherapy were unsatisfactory There is no publication available which states inferior outcomes after proton radiation therapy as compared to conventional radiation therapies (x-rays, electrons, both combined, brachytherapy)

19 Clinical Concept and History of Protons (1954 ongoing) The spectrum of indications for proton treatments has been extended with improving technologies - e.g. gantries, variable and higher energies, beam scanning (at PSI only), and with increasing capacities in hospital based facilities and dedicated projects Modern treatment planning tools for both proton and conventional radiotherapy led to numerous studies comparing 3-d dose distributions to targets, dose loads to OARs and integral dose to anatomical compartments There are no comparative treatment planning studies virtual or for real patients which show a disadvantage for proton beams. Even though IMXT may offer comparable dose conformality to target volumes, the use of protons results generally in significant reduction of irradiation of normal tissues; this is the strongest argument for proton radiotherapy in pediatrics, where localized outside-target target dose and integral dose have particular impact on the growing organism

20 Clinical Concept and History of Protons (1954 ongoing) Conformality - Relevance and Limitations The clinical concept of high precision radiotherapy with protons has not changed in principle, though today s applications may include diseases that are less well circumscribed than e.g. oc. melanomas or skullbase chordomas For instance, H&N tumors, NSC lung cancer, esopageal cancer, pediatric CNS malignancies and other diseases may require target volumes extending substantially further than the gross tumor (e.g. cranio-spinal axis irradiation in pediatric patients) The potential of protons to reduce outside-target dose makes them THE radiation therapy modality for large volumes - as the volume which receives integral dose increases with increasing target volume - and for multi-modality treatments in oncology

21 Conformality - Relevance and Limitations The amount and the geometry of dose reduction in OARs is relevant t for the applicable total dose; the dose gradient matters: conformality does not necessarily mean zero dose outside a target or inside an OAR 4 fields IMPT OAR: cauda equina 3 fields IMPT Sacral chordoma, 10 year old girl OAR: brainstem & center Skull base chordoma

22 Conformality - Relevance and Limitations The therapeutical dose for a radiation treatment consists usually of partial doses to defined target volumes, which are delivered via individual plans; the sum of the partial doses is the total dose. Applied dose levels have to be balanced with dose constraints for OARs sacral chordoma GTV OAR rectal mucosa CTV1 (68 Gy RBE) = risk CTV for unclear microscop. tumor spread PTV 1 = CTV1 + 7mm PTV 2 = CTV2 + 7mm CTV2 (74 Gy RBE) = CTV1 reduced to avoid toxicity in the pelvic nerv-vessel vessel bundle)

23 Conformality - Relevance and Limitations Multi-modality cancer treatments are inevitably always multi-toxicity treatments Reduced toxicity for one modality will influence overall toxicity and may allow for dose escalation of this or/and other modalities (e.g. less dose to oral mucosa allows for higher radiation dose and/or stronger chemotherapy) The use of protons in combined treatments should lead to a critical review of those oncological concepts, where the component of local therapy might be improved (e.g. H&N cancer, pediatric malignancies) In case of radiation being the single agent cancer treatment, protons can be the tool to overcome dose limitations through normal tissue constraints; this may result in re-designing treatment concepts which have unsatisfactory outcomes due to insufficient radiation dose (e.g. inoperable NSC lung cancer, inoperable sarcoma in adult patients, H&N tumors...) Protons may even allow to include radiation therapy in treatment concepts, which have so far excluded radiation due to unacceptable toxicity (e.g. pre-op RT)

24 Conformality - Relevance and Limitations Conformality of radiation dose in a patient is a 3-d factum there is no such thing as irradiating a field, which is 2-d Dose conformation has two aspects: dose which is supposed to be deposited and dose which is supposed to be avoided; both are key issues in all clinical concepts which include radiotherapy Physics law does not allow to deliver any wanted dose without some level of unwanted dose Dose conformation can therefore only be optimized (not idealized) physically / technically by choosing the best suited radiation quality (x-rays, e -, p +, other particles) appropriate energy sophisticated technology and medically by target definition and dose prescription and other details of a clinical concept

25 Conformality - Relevance and Limitations Beam application techniques can have strong impact on 3-d dose distribution; site, size and shape of a target may require scanning beams to improve conformality Bowel and intestines Tumor Liver Kidneys Passive scattering Spot scanning

26 Conformality - Relevance and Limitations Ultimately, the degree of possible dose conformation depends on the physics of protons in matter and the size and/or shape of the structure(s) which should be conformally treated and/or avoided 1 field 1 field Spot scanning 3 fields 3 fields Slide courtesy of M. Goitein Passive scattering

27 Conformality - Relevance and Limitations Dose conformation has two aspects: dose which is supposed to be deposited and dose which is supposed to be avoided OAR: inner ear Undifferentiated sarcoma, 30 y/o male total dose 74 Gy RBE The dose to be avoided in the inner ear/cochlea is the difference between the two dose levels in this plan, represented by red (>90%) and blue (80-90%)

28 Conformality - Relevance and Limitations The degree of possible dose conformation when using scanning beams is influenced by the fact, that spots cannot be made infinitely small Mini target or mini OAR Avoiding structures of about spot size, which are embedded in a target, or covering such small volumes (mini target) exclusively - which would be the ultimate conformality is illusionary However, beam application technique and treatment performance help to increase 3-d dose conformation by e.g. (additional) collimation, choice of energy, beam angles, optimized beam scanning, patient set-up, sophisticated treatment planning (e.g. IMPT)

29 Conformality - Relevance and Limitations Sophisticated treatment planning for spot scanning proton therapy of skull base chordomas: IMPT (second series plans) using 3 beam directions ( fields) to reduce dose to small structures: chiasm, optic nerves, brainstem/center 2 nd series plans, delivered in 2002, for skull base chordomas, total dose 74 Gy RBE)

30 Conformality - Relevance and Limitations Target- and/or organ motion are the antidote to dose conformality Physiological motion respiration, pulsation, peristalsis cannot be suppressed; if compensation by gating, triggering or other (upcoming) technologies is not possible, uncertainties in dose amount and deposition have to be estimated and taken care of in treatment planning and clinical concept Accidental and arbitrary motions can be reduced by immobilisation devices and comfortable, pain-free patient position Motion control by sensors or image guidance/visually can deliver qualitative and quantitative information about mal-position and deformation of targets and non-target tissues, which result in altered tissue densities along the beam paths and in miss-match between target volume and high dose volume The effect of altered and/or changing tissue densities on proton beams is increasing with atomic numbers of the tissue materials; broad beams are less sensitive to tissue motion than scanned beams

31 Summary Clinical Concept and History of Protons Clinical concepts in oncology are primarily not proton-specific, and they have not changed substantially since the very early radiotherapy adventures However, as protons are excellent tools in radiation therapy, clinical concepts have been developed which focus on protons as single agent or as component in multi modality regimens 3-d d dose conformation is condition for optimized = sufficiently high dose levels and clinically appropriate target volumes as well as for avoiding unnecessary dose to normal tissues; this was and is the guideline in proton radiation therapy as in every other RT

32 Summary Clinical Concept and History of Protons The pioneers were right, their guideline has never proven to be wrong Good thinking, broad knowledge in physics, technology and medicine, and good performance are all together timeless and lead to success Excellent and never before reached treatment outcomes for sarcomas of the skull base and for ocular melanomas have paved way for ongoing technical developments and triggered new medical needs

33 Summary Conformality relevance and limitations Improved dose conformation as compared to any other radiation treatment modality was the precondition for the medical use of protons Conformality is a most relevant element in all clinical concepts which include radiation; higher target doses and reduced non-target dose levels are supposed to make treatments more efficient and less toxic Limitations of conformality are based on physics laws, available technologies (hard- and soft ware), and on conditions of the human body

34 Summary Conformality relevance and limitations Wherever possible, information about limitations should be qualitative and quantitative; this is particularly important in case of motions of targets and/or normal structures Limitations of conformality need to be recognized, understood and taken care of in all procedures of proton radiotherapy The ultimate, ideal conformality does not exist Therefore, we must not promise perfect conformation in proton radiation therapy; honesty has to characterize promotion of protons not business We have to continuously work on improving proton therapy by thinking, learning, critical reflection and serious performance

35 Thank you for listening Enjoy the PSI Winter School 2010 and stay on Robert Wilson s s way These properties (of protons, as described before) make it possible to irradiate intensily a strictly localized region within the body, One naturally asks what are the advantages of fast protons over high-energy electrons such as those from a betatron.. This question can be answered only by medical workers (who( are all professionals involved in proton radiation therapy), and the answers will probably be different for different kinds and a sizes of tumors.