Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 26, 2008
Presenter: Eugen Hug, M.D.
Presenter's Affiliation: Paul Scherrer Institute
Type of Session: Scientific
Introduction Dr. Eugen Hug initiated his discussion of the indications for particle based radiotherapy in treatment of sarcomas by explaining his assessment of the need for improvements in treatment of both adult and pediatric sarcomas. He noted hat the impetus for investigation of the role of particle based therapy for sarcomas is the simultaneous need to improve outcome, and decrease acute and late effects that may affect general and health-oriented quality of life. He went on to discuss the available literature, albeit limited in certain circumstances, for several common sarcoma diagnoses. Osteosarcoma Long-term data regarding photon-based radiotherapy for osteosarcoma (OS) is available from several centers. One such study by Ozaki and colleagues was published in the Journal of Clinical Oncology in 2003, and regarded the outcomes of 1982 patients treated on Cooperative Osteosarcoma Study Group (COSS) protocols for sarcomas, 67 of whom had diagnoses of pelvic OS. Of these 67 patients, 11 underwent photon-based radiotherapy; the local failure rate among this group was 48%. Dr. Hug noted that most of the patients receiving radiotherapy for pelvic OS did not have tumors that were surgically resectable; clearly, local failure rates after definitive radiotherapy in this disease remain unacceptably high. Dr. Hug explained that increased radiotherapy doses are appealing in efforts to improve local control rates for OS, but that this appeal is offset by increased incidence of toxicites such as fracture, muscle fibrosis, neuropathies, and wound complications with radiotherapy doses greater than 63 – 66 Gray (Gy). He noted that increased dose is potentially more feasible with particle-based radiotherapy since improved dose conformality is expected to reduce long-term complications in neighboring tissues. To this end, he described specific incidences in OS in which particle therapy is particularly appealing, including in the treatment of large tumors, unresectable tumors, and those in high-risk anatomical sites. Very limited data is available with regards to particle-based radiotherapy in treatment of OS. Data from Massachusetts General Hospital (MGH) regarding treatment of OS with combined photon and proton radiotherapy was published by Delaney and colleagues in 2005. The five-year local control in this study was 68%; no difference in outcomes was noted based on tumor location, but significantly improved local control was noted for patients who underwent surgical resection followed by radiotherapy versus those who underwent biopsy only (78% versus 40%, respectively). The role of carbon ion radiotherapy has been investigated by colleagues in Chiba, Japan, and local control rates in OS have been found to be 65%. Dr. Hug notes that treatment of large tumors may be particularly feasible with carbon ion radiotherapy. Chondrogenic Tumors More comprehensive data on treatment of chordomas and chondrosarcomas is available, the majority of which has also been gathered at MGH. A combined proton/ photon approach for treatment of these tumors has been employed at MGH since 1973, and proton-based radiotherapy for chondrogenic tumors has been employed in more limited numbers at other United States centers, as well as centers in Switzerland and France. Outcomes for 622 patients treated at MGH for skull base chordomas and chondrosarcomas were published by Muzenrider and colleagues in 1998. In this publication, five- and ten-year local recurrence-free survival rates for chondrosarcomas were excellent (98% and 95%, respectively), while those for chordomas were somewhat less promising (73% and 54%, respectively). Risk classification for local recurrence of chordomas in this study appeared to be based on both gender and tumor size. Side effects from this skull base radiation included a 7-8% risk of grade 3 or higher toxicity; this risk appeared to be increased in treatment of large tumors, those causing compression of normal brain, and those involving critical normal structures. Increased dose to normal tissues, prior neurosurgery, smoking, diabetes, and hypertension were also associated with increased toxicity. A cohort of patients with extracranial chordomas of the axial skeleton were treated at the Paul Scherrer Institute (PSI), and these results were recently published. Proton radiotherapy was delivered to a median dose of 72 Gray Equivalents (GyE) (range 59.4 – 78 GyE). Local control was 60% at five-years of follow-up; interestingly, over half of local failures (12/ 21) occurred in patients who had undergone surgical resection/ stabilization. Only one patient of 19 who did not undergo surgical stabilization experienced local failure. Dr. Hug discussed the possibility that this discrepancy was due to artifactual effects of orthopedic hardware on proton dosing; however, he acknowledged that need for surgical stabilization could also simply be a surrogate for worse, less curable, tumors at time of diagnosis. Soft Tissue Sarcomas Particle therapy for soft tissue sarcomas (STS) has been less well-studied in the adult population; however, several groups have published their findings using proton therapy to treat pediatric STS patients. Recently, Timmerman and colleagues published outcomes data on a group of 16 pediatric STS patients treated at PSI. The children were of median age 3.7 years (range 1.4 – 14.7 years), and median tumor dose was 50.4 GyE. Local control was 75% at two years, with failures occurring in 2/ 12 patients treated for rhabdomyosarcoma, and 2/ 4 treated for other STS. Additionally, Dr. Hug and colleagues published the results of proton radiotherapy delivered at MGH and Loma Linda University Hospital to 19 children with skull base sarcomas. Median dose delivered was 70 GyE (range 45 – 78.6 GyE), and five-year local control was 72%. Dr. Hug makes an interesting point that the cooperative group trials on which the majority of pediatric cancer patients are treated may limit adequate particle therapy dosing. Although these trials have allowed a great deal of advancement in pediatric oncology thus far, a paradigm shift may be necessary at this point allowing higher radiotherapy dosing when protons or other particles are used in order to attempt to improve outcomes. Indications for Particle Therapy in Treatment of Sarcomas Dr. Hug went on to explain the role of particle-based radiotherapy in treatment of sarcomas in several different clinical situations. Although data is certainly very limited in certain situations, extrapolation from other sarcoma literature can offer guidance as we await the maturation of data in larger cohorts of patients in varied clinical situations. Pre-operative Setting: Dr. Hug noted that although pre-operative particle-based radiotherapy is delivered uncommonly in treatment of sarcomas, and has certainly not been well-studied, it is an appealing prospect for several reasons. Among these are possibilities for decreased radiotherapy volumes, as well as potential decrease in risk of wound-healing complications based on extrapolation from data on photon radiotherapy in the pre-operative setting. Dr. Hug also demonstrated dosimetrically the potential for proton radiotherapy to deliver dose to the unresected tumor, but also for the radiation oncologist to avoid dosing the planned surgical access route. This would of course require excellent communication on the part of the radiation oncologist and the surgeon, but could be possible because of the markedly reduced exit dose with use of proton radiotherapy. Extremity Sarcomas: Dr Hug noted that particle based radiotherapy is rarely used in treatment of extremity sarcomas, but that it could potentially be employed to decrease radiotherapy volumes (and in turn the muscle volume at risk for fibrosis), and could also spare circumferential dose to bones, decreasing the risk of late fracture. Centrally Located Sarcomas: Based on the review of the literature presented prior, well-established indications for particle-based radiotherapy exist for treatment of axial and central sarcomas, particularly in the pediatric population. In Presence of Co-morbid Disease: In the adult population, particle-based radiotherapy has been demonstrated in dosimetric studies to decrease the integral volume of tissue treated; particularly in patients with co-morbid conditions such as irritable bowel syndrome, Crohn’s disease, and ulcerative colitis requiring treatment to the pelvis or abdomen. Dr. Hug made note that safe organ-at-risk doses have not yet been established for particle-based radiotherapy. Possible Clinical Trial Design Finally, Dr. Hug raised several possibilities for trial design to further evaluate the use of particle therapy in treatment of sarcomas. Certainly, a randomized controlled trial comparing proton and photon irradiation could be a gold standard for this assessment. Dr. Hug pointed out several issues that could create difficulty with such a trial: First, patients would need to be amenable to the randomization, which is certainly not always the reality. Second, doses could well not be equivalent with the two forms of radiotherapy, and photon dosing could limit particle beam dosing due to toxicity, thus limiting the potential benefit of particle beam radiotherapy. To this end, Dr. Hug suggested two methods for trial design to better assess dose-escalation potential, including a phase II dose-escalation trial using combination photon/ proton radiotherapy in unresectable STS, and a phase II trial of high-dose radiotherapy for STS using stereotactic precision-modality proton radiotherapy.