Module 5: Clinical Outcomes by Disease Site - The Use of Proton Therapy in the Treatment of Cancers of the Connective Tissues and Bone

Eric Shinohara MD, MSCI
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 15, 2009


Proton based therapy for sarcomas is being heavily investigated due to the need to both improve outcomes and decrease acute and late effects that may affect general and health-oriented quality of life. Several centers have published their long term data regarding proton treatment of osteosarcomas (OS). 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%. 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. Increased radiotherapy doses are appealing in efforts to improve local control rates for OS, but that this appeal is offset by increased incidence of toxicities such as fracture, muscle fibrosis, neuropathies, and wound complications with radiotherapy doses greater than 63 – 66 Gray (Gy). However, increasing dose is potentially more feasible with proton radiotherapy since improved dose conformality is expected to reduce long-term complications in neighboring tissues. Protons may be particularly useful 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%.

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 (73% and 54%, respectively) but still better then that was has been historically reported with photon irradiation.. 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. This discrepancy maybe due to artifactual effects of orthopedic hardware on proton dosing; however, there needs for surgical stabilization could also simply be a surrogate for worse, less curable, tumors at time of diagnosis.

Links to reviews of recent abstracts and presentations regarding proton therapy for sarcomas of the base of skull, spinal cord and paraspinal soft tissue sarcomas:

Soft Tissue Sarcomas

Proton 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. Results of proton radiotherapy delivered at MGH and Loma Linda University Hospital to 19 children with skull base sarcomas has also recently been published. Median dose delivered was 70 GyE (range 45 – 78.6 GyE), and 5-year local control was 72%.

However, there is now emerging data being publish in the adult population. Dosimetrically, proton radiotherapy may be able to deliver a higher dose to the tumor safely. A recent study out of Massachusetts General Hospital examined spinal sarcomas in adults (patients older than 16) (Delany TF. et al., Int J Radiat Oncol Biol Phys. 2008 Dec 16. [Epub ahead of print]). Patients had to have no metastasis and tumors involving the thoracic, lumbar or sacrum. Paraspinal masses were also included in this study. Patients with recurrent disease could be included in this trial. Patients were treated with either pre or post-operative radiation. Subclinical disease was treated with 50.4 CGE, microscopic disease to 70.2 CGE, and gross disease to 77.4 CGE in 1.8 CGE fractions. 5 year local control, recurrence free survival and overall survival were 78%, 63%, and 87%, respectively. Toxicities included three sacral neuropathies (of 50 patients) but no cases of myelopathy. This study found a high rate of local control in patient treated at the time of diagnosis, however it was lower for patients treated for recurrence.

At present, data is very limited in certain treatment situations in adults and extrapolation from other sarcoma literature can offer guidance as we await the maturation of data in larger cohorts of patients in varied clinical situations. However there is some data available from smaller studies. The Paul Scherrer Institute has published its experience using spot scanning protons to treat adults with soft tissues sarcomas (Weber DC et al., Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):865-71.). Various tumor histologies were included and all tumors abutted critical structures. All patients had non-R0 resection, recurrent disease, or unresectable tumors. The median dose patients were treated to was 69.4 CGE with a median dose of 1.9 CGE per fraction. At a median follow up of 48.1 months 11/13 patients were alive with 3/13 patients having local recurrence. These patients received 60 CGE or less. The 4 year local control and metastasis free survival rate was 74.1% and 84.6%, respectively. Two patients had grade 2 or greater toxicity. These findings suggest that scanning beam proton therapy is safe and effective in patients with soft tissue sarcomas abutting critical structures.

Pre-operative proton therapy has not been well studied but is appealing 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. Dosimetrically, proton radiotherapy may be able to deliver higher dose to the unresected tumor while also limiting dose to 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. Proton base radiotherapy is rarely used in extremity sarcomas, but protons may be of benefit. Protons 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. In the adult population, proton therapy has been demonstrated in dosimetric studies to decrease the integral volume of tissue treated. This would be of particularly use in patients with co-morbid conditions such as irritable bowel syndrome, Crohn’s disease, and ulcerative colitis who require treatment to the pelvis or abdomen. However, at present safe organ-at-risk doses have not yet been established for proton therapy.

Links to reviews of recent abstracts and presentations regarding proton therapy for soft tissue sarcomas:

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