Particle Therapy for Sarcomas

Reviewer: Christine Hill-Kayser, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

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Presenter: T. Delaney
Presenter's Affiliation: Massachusetts General Hospital, Boston, MA
Type of Session: Scientific

Background

  • Sarcomas of bone and soft tissues represent only 1% of adult malignancies.
  • They generally require multidisciplinary treatment, with a combination of surgery and radiotherapy, with or without chemotherapy:
    • Soft tissue sarcomas may require radiotherapy in combination with surgery because they frequently invade peritumoral tissue by growing along tissue planes. Lymph node invasion is uncommon.
      • Wide resection alone may be appropriate for tumors that are low grade, superficial, small (less than 5 cm), and fully resected with negative margins of at least 1 cm.
      • Most tumors greater than 5 cm will require a combination of surgery and radiotherapy in order to reduce risk of local recurrence (LR). Local recurrence has previously been demonstrated to increase risk of distant metastasis and death (Pisters, 1996), and so avoidance is obviously very important.
    • Sarcomas of bone are primarily treated with surgical resection when possible; however, acceptable margins may be difficult to achieve when tumors are located in the axial skeleton. Radiotherapy may be added to improve local control following surgical resection.
  • In the case of either soft tissue or bone sarcomas, radiotherapy must be integrated into the multidisciplinary treatment plan.
    • Neoadjuvant radiotherapy may improve chances of full or functional resection, decrease risk of tumor wound seeding, and decrease radiation volume when compared to adjuvant radiation.
    • Adjuvant radiation may be utilized following resection when close/positive margins are identified, or when tumors are considered high-risk due to size, pathology, presentation with pathologic fracture, or placement of intramedullary rod.
    • In certain clinical situations, radiotherapy may also be used as definitive treatment. This may occur when tumors are considered medically inoperable, with goals of functional preservation, or when tumors are located in the pelvis, base of skull, or sinuses.

Materials and Methods

  • Dose and type of radiotherapy used may be highly variable based on tumor location, risk features, and histology.
    • In treatment of soft tissue sarcomas, doses of 50 Gray (Gy) are considered appropriate in the pre-operative setting, while doses of 60 Gy are recommended in post-operative cases. These doses may result in local control rates ranging from 75 – 90%. Definitive radiotherapy of at least 63 Gy, when surgery is not utilized, has been demonstrated to be more effective than radiotherapy with lesser doses (Kekpka, 2005).
    • In treatment of Ewing’s sarcoma, 50.4 Gy is recommended for microresidual disease, while doses of 55.8 Gy or higher may be employed for gross residual disease.
    • Dose of 66 – 70 Gy may be required in treatment of chondrosarcoma and osteosarcoma, depending on degree of residual disease following surgery.
    • Chordomas may require dose greater than 75 Gy for gross disease, or 70 Gy for microscopic.
  • Treatment with conformal radiotherapy, photon-based intensity modulated radiation treatment (IMRT), particle therapy, and stereotactic radiosurgery has been employed in treatment of sarcomas at various sites throughout the world.
    • Proton radiation may be delivered with improved conformality due to physical properties of proton beams. This may allow delivery of higher dose to the target volume, with reduction in integral dose. Use of protons in treatment of sarcomas may be used to spare visceral structures, as well as joints, bones, and perineal structures. Proton treatment may be given in combination with photons, and this has been performed at Massachusetts General Hospital since 1975.
      • Protons have been demonstrated to offer improved local control for chondrosarcoma and chordoma of the base of skull when compared to conventional treatment, although these two techniques have never been directly compared:
  • Proton treatment has yielded local control rates of 98% and 95% at 5 and 10 years for treatment of chondrosarcoma, and 73% and 54%, respectively, for treatment of chordoma (Muzenrider, 1999). This is compared to other groups demonstrating 5-year rates of local control of only 20 –25% using conformal photon radiation.
    • IMRT may also allow excellent conformality, although this technique leads to increased integral dose and a low-moderate “dose bath”, the significance of which is not fully understood.
    • Stereotactic radiosurgery has been utilized at the University of Heidelberg for treatment of chordomas, yielding 50% 5-year local control.
    • Gamma Knife has been utilized at the Mayo Clinic, also for treatment of chordomas, yielding local control rates of 32% at 5 years.
    • Finally, carbon ions have been utilized at several centers, and are hoped to be beneficial due to higher radiobiologic equivalent when compared to protons, and thus higher effective tumor dose. Indeed, treatment with carbon ions has recently been demonstrated to yield local control rates of 95% and 81% for chondrosarcomas and chordomas, respectively, with three years of follow-up.
  • Treatment of tumors near or involving the vertebral bodies or spinal column may be particularly difficult to treat.
    • Surgical resection may be difficult or impossible due to proximity to spinal cord. In addition, tumors may contact or invade the dura and/or seed the cerebrospinal fluid.
    • As a result, local failure rates remain high with standard treatment.
    • Effective radiotherapy may be impossible to deliver due to proximity of the target to spinal cord and nerve roots.
    • In a recent publication from Massachusetts General Hospital, patients with tumors of the spinal column were treated with surgical resection, with or without intraoperative brachytherapy, followed by combination photon/proton radiation to doses ranging from 70.2 – 77.4 Cobalt-Gray equivalents (CGE).
      • CT myelogram was performed for delineation of the spinal cord for all tumors above the conus medullaris. The surface of the spinal cord was constrained to receive 63 CGE, and the center to receive 54 CGE.
      • 50 patients were treated as part of this study:
  • 25 patients had gross residual disease following resection.
  • An additional 13 underwent biopsy alone.
  • Patients with gross residual disease received a total dose of 76.6 CGE via external beam radiation. Three patients received dural plaques delivering 10 Gy via Y-90 for dural involvement at the time of surgery.
  • With median follow-up of 48 months, 9 patients experienced local failures (5 local failure alone, 4 concurrent local failure and distant metastasis).
  • Of the 9 patients experiencing local failures, 7 had been treated for local failure following surgery alone, while 2 were treated with surgery and radiotherapy as primary treatment.
  • Of 29 patients treated for chordoma, three experienced failures. One of these did not undergo surgical resection, but biopsy alone.
    • Overall survival for the entire group was 60% at 5- years.
    • Toxicity included:
  • 1 patient with sacral insufficiency fracture
  • 2 patients with sacral neuropathies
  • 1 patient with rectal bleeding
  • 1 patient with erectile dysfunction.

Results

Author's Conclusions

  • The author concludes that high-dose particle therapy may be safely delivered as part of treatment for sarcomas of the skull base and axial skeleton, although he notes potential concern of sacral nerve toxicity.
  • He notes that radiation at the time of presentation appears to be preferable to radiation at the time of local failure.
  • He describes potential further roles for proton and carbon radiotherapy in treatment of these tumors, both of which appear to be promising techniques and may be used in combination with photon radiation.

Clinical/Scientific Implications

  • Dr. Delaney gives a comprehensive review of radiotherapeutic treatment options for sarcomas of the skeleton and soft tissues.
  • As he points out, higher dose delivery through use of particle therapy appears to offer improved outcomes, particularly for tumors of the axial skeleton, spine, and skull base.
  • Benefits of particle therapy include reduction of integral dose and reduction of dose to normal tissues when compared to conformal radiotherapy or IMRT.
  • Despite these seeming benefits, particle therapy has not been compared directly in a randomized setting to photon radiation, and may never be.
  • Sarcomas represent a diverse group of tumors, all of which require an individualized, multidisciplinary approach. Certainly, the data presented here support the use of particle therapy for treatment of many of them; other radiotherapeutic options that may be employed include brachytherapy, stereotactic radiosurgery, and IMRT. Data with concurrent particle therapy and chemotherapy is quite limited; particularly in the setting of concurrent chemotherapy, particular attention to selection of treatment modality should be paid.


News
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