Carbon Ion Radiotherapy for Bone and Soft Tissue Sarcomas

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

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Presenter: Dr. Tadashi Kamada
Presenter's Affiliation: Research Center for Charged Particle Therapy, Chiba, Japan
Type of Session: Scientific

Background

  • The results from a phase I/II dose escalation study using carbon ion therapy in the treatment of bone and soft tissue sarcomas are presented here. Many patients in this study had osteosarcomas, chordomas or chondrosarcomas, although a variety of histologies were included
  • Osteosarcomas are rare tumors, but do comprise approximately 30% of sarcomas of the bone. They are generally treated with surgery and chemotherapy; however, in areas where negative margins are difficult to achieve, radiation plays an important role
  • Chordomas are rare, slow growing tumors which are thought to arise from remnants of the notochord. Though slow growing, they can be locally aggressive and tend to involve the axial skeleton, often involving the base of skull
  • Chondrosarcomas are malignant cartilaginous tumors which account for approximately 6% of base of skull tumors
  • Surgical resection is generally done initially for debulking and to obtain a diagnosis. Complete resection is preferable, however, this is often difficult. As there is often residual disease, post operative radiation therapy is often used. With involvement of the base of skull, it can be difficult to get adequate dose to the tumor while still sparing critical structures such as the brainstem, optic nerves and chiasm.
  • Charged particle therapy has the potential to improve local control rates due to greater conformality, which may allow higher radiation doses to be delivered safely.

Materials and Methods

  • Phase I
    • 57 patients were accrued and 64 lesions were treated from June 1996 to February 2000
    • All patients were unresectable or refused surgery
    • Patients were treated with doses from 52.8 to 73.6 GyE using 16 GyE fractions over the course of four weeks
    • Fraction sizes ranged from 3.3-4.6 GyE
  • Phase II
    • Enrollment into the phase II portion of the study began in April of 2000 and continued into August of 2008, with a total of 362 patients enrolled
    • All patients were unresectable or refused surgery
    • Ten lesions were treated with 73.6 GyE in 4.6 GyE fractions, 21 with 67.2 GyE in 4.2 GyE fractions, and 19 with 64.0 GyE in 4 GyE fractions. The remaining 299 lesions were treated to 70.4 GyE in 4.4 GyE fractions

Results

  • Phase I:
    • 7/17 patients had grade 3 acute skin reactions at 73.6 GyE, and dose escalation was halted at this point. No other grade 3 or greater toxicity was encountered. Hence, in patients with skin problems, the recommended dose was 70.4 GyE when using 16 fractions over four weeks, whereas in patients without skin issues the recommended dose was 73.6 GyE
    • Local control rates were 89%, 63%, and 63% at 1, 3, and 5 years respectively
    • However, the authors did note a significantly higher rate of local control in patients treated with 57.6 GyE or less versus those treated with 64.0 GyE or more.
    • Median survival was 31 months, with overall survivals of 82%, 47%, and 37% at 1,3, and 5 years respectively
  • Phase II
    • At present, the local control has been 88% and 79% at 2 and 5 years, respectively
    • Overall survival was 61% at 5 years
    • Acute grade 3 or greater toxicity was seen in two patients with grade 3 skin toxicity. Late grade 3 or greater skin toxicity was seen in seven patients, with six patients having grade 3 toxicity and one patients with grade 4 toxicity
    • This group identified several factors which may be related to late skin reactions
      • subcutaneous tumor invasion
      • larger tumor volume
      • sacral location of the tumor
      • prior surgery
      • the addition of chemotherapy
      • irradiation using two portals
    • Per the authors, it appeared possible to prevent these reactions by decreasing total dose, by reducing skin margin, and by using three or more portals to reduce the skin dose
  • 339 patients were analyzable for the phase II portion of the study
  • Survival data from this cohort of patients compared with historical surgical series are presented in the table below
 

1 year OS

2 year OS

5 year OS

Resectable Sarcomas

80-85%

70-75%

32-55

Unresectable Sarcomas

15%

   

Proton Therapy

91%

78%

61%

  • The authors then presented their experience with various sarcoma subsets within the phase II cohort, as below:
  • Chordoma:
    • 3% of all primary bone tumors, 50% arise from the sacrum
    • Of the 95 patients with chordomas (excluding patients with primaries of the base of skull), the local control rate was 88% at five years, and the overall survival was 86% at five years
    • Median survival was 42 months, and median time to failure was 35 months
    • Toxicity: 4 patients had a grade 3 or higher skin reaction, and 15 patients required chronic pain medication for sacral neuropathy
      • Sacral neuropathy appeared to be associated with treating an area greater than 10 cm in size and using doses greater than 70 CGE
      • At present, the preferred dose for chordoma of the sacrum is 67.4 CGE
    • Conclusions:
      • Outcomes with carbon ion therapy appear to be comparable with surgery
      • Further studies regarding quality of life are needed
  • Osteosarcoma
    • Overall survival for all patients was 29% at five years and local control was 65% at five years
    • In patients with tumors that were less than 700 cc’s, overall survival was 45% at five years and local control was 96% at five years
    • Conclusions
      • Lung metastasis remain a major problem
      • Results appear to be similar to surgery
      • Big tumors may be good candidates for carbon ion beam therapy, as local control can still be achieved
  • Retroperitoneal sarcoma
    • Represent 15% of all sarcomas
    • They are often difficult to resect
    • Overall survival was 69% at 5 years, and local control was 65% at five years
    • Gortex spacers were used in some patients to facilitate carbon ion therapy
    • Conclusions:
      • Outcomes are similar to surgery
      • Gortex spacers can facilitate treatment and limit toxicity
  • Primary sarcomas of the spine
    • A patch technique was employed to treat tumors while avoiding the spinal cord
    • 16 patients were treated in this series
    • There was no myelopathy seen in any patients
    • Three patients had compression fractures which required surgery after treatment
    • Overall survival was 52%, and local control was 86% at five years
    • Conclusions
      • The patch technique is feasible with carbon ion therapy of the spine
      • There is acceptable morbidity associated with carbon ion therapy of the spine
  • Extremity Sarcomas
    • Represent less than 5% of sarcomas
    • Total of 16 patients were treated in this series
    • Overall survival was 69% at four years and local control (limb sparing) was 75%.
    • Median survival was 29 months
    • Conclusions:
      • Carbon ion therapy is feasible in the treatment of extremity sarcomas

Author's Conclusions

  • See individual conclusions for each tumor type above
  • Overall, carbon ion therapy appears to be effective with comparable results compared with surgery. It may be a viable alternative therapy to surgery

Clinical/Scientific Implications

  • Radiation can add to local control after surgery, even with positive margins, though higher doses are generally needed. In unresectable patients or those who refused surgery, greater local control was seen with doses greater than 63 Gy compared with doses lower than 63 Gy (Kepka, IJROBP, 2005). Data from Harvard suggests that in chordomas and chondrosarcomas with gross residual disease, doses in the 70 Gy range should be used. However, patients with tumors which involve the base of skull, or other areas that are difficult to operate on, often have residual gross disease or are unresectable. This problem is often compounded by the proximity of the tumor to critical structures, impairing the delivery of adequate radiation doses. A number of studies have suggested that protons may allow higher doses to be delivered safely.
  • The use of carbon ions may provide two potential benefits. First, carbon ions have a higher RBE compared with photons. Secondly, carbon ions can have a superior dose distribution compared with photon based therapy, and there may be less lateral scatter and a sharper Bragg peak compared with proton therapy. This study suggests that carbon ion therapy is feasible and has results similar to surgery in many types of sarcomas. This study also suggests that relatively large fractions can be given with limited toxicity. The local control and overall survival rates in this study are encouraging and warrant further study.



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