What are the indications for IMRT, brachytherapy, intraoperative radiotherapy (IORT), extra-corporeal radiotherapy and particle therapy in the management of BSTTs?

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Introduction

The standard adjuvant radiotherapy, whether used pre-operatively or post-operatively in the management of sarcomas tends to be 3-D Conformal Radiotherapy (3-DCRT). However, there are additional older (brachytherapy) and newer (IMRT, particle therapy etc) methods of delivering the radiation that may have advantages in specific situations.

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Brachytherapy

There is definite evidence that adjuvant brachytherapy improves local control over surgery alone in the management of high grade soft tissue sarcomas of the extremity and superficial trunk.[1][2] The enhancement of local control however does not extend to low grade tumours.[1][3][2] The addition of brachytherapy does not seem to increase morbidity significantly over surgery alone, though a higher wound complication rate is noted,[4] as with pre-operative radiation. Brachytherapy may have a higher early wound complication rate when compared with External Beam Radiation alone.[5]

Brachytherapy has been used as a “boost” in retroperitoneal sarcomas (RPS), intraoperatively, either with pre-operative[6] or post-operative[7] external beam radiation. An enhancement of local control has been suggested in several case series. A small randomised study showed benefit with use of HDR–IORT.[8] However no advantage with HDR–IORT is seen in local control or overall survival at 10 years when combined with preoperative radiotherapy. [9]

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Intra-operative radiotherapy (IORT)

IORT is used as a method to boost radiation doses to areas of subclinical and microscopic disease positivity identified during time of the surgery. The advantages are it allows high doses to be delivered to areas of clinical concern while sparing normal tissue. IORT can be delivered with an external beam method,[10] using electrons or with high dose rate brachytherapy (HDR).[7] A small randomised study of 35 patients compared post-operative external beam radiation alone in one arm with IORT boost followed by smaller doses of external radiation for patients with retroperitoneal sarcomas. Lower local recurrences (6 out of 15) were reported with IORT compared with post-operative external radiation alone (16 out of 20). Significantly lower radiation enteritis was noted in the IORT arm than the control arm; however a higher rate of neuropathy was reported.[8]

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Intensity modulated radiotherapy (IMRT)

IMRT or Intensity modulated radiotherapy is a radiation planning and delivery technique that is more complicated and potentially more precise than conventional methods of radiotherapy that use forward planned 3-D Conformal Radiation techniques.

IMRT has been evaluated to reduce wound complications by sparing the uninvolved tissues.[11] There are case reports of excellent local control and better sparing of normal tissue when used adjuvant with surgery[12][13][14][15] in limb and truncal sarcomas.

For retroperitoneal sarcomas there are a few plan comparison studies and case reports suggesting better dose conformity to the target and lower doses to organs at risk with IMRT technique.[16][17]

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Intraoperative extra-corporeal radiotherapy

Management of bone and soft tissue tumours (BSTTs) at times may involve resecting the diseased segment of the bone of a patient with bone or soft tissue tumour. The resected specimen can be replaced by an allograft or prosthesis. The use of Extracorporeal Radiotherapy to the bone fragment allows the patients own resected bone specimen to be use as an “autograft”.

The process involves “en bloc” wide excision of tumour, curettage and removal of tumour in theatre, than transportation of the specimen for Extracorporeal Radiation to a dose of 50Gy to 300Gy in a single fraction[18][19][20][21][22][23][24] and re-implantation in the patient, as an autograft.

There are a few case series around the world reporting generally good functional outcomes.[18][19][20][21][22][23][24] A higher complication rate, mainly infection and delayed healing is noted in some case series.[23]

Histopathological examination after Extracorporeal radiotherapy in one case series showed complete sterilization of tumour cells in all specimens examined, but viable chondrocytes capable of laying matrix.[20]

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Particle therapy

Standard radiotherapy utilises high energy X-Rays (gamma rays) or photon beams for treatment. Particle therapy is a form of external beam radiotherapy using beams of energetic protons, neutrons, or positive ions such as Carbon ions for cancer treatment. The most common type of particle therapy is proton therapy.

For protons and heavier ions, the dose increases while the particle penetrates the tissue and loses energy continuously. Hence the dose increases with increasing thickness up to the Bragg peak that occurs near the end of the particle's range. Beyond the Bragg peak, the dose drops to zero (for protons) or almost zero (for heavier ions). The perceived advantage of this energy deposition profile is that less energy is deposited into the healthy tissue surrounding the target tissue. There is no available confirmatory evidence comparing particle beam radiation with photon beam therapy (conventional radiation) in management of bone and soft tissue sarcomas. There are a number of published case series describing outcomes with proton beam[25][26][27][28] and carbon ion therapy[29][30][31][32] for bone and soft tissue tumours. A phase 2 study of patients with spinal and paraspinal sarcomas treated with particle beam therapy after biopsy or resection had a five-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively[33] Serizawa et al[31] from Chiba, Japan report on 24 patients with unresectable retroperitoneal sarcomas treated with Carbon ion therapy. The five year local for this group of unresectable patients is 69%, with no toxicity greater than grade 2. Scultz-Ertner[30] from Germany report 81% local control for Chordoma and 100% local control at three years for Chondrosarcoma in their experience. No grade 4/5 complications were noted.

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Evidence summary and recommendations

Brachytherapy

Evidence summary Level References
Brachytherapy improves local control over surgery alone in the management of high grade soft tissue sarcomas of the extremity and superficial trunk. II [1], [3]
Effect does not extend to low grade tumours. II [1], [3], [2]
Brachytherapy may have higher wound complication rate compared to External Beam Radiation. III-2 [5]
Brachytherapy boost with IORT may add small benefit over post operative external radiation alone for retroperitoneal sarcomas. II [8]
Brachytherapy boost with IORT adds no benefit to preoperative radiation alone for retroperitoneal sarcomas. III-2 [9]


Evidence-based recommendationQuestion mark transparent.png Grade
Brachytherapy (as an alternate or as a boost to external beam radiation) improves local control over surgery alone for high grade sarcomas for the limb and trunk.
B


Intraoperative radiotherapy (IORT)

Evidence summary Level References
IORT when combined with surgery and external beam radiotherapy may improve local control. II [8]
Other combinations and forms of delivering IORT, such as electron beam, may offer benefit. IV [7], [6], [10]
Evidence-based recommendationQuestion mark transparent.png Grade
IORT boost to external radiation could be considered in combination with surgery for management of retroperitoneal sarcomas.
B


Intensity modulated radiation therapy (IMRT)

Evidence summary Level References
Insufficient evidence to confirm IMRT results in lesser complications by more normal tissue sparing. Better conformity in plans and lower doses to normal tissues noted for both limb and retroperitoneal sarcoma plans. III-2, IV [11], [12], [14], [15]
Evidence-based recommendationQuestion mark transparent.png Grade
It maybe reasonable to consider IMRT for patients with retroperitoneal and extremity/truncal sarcomas as adjuvant to surgery, if resource permits, for potential advantages in reduction of radiation dose to normal tissues.
D


Intraoperative extra-corporeal radiotherapy

Evidence summary Level References
Case series from few centres around the world suggests en Bloc wide local excision, removal of tumour and reimplant of the “autograft” after a single large fraction of radiation to the resected fragment of bone is a viable option for reconstruction with satisfactory to good functional outcomes.

Doses of radiation used are 50Gy to 300Gy.

There appears to be complete sterilization of tumour at these dose levels.

IV [18], [19], [20], [21], [22], [23], [24]
Evidence-based recommendationQuestion mark transparent.png Grade
Reconstruction using the patients own resected bone (previously bearing the sarcoma) fragment after a large extra-corporeal dose of radiation is a possible option reported to have satisfactory to good functional outcomes.
D


Particle therapy

Evidence summary Level References
Particle beam therapy such as proton and carbon ion therapy appear to provide excellent local control in unresectable and partially resected sarcomas, particularly Chordomas, Chondrosarcomas of sacrum and skull base and retroperitoneal sarcomas. Toxicity reported appears to be low.

No direct comparison between particle beam therapy and equivalent doses of photon beam therapy exists for sarcomas.

IV [25], [26], [33], [29], [30], [31], [32], [28]
Evidence-based recommendationQuestion mark transparent.png Grade
Particle beam therapy appears to offer good local control with acceptable toxicity.
D


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Issues requiring more clinical research study

A number of gaps in the evidence have been identified. These include:

IORT

• Consensus / Confirmation that radiotherapy improves local control in Retroperitoneal Sarcomas.

• If above consensus/confirmation is reached, value of IORT as an additional boost to EBRT to further improve local control can be tested.

IMRT

• Comparative study of 3DCRT and IMRT for Retroperitoneal and Limb/Truncal Sarcomas to demonstrate lower normal tissue toxicity with IMRT.

Intraoperative extra-corporeal radiotherapy

• Comparative study to determine function outcome differences between use of prosthesis, bone bank allografts and extra-corporeally radiated autografts.

Particle therapy

• Study comparing particle beam therapy and photon therapy for sarcomas with local control and toxicity as end points.

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References

  1. 1.0 1.1 1.2 1.3 Harrison LB, Franzese F, Gaynor JJ, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 1993 Sep 30;27(2):259-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8407399.
  2. 2.0 2.1 2.2 Pisters PW, Harrison LB, Woodruff JM, Gaynor JJ, Brennan MF. A prospective randomized trial of adjuvant brachytherapy in the management of low-grade soft tissue sarcomas of the extremity and superficial trunk. J Clin Oncol 1994 Jun;12(6):1150-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8201376.
  3. 3.0 3.1 3.2 Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996 Mar;14(3):859-68 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8622034.
  4. Alektiar KM, Zelefsky MJ, Brennan MF. Morbidity of adjuvant brachytherapy in soft tissue sarcoma of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 2000 Jul 15;47(5):1273-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10889381.
  5. 5.0 5.1 Emory CL, Montgomery CO, Potter BK, Keisch ME, Conway SA. Early Complications of High-dose-rate Brachytherapy in Soft Tissue Sarcoma: A Comparison With Traditional External-beam Radiotherapy. Clin Orthop Relat Res 2012 Mar;470(3):751-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21960155.
  6. 6.0 6.1 Jones JJ, Catton CN, O'Sullivan B, Couture J, Heisler RL, Kandel RA, et al. Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002 May;9(4):346-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11986186.
  7. 7.0 7.1 7.2 Alektiar KM, Hu K, Anderson L, Brennan MF, Harrison LB. High-dose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):157-63 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10758318.
  8. 8.0 8.1 8.2 8.3 Sindelar WF, Kinsella TJ, Chen PW, DeLaney TF, Tepper JE, Rosenberg SA, et al. Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg 1993 Apr;128(4):402-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8457152.
  9. 9.0 9.1 Smith MJ, Ridgway PF, Catton CN, Cannell AJ, O'Sullivan B, Mikula LA, et al. Combined management of retroperitoneal sarcoma with dose intensification radiotherapy and resection: long-term results of a prospective trial. Radiother Oncol 2014 Jan;110(1):165-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24411227.
  10. 10.0 10.1 Pisters PW, Ballo MT, Fenstermacher MJ, Feig BW, Hunt KK, Raymond KA, et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol 2003 Aug 15;21(16):3092-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12915599.
  11. 11.0 11.1 O'Sullivan B, Griffin AM, Dickie CI, Sharpe MB, Chung PW, Catton CN, et al. Phase 2 study of preoperative image-guided intensity-modulated radiation therapy to reduce wound and combined modality morbidities in lower extremity soft tissue sarcoma. Cancer 2013 Feb 19 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23423841.
  12. 12.0 12.1 Alektiar KM, Brennan MF, Healey JH, Singer S. Impact of intensity-modulated radiation therapy on local control in primary soft-tissue sarcoma of the extremity. J Clin Oncol 2008 Jul 10;26(20):3440-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18612160.
  13. Alektiar KM, Hong L, Brennan MF, Della-Biancia C, Singer S. Intensity modulated radiation therapy for primary soft tissue sarcoma of the extremity: preliminary results. Int J Radiat Oncol Biol Phys 2007 Jun 1;68(2):458-64 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17363186.
  14. 14.0 14.1 Lin C, Donaldson SS, Meza JL, Anderson JR, Lyden ER, Brown CK, et al. Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803--a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 2012 Apr 1;82(5):1764-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21470795.
  15. 15.0 15.1 Mounessi FS, Lehrich P, Haverkamp U, Willich N, Bölling T, Eich HT. Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy. Strahlenther Onkol 2013 Apr;189(4):308-14. doi: 10.1007/s00066-012-0304-z. Epub 2013 Feb 28. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23443613.
  16. Koshy M, Landry JC, Lawson JD, Staley CA, Esiashvili N, Howell R, et al. Intensity modulated radiation therapy for retroperitoneal sarcoma: a case for dose escalation and organ at risk toxicity reduction. Sarcoma 2003;7(3-4):137-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18521378.
  17. Bossi A, De Wever I, Van Limbergen E, Vanstraelen B. Intensity modulated radiation-therapy for preoperative posterior abdominal wall irradiation of retroperitoneal liposarcomas. Int J Radiat Oncol Biol Phys 2007 Jan 1;67(1):164-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17084556.
  18. 18.0 18.1 18.2 Anacak Y, Sabah D, Demirci S, Kamer S. Intraoperative extracorporeal irradiation and re-implantation of involved bone for the treatment of musculoskeletal tumors. J Exp Clin Cancer Res 2007 Dec;26(4):571-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18365554.
  19. 19.0 19.1 19.2 Davidson AW, Hong A, McCarthy SW, Stalley PD. En-bloc resection, extracorporeal irradiation, and re-implantation in limb salvage for bony malignancies. J Bone Joint Surg Br 2005 Jun;87(6):851-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15911672.
  20. 20.0 20.1 20.2 20.3 Hatano H, Ogose A, Hotta T, Endo N, Umezu H, Morita T. Extracorporeal irradiated autogenous osteochondral graft: a histological study. J Bone Joint Surg Br 2005 Jul;87(7):1006-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15972922.
  21. 21.0 21.1 21.2 Hong A, Stevens G, Stalley P, Pendlebury S, Ahern V, Ralston A, et al. Extracorporeal irradiation for malignant bone tumors. Int J Radiat Oncol Biol Phys 2001 Jun 1;50(2):441-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11380232.
  22. 22.0 22.1 22.2 Puri A, Gulia A, Jambhekar N, Laskar S. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradiation and re-implantation of the host bone: extracorporeal irradiation as an option for reconstruction in diaphyseal bone sarcomas. J Bone Joint Surg Br 2012 Jul;94(7):982-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22733957.
  23. 23.0 23.1 23.2 23.3 Sabo D, Bernd L, Buchner M, Treiber M, Wannenmacher M, Ewerbeck V, et al. [Intraoperative extracorporeal irradiation and replantation in local treatment of primary malignant bone tumors]. Orthopade 2003 Nov;32(11):1003-12 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14615850.
  24. 24.0 24.1 24.2 Poffyn B, Sys G, Mulliez A, Van Maele G, Van Hoorebeke L, Forsyth R, et al. Extracorporeally irradiated autografts for the treatment of bone tumours: tips and tricks. Int Orthop 2011 Jun;35(6):889-95 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20652247.
  25. 25.0 25.1 Amichetti M, Amelio D, Cianchetti M, Enrici RM, Minniti G. A systematic review of proton therapy in the treatment of chondrosarcoma of the skull base. Neurosurg Rev 2010 Apr;33(2):155-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19921291.
  26. 26.0 26.1 Ares C, Hug EB, Lomax AJ, Bolsi A, Timmermann B, Rutz HP, et al. Effectiveness and safety of spot scanning proton radiation therapy for chordomas and chondrosarcomas of the skull base: first long-term report. Int J Radiat Oncol Biol Phys 2009 Nov 15;75(4):1111-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19386442.
  27. Delannes M, Thomas L, Martel P, Bonnevialle P, Stoeckle E, Chevreau C, et al. Low-dose-rate intraoperative brachytherapy combined with external beam irradiation in the conservative treatment of soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):165-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10758319.
  28. 28.0 28.1 Rombi B, DeLaney TF, MacDonald SM, Huang MS, Ebb DH, Liebsch NJ, et al. Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 2012 Mar 1;82(3):1142-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21856094.
  29. 29.0 29.1 Schulz-Ertner D, Nikoghosyan A, Thilmann C, Haberer T, Jäkel O, Karger C, et al. Carbon ion radiotherapy for chordomas and low-grade chondrosarcomas of the skull base. Results in 67 patients. Strahlenther Onkol 2003 Sep;179(9):598-605 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14628125.
  30. 30.0 30.1 30.2 Schulz-Ertner D, Nikoghosyan A, Thilmann C, Haberer T, Jäkel O, Karger C, et al. Results of carbon ion radiotherapy in 152 patients. Int J Radiat Oncol Biol Phys 2004 Feb 1;58(2):631-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14751537.
  31. 31.0 31.1 31.2 Serizawa I, Kagei K, Kamada T, Imai R, Sugahara S, Okada T, et al. Carbon ion radiotherapy for unresectable retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys 2009 Nov 15;75(4):1105-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19467578.
  32. 32.0 32.1 Kamada T, Tsujii H, Tsuji H, Yanagi T, Mizoe JE, Miyamoto T, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol 2002 Nov 15;20(22):4466-71 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12431970.
  33. 33.0 33.1 DeLaney TF, Liebsch NJ, Pedlow FX, Adams J, Dean S, Yeap BY, et al. Phase II study of high-dose photon/proton radiotherapy in the management of spine sarcomas. Int J Radiat Oncol Biol Phys 2009 Jul 1;74(3):732-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19095372.

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Appendices

Further resources