Radiation Oncology/Chordoma

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Contents 1 Epidemiology 2 Anatomy 3 Presenting Symptoms 4 Histologic Subtypes 5 Treatment Overview 6 Surgery 6.1 Skull Base 6.2 Mobile Spine Chordoma 6.3 Sacral Chordoma 7 Photon Therapy 7.1 Conventional 8 Proton Beam Therapy 9 Carbon Ion Radiotherapy 10 Treatment Toxicity 10.1 Temporal Lobe Damage 10.2 Visual Complications 11 Review

[edit] Epidemiology

• Arise from embryonic notochordal remnants along neuraxis, which in adults are primarily located at skull base and in sacrum
• Rare tumor; US incidence 0.08/100,00
  • Represents 6% of skull base tumors; but 2-4% of primary bone neoplasms
• Median age is 60 (though in blacks age 27)
• More common in males (incidence 0.10/100,000) than females (0.06/100,000)
• Predominately in whites (91%), rare in blacks (2%)
• Characterized by slow growth, with local destruction of bone and extension into adjacent soft tissues. Typically have an indolent course with multiple local recurrences
• As many as 30-40% may metastasize, but typically toward the end of disease course

• NCI/SEER; 2001 PMID 11227920 -- "Chordoma: incidence and survival patterns in the United States, 1973-1995." (McMaster ML, Cancer Causes Control. 2001 Jan;12(1):1-11.)
  • SEER database. 400 cases, microscopically confirmed chordoma.
  • Epidemiology: Incidence 0.08/100,000; more common in males (0.10) than females (0.06); more common in whites (91%). Youngest age quartile cranial presentation (54%) vs. oldest age quartile sacral presentation (41%)
  • Treatment: Surgery alone 48%, surgery + EBRT 38%, RT only 14%. Sacral lesions more likely RT alone (32% vs. 11%)
  • Outcome: median OS 6.3 years; 5-year OS 68%, 10-year OS 40%

[edit] Anatomy

• In adults, remnants of notochord are present as the nucleus pulposus of the intravertebral discs, and distribution of tumors matches distribution of the remnants
  • ~35% in sphenooccipital region (almost always involving clivus)
  • 15-30% in vertebral column
  • 30-50% in sacrococcygeal region

• NCI/SEER; 2001 (1973-1995) PMID 11227920 -- "Chordoma: incidence and survival patterns in the United States, 1973-1995." (McMaster ML, Cancer Causes Control. 2001 Jan;12(1):1-11.)
  • SEER database. 400 cases, microscopically confirmed.
  • Outcome: Cranial 32%, spinal 33%, sacral 29%

• Mayo Clinic; 1973 (1910-1971) PMID 4722921 -- "Chordomas and cartilaginous tumors at the skull base." (Heffelfinger MJ, Cancer. 1973 Aug;32(2):410-20.)
  • Retrospective. 155 chordomas. 49% sacro-coccygeal, 36% spheno-occipital, 15% vertebral column. Presentation, pathology, and outcomes reviewed

[edit] Presenting Symptoms

• Location-dependent
• Combination of pain, weakness, sensory abnormalities, motor abnormalities and bowel/bladder dysfunction
• Pain onset typically insidious; median duration 14 months (4-24 months) in one study
• Sacral:
  • Tumors can grow to a large size
  • Primary presenting complaint is lower back / sciatic pain, and constipation
• Mobile spine:
  • Neurologic deficit more common than in sacrum, approaching 50%
  • Airway obstruction or dysphagia in cervical spine
• Skull base:
  • May be intracranial or extracranial, with mass effect symptoms depending on location
  • Headaches and/or facial pain are common
  • Pituitary insufficiency, hemianopsia/diplopia, cranial nerve deficits, nasal stuffiness.

[edit] Histologic Subtypes

• Conventional
• Chondroid
  • Better prognosis
  • Subtype with predilection for skull base location
• Dedifferentiated

• Memorial Sloan Kettering; 2008 PMID 18641983 -- "Chordoma and chondrosarcoma gene profile: implications for immunotherapy." (Schwab JH, Cancer Immunol Immunother. 2008 Jul 19. [Epub ahead of print])
  • Affymetrix gene expression profiles, 6 chordoma and 14 chondrosarcoma. Validation by qPCR and IHC
  • Outcome: Both show overexpression of extracellular matrix genes compared to other sarcoma types. Chordoma selective expression of T Brachyury and CD24; chondrosarcoma Type IX and XI collagen. HMW-MAA expressed in chordoma 62%, chondrosarcoma 48%
  • Conclusion: Similar gene profile of upgregulated ECE matrix genes

[edit] Treatment Overview

• Maximal resection followed by proton beam irradiation.
  • Overall survival is dependent upon local control of disease. Prognostic factor for local control of disease is amount of residual tumor after original surgery (<25cc residual tumor is better).
  • Clear margins are achieved in <50% of skull base chordomas.
  • Doses of 70 CGE necessary for control of residual disease.

[edit] Surgery

• Most important prognostic factor is en bloc resection with negative surgical margins
• Technically, this may be achieved in ~50% of patients, and leads to 70% long-term control rate
  • Extensive infiltrating disease at presentation
  • Nearby critical structures, resulting in severe morbidity from radical approaches
• Primary operation is critical, as reoperation has significantly lower rates of technical success
• Subtotal resection results in ~70% recurrence rate

[edit] Skull Base

• Hannover; 2007 (Germany) PMID 17695386 -- "Chordomas of the skull base: surgical management and outcome." (Samii A, J Neurosurg. 2007 Aug;107(2):319-24.)
  • Retrospective. 49 patients. Transethmoidal approach 36%, pterional 23%, retrosigmoid 23%.
  • Outcome: GTR 49%, subtotal resection 51%. Initial surgery GTR 78%. 5-year OS 65%, 10-year OS 39%
  • Toxicity: New neurological deficit 12%
  • Conclusion: Chordoma cannot be regarded as surgically curable tumors, given the 5- and 10-year OS

• University of Washington; 2006 (1988-2004) PMID 16883163 -- "Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas." (Tzortzidis F, Neurosurgery. 2006 Aug;59(2):230-7; discussion 230-7.)
  • Retrospective. 74 patients, aggressive microsurgical resection of cranial base chordomas, 121 procedures. Primary operation 63%, re-operation 37%. Mean F/U 8 years
  • Outcome: Gross total resection 72%, subtotal resection 28%. During F/U, NED 32%, alive with disease 50%, died of disease 15%, died of complications 3%. 10-year RFS 31% (primary surgery 42% vs reoperation 26%, SS)
  • Conclusion: Aggressive microsurgical resection can be followed by long-term tumor free survival, with good functional outcome

[edit] Mobile Spine Chordoma

• Bologna; 2006 PMID 16481964 -- "Chordoma of the mobile spine: fifty years of experience." (Boriani S, Spine. 2006 Feb 15;31(4):493-503.)
  • Retrospective. 52 chordomas of mobile spine, 37 cases 1991-2002.
  • Outcome: Post-op mortality 8%. If en bloc resection, 67% (12/18) without relapse at median F/U 8 years, 100% of relapses (6/6) had prior inadequate resections. All others (RT alone, surgery with SM+, or surgery with SM+ and adjuvant RT) had recurrences <2 years. Intralesional excsion + RT high rate of recurrence 75%
  • Conclusion: The only protocol associated with continuously disease-free survival is margin-free en bloc resection

[edit] Sacral Chordoma

• Mayo Clinic; 2005 (1980-2001) PMID 16203885 -- "Operative management of sacral chordoma." (Fuchs B, J Bone Joint Surg Am. 2005 Oct;87(10):2211-6.)
  • Retrospective. 52 patients with sacro-coccygeal chordoma. Posterior approach 42%, combined anteroposterior approach 58%. Wide surgical margin 40%. Median F/U 7.8 years
  • Outcome: LR 44%; RFS 5-years 59%, 10-years 46%. OS 5-years 74%, 10-years 52%, 15-years 47%. Wide surgical margin most important predictor for survival (100%)
  • Conclusion: Wide surgical margin most important predictor of survival and local recurrence

• Goteborg; 2000 (Sweden)(1968-1998) PMID 10813725 -- "Prognostic factors in chordoma of the sacrum and mobile spine: a study of 39 patients." (Bergh P, Cancer. 2000 May 1;88(9):2122-34.)
  • Retrospective. 39 patients with chordoma, 30 sacral and 9 vertebral. Modern surgical techniques. Mean F/U 8.1 years
  • Outcome: wide SM 59%. LR 44%, DM 28%. 5-year OS 84%, 10-year OS 64%
  • Conclusion: Improved local control and survival with new surgical techniques

• MD Anderson; 1999 (1954-1994) PMID 9894966 -- "Sacral chordoma: 40-year experience at a major cancer center." (York JE, Neurosurgery. 1999 Jan;44(1):74-9; discussion 79-80.)
  • Retrospective. 27 patients with sacral chordoma. 26/27 pain, 17/27 autonomic dysfunction. Single operation 44%, two surgeries 33%, multiple surgeries 22%. RT used in 19% of operations
  • Outcome: median OS 7.4 years. Recurrence in 70% of surgeries. Median DFS radical surgery 2.3 years vs. subtotal surgery 8 months (SS). If subtotal resection, adjuvant RT 2.1 years vs. no RT 8 months (SS)
  • Conclusion: Frequent recurrences. Radical resection leads to improved DFS; adjuvant RT after subtotal resection also leads to improved DFS

[edit] Photon Therapy

[edit] Conventional

• Princess Margaret; 1996 (1958-1992) PMID 8961370 -- "Chordoma: long-term follow-up after radical photon irradiation." (Catton C, Radiother Oncol. 1996 Oct;41(1):67-72.)
  • Retrospective. 48 patients with chordoma (sacrum 48%, 42%, mobile spine 10%) referred for consideration, 44 post-op with gross residual disease, 4 microscopic residual disease. RT 26 patients 50/25, 8 patients hyperfractionated 40/44 @ 1 Gy/fx TID, 3 referred for charged particles. 67% patient symptomatic (neurological or pain)
  • Outcome: median OS 5.2 years, median TTP 2.9 years. 5-year PFS 23%, 10-year PFS 15%. 1/23 complete response, but good palliation in 85%. No difference between median dose 40 Gy and 60 Gy groups. Median OS after re-treatment 1.5 years. Dead of disease 78%, alive with disease 17%, NED 5%
  • Conclusion: Overt residual chordoma rarely cured with conventional EBRT, but treatment does provide useful and prolonged palliation. Suitable patients should be referred for stereotactic photon or particle beam therapy

[edit] Proton Beam Therapy

• Orsay; 2008 (France)(1996-2006) PMID 18440726 -- "Proton therapy in pediatric skull base and cervical canal low-grade bone malignancies." (Habrand JL, Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):672-5. Epub 2008 Apr 25.)
  • Retrospective. 30 children with chordoma (n=26), chondrosarcoma (n=3), and chondroma (n=1). Location in skull base (n=13), skull base with extension to cervical canal (n=12), or cervical canal (n=1). Median age 13.5 years. Surgery followed by photon/proton therapy. Mean total dose 68.4 CGE (54.6-71); mean photon dose 37.4 Gy (30.6-45), mean proton dose 32.1 CGE (20-70.2). F/U 2.2 years
  • Outcome: Local control chordoma 21/26 (81%), chondrosarcoma 3/3 (100%), chondroma 1/1 (100%). 5-year PFS chordoma 77%, chondrosarcoma 100%
  • Toxicity: Grade 3 auditory toxicty 1 patient, Grade 2 pituitary failure 7 patients
  • Conclusion: Well tolerated, excellent local control

• Institut Curie; 2005 (1992-2002) PMID 16227160 -- "Chordomas of the base of the skull and upper cervical spine. One hundred patients irradiated by a 3D conformal technique combining photon and proton beams." Noel G et al. Acta Oncol. 2005;44(7):700-8.
  • Retrospective. 100 patients w/ skull base or upper cervical spine chordoma tx'd w/ proton/photon therapy. Median total dose to tumor 67 CGE.
  • 2 yr local control rate 86.3%, 4 yr local control rate 53.8%.
  • Multivariate analysis showed minimal dose to tumor <56 CGE and failure to encompass 95% tumor w/ 95% isodose line were independent factors for local control.

• Harvard/Loma Linda; 2002 (1992-1999) PMID 11958897 -- "Proton radiotherapy in management of pediatric base of skull tumors." (Hug EB, Int J Radiat Oncol Biol Phys. 2002 Mar 15;52(4):1017-24.)
  • Retrospective. 29 patients. Chordoma (n=10), chondrosarcoma (n=3), rhabdomyosarcoma (n=4), other sarcomas (n=3), giant cell tumors (n=6), angiofibromas (n=2), chondroblastoma (n=1). Dose 45 - 78.6 CGE in standard fractions. Mean F/U 3.3 years
  • Outcome: Malignant tumors - LC 75% (chordoma 60%, chondrosarcoma 100%, rhabdo 100%, other sarcomas 66%), 5-year OS 56%. Benign tumors - LC 8/9, 5-year OS 100%
  • Toxicity: Severe late in 7% (motor weakness, sensory deficits)
  • Conclusion: Proton RT after major skull base surgery can offer considerable tumor control and survival

• Loma Linda; 1999 (1992-98) - PMID 10470818 -- "Proton radiation therapy for chordomas and chondrosarcomas of the skull base." Hug EB et al. J Neurosurg. 1999 Sep;91(3):432-9.
  • Retrospective. 33 chordoma pts (and 25 chondrosarcomas) tx'd w/ proton beam irradiation after maximal surgery. Dose range of 64.8-79.2 CGE.
  • 5yr OS for chondrosarcoma was 79%. 5yr local control for chondrosarcoma was 76%.
  • Control rates were influenced by brainstem involvement and tumor volume.
  • Chordoma with worse outcomes than chondrosarcoma.

• MGH; 1995 (1975-93) - PMID 7558946 -- "Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse." Fagundes MA et al. Int J Radiat Oncol Biol Phys. 1995 Oct 15;33(3):579-84.
  • 63 pts w/ treatment failure who were tx'd at MGH w/ surgery + combined photon/proton RT to median dose of 70 CGE (66.6-77.4).
  • 95% of these pts had local failure as element of their disease failure; 78% had local failure as site of first failure.

[edit] Carbon Ion Radiotherapy

• Heidelberg, Germany, 2007 (1998-2005) - PMID 17363188 -- "Effectiveness of carbon ion radiotherapy in the treatment of skull-base chordomas." Schulz-Ertner D et al. Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):449-57.
  • 96 pts w/ skull base chordoma tx'd w/ carbon ion radiotherapy. All pts had gross residual tumor. Median total dose of 60 CGE (range 60-70). 20 fx over 3 wks.
  • 80.6% local control at 3 yrs, 70% local control at 5 yrs.
  • 91.8% OS at 3 yrs, 88.5% OS at 5 yrs.

[edit] Treatment Toxicity

[edit] Temporal Lobe Damage

• MGH, 1998 (1984-93) - PMID 9588918 -- "Temporal lobe (TL) damage following surgery and high-dose photon and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of the base of the skull." Santoni R et al. Int J Radiat Oncol Biol Phys. 1998 Apr 1;41(1):59-68.
  • 99 pts w/ chordoma or chondrosarcoma of skull base tx'd w/ photon/proton radiotherapy.
  • 10 pts developed temporal lobe damage w/ 8 pts having moderate to severe symptoms.
  • Actuarial temporal lobe damage rate was 7.6% at 2 yrs, 13.2% at 5 yrs.

[edit] Visual Complications

• Liverpool; 2003 (UK) PMID 12724692 -- "Visual complications of proton beam therapy for clival chordoma." (Bowyer J, Eye. 2003 Apr;17(3):318-23.)
  • Case report. 4 patients referred for post-op proton therapy.
  • Outcome: Bilateral visual loss in 2/4 (50%) patients at 1 and 2 years post proton therapy
  • Conclusion: Proton beam therapy not innocuous

[edit] Review

• Milan; 2006 (Italy) PMID 17545801 -- "Chordoma." (Casali PG, Curr Opin Oncol. 2007 Jul;19(4):367-70.)

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