# Radiation Oncology/Chordoma
## 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%

## 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

## 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.

## 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

## 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.

## 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

### 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

### 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

### 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

## Photon Therapy
### 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

## 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.

## Carbon Ion Radiotherapy

* Nagoya; 2011 (1990-2007) PMID 20400242 -- "Clinical outcome of sacral chordoma with carbon ion radiotherapy compared with surgery." (Nishida Y, Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):110-6. Epub 2010 Apr 17.)
** Retrospective. 17 patients, primary sacral chordoma, treated with surgery (n=10) or carbon ion RT (n=7). Median dose GyE 70.4. Median F/U surgery 6.3 years, RT 4.1 years
** Outcome: 5-year LRFS surgery 62% vs RT 100%, DSS 86% vs 53%. Functional outcome surgery 55% vs RT 75%
** Toxicity: Urinary-anorectal function worse in 60% of surgery patients, unchanged in RT patients.
** Conclusion: Carbon ion RT results in high local control and preservation of function compared with surgery
* 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.

## Treatment Toxicity
### 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.

### 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

## Review

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