A 67-year-old female presented with a large unresectable sacral chordoma. Chordomas are rare tumors that arise from notochord remnants in the spine or skull. She received radiotherapy but the tumor recurred. Adjuvant radiation therapy improves local control rates for chordoma compared to surgery alone, but conventional radiation doses were often too low. Modern intensity-modulated radiation therapy allows safer dose escalation and achieves better local control and survival compared to older techniques. Particle therapy may further improve outcomes by concentrating the high radiation dose in the tumor.

1. Unresectable sacral
chordoma

2. Female patient 67 yrs old
presented in 5/2017 with iliac bone pain more on RT side of
4ms duration.
**Pain of insidious onset & progressive course, not respond
to simple analgesics.
Examination: All free except tender in the lower back &
sacro- coccgeal region.
PS:2

3. MSCTPA show:
Destructive soft tissue mass lesion seen involving the RT side
of the sacrum & showing intra pelvic extensions with clear fat
plane between the mass & rectum Plus extra pelvic
extensions extending to the RT gluteal region.
The mass measure 10.7 * 7.2 * 8.8 cm

4. MRI pelvic show:
Huge Rt side & para median sacro -coccgeal tumor mass with
anterior presacral space extension.
The mass infiltrating the lower part of the iliac bone
Mass:
11*9*8 cm.
(huge Rt side of the sacrum & Rt para median chordoma)

5. TCNB :
Conventional chordoma

6. The pt with unresectable mass
so
received radiotherapy 16 sessions from Phase 1 (50.4
Gy/28 f) in our department last one in 18/6/2017 ,but our
device became out of function & she referred to army forces
center & received 22 sessions.
Total dose (70Gy/38 f) with 3D technique.

7. Follow up MSCT PA:
Ill defined destructive soft tissue mass lesion involving sacrum
Mass 10 .7*10.6*6.6 cm with no definitive infiltration of
surrounding muscle .
Haziness of surrounding fat planes mostly Rth sequel

8. r management ?

9. Wh
i
Chord
?

10. Chordoma
Is a rare slow-growing neoplasm thought to arise from cellular
remnants of the notochord which is a structure in an embryo that helps
in the development of the spine.
The notochord disappears when the fetus is about 8 weeks old, but
some notochord cells remain behind in clivus and sacrococcygeal
regions . Very rarely, these cells turn into cancer called chordoma.
Chordoma associated with high rate of local recurrence.
In about 30 to 40 percent of patients, the tumor eventually spreads, or
metastasizes, to other parts of the body.

11. Epidemiology:
In the US the annual incidence of chordoma is approximately 1 in one
million (300 new patients each year).
There are currently no known environmental risk factors for chordoma.
germ line duplication of brachyury gene has been identified as a major
susceptibility mechanism in several chordoma families.
A possible association with tuberous sclerosis complex(TSC1 or TSC2)
has been suggested
rare multisystem genetic disease that causes benign tumors to grow in
the brain and on other vital organs such as the kidneys, heart , liver
, eyes , lungs , and skin.

12. There are 3 histological variants of chordoma:
*classical (or "conventional")
*chondroid
*dedifferentiated.
classical chordoma is of a lobulated tumor composed of
groups of cells separated by fibrous septa. The cells have
small round nuclei and abundant vacuolated cytoplasm,
** sometimes described as physaliferous (having bubbles
or vacuoles.
Chondroid chordomas show features of both chordoma
and chondrosarcoma (cartilage element).
Dedifferentiated chordoma: feature of high grade
pleomorphic spindle cell soft tissue sarcoma, more aggressive

14. Presentation:
The most common locations are
sacrum 50%
clivus (skull base) 25%
Spine 15%
Spine : Deep pain , Radicuolopathy
cervical : Air way obstruction, Dysphasia, Oropharyngeal
mass
Skull base & mobile spine: neurological deficits

16. Work up:
*History & physical examination .
*CT ,MRI (with contrast ) to the primary site
CT: bone involvement ,calcification, soft tissue & epidural involvement
MRI: superior contrast with surrounding soft tissue as compared with Ct detect
Tumor extension, Cord compression, Recurrence , Residual, Mets
*Screening MRI of spinal axis.
*CT scan of chest ,abdomen, pelvis.
*PET scan or bone scan ( if PET scan is negative) for unusual
cases.
* Biopsy: (dorsally rather than trans- rectal in suspected sacral chordoma)

17. Treatment
1- Surgical resection of spinal and sacral chordoma :
remains the standard for control of macroscopic disease; however, it is
associated with significant morbidity and reduction in ambulation
**Surgical margins are defined according to the Enneking classification
system as :
•Intra lesional
•Marginal
•Wide
•radical.

18. An intra lesional margin resection is created if we
entered to resect the tumor.
A marginal margin resection occurs if the dissection
extends into or through the reactive zone that
surrounds the tumor but does not violate the tumor
wide margin occurs if dissection is performed through
healthy tissues.
A radical margin is created when the entire bony or
myofascial compartment containing the tumor is
resected.

19. In the axial spine and sacrum,
en bloc resection to achieve wide margins is the best
method to achieve a cure and offers the best chance of local
tumor control.
BUT
Wide resection is associated with the bilateral S1-2 nerve
roots responsible for bladder and rectal function
result in a substantial new deficit and reduction overall
quality of life.

20. 2- Radiotherapy
Although surgery is an effective therapy for macroscopic
disease control and the quality of surgical margin is the most
important factor for local control and overall survival,
Effective radiation therapy (RT) may have a role in addressing
microscopic disease. Therefore, the combination therapy of
surgical resection and radiation therapy may be associated
with higher rates of local control and overall survival.

21. RTH may be:
Adjuvant Radiation Therapy for Spinal and Sacral
Chordoma?
Salvage Radiation Therapy for Recurrent Spinal and Sacral
Chordoma
Primary Radiation Therapy for Primary/de novo Spinal and
Sacral Chordoma?

22. What Are the Toxicity and Local Control Rates for
Adjuvant Radiation Therapy for Spinal and Sacral
Chordoma?

23. A - Photon-based Intensity Modulated Radiation Therapy IMRT:
Local recurrence and progression of disease occurs frequently even with
optimal tumor resection because of the inability to achieve wide
margins.
Hence, adjuvant (RT) may improve (LC) and (OS).
However, the tolerance dose of the many of the organs and tissues
surrounding the spinal column results in limitation of total RT dose that
can safely be delivered to the tumor using non conformal radiotherapy.
Thus, the majority of older publications that used conventional photon
radiotherapy did not exceed 60 Gy and investigators report :
poor LC of spinal and sacral chordomas with radical surgery and
conventional radiation at doses below 60 Gy.

24. Numerous publications on the use of photon RT with doses
less than 60 Gy have shown eventual recurrence rates of 50%
to 100%
and 5-year PFS rates of less than 25%.
This poor LC is as a result of the relative radio resistance of
chordoma and the limitations of available technology to
deliver adequately high doses to the tumor without exceeding
dose safety limits for nearby normal tissues.

25. IMRT
is a technique that can custom modulate each photon beam
to conform to the 3D characteristics of the tumor by
minimizing the dose to surrounding tissues, thus
concentrating the radiation exposure to tumor tissues and
decreasing the risk of radiation toxicity to surrounding tissues.
Allowing dose escalation to tumors that were previously only
achievable with proton beam treatment.

26. The LC was significantly higher in doses >60 Gy compared with total
doses <60 Gy with only moderate SE of RTH & patients receiving >60 Gy
showed a significantly improved OS (85% vs. 43%, P < 0.01).
From mixed cohort of 34 patients treated with IMRT, this group LC was
projected to be 79%, 55%, and 27% after 1, 2, and 5 years, respectively.
In addition, the OS projected to be 97%, 91%, and 70% at 1, 2, and 5
years, respectively.
** chordoma progression was significantly associated with an increased
risk of metastasis and tumor-related death, thus improved LC may result
in improved systemic control and survival.

27. Adjuvant RT after surgery has higher 5yrs LC rates than patient referred
for salvage treatment of recurrent disease. (88% VS 9%)
The median radiation dose delivered was 70 Gy relative biologic
effectiveness (RBE) (range: 56–78 Gy RBE) delivered in 2 Gy per daily
fraction.
Higher recurrence rates were found with sacral tumors 84.6% vs. 15.4%
of non-sacral tumors.

28. B_ High-dose Single-fraction or Hypofractionated Photon Therapy:
The use of IGRT coupled with IMRT has allowed for a very high dose of
RT to the spine and sacrum in a single fraction(SRS) or hypof-ractionated
(<5 fractions) (SBRT) manner.
2yrs LC in greater than 95% of cases for typically radioresistant
chordoma
SRS:
The spinal cord maximum dose of 14Gy to a single voxel and the median
prescribed dose was 24Gy (18-24 Gy) to the selected tumor volume
FSRT: 5 fraction in a median dose of 37.5 Gy (range:25-40)

29. SRS & SBRT offers biological advantages for the treatment of
chordoma due to:
1-Higher doses / fraction result in irreparable DNA damage, w
is important for the treatment of chordoma radioresistance….
(ability to repair radiation injured DNA).
2-increased endothelial cell apoptosis, a phenomenon only
seen with high dose per fraction therapy.

30. Particle therapy:

36. This allows a higher radiation dose to be delivered to the tumor target,
with a lower risk of radiation toxicity to neural tissues.
primary spine column tumors treated with combined high dose
photon/proton RT, patients with sacral tumors a median dose of 50.4
CGE Cobalt Gy Equivalent [CGE = 1.1 x Gy Relative Biological
Effectiveness(RBE)] (at 1.8 Gy RBE daily)
sacral tumors received 19.8 peri-operatively and another 30.6 after
wound healing.
The patients then received a second round of radiation of 19.8 CGE in 11
fractions for – margins and a 7.2 CGE boost for those with +margins
Thus, a total median of 70.2 Gy RBE was given to tumors with
R0 resections and 77.4 CGE for tumors with R1/R2 resections

37. Remarkably, they report a >90% local control rate at median
7.3 year
follow up for primary chordomas (4.3%) patients treated for
primary chordoma developing a local recurrence.
None who had a R0 resection developed a local recurrence,
indicating the importance of surgical resection to obtain
optimal local control.

40. Heavy Ion Particle Radiation Therapy
Compared with protons, carbon ions have a biological advantage because
of their increased relative biological effectiveness (RBE), likely because of complex
double-stranded breaks.
Carbon ion beams deliver a larger (LET), than protons and photons.
In addition, the LET of carbon ion beams increases steadily from the initial value at the
entrance point as it passes through the body, reaching its maximal value at the end of
its range. Thus, carbon ion beam enables operators to avoid radiation-induced injuries
to critical organs and to apply enough doses to control tumor and the higher LET and
RBE of the carbon ion beam may contribute to the control of radioresistant tumor.
The cohort of 41 patients with primary sacral chordomas received either carbon ion
radiation or a combination of IMRT with a carbon ion boost, with a median of dose of
75 GyRBE (range, 68.8 to 82.5 Gy) with a median follow-up of 25 months

41. Primary chordoma treatment resulted in an 85% 2-year LC rate, which is
marginally less than what is reported for single-fraction photon RT
(>90% at 2 years) and proton/photon combination RT (>90% at 5 years).
carbon ion RT have LC rates greater than >88% and an OS rates greater
than >80% at 3 to 5 years follow up.
When carbon ion RT is compared with surgery only, the LC rates and OS
rate could support better outcomes with carbon RT.
The carbon ion RT cohort received a median of 70.4 Gy (range, 54–73.6)
and a median follow up of 4 years. Although the surgery only group had
a median follow up of 6.3 years.
The LC at 5 years was 62.5% for the surgery and 100% for the carbon
ion RT group

44. What Are the Toxicity and Local Control Rates for Salvage
Radiation Therapy for Recurrent Spinal and Sacral
Chordoma?
surgical resection is typically not an effective option to address
macroscopic disease for locally recurrent chordoma. Thus, radiation
plays an even more important role in obtaining significant disease
control. Second, the tumor biology of the recurrent disease is likely
different from the initial disease.
A recurrent chordoma composed of cells that have a higher intrinsic
ability to repair double strained breaks and thus these recurrent
chordomas are likely even more radioresistant then primary chordomas.
Salvage therapy for the treatment of recurrent chordoma has
significantly lower rates of LC, however no significant decrease in OS
rates.

45. LC rate of 47% at 4.5 years decrease to 24% with salvage
IMRT.
However, both primary RT and salvage RT for chordoma
results in a 74% OS rate at 4.5 years.
using proton beam therapy with or without photon RT.
Macdonald et al investigated the outcome of treating
recurrent chordoma with proton therapy, and reported a 2-
year LC and OS of 85% and 80%, respectively, for a cohort of
16 patients.
Current evidence suggests that the rates for LC with proton
beam RT and carbon ion RT are higher than for photon RT.

46. What Are the Toxicity and Local Control Rates for Primary Radiation
Therapy for Primary/de novo Spinal and Sacral Chordoma?
The use of radiation therapy as a primary treatment for chordoma could
save patients from the morbidity and recovery from surgery.
However, there is no evidence comparing primary RT and surgery with
adjuvant RT.
The use of single-fraction photon RT as a neoadjuvant treatment has show
encouraging results, with seven of 13 (53.8%) patients who underwent
single-fraction SRS as a planned preoperative neoadjuvant treatment neve
proceeding to surgery after SRS based on radiographic and clinical stability
and patient preference over a 2-year follow-up period.
proton beam RT with photon RT in a cohort of 24 patients with
unresectable sacral chordomas to achieve a very favorable 90.4% 3-year L
rate (79.8% 5-year LC rate) and 91.7% 3-year OS rate (78.1% 5-year OS
rate).

47. From both the proton beam RT studies and the heavy ion RT
studies the data shows a clear trend towards optimal LC rates
with primary RT for de novo chordoma only when the dose
deliver is >70 Gy RBE in 16 fractions. However, such a
treatment modality is also associated with higher toxicity
rates and adverse effects. The majority of patients with toxic
effects had radiation dermatitis; however,
mucositis/esophagitis was reported for after cervical RT,
urinary-anorectal dysfunction was reported after sacral RT.
However, there is a trend towards a reduced amount of
toxicity by using a hyperfractionated schedule of >30 fractions

48. CONCLUSION:
Though there is limited literature comparing the effectiveness of various
radiation therapy modalities to achieve maximal LC and OS, there are
promising trends specifically with doses >70 Gy RBE.
Proton beam and carbon ion therapy both show to have higher LC rates
than conventional IMRT, however OS rates are not significantly different.
This is likely because even after optimal local control is obtained,
systemic and metastatic disease must be addressed to substantially
change the overall survival for patient with chordoma.
In other words, progressive local disease can cause increased morbidity
and decreased functionality for the patient, but it is ultimately distant
metastasis that results in progressive multiple system deterioration and
death.

49. Systemic therapy:
Chordoma are not sensitive to CTh except dedifferentiated type.
In a tissue microarray containing 21 chordomas Platelet-derived growth factor
receptor-beta (PDGFR-b), epidermal growth factor receptor(EGFR), were detected .
mTOR signaling is hyperactive in sporadic sacral chordomas: in one study 10 out of 10
sacral chordomas exhibited
There are no drugs currently approved to treat chordoma, however a clinical trial
conducted in Italy using the PDGFR inhibitor:
Imatinib (Gleevec) demonstrated a modest response in some chordoma
patients……stable disease 74%,PFS:9.9 ms
the combination of imatinib with platinol or sirolimus (rapamycin: MTOR I) caused a
response in several patients whose tumors progressed on imatinib alone.
EGFRI (lapatinib or erlotinib used in advanced chordoma resistant to Imatinib.

51. Vaccine Therapy for Unresectable Chordoma
Most chordoma cells produce a protein called brachyury.
Normally, this protein is produced by embryonic cells, but it
is not produced by the cells of normal adult tissue.
This differential production by cancer cells versus normal
adult cells makes brachyury an attractive target
for immunotherapy
Researchers at NCI are developing a cancer
vaccine(named GI-6301) that targets brachyury.

52. The vaccine uses yeast cells that have been genetically modified to
express human brachyury protein.
The modified yeast cells are then killed with heat to inactivate them and
injected under the skin, where they will be recognized by the immune
system as foreign pathogens. Dendritic cells, which are a type of
immune cell, will take up the modified yeast cells and process their
proteins, including brachyury, for presentation as antigens to other
immune cells called T cells.
The researchers hope that the T cells will then target and kill cancer cells
that produce brachyury.
Radiation may play a role in the efficacy of the vaccine, at least in
chordoma patients.