Sarcoma

Question 1

what are the two broad categories of sarcoma

Answer 1

soft tissue sarcoma (80%)
bone sarcoma (20%)

Question 2

classification of sarcoma

Answer 2

• numerous different types
• various tools used to define them
  biological behaviour
  tissue of origin
  grade
  frequently require review by international specialists

Question 3

sarcoma location

Answer 3

9% H&N
25% GI tract
15-20% retroperitoneum/intra-abdominal
60% arms or legs

Question 4

risk factors

Answer 4

• probably arise de novo
• multifactorial including exposure to radiation, chemotherapy, carcinogens, chronic lymphoedema, HIV/HSV8 (Kaposi’s), around 10% genetic

Question 5

clinical presentation

Answer 5

• usually slow growing painless lumps
• mean time before attending GP 4 months
• symptoms related to site of tumour
• metastases unusual at presentation
  can be very easily mistaken for number of non-cancerous conditions

Question 6

warning signs that a lump in soft tissue might be a sarcoma

Answer 6

• measures >4cm - the side of a golf ball
• is getting bigger
• lies deep to fascia
• is non tender (but pain occasionally)
• is in the leg, arm or back

Question 7

spread of sarcoma

Answer 7

direct
- occasionally with skip areas
- generally extend along tissue planes

regional LN
- involvement infrequent
- around 5-10% (1st site of metastases) except rhabdomyocin sarcoma, epithelioid sarcoma, vascular sarcomas
- more common with increasing grade: G1 0%, GII 2.5%, GIII 12%

direct metastases
- uncommon at presentation
- often present later in disease course - related to grade and size of tumour
- 1st site usually lung (70-80%)

Question 8

diagnosis

Answer 8

• complete history and physical examination
• bloods: FBC, U/E, LFT
• Biopsy
  -> crucial
  -> incisional (open), core, FNA or exceptionally total excision
  -> must be performed by experienced surgeons
  -> must be carefully planned - to be incorporated within later operative bed
• Imaging
  -> plain films, ultrasound, MRI (soft tissue extent) and CT (bone destruction, lymph nodes)
  -> CT thorax
  -> role of PET/CT is unclear
  -> bone scan is not usually helpful for initial staging (except primary bone tumours)

Question 9

staging

Answer 9

AJCC 6th Edition (2002)
T1 <5cm a - superficial, b - deep
T2 >5cm a- superficial, b - deep

stage IA/B | T1a-b T2a-b | Grade 1-2
stage IIA/B | T1a-b T2a | Grade 3
stage III | T2b | Grade 3

Question 10

poor prognostic factors

Answer 10

for local stage:
- increased size of tumour
- deep vs superficial location
- high grade
- symptoms at presentation
- retroperitoneum vs extremities
- R1-2 (micro/macro incomplete) vs R0 (complete) resection
- increased age of patient

Question 11

Treatment

Answer 11

surgical resection is only potentially curative therapy
- sole treatment for superficial low grade tumours <= 5cm
- aims of surgery: total en bloc excision of 1deg without cutting through tumour
- most important surgical variable that influences local control is presence or absence of tumour cells at surgical margin
- occasionally amputation is only option

RT and chemo (given before or after surgery) are aimed at:
1. marking a sarcoma easier to remove
2. reducing the risk of the sarcoma coming back in the area it started
3. reducing the risk of the sarcoma travelling to other organs

Question 12

palliative treatment

Answer 12

• when a sarcoma is not curable and the aim of treatment is to alleviate the symptoms it is causing
• most frequently achieved by:
  RT
  chemo
  non-chemo medication
  psychological support

Question 13

impact of RT

Answer 13

• reduces risk of local relapse
• no impact on survival
• QoL and limb function depend on good local control

Question 14

role of RT

Answer 14

adjuvant RT improves local control
- Yang (1998) 141 Pts EBRT vs no EBRT (64% high grade). HG LR 0% vs 22% (p = 0.0001). LG LR (p = 0.003)
- Pisters (1996) 164 Pts Brachy vs none. LR 18% vs 31% at 5 years (p=0.04)
permits limb sparing

Question 15

indications for RT in localised soft tissue sarcoma

Answer 15

• intermediate and high grade tumours
• tumour >= 5cm
• deep tumours (deep to fascia)
• ‘close’ resection margins
• microscopically positive resection margins, if further surgery not possible
• low grade tumours, if marginally resected and further resection at relapse will be difficult

Question 16

timing of RT

Answer 16

• given alone
  palliation (inoperable)
  occasionally -> long term control
• pre-op
  5 weeks treatment centred on gross tumour
• post-op
  6-6.5 weeks treatment
  2 phases
  need to treat operative bed

Question 17

RT scheduling (pre vs post-op)

Answer 17

only one randomised phase III trial (O’ Sullivan 2002)
190 Pts. median follow up 6.9 years. pre-op 50Gy/25# (+16Gy boost if margin +ve) vs, post-operative (66Gy/33#)
1st end point: wound complication rate
2nd end point: late complications/function/QoL

• no difference in LR, regional/distant failure rate, PFS
• trial closed before completion
  -> wound complication rate in pre-op arm (35% vs 17%)
  -> lower extremity > upper (43% vs 5%)
• increased late effects in post-op arm
  -> tissue oedema/fibrosis
  -> impaired function
  -> fractures

Question 18

target volume (pre-op)

Answer 18

Single phase (50Gy/25#)

Proximal/distal margins: 2-4cm proximal and distal to site of disease

radical margins: 2cm or up to bone, interosseous membrane, major fascial plane
aim to spare corridor (around 1/3 limb circumference) of normal tissue (lymphatic drainage)

GTV defined using T1W MRI but with oedema included (T2W images)

Question 19

RT target volume (post-op)

Answer 19

Phase I (50Gy/25#/5 weeks)

proximal/ distal margins: >= 4cm proximal and distal to site of original disease - ideally to include scar/drain sites i.e. potential sites of contamination

radical margins: 2cm or up to bone, interosseous membrane, major fascial plane
>2cm if plane has been violated
aim to spare corridor of normal tissue (lymphatic drainage)

Phase II (10-16Gy/5-8#/1-1.5 weeks)

proximal/distal margins: >= 2cm proximal and distal to site of original disease

radical margins: 2cm or up to bone, interosseous membrane, major fascial plane
>2cm if plane has been violated
aim to spare corridor of normal tissue (lymphatic drainage)

Question 20

late normal tissue toxicity

Answer 20

subcutaneous fibrosis
joint
oedema
generally all greater in post-op arm compared to pre-op complications

Question 21

RT-induced bone fractures

Answer 21

• morbidity significantly higher than normal fracture (around 20%)
• lower limb > upper limb
• delayed union
• multiple operations
• increased infection rate
  –> endoprosthetic replacement or amputation
• limited RT dose volumetric data

Question 22

late bone toxicity

Answer 22

retrospective Princess Margaret Hospital study (Dickie 2009) (6% fracture rate)
21 patient plans (24 fractures) treated 1995-2004
matched (2:1) to non-fracture cohort
risk of radiation induced fracture significantly reduced if:
- maximum dose <60Gy
- mean dose <38Gy
- % of bone irradiated to >=40Gy is <66%

Question 23

minimising toxicity

Answer 23

• optimising volume increasing conformality
• role of IMRT
  -> offers potentially less normal tissue morbidity
  -> two recent prospective phase II trials: RTOG 0630 trial (Wang 2011), Princess Margaret Hospital trial (Dickie 2010)
  -> both specifically assess effect of IMRT on the reduction of late toxicity
• optimising volume - better immobilisation
  -> customised device

Question 24

summary

Answer 24

• RT decreased LR if given before/after limb sparing surgery soft tissue sarcomas
• late normal toxicity has significant impact on QoL
• minimising irradiated volume essential: conformal techniques, clinical trials, better immobilisation

Question 25

Gastrointestinal stromal tumour (GIST)

Answer 25

- most common sarcoma (18%) - ages 40-80 - incidence around 12 per million - stomach and small intestine most common sites - originates from the Interstitial cells of Cajal - surgery is the only curative therapy - Adjuvant Imantinib -> reserved for high risk cases (location, mitosis, size, grade)

Question 26

Retroperitoneal sarcoma

Answer 26

- 15-20 cases per year in Ireland - usually low grade liposarcoma - often require multi-visceral resection - require specialised centres (>12 cases/year) - RT may minimised risk of LR especially for liposarcomas - best given pre-operatively - no proven role for chemo (excluding in certain sub-types)

Question 27

gynaecological sarcomas

Answer 27

- low/high grade endometrial stromal sarcoma - leiomyosarcoma - adenosarcoma total hysterectomy +/- bilateral salpingo-oopherectomy is standard role of adjuvant therapies uncertain

Question 28

thoracic/paraspinal/trunk/H&N

Answer 28

- surgery - +/- RT - role of chemo unproven

Question 29

Bone sarcomas

Answer 29

- osteosarcoma - Ewing's sarcoma - chondrosarcoma - chordoma

Question 30

osteosarcoma

Answer 30

- usually arise in long bones (often around knee) - involvement of axial skeleton and craniofacial bones - primarily in adults - multiagent chemo + surgery dominate therapy RT - relatively radioresistant - only considered if tumour is unresectable or incompletely (R2) resected - but might change with increasing availability of IMRT/protons, small cell osteosarcoma, patient refuses surgery, palliation

Question 31

Ewings

Answer 31

- chemo and radio sensitive - peak age 10-20 years - 80-90% receiving local therapy alone relapse - intensive multiagent chemo is SoC and has dramatically increased survival RT - local control localised disease - surgery or RT provide effective LC - surgery - preferred if lesion seems resectable with negative margins and without excessive morbidity - if no function-preserving surgical option because of location (e.g vertebra/pelvis) or extent then RT used RT - post-op indications not firmly established but considered in: - bulky tumours in difficult sites (e.g. pelvis) - pre or post-op - residual (unintentional) microscopic, gross disease or inadequate surgical margins (marginal or intralesional resection) - significant viable tumour (>10%) in resected specimen following NA chemo and less than wide surgical margins

Question 32

chondrosarcoma

Answer 32

- age 30-60 years - most common bone sarcoma in adults - site: centrally in diametaphyses of long bones, but also pelvis, rib and scapula RT - surgery dominates management - optimal is R0 resection - notoriously chemo and radio resistant but institutional series report excellent outcomes when RT is given adjuvantly (following marginal or intra-lesional surgery) or in irresectbale sites - high doses (>60Gy) and highly conformal - 80-90% local control rates

Question 33

chordomas

Answer 33

- sacrum or skull base - high dose RT using proton beams or carbon ion therapy

Question 34

summary

Answer 34

- uncommon tumours - curative treatment may involve surgery, RT and/or chemo depending on the histological sub-type and tumour location - most are cured - especially if diagnosed easily - when indicated RT requires complex planning - best outcomes are in specialised centres