Key points
- Sarcoma is a rare cancer that starts in the body's supporting tissues: muscle, fat, blood vessels, nerves, connective tissue and bone. About 80 types of soft tissue sarcoma are recognised [1, 5].
- The most common sign of a soft tissue sarcoma is a lump, which is often painless [5]. A lump that is getting bigger, lies deep or measures 5 cm or more should be checked with imaging before any surgery [1, 13].
- Bone pain that does not go away and is worse at night, or swelling over a bone in a child or teenager, should be checked with an X-ray [2, 13].
- Biopsy and surgery for sarcoma are best done at a specialist sarcoma centre. Removing a lump without a plan makes it more likely that the cancer comes back in the same place [14, 1].
- The main treatment for soft tissue sarcoma is complete surgery that removes the tumour with a layer of healthy tissue around it, often together with radiotherapy [1].
- GIST (gastrointestinal stromal tumour) is the most common sarcoma of the digestive tract. Imatinib tablets control it well, and after surgery for a high-risk GIST, 3 years of imatinib helps people live longer [3, 35].
- Osteosarcoma and Ewing sarcoma are treated with chemotherapy before and after surgery or radiotherapy. When the disease has not spread, most patients survive and are cured [2, 41].
What is sarcoma?
Sarcoma is a cancer that starts in the body's “soft tissues”, such as muscle, fat, blood and lymph vessels, nerves, tendons and the tissue around joints, or in bone [5, 2]. There are two main groups: soft tissue sarcoma and bone sarcoma (primary bone cancer). The World Health Organization recognises about 80 types of soft tissue sarcoma, and each type is treated a little differently [1].
Sarcomas are rare. In Europe, about 4 to 5 in every 100,000 people develop a soft tissue sarcoma each year [1]. Primary bone cancer is even rarer, making up fewer than 2 in every 1,000 cancers [2]. Soft tissue sarcoma is most often found in the arms and legs, inside the abdomen and at the back of the abdomen, but it can appear anywhere in the body [5, 4].
Sarcoma can occur at any age. Some types, such as osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, are more common in children, teenagers and young adults [2, 11], and others, such as GIST, are more common in middle-aged and older people [3].
Not every lump or bone pain is a sarcoma. In adults over 40, most cancers found in the bone have spread there from elsewhere in the body (metastasis) or are multiple myeloma [2]. Despite its name, Kaposi sarcoma is a separate disease: it is linked to a virus called HHV-8, mostly affects people with a weakened immune system and is treated differently, so it is not covered on this page [12, 1]. Uterine sarcoma is a type of soft tissue sarcoma that starts in the muscle or supporting tissue of the womb and is different from womb cancer (endometrial cancer) [1].
| Group | Where is it found? | Who gets it most? | Main treatment |
|---|---|---|---|
| Soft tissue sarcoma of the arms, legs and trunk | Muscle, fat and soft tissues of the limbs and body wall | Adults | Complete surgery with a healthy margin, often with radiotherapy |
| Sarcoma at the back of the abdomen (retroperitoneum) | The space behind the bowel and around the kidneys | Adults | Complete removal in one piece at a specialist centre |
| GIST (gastrointestinal stromal tumour) | Wall of the stomach and small bowel | Mostly older adults | Surgery; imatinib tablets if high risk or if it has spread |
| Osteosarcoma | Long bones, most often around the knee | Teenagers and young adults; sometimes older people | Chemotherapy before and after surgery |
| Ewing sarcoma | Bones of the leg, arm, pelvis, ribs or spine, or soft tissue | Children, teenagers and young adults | Chemotherapy, then surgery or radiotherapy, then more chemotherapy |
| Rhabdomyosarcoma | Muscle; the head and neck, urinary and genital organs and other places | Children | Chemotherapy with surgery and/or radiotherapy [11] |
This table is a general guide; each person's treatment depends on the exact type of sarcoma, its grade, size and location.
Symptoms of sarcoma
The signs depend on where the sarcoma is:
- Soft tissue sarcoma of the arm, leg or trunk: usually a painless lump under the skin or deep in a muscle that slowly gets bigger. When it grows and presses on a nerve, muscle or blood vessel, it may cause pain [5].
- Sarcoma inside the abdomen or at the back of the abdomen: may cause no signs until it is very large; as it grows and presses on nearby organs, it may cause pain or shortness of breath [5].
- GIST: blood in the stool (bright red or very dark) or in vomit, pain in the abdomen, feeling very tired, difficulty or pain when swallowing, and feeling full after eating only a little [7].
- Bone sarcoma (osteosarcoma and Ewing sarcoma): bone pain that does not go away, slowly gets worse and is often noticed at night; swelling or a lump over a bone; a stiff joint, a limp, or a bone that breaks for no clear reason [2, 8]. Ewing sarcoma may also cause unexplained fever, tiredness and weight loss [10].
Swelling and difficulty moving are usually later signs of a bone sarcoma, so do not wait for swelling: get pain that does not go away checked [2]. These signs have other causes too; for example, bone infection and benign bone tumours are more common than bone sarcoma [2, 5]. Only an examination and imaging can find the cause. Read more: What is the difference between a benign and a malignant tumour? and Warning signs of cancer in children.
When should I see a doctor urgently?
If you have any of the following, see a doctor within the next few days and ask for imaging before anything else is done [13, 1, 2]:
- A lump in the soft tissues that is getting bigger, measures 5 cm or more, or lies deep in a muscle
- Bone pain that does not go away and is worse at night, or swelling over a bone, especially in children, teenagers and young adults
- Blood in the stool or very dark stool, blood in vomit, or a lot of tiredness without a clear reason [7]
Before any operation: if a lump is going to be removed, ask whether an ultrasound and, if needed, an MRI have been done first, and whether it could be a sarcoma. If a sarcoma is possible, have the biopsy and the surgery done at a specialist sarcoma centre [1, 14].
Take vomiting blood, black stools with dizziness or severe weakness, or a bone that suddenly breaks seriously: call your local emergency number.
Risk factors and screening
Most sarcomas appear without a clear cause, in people who have no risk factors [5, 4]. Known risk factors include:
- Previous radiotherapy for another cancer; a sarcoma may appear in the area that was treated [4, 1].
- Inherited conditions: such as Li-Fraumeni syndrome (a change in the TP53 gene), neurofibromatosis type 1 (NF1), hereditary retinoblastoma and a few other rare syndromes [4, 2].
- Long-lasting swelling of an arm or leg caused by poor lymph drainage (lymphoedema) [4].
- Exposure to certain chemicals such as vinyl chloride, arsenic and the old contrast agent Thorotrast, which are linked to sarcoma of the blood vessels of the liver [4].
- For osteosarcoma: Paget disease of bone in older people, previous chemotherapy or radiotherapy, and some inherited conditions [2, 8].
- For GIST: rarely, certain syndromes such as neurofibromatosis type 1 or the Carney syndromes [3, 7].
Because sarcoma is rare, the most important thing is to take a growing lump or bone pain that does not go away seriously and get it checked early [13]. For people with Li-Fraumeni syndrome, the European guideline recommends a whole-body MRI scan every year [1]. If you had a sarcoma at a young age and several relatives were diagnosed young with breast cancer, sarcoma or a brain tumour, ask about genetic counselling [1]. Read more: Is cancer hereditary?
For physicians
Germline genetic testing in sarcoma
Germline TP53 testing: the ESMO–EURACAN–GENTURIS guideline recommends it, if possible before treatment starts, in (1) patients under 46 years with soft tissue sarcoma and at least one first- or second-degree relative under 56 years with a TP53 core tumour (breast cancer, soft tissue sarcoma, bone sarcoma, central nervous system tumour, adrenocortical carcinoma); or (2) patients with soft tissue sarcoma (especially in a radiotherapy field) and another TP53 core tumour before the age of 46 [IV, A]. In TP53 carriers, radiotherapy should be avoided where possible after multidisciplinary discussion, and annual whole-body MRI is recommended [1].
GIST: in GIST without KIT/PDGFRA mutations, SDHB immunohistochemistry identifies SDH-deficient GIST, and in quadruple-negative GIST (KIT, PDGFRA, BRAF and SDH) an unrecognised NF1 syndrome should be excluded. Carney–Stratakis syndrome is caused by germline mutations of SDH subunit genes, and the Carney triad by SDHC hypermethylation [3]. In the French national registry, a history of NF1 was one of the strongest adverse prognostic factors for local relapse-free survival, event-free survival and overall survival [15]. More: Germline genetic testing in cancer.
Diagnosis and staging
The path to a sarcoma diagnosis
- 1
Imaging before anything else
- 2
- 3
A planned needle biopsy
- 4
Review by a pathologist who specialises in sarcoma
Sarcoma is hard to diagnose. When the sample is reviewed again by a specialist sarcoma pathologist, the diagnosis changes substantially in about 1 in every 10 people [1]. Molecular tests (looking for gene changes in the tumour) pin down the exact type of sarcoma and sometimes decide the treatment [1].
- 5
Checking for spread
Everyone needs a CT scan of the chest, because sarcoma most often spreads to the lungs. Depending on the type of sarcoma, a CT of the abdomen and pelvis, a bone scan, a whole-body MRI or a PET scan may also be done [1, 2]. Read more: What is a PET scan?
- 6
Planning by a multidisciplinary team
The surgeon, radiologist, pathologist, oncologist and radiotherapy specialist plan the treatment together [1].
Sometimes a lump that looks like “just a fatty lump” is removed without imaging or a biopsy, and only afterwards does it turn out to be a sarcoma. After such an unplanned operation, cancer cells may be left behind [14]. In a review of more than 16,000 patients, these patients more often had the cancer come back in the same place [14], and a second operation at a sarcoma centre is often needed [1].
In France, sarcoma surgery at specialist centres was linked to fewer recurrences and longer survival [15]. So if a sarcoma is possible, go to a sarcoma centre before any operation. Read more: Does a biopsy make cancer spread?
Grade and stage of sarcoma
For a soft tissue sarcoma, the pathologist gives a “grade” from 1 to 3. A grade 1 sarcoma grows slowly and spreads less often; grade 2 and 3 sarcomas are more likely to come back and spread [4, 1]. The stage of a sarcoma is based on its grade, the size of the tumour, whether lymph nodes are involved and whether it has spread to distant organs [4]. Even so, when choosing treatment, doctors look more at the type of sarcoma, its grade, size and location than at the stage number [1, 4]. Read more: What are the stages of cancer?
For physicians
| Criterion | Score 1 | Score 2 | Score 3 |
|---|---|---|---|
| Tumour differentiation | Closely resembles normal adult mesenchymal tissue (e.g. low-grade liposarcoma) | Sarcoma of certain histological type (e.g. myxoid liposarcoma) | Embryonal or undifferentiated sarcoma, sarcoma of doubtful type, synovial sarcoma, soft tissue osteosarcoma, soft tissue Ewing sarcoma |
| Mitotic count per 10 high-power fields | 0 to 9 | 10 to 19 | 20 or more |
| Tumour necrosis | Less than 50% | 50% or more | — |
No necrosis scores 0. Grade = sum of the three scores: G1 total 2 or 3, G2 total 4 or 5, G3 total 6 to 8 [4]. Grade cannot be assigned after preoperative chemotherapy or radiotherapy, and the mitotic rate should be reported separately whenever possible [1]. In bone sarcoma, the histological type determines the grade, with few exceptions [2]. In GIST, the mitotic count is reported per 5 mm² (equivalent to 50 high-power fields) [3].
| Stage | T | N | M | Grade |
|---|---|---|---|---|
| IA | T1 | N0 | M0 | GX or G1 |
| IB | T2, T3 or T4 | N0 | M0 | GX or G1 |
| II | T1 | N0 | M0 | G2 or G3 |
| IIIA | T2 | N0 | M0 | G2 or G3 |
| IIIB | T3 or T4 | N0 | M0 | G2 or G3 |
| IIIB in the retroperitoneum or IV in the trunk and extremities | Any T | N1 | M0 | Any G |
| IV | Any T | Any N | M1 | Any G |
T1: 5 cm or less; T2: more than 5 to 10 cm; T3: more than 10 to 15 cm; T4: more than 15 cm. No stage grouping is recommended for sarcoma of the head and neck or of the abdominal and thoracic visceral organs [4]. ESMO considers UICC/AJCC staging of limited clinical value and prefers risk assessment with nomograms (such as Sarculator) [IV, A] [1].
Diagnostic and staging details
Soft tissue sarcoma: MRI is the main imaging modality in the extremities, pelvis and trunk; CT is used for calcified lesions, pleuropulmonary sarcomas and retroperitoneal sarcoma (where its performance equals MRI); ultrasound may be the first imaging test, but any suspicion of sarcoma should be followed by CT or MRI. The standard approach is multiple core needle biopsies, possibly with 14–16 G needles; an excisional biopsy may be the most practical option only for superficial lesions under 3 cm. The biopsy is done by a surgeon or radiologist after multidisciplinary discussion, and its tract must be removable at definitive surgery (except in the retroperitoneum); the entry point can be tattooed. A biopsy may underestimate the grade [1].
Discordance between diagnoses made outside reference centres and those of a specialised soft tissue and bone pathologist is considerable (8% to 11% major and 16% to 35% minor discordance), so expert pathological validation is required whenever the original diagnosis was made outside a reference centre, using the 2020 WHO classification [IV, A]. Molecular pathology is needed when the diagnosis is doubtful, the presentation is unusual, it has prognostic or predictive value (such as NTRK rearrangement) or the entity is defined by a specific molecular aberration [1].
Staging of soft tissue sarcoma: contrast-enhanced chest CT for all; abdominal and pelvic CT in most types, especially myxoid liposarcoma and leiomyosarcoma [III, B]; whole-body MRI as an alternative in selected histotypes; brain imaging only in alveolar soft part sarcoma, clear-cell sarcoma and angiosarcoma; FDG-PET/CT only as a problem-solving tool in equivocal cases [IV, A]. Regional lymph node metastases are usually under 1%, except in epithelioid, clear-cell and synovial sarcoma and angiosarcoma [1].
Bone sarcoma: persistent, progressive non-mechanical bone pain, especially at night, should prompt imaging: first two-plane radiographs and, if malignancy cannot be excluded, MRI of the whole compartment with the adjacent joints. Under 5 years of age, a destructive bone lesion is mostly metastatic neuroblastoma or Langerhans cell histiocytosis, and over 40 years bone metastases and myeloma. Any lesion suspected to be a primary bone sarcoma should be referred to a reference centre; the biopsy is done by the team that will perform the definitive surgery or by an interventional radiologist after discussion with the surgeon, and the biopsy tract is removed with the surgical specimen. Staging: chest CT, bone scintigraphy and/or whole-body MRI and/or FDG-PET; baseline ALP and LDH in osteosarcoma and Ewing sarcoma [III, B]. Before chemotherapy: renal function tests, cardiac assessment and an audiogram (with platinum agents), and sperm storage for men of reproductive age [2].
GIST: for oesophagogastric or duodenal submucosal nodules under 2 cm, endoscopic ultrasound is the standard approach; lesions of 2 cm or more and all rectal nodules are biopsied or excised [IV, C]. For a large mass likely to need multivisceral resection, multiple core biopsies (EUS-guided or percutaneous) are standard. The diagnosis rests on CD117 (KIT) and/or DOG1 (about 5% are CD117-negative). Mutational analysis of KIT/PDGFRA is standard in the work-up of all GISTs [II, A] (possibly excluding non-rectal GISTs under 2 cm). Staging and follow-up use triple-phase contrast-enhanced CT of the abdomen and pelvis (MRI for rectal GIST) plus chest CT [3].
Soft tissue sarcoma of the arms, legs, trunk and back of the abdomen
Treatment regimens and doses: index17 regimens
Surgery is the main treatment. A surgeon who specialises in sarcoma removes the tumour in one piece together with a layer of healthy tissue around it, so that the edges of the specimen (the “margins”) are free of cancer [1]. Today the arm or leg can be saved in most patients, and amputation is needed only in special cases [4, 1].
Radiotherapy is usually added to surgery for grade 2 and 3 sarcomas and lowers the chance of the tumour coming back in the same place [1, 18]. Today it is often given before surgery: a lower dose is needed and long-term effects such as stiffness, swelling and bone fractures are less common, although problems with wound healing after the operation are more frequent [1, 17, 19]. Grade 1 sarcomas are mostly treated with surgery alone [1]. Read more: What is radiotherapy?
Chemotherapy before or after surgery is not needed for everyone. In fit patients at high risk of the cancer coming back (for example, a large, deep, high-grade tumour), at least 3 cycles of chemotherapy, preferably before surgery, may be offered [1].
Sarcoma at the back of the abdomen (retroperitoneum) has its best chance of cure at the first operation: complete removal of the tumour in one piece, sometimes with the organs stuck to it, at a centre that does this surgery often [1]. In a large study, radiotherapy before surgery did not help most of these patients and is not routinely recommended [20, 1].
If the sarcoma has spread to only a few spots in the lungs, these can sometimes be removed by surgery [1]. The main treatment for sarcoma that has spread is chemotherapy, usually starting with doxorubicin; after that, depending on the type of sarcoma, gemcitabine with docetaxel, pazopanib tablets, eribulin or trabectedin may be used. The aim of these treatments is to control the disease, ease symptoms and help people live longer [1]. Read more: What does metastasis mean?
Chance of cure: the outcome depends mostly on the grade, size and location of the tumour and on whether surgery removes it completely [4]. Small, low-grade sarcomas of the arms, legs and trunk are often cured by surgery alone [4]. In a large study of high-risk sarcomas that had been completely removed, about 2 in every 3 people were alive after 5 years [22]. In France, after a national network of sarcoma centres was set up, survival improved across the whole country [16].
For physicians
Local treatment
Standard surgery is en bloc excision with R0 margins [II, A]; the minimal adequate margin depends on histotype, preoperative treatment and resistant anatomical barriers (fascia, vascular adventitia, periosteum, epineurium). For atypical lipomatous tumours, marginal excision along the pseudocapsule is advised [IV, B]. Radiotherapy is part of the standard treatment of high-grade (G2–3) lesions [II, B] and is not needed after a truly compartmental resection [IV, E]. The timing of radiotherapy does not affect local control or overall survival, but preoperative radiotherapy offsets the adverse effect of R1 margins better and should be considered when preserving a critical structure is the goal; the preoperative dose is 50 Gy in 1.8–2 Gy fractions, postoperative doses go up to 66 Gy, and surgery follows 4–8 weeks after the last fraction [1].
In a randomised trial (190 patients with limb sarcoma), wound complications occurred in 35% with preoperative radiotherapy (50 Gy in 25 fractions) versus 17% with postoperative radiotherapy (66 Gy in 33 fractions) (difference 18%; 95% CI 5 to 30; P = 0.01), and overall survival was slightly better with preoperative radiotherapy (P = 0.0481) [17]. In another randomised trial (91 high-grade patients), postoperative radiotherapy reduced local recurrence (P = 0.0028) without a difference in overall survival [18]. The ESTRO guideline (endorsed by ASTRO, 2026) keeps preoperative, conventionally fractionated radiotherapy with highly conformal techniques as the preferred sequence and does not bring preoperative hypofractionation or combinations with immunotherapy into routine practice until more evidence is available [19].
Unplanned excision: re-excision at a reference centre must be considered when adequate margins can be achieved without major morbidity [IV, A]; after R2 surgery it is mandatory [1]. In a meta-analysis of 16,946 patients (35.5% after unplanned excision), unplanned excision was associated with worse 5-year local recurrence-free survival (RR 1.35; P = 0.019) and residual tumour in the tumour bed with an RR of 2.59 (P less than 0.001), but 5-year overall survival did not differ significantly (RR 0.90; P = 0.16) [14].
Retroperitoneum: a pretreatment biopsy is standard (preferably by a retroperitoneal approach; open or laparoscopic biopsy must be avoided); the risk of needle-tract seeding is minimal. Surgery aims at a single en bloc specimen with macroscopically complete resection and minimal R1 margins, resecting adherent structures [III, A]; grossly incomplete resection is potentially harmful and only palliative in selected patients [1]. In STRASS (EORTC 62092; 266 patients), preoperative radiotherapy (50.4 Gy in 28 fractions) did not improve abdominal recurrence-free survival (median 4.5 vs 5.0 years; HR 1.01; 0.71 to 1.44; P = 0.95), with grade 3–4 lymphopenia in 77% and serious adverse events in 24% vs 10% [20]. ESMO: preoperative radiotherapy is not standard [I, D]; it can be discussed in low- to intermediate-grade liposarcoma, but not in leiomyosarcoma or high-grade dedifferentiated liposarcoma [1].
Adjuvant and neoadjuvant chemotherapy
Adjuvant or neoadjuvant anthracycline plus ifosfamide (AI) is not standard, but can be proposed to fit patients at high risk of death: with Sarculator, patients with a predicted 10-year overall survival below 60% are selected and at least 3 cycles are given, preferably preoperatively [II, B]; AI-refractory types such as alveolar soft part sarcoma and clear-cell sarcoma should not receive it, and chemotherapy never compensates for inadequate surgery [1]. In a meta-analysis of 18 trials (1,953 patients), chemotherapy reduced local recurrence (OR 0.73; P = 0.02) and distant and overall recurrence (OR 0.67; P = 0.0001); doxorubicin alone did not significantly improve survival (OR 0.84; P = 0.09), but the combination with ifosfamide did (OR 0.56; 95% CI 0.36 to 0.85; P = 0.01) [21]. In EORTC 62931 (351 patients with grade II–III tumours; 5 cycles of doxorubicin 75 mg/m² and ifosfamide 5 g/m² with lenograstim), neither overall survival (HR 0.94; P = 0.72) nor relapse-free survival (HR 0.91; P = 0.51) improved, and 5-year overall survival was 66.5% vs 67.8% [22]. Neoadjuvant chemotherapy with regional hyperthermia is another individualised option [I, B] [1].
Advanced disease
Metachronous (disease-free interval of 1 year or more), resectable lung metastases without extrapulmonary disease are treated with surgery [IV, B]. Standard first-line treatment is anthracycline-based [I, A] [1]. In EORTC 62012 (455 patients aged 18–60), intensified doxorubicin plus ifosfamide versus doxorubicin alone did not significantly improve overall survival (median 14.3 vs 12.8 months; HR 0.83; 95.5% CI 0.67 to 1.03; P = 0.076), but progression-free survival (7.4 vs 4.6 months; HR 0.74; P = 0.003) and overall response (26% vs 14%) were better, with febrile neutropenia in 46% vs 13% [23]. AI at adequate doses is therefore preferred when a tumour response would be advantageous, the histotype is ifosfamide-sensitive and performance status is good [I, B]; doxorubicin plus dacarbazine is a first-line multi-agent option for leiomyosarcoma and solitary fibrous tumour [IV, B] [1]. In GeDDiS (257 patients), first-line gemcitabine and docetaxel were not better than doxorubicin (alive and progression-free at 24 weeks: 46.4% vs 46.3%; HR for progression-free survival 1.28; P = 0.06) [24], and ESMO does not recommend it first line [I, D] [1].
Later lines: in SARC002 (randomised phase 2 trial, 122 patients), gemcitabine–docetaxel versus gemcitabine alone gave a median progression-free survival of 6.2 vs 3.0 months and overall survival of 17.9 vs 11.5 months, with more toxicity [25]; ESMO considers this combination or dacarbazine–gemcitabine an option after doxorubicin [II, B] [1]. In PALETTE (369 patients with non-adipocytic sarcoma), pazopanib 800 mg daily gave a median progression-free survival of 4.6 vs 1.6 months (HR 0.31; P less than 0.0001) without a significant difference in overall survival (12.5 vs 10.7 months; HR 0.86; P = 0.25) [28]. Eribulin versus dacarbazine in liposarcoma and leiomyosarcoma (452 patients) improved median overall survival to 13.5 vs 11.5 months (HR 0.77; 95% CI 0.62 to 0.95; P = 0.0169), with grade 3 or worse adverse events in 67% vs 56% [27]; in the liposarcoma subgroup the difference reached 7 months [1]. Trabectedin versus dacarbazine (518 patients with liposarcoma or leiomyosarcoma) gave a median progression-free survival of 4.2 vs 1.5 months (HR 0.55; P less than 0.001) without an overall survival benefit at the interim analysis (12.4 vs 12.9 months; HR 0.87; P = 0.37) [26].
ESMO recommendations: trabectedin is an option in second and further lines [I, B]; pazopanib in non-adipogenic sarcoma [I, B]; eribulin in liposarcoma [II, A]; high-dose ifosfamide as a 14-day continuous infusion for patients pretreated with standard-dose ifosfamide [IV, C]; angiosarcoma is sensitive to taxanes [III, B]; imatinib is standard therapy for advanced dermatofibrosarcoma protuberans [III, A] and NTRK inhibitors (larotrectinib, entrectinib) are standard for NTRK-rearranged sarcomas [III, A]; pan-NTRK immunohistochemistry has a sensitivity of about 80% and a specificity of about 75% in soft tissue sarcoma, so a positive result needs molecular confirmation [1].
- Doxorubicin: the risk of cardiomyopathy rises with cumulative dose (1% to 20% at cumulative doses of 300 to 500 mg/m² given every 3 weeks); assess LVEF before, during and after treatment; risk of secondary AML and MDS and of tissue necrosis on extravasation; reduce the dose in hepatic impairment [45]. Cumulative anthracycline dose, cardiac monitoring and chemotherapy extravasation.
- Ifosfamide: hydration of at least 2 litres a day and mesna to prevent haemorrhagic cystitis; infuse over at least 30 minutes; monitor for central nervous system toxicity and stop treatment for encephalopathy; nephrotoxicity can be severe [46].
- Trabectedin: only through a central venous line as a 24-hour infusion; dexamethasone 20 mg IV 30 minutes before each dose; monitor neutrophils, CPK (withhold if CPK is more than 2.5 times the upper limit), liver tests and LVEF; the risk of cardiomyopathy is higher with low LVEF, prior cumulative anthracycline dose of 300 mg/m² or more, age 65 or over and cardiovascular disease [55].
- Pazopanib: boxed warning for severe and fatal hepatotoxicity; monitor liver tests and interrupt, reduce or stop as per the label; take on an empty stomach [54].
- Eribulin: check a full blood count and peripheral neuropathy before each dose; do not give with ANC below 1,000, platelets below 75,000 per microlitre or grade 3–4 non-haematological toxicity [56].
- Support: in EORTC 62012 the doxorubicin–ifosfamide regimen was given with pegfilgrastim [23]; G-CSF decision tool and antiemetic regimen.
For physicians
Radiotherapy for soft tissue sarcoma of the limbs and trunk
Preoperative radiotherapy 50 Gy (soft tissue sarcoma)
Grade 2 or 3 soft tissue sarcoma of a limb or the trunk, with en bloc surgery; the preferred sequence, especially when preserving a critical structure is the goalCycle length: —
Grade 2 or 3 soft tissue sarcoma of a limb or the trunk, with en bloc surgery; the preferred sequence, especially when preserving a critical structure is the goal
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| External beam radiotherapy (IMRT or a similar conformal technique) | 50 Gy in 1.8–2 Gy fractions (in the trial: 50 Gy in 25 fractions) | External beam radiotherapy | Daily fractions |
Dose and timing per ESMO [1] and the randomised trial of preoperative versus postoperative radiotherapy [17]. More wound complications (35% vs 17%) but less late fibrosis, oedema, fracture and joint stiffness [17, 1]. ESTRO 2026: conventional fractionation is preferred and hypofractionation is not yet routine [19]. Avoid where possible in TP53 carriers [1].
Postoperative radiotherapy up to 66 Gy (soft tissue sarcoma)
When preoperative radiotherapy was not given; dose depending on margins, age and presentationCycle length: —
When preoperative radiotherapy was not given; dose depending on margins, age and presentation
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| External beam radiotherapy | Up to 66 Gy (in the trial: 66 Gy in 33 fractions) | External beam radiotherapy | Daily fractions |
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Advanced soft tissue sarcoma: first line
Single-agent doxorubicin (soft tissue sarcoma)
Advanced or metastatic unresectable soft tissue sarcoma, first line (ESMO standard [I, A])Cycle length: Every 21 days
Advanced or metastatic unresectable soft tissue sarcoma, first line (ESMO standard [I, A])
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Doxorubicin | 75 mg/m² | IV (bolus or 72-hour continuous infusion) | Day 1 |
Dose and schedule as in the doxorubicin arm of EORTC 62012 [23] and GeDDiS (6 cycles) [24]; FDA label: single agent 60 to 75 mg/m² every 21 days [45]. Baseline and periodic LVEF; dose reduction in hepatic impairment per the label [45]. Place in therapy per ESMO [1].
Evidence: EORTC 62012 (2014)
Doxorubicin + ifosfamide (AI, soft tissue sarcoma)
Advanced soft tissue sarcoma, first line in patients with good performance status when tumour response is the goal or the histotype is ifosfamide-sensitive (ESMO [I, B]); in EORTC 62012: aged 18–60, performance status 0 or 1Cycle length: Every 21 days
Advanced soft tissue sarcoma, first line in patients with good performance status when tumour response is the goal or the histotype is ifosfamide-sensitive (ESMO [I, B]); in EORTC 62012: aged 18–60, performance status 0 or 1
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Doxorubicin | 25 mg/m² per day (total 75 mg/m²) | IV | Days 1 to 3 |
| Ifosfamide | 10 g/m² per cycle, divided over 4 days (2.5 g/m² per day) | IV | Days 1 to 4 |
| Mesna | With ifosfamide | ||
| Pegfilgrastim | Per protocol |
Doses per EORTC 62012: intensified doxorubicin 75 mg/m² (25 mg/m² per day, days 1–3) plus ifosfamide 10 g/m² over 4 days with mesna and pegfilgrastim, every 3 weeks for up to 6 cycles [23]; mesna and pegfilgrastim doses are not given in the abstract (dose details in the full text). Hydration of at least 2 litres a day and monitoring for encephalopathy and renal function [46]. More grade 3–4 toxicity than doxorubicin alone: febrile neutropenia 46%, anaemia 35% and thrombocytopenia 33% [23]. Full regimen page: Doxorubicin and ifosfamide in soft tissue sarcoma.
Evidence: EORTC 62012 (2014)
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Advanced soft tissue sarcoma: later lines
Gemcitabine + docetaxel (soft tissue sarcoma)
Advanced soft tissue sarcoma after doxorubicin (ESMO [II, B]), especially leiomyosarcoma and undifferentiated pleomorphic sarcoma; not generally recommended first line [I, D]Cycle length: Every 21 days
Advanced soft tissue sarcoma after doxorubicin (ESMO [II, B]), especially leiomyosarcoma and undifferentiated pleomorphic sarcoma; not generally recommended first line [I, D]
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Gemcitabine | 675 mg/m² | IV over 90 minutes | Days 1 and 8 |
| Docetaxel | 75 mg/m² | IV over 60 minutes, after gemcitabine | Day 8 |
Doses per GeDDiS: dose reductions of 20% and then 33% for grade 3 or worse febrile neutropenia, grade 2 neuropathy or any grade of pulmonary toxicity; G-CSF after an episode of febrile neutropenia [24]. SARC002 used higher doses with more toxicity and dose reductions (dose details in the full text) [25, 24]. In patients with cardiac dysfunction that contraindicates doxorubicin, this combination is an option [24]. Place in therapy per ESMO [1].
Pazopanib (soft tissue sarcoma)
Advanced non-adipocytic soft tissue sarcoma after prior chemotherapy (ESMO [I, B]); efficacy not shown in adipocytic sarcoma or GISTCycle length: Continuous
Advanced non-adipocytic soft tissue sarcoma after prior chemotherapy (ESMO [I, B]); efficacy not shown in adipocytic sarcoma or GIST
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Pazopanib | 800 mg | Oral, without food (at least 1 hour before or 2 hours after a meal) | Once daily, continuously |
Eribulin (liposarcoma)
Unresectable or metastatic liposarcoma after an anthracycline-containing regimen (FDA label; ESMO [II, A])Cycle length: Every 21 days
Unresectable or metastatic liposarcoma after an anthracycline-containing regimen (FDA label; ESMO [II, A])
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Eribulin | 1.4 mg/m² | IV over 2 to 5 minutes | Days 1 and 8 |
Dose per the FDA label; mild hepatic impairment (Child-Pugh A): 1.1 and moderate (Child-Pugh B): 0.7 mg/m²; CrCl 15 to 49 mL/min: 1.1 mg/m²; after defined toxicities, permanent reduction to 1.1 and then 0.7 mg/m²; do not give with dextrose-containing solutions [56]. Phase 3 trial versus dacarbazine [27]; place in therapy per ESMO [1].
Trabectedin (liposarcoma and leiomyosarcoma)
Unresectable or metastatic liposarcoma or leiomyosarcoma after an anthracycline-containing regimen (FDA label); ESMO: option in second and further lines in soft tissue sarcoma [I, B]Cycle length: Every 21 days
Unresectable or metastatic liposarcoma or leiomyosarcoma after an anthracycline-containing regimen (FDA label); ESMO: option in second and further lines in soft tissue sarcoma [I, B]
Before prescribing: Shared safety points: soft tissue sarcoma| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Dexamethasone | 20 mg | IV | 30 minutes before each trabectedin dose |
| Trabectedin | 1.5 mg/m² | 24-hour IV infusion through a central venous line | Day 1 |
Dose per the FDA label; moderate hepatic impairment: 0.9 mg/m², not to be given in severe impairment; dose reductions to 1.2 and then 1.0 mg/m²; delay the dose for platelets below 100,000, ANC below 1,500 or bilirubin above the upper limit of normal [55]. Phase 3 trial versus dacarbazine [26]; place in therapy per ESMO [1].
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Gastrointestinal stromal tumour (GIST)
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GIST is the most common sarcoma of the digestive tract and is most often found in the stomach (about 6 in every 10) and the small bowel (about 3 in every 10) [6, 3]. It is seen mostly in older adults [6] and is very rare in children [3]. In most patients the main cause is a change in the KIT or PDGFRA gene within the tumour itself, and it is not inherited [6]; these changes are why targeted tablets work so well in GIST [3]. Read more: What is targeted cancer therapy?
The diagnosis is made with endoscopy, endoscopic ultrasound, a CT scan and a biopsy. Testing the tumour's genes (KIT and PDGFRA) is recommended for everyone, because it decides which drug and which dose to use [3].
Treatment of GIST:
- GIST that has not spread: complete surgical removal of the tumour, without the need to remove lymph nodes [3].
- After surgery, if the risk of the tumour coming back is high: 3 years of imatinib tablets. In a large study, 3 years compared with 1 year of imatinib meant fewer recurrences and longer survival; over the first 10 years, the number of deaths was nearly halved [35, 3].
- A large tumour, or one in a place that is hard to operate on: first 6 to 12 months of imatinib to shrink the tumour, then surgery [3].
- GIST that has spread: imatinib tablets every day, without stopping, for as long as they work. Stopping the drug, even after several years of control, usually makes the tumour grow again [3, 32]. In one study, nearly half of the people with GIST that had spread who took imatinib lived for more than 5 years [31].
- If imatinib stops working: the next drugs, in order, are sunitinib, regorafenib and ripretinib [3].
- Special gene types: with a particular change in the PDGFRA gene called D842V, imatinib does not work and avapritinib is used instead. GISTs without a KIT or PDGFRA change (for example, the “SDH-deficient” type or GIST linked to neurofibromatosis) do not respond to imatinib and are treated differently [3].
Take imatinib every day with food and a large glass of water. Its most common side effects are diarrhoea, tiredness, nausea, swelling, anaemia, rash, vomiting and abdominal pain. Tell your doctor about any new medicine, because some drugs, such as the tuberculosis drug rifampicin or the epilepsy drugs carbamazepine and phenytoin, make imatinib less effective [49]. Read more: Imatinib (Gleevec).
For physicians
Adjuvant treatment: in ACOSOG Z9001, imatinib 400 mg daily for 1 year after resection of a GIST of 3 cm or more increased 1-year recurrence-free survival to 98% vs 83% with placebo (HR 0.35; 95% CI 0.22 to 0.53) [33]. In SSG XVIII/AIO (400 high-risk patients by the modified NIH criteria), 36 versus 12 months gave 5-year recurrence-free survival of 65.6% vs 47.9% (HR 0.46) and 5-year overall survival of 92.0% vs 81.7% (HR 0.45; P = 0.02) [34]; at a median follow-up of 119 months, 10-year recurrence-free survival was 52.5% vs 41.8% (HR 0.66; P = 0.003) and 10-year overall survival 79.0% vs 65.3% (HR 0.55; 95% CI 0.37 to 0.83; P = 0.004) [35].
ESMO recommendations for adjuvant therapy: imatinib 400 mg daily for 3 years for a significant risk of relapse [I, A]; shared decision-making at intermediate risk (30% to 50%); with a KIT exon 9 mutation, 800 mg daily may be considered [II, B]; PDGFRA D842V and NF1-related or SDH-negative GIST should not receive adjuvant therapy [IV, D]; after tumour rupture the risk of relapse is very high and imatinib should be considered [IV, A]; microscopic margin status should not dictate adjuvant decisions. When R0 surgery is not possible without major sequelae, preoperative imatinib (usually 6 to 12 months) is standard [III, A], and in PDGFRA D842V preoperative avapritinib may be considered [III, A] [3].
Advanced disease: imatinib 400 mg daily is standard [I, A], and 800 mg daily with a KIT exon 9 mutation [III, B] [3]. In the MetaGIST meta-analysis (1,640 patients), the high dose gave only a small progression-free survival advantage, with no overall survival benefit, and a KIT exon 9 mutation was the only factor predicting that benefit [30]. In the pivotal trial (147 patients), imatinib 400 or 600 mg daily produced a partial response in 53.7% and stable disease in 27.9%, with no significant difference between the two doses [29]; in the long-term follow-up of the same trial (median 63 months), median overall survival was 57 months [31]. In BFR14, stopping imatinib after 3 years of control gave a 2-year progression-free survival of 16% vs 80% with continued treatment [32]; treatment therefore continues until progression or intolerance [I, A]. On progression at 400 mg, the dose can be increased to 800 mg [III, B]; first rule out pseudo-progression, non-adherence and drug interactions. In limited progression, resection of the progressing lesion while continuing imatinib is an option [IV, C] [3].
Later lines: sunitinib 50 mg on a 4 weeks on, 2 weeks off schedule increased median time to progression to 27.3 vs 6.4 weeks (HR 0.33; P less than 0.0001) [36], and continuous 37.5 mg daily is an alternative schedule [III, C]. Regorafenib 160 mg on days 1 to 21 in GRID gave a median progression-free survival of 4.8 vs 0.9 months (HR 0.27; P less than 0.0001), with grade 3 or worse hypertension in 23% and hand–foot skin reaction in 20% [37]. Ripretinib 150 mg daily in INVICTUS (fourth line) gave a median progression-free survival of 6.3 vs 1.0 months (HR 0.15; P less than 0.0001) [38]. ESMO: sunitinib second line [I, A], regorafenib third line [I, A] and ripretinib fourth line [I, A]; imatinib rechallenge or continuing a TKI beyond progression is an option [II, B], and TKI combinations are discouraged outside trials [3].
Special genotypes: in PDGFRA exon 18 D842V, avapritinib 300 mg daily is the standard first-line treatment [III, A] [3]; in NAVIGATOR, 49 of 56 patients (88%) responded (9% complete responses) [39]. SDH-deficient GIST is insensitive to imatinib and may respond to sunitinib and regorafenib [III, B]; NTRK-rearranged GIST responds to NTRK inhibitors [III, A] and BRAF-mutated GIST to BRAF inhibitors [V, B] [3]. Response assessment: a decrease in density on CT, even with an initial increase in size, can indicate response, and the “nodule within a mass” pattern indicates progression; early progression should be confirmed by an experienced team [3].
- Imatinib: with a meal and a large glass of water; 800 mg is given as 400 mg twice a day. Oedema and fluid retention: weigh regularly. Avoid strong CYP3A4 inducers; if one must be used, increase the dose by at least 50%. Bilirubin more than 3 times or transaminases more than 5 times the upper limit: withhold until bilirubin is below 1.5 times and transaminases below 2.5 times, then resume at a lower dose (400 to 300, 600 to 400 and 800 to 600 mg). In GIST, ANC below 1,000 or platelets below 50,000: stop until ANC 1,500 and platelets 75,000, then resume at 400 mg; if it recurs, 300 mg. Severe hepatic impairment: 300 mg [49].
- Sunitinib: dose reductions in GIST to 37.5 mg and then 25 mg daily; grade 3 hepatotoxicity: withhold until resolution and resume at a lower dose, and discontinue if it recurs [50].
- Regorafenib: boxed warning for hepatotoxicity; monitor liver function before and during treatment; reduce in 40 mg steps to a minimum of 80 mg; take after a low-fat meal [51].
- Ripretinib: dose reduction to 100 mg daily, and permanent discontinuation if this is not tolerated [52].
- Avapritinib: intracranial haemorrhage in 2.9% of patients with GIST or advanced systemic mastocytosis: discontinue permanently for any grade; manage cognitive effects by severity; dose reductions to 200 mg and then 100 mg [53]. ESMO also stresses early recognition of neurocognitive toxicity, brain bleeds and seizures [3].
For physicians
GIST: adjuvant and first-line treatment
Adjuvant imatinib for 3 years (GIST)
After complete resection of a GIST with a significant risk of relapse (for example high risk by the modified NIH or AFIP criteria) and an imatinib-sensitive genotypeCycle length: Continuous
After complete resection of a GIST with a significant risk of relapse (for example high risk by the modified NIH or AFIP criteria) and an imatinib-sensitive genotype
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Imatinib | 400 mg | Oral, with a meal and a large glass of water | Once daily |
Dose and duration per the FDA label (3 years recommended in the population of Study 2) [49] and ESMO [I, A] [3]. With a KIT exon 9 mutation, 800 mg may be considered [II, B] [3]. PDGFRA D842V and NF1-related or SDH-negative GIST do not receive adjuvant therapy [3]. Evidence: SSG XVIII/AIO [34, 35].
Evidence: One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor (2012)
Imatinib 400 mg (advanced GIST)
Unresectable or metastatic GIST with a sensitive genotype (except KIT exon 9); also after resection of all metastasesCycle length: Continuous
Unresectable or metastatic GIST with a sensitive genotype (except KIT exon 9); also after resection of all metastases
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Imatinib | 400 mg | Oral, with a meal | Once daily |
Imatinib 800 mg (GIST with a KIT exon 9 mutation)
Advanced GIST with a KIT exon 9 mutation (ESMO [III, B])Cycle length: Continuous
Advanced GIST with a KIT exon 9 mutation (ESMO [III, B])
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Imatinib | 400 mg twice daily (800 mg per day) | Oral, with a meal | Daily |
Avapritinib (GIST with a PDGFRA exon 18 mutation)
Unresectable or metastatic GIST with a PDGFRA exon 18 mutation, including D842V (FDA label; ESMO first line in D842V [III, A])Cycle length: Continuous
Unresectable or metastatic GIST with a PDGFRA exon 18 mutation, including D842V (FDA label; ESMO first line in D842V [III, A])
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Avapritinib | 300 mg | Oral | Once daily |
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
GIST: later lines
Sunitinib (GIST, second line)
GIST after progression on, or intolerance of, imatinib (ESMO [I, A])
GIST after progression on, or intolerance of, imatinib (ESMO [I, A])
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Sunitinib | 50 mg | Oral, with or without food | Once daily, 4 weeks on and 2 weeks off |
Regorafenib (GIST, third line)
GIST after imatinib and sunitinib (ESMO [I, A])Cycle length: Every 28 days
GIST after imatinib and sunitinib (ESMO [I, A])
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Regorafenib | 160 mg (four 40 mg tablets) | Oral, after a low-fat meal | Once daily, days 1 to 21 |
Ripretinib (GIST, fourth line)
Advanced GIST after imatinib, sunitinib and regorafenib (ESMO [I, A])Cycle length: Continuous
Advanced GIST after imatinib, sunitinib and regorafenib (ESMO [I, A])
Before prescribing: Shared safety points: GIST drugs| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Ripretinib | 150 mg | Oral, with or without food | Once daily |
Before prescribing, check each dose against the drug label, laboratory tests and the patient’s condition.
Osteosarcoma: the most common primary bone cancer
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Osteosarcoma is the most common primary bone cancer. It is seen most often in teenagers (especially at 15 to 19 years of age) and becomes more common again in older people [2]. It usually starts near the end of a long bone, most often around the knee [2, 8], and it most often spreads to the lungs [2].
Treatment combines chemotherapy and surgery [2]: usually about 10 weeks of chemotherapy, then surgery to remove the tumour, then more chemotherapy; the whole treatment takes about 7 months [40]. A combination of three drugs called MAP (high-dose methotrexate, doxorubicin and cisplatin) is the most widely used regimen in children and young adults [2]. Most patients can keep their arm or leg; surgery should be done at a centre experienced in bone reconstruction, especially of children's growing bones [2].
After surgery, the pathologist measures how much of the tumour was destroyed by chemotherapy. This “response” shows the chance of cure, but changing the drugs based on it has not improved results [2, 40].
Chance of cure: chemotherapy together with surgery has multiplied the chance of cure for osteosarcoma that has not spread; today more than 6 in every 10 of these patients stay free of disease [2]. In a large study of more than 2,000 young patients, about 7 in every 10 were alive 5 years after diagnosis [41]. When the cancer has already spread at diagnosis, the chance is lower (about 2 to 3 in every 10 stay free of recurrence), but if all the places the cancer has spread to can be removed, some patients are cured [9, 2]. Read more: Can childhood cancer be cured?
For physicians
Curative treatment of high-grade osteosarcoma is chemotherapy combined with surgery [II, A]; compared with surgery alone, it raises disease-free survival from under 20% to over 60%. Doxorubicin, cisplatin, HD-MTX and ifosfamide are active [I, A], and MAP is the most frequently used first-line regimen in children and young adults; in patients over 40, regimens combining doxorubicin, cisplatin and ifosfamide are preferred [III, B]. Adding pegylated interferon alfa-2b in good responders, ifosfamide and etoposide in poor responders, or preoperative zoledronic acid did not improve outcome [I, D]. Mifamurtide (MTP) is approved in Europe for patients under 30 with resected localised disease, but there is no consensus on its use [II, C]. R1 and R2 margins increase local recurrence and reduce survival; internal fixation is contraindicated in a pathological fracture [2].
In EURAMOS-1 (2,260 registered patients aged 40 or younger; 618 poor responders, i.e. 10% or more viable tumour, randomised), MAPIE versus MAP did not improve event-free survival (HR 0.98; 95% CI 0.78 to 1.23; 3-year event-free survival 53% vs 55%), but grade 4 non-haematological toxicity (24% vs 12%) and febrile neutropenia without documented infection (73% vs 50%) were more frequent, and second malignancies occurred in 10 vs 3 patients [40]. In the whole EURAMOS-1 cohort, 3- and 5-year event-free survival were 59% and 54% and 3- and 5-year overall survival from biopsy 79% and 71%; pulmonary metastases (HR 2.34), non-pulmonary metastases (HR 1.94) and an axial site (HR 1.53) were the strongest adverse factors, and in localised disease a poor histological response increased the risk after surgery (HR 2.13) [41]. Patients with metastases at diagnosis have an event-free survival of about 20% to 30% [9]. At relapse, complete removal of all resectable metastases is key, and more than one-third of patients with a second surgical remission survive for more than 5 years; overall, 5-year post-relapse survival is under 20%, and second-line chemotherapy usually includes ifosfamide or cyclophosphamide, possibly with etoposide and/or carboplatin [III, B] [2].
- High-dose methotrexate: leucovorin rescue is required for doses of 500 mg/m² or more; IV fluids starting before the dose and urine alkalinisation (pH 7 or higher) throughout; monitor creatinine, electrolytes and methotrexate levels at least daily; glucarpidase for toxic levels (above 1 micromole per litre) with delayed clearance due to renal impairment [47]. In EURAMOS-1, leucovorin 15 mg/m² was started 24–48 hours after the start of the infusion and continued until the methotrexate level was below 0.1 micromolar, adjusted with a nomogram [40].
- Cisplatin: adequate hydration and monitoring of renal function and electrolytes; highly effective antiemetics; cumulative ototoxicity, especially in children: monitor audiometry [48]. Baseline audiogram before treatment [2].
- Doxorubicin: baseline cardiac assessment (EURAMOS-1 required a shortening fraction above 28%) and LVEF monitoring [40, 45].
- Starting cycles: cisplatin–doxorubicin cycles with ANC of at least 750 and platelets of at least 75,000 per microlitre; HD-MTX with ANC of at least 250 and platelets of at least 50,000 [40].
- Fertility: sperm storage for men and fertility counselling for women before treatment [2]; Fertility preservation before cancer treatment.
For physicians
Osteosarcoma: MAP chemotherapy
MAP (osteosarcoma)
Resectable high-grade osteosarcoma, aged 40 or younger (the EURAMOS-1 population); before and after surgery; continue the same MAP after surgery even with a poor histological response
Resectable high-grade osteosarcoma, aged 40 or younger (the EURAMOS-1 population); before and after surgery; continue the same MAP after surgery even with a poor histological response
Before prescribing: Shared safety points: the MAP regimen| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Each 5-week MAP cycle | |||
| Cisplatin | 120 mg/m² | IV: 60 mg/m² per day over 4 hours for 2 days, or a 72-hour continuous infusion | Week 1 |
| Doxorubicin | 37.5 mg/m² per day (total 75 mg/m²) | IV (in the trial registry: 48-hour continuous infusion) | Days 1 and 2 of week 1 |
| High-dose methotrexate | 12 g/m² (maximum 20 g per dose) | 4-hour IV infusion with hyperhydration and urine alkalinisation | Weeks 4 and 5 |
| Leucovorin | 15 mg/m² | Per protocol | From 24–48 hours after methotrexate until the level is below 0.1 micromolar |
Doses per the EURAMOS-1 full text (maximum methotrexate dose 20 g at COG centres) [40]; FDA methotrexate label: typically 12 g/m² (maximum 20 g per dose) as a 4-hour infusion with leucovorin rescue [47]. Start cisplatin–doxorubicin cycles with ANC 750 and platelets 75,000, and HD-MTX with ANC 250 and platelets 50,000 per microlitre [40]. Timing of the postoperative cycles per the trial registration on ClinicalTrials.gov [57]. In patients over 40, HD-MTX is more difficult and regimens of doxorubicin, cisplatin and ifosfamide are alternatives [2].
Evidence: EURAMOS-1 (2016)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Ewing sarcoma and sarcomas in children
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Ewing sarcoma is the second most common bone cancer in children and young people; it is most often diagnosed in the teenage years (around 15) and is slightly more common in boys [2]. It is most often found in the bones of the arms and legs, the pelvis, the ribs and the spine; about 3 in every 10 cases start in soft tissue, which is more common in adults [2]. The diagnosis is confirmed by a biopsy and a genetic test of the tumour: in most patients two genes called EWSR1 and FLI1 are fused together [2].
Treatment has three stages: first several months of chemotherapy with several drugs, then surgery and/or radiotherapy to the main tumour, and then more chemotherapy; the whole treatment takes about 10 to 12 months [2]. Today an “interval-compressed” regimen, which gives the cycles every 2 weeks instead of every 3 weeks, is preferred; in a large study it reduced recurrence and helped people live longer, without more side effects [42, 43, 2]. Complete surgery, where possible, is the best way to control the main tumour, and when surgery is not possible or would cause too much harm, radiotherapy takes its place [2].
Chance of cure: when the disease has not spread, most patients (about 6 to 7 in every 10) are alive after 5 years, and when it has spread, 2 to 4 in every 10 [2]. In the study of the interval-compressed regimen, about 3 in every 4 people in the group that received it were alive after 10 years [43].
Rhabdomyosarcoma is the most common soft tissue sarcoma in children and starts in muscle cells [11]. It can appear in the head and neck, around the eye, in the urinary and genital organs, in the arms or legs or elsewhere. The main sign is a lump or swelling that keeps getting bigger or does not go away; depending on where it is, a bulging eye, headache, blood in the urine or problems passing urine or stools may also occur [11]. Every child with rhabdomyosarcoma receives chemotherapy and, depending on the site, surgery and/or radiotherapy [11].
Children and teenagers with sarcoma should be treated at a specialist children's cancer centre or a sarcoma centre experienced in treating this age group [1, 2]. Read more: Warning signs of cancer in children and Can childhood cancer be cured?
For physicians
Molecular confirmation is mandatory to distinguish Ewing sarcoma from other round cell sarcomas [V, A]: t(11;22)(q24;q12) with an EWSR1-FLI1 fusion in 85% and t(21;22) with EWSR1-ERG in about 10%. FDG-PET/CT or whole-body MRI is preferred over a bone scan [V, B], and with a negative FDG-PET/CT, bone marrow aspirates and biopsies are not mandated [V, C]. About 25% of patients have metastases at diagnosis; multiple bone metastases carry a worse outcome than lung or pleural metastases (5-year survival under 20% vs 50% to 60%). Other adverse factors: tumour volume, LDH, axial site, age over 15, poor histological response and incomplete or no surgery of the primary [2].
In AEWS0031 (568 patients under 50 with localised disease), VDC/IE every 2 weeks versus every 3 weeks (14 cycles with filgrastim) increased 5-year event-free survival to 73% vs 65% (P = 0.048; HR 0.74; 95% CI 0.54 to 0.99), and overall survival was 83% vs 77% (P = 0.056), without more toxicity; patients aged 18 or older had a much lower 5-year event-free survival (47% vs 72%) [42]. At 10 years, event-free survival was 70% vs 61% (P = 0.03) and overall survival 76% vs 69% (P = 0.04), with no increase in second cancers; the benefit was greater with a tumour volume of 200 mL or more [43]. In EURO EWING 2012 (640 patients aged 2–49, all stages), interval-compressed VDC/IE versus VIDE gave a 3-year event-free survival of 67% vs 61% (adjusted HR 0.71; 95% credible interval 0.55 to 0.92), with less grade 3–5 febrile neutropenia (58% vs 74%) [44]; ESMO considers it the preferred first-line regimen [I, B] [2].
Local control: complete surgery, where feasible, is the best modality [IV, A] and must remove all tissues involved before chemotherapy; intralesional surgery has no benefit over radiotherapy alone. Definitive radiotherapy is used when complete surgery is not possible or the site (axial, spinal) would mean unacceptable morbidity [IV, A]; adjuvant radiotherapy (45–60 Gy) for volumes over 200 mL, poor histological response or inadequate margins [IV, B], and for non-sacral pelvic Ewing sarcoma regardless of margins [II, B]. BuMel with autologous rescue may be considered for a poor response to VIDE or a volume over 200 mL [I, B], but has not been evaluated after interval-compressed VDC/IE. At relapse, alkylating agents with topoisomerase inhibitors, irinotecan with temozolomide, gemcitabine–docetaxel, high-dose ifosfamide or carboplatin–etoposide are used [III, B], and preliminary rEECur data showed gemcitabine–docetaxel to be the weakest option [2]. Indications for stem cell transplantation.
- Ifosfamide and cyclophosphamide: mesna with both (as in AEWS0031); with ifosfamide, hydration of at least 2 litres a day and monitoring for encephalopathy, renal function and haemorrhagic cystitis [42, 46].
- Doxorubicin: in AEWS0031 the cumulative dose was 375 mg/m² for all patients; monitor LVEF [42, 45].
- Filgrastim between cycles is part of the regimen; the next cycle starts when ANC is above 750 and platelets above 75,000 per microlitre and 24 hours after the last filgrastim dose [42].
- Vincristine: maximum 2 mg per dose [42]; peripheral neuropathy.
- Second cancers: in AEWS0031, 16 patients developed second cancers, including 11 acute myeloid leukaemias and 3 osteosarcomas in radiation fields [42]; monitor late effects for more than 10 years [2].
For physicians
Ewing sarcoma: interval-compressed VDC/IE
Interval-compressed VDC/IE every 2 weeks (Ewing sarcoma)
Localised Ewing sarcoma (in AEWS0031: under 50 years); ESMO: preferred first-line regimen [I, B]; in EURO EWING 2012 all stages, aged 2–49
Localised Ewing sarcoma (in AEWS0031: under 50 years); ESMO: preferred first-line regimen [I, B]; in EURO EWING 2012 all stages, aged 2–49
Before prescribing: Shared safety points: VDC/IE| Drug | Dose | Route | Schedule |
|---|---|---|---|
| VDC cycles (alternating with IE) | |||
| Vincristine | 1.5 to 2 mg/m², maximum 2 mg (see notes) | IV | Day 1 |
| Doxorubicin | 37.5 mg/m² per day | IV | Days 1 and 2 |
| Cyclophosphamide | 1,200 mg/m² | IV, with mesna | Day 1 |
| IE cycles | |||
| Ifosfamide | 1,800 mg/m² per day | IV, with mesna | Days 1 to 5 |
| Etoposide | 100 mg/m² per day | IV | Days 1 to 5 |
| Between cycles | |||
| Filgrastim | 5 micrograms/kg per day | Subcutaneous or IV (per the label) | From at least 24 hours after chemotherapy until count recovery |
Doses per AEWS0031 (Figure 1 and the appendix table of the article) [42]. The vincristine dose is given as 1.5 mg/m² in Figure 1 of the article and as 2 mg/m² in the abstract and appendix table; both cap it at 2 mg [42]. Filgrastim dose per the FDA label for myelosuppressive chemotherapy (5 micrograms/kg per day, at least 24 hours after chemotherapy and not within the 24 hours before it) [58]. Radiotherapy in AEWS0031: 45 Gy to the initial volume and 55.8 Gy to the final volume of unresected tumours, in 1.8 Gy fractions [42]. EURO EWING 2012 [44]; place in therapy per ESMO [2].
Evidence: AEWS0031 (2012)
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Life after treatment: follow-up, fertility and late effects
After treatment, regular check-ups and scans are needed. In high-risk sarcomas, most recurrences happen in the first 2 to 3 years and most often in the lungs, so follow-up is closer in the first years, for example every 3 to 4 months, and then the gaps get longer [1]. For bone sarcoma, follow-up continues for many years [2]. In GIST, recurrences are most often in the liver and the lining of the abdomen, and follow-up uses CT or MRI of the abdomen [3]. Read more: What is cancer recurrence?
Fertility: chemotherapy for sarcoma can reduce the ability to have children. Before treatment starts, sperm storage is recommended for men and a consultation with a fertility specialist for women [2]. Even if you do not plan to have children now, ask about it before the first cycle of chemotherapy. Read more: Fertility and sex during cancer treatment.
Late effects: some drugs have side effects that may appear during or after treatment: doxorubicin can damage the heart [45], cisplatin the hearing [48] and ifosfamide the kidneys [46]. Chemotherapy and radiotherapy also increase the risk of a second cancer [8, 10]. After bone sarcoma, monitoring for these effects should continue for more than 10 years [2].
Reconstruction and getting back to life: after surgery, plastic surgery or vessel grafts are used for reconstruction when needed [1], and in children, reconstructing a growing bone needs an experienced surgeon [2]. Read more: Returning to work and everyday life.
For physicians
Follow-up schedule (a practical, expert-based approach): intermediate- or high-grade soft tissue sarcoma: every 3–4 months in the first 2–3 years, then twice a year up to year 5 and annually thereafter; low grade: every 6 months for 5 years, then annually; MRI for local relapse and chest CT for lung metastases [1]. High-grade bone sarcoma: physical examination, cross-sectional imaging and radiographs of the primary site with chest X-ray or CT [IV, B], roughly every 3 months in the first 2 years, every 6 months in years 3–5 and every 6–12 months in years 5–10 [V, B]; monitor late effects for more than 10 years [V, B] [2]. High-risk GIST (one institution's example): abdominal CT or MRI every 3–6 months during 3 years of adjuvant therapy, then every 3 months for 2 years after stopping, then every 6 months until 5 years after stopping and annually for another 5 years; low-risk GIST: every 6–12 months for 5 years; in low-risk disease, MRI is an alternative to limit radiation [3].
What should I do after a diagnosis?
Frequently asked questions
What is sarcoma?
Sarcoma is a cancer that starts in the body's supporting tissues, such as muscle, fat, blood vessels, nerves, connective tissue or bone [5, 2]. Sarcoma is rare and about 80 types of soft tissue sarcoma are recognised, which is why it is best diagnosed and treated at specialist centres [1].
Can sarcoma be cured?
Yes, especially when it is found early and removed completely. Small, low-grade sarcomas of the arms, legs and trunk are often cured by surgery alone [4]. In osteosarcoma and Ewing sarcoma that have not spread, most patients survive with combined treatment [2, 41]. GIST that has spread can also be controlled with tablets for years in many patients [31].
What are the symptoms of bone cancer?
Bone pain that does not go away and is often worse at night, swelling or a lump over a bone, a limp, a stiff joint and a bone that breaks for no clear reason [2, 8]. Ewing sarcoma may also cause fever and weight loss [10]. In adults over 40, most cancers found in the bone have spread there from elsewhere in the body or are multiple myeloma [2].
Is a painless lump under the skin dangerous?
Does a biopsy make sarcoma spread?
A biopsy is needed to choose the right treatment. For sarcoma at the back of the abdomen, the risk of cells being seeded along the needle track is minimal and should not be a reason to avoid a biopsy [1]. In the arms and legs, the needle track is chosen so that it is removed with the tumour at the main operation [1]. Read more: Does a biopsy make cancer spread?
Does a sarcoma of the arm or leg mean amputation?
What is GIST and can it be treated with tablets?
GIST is a type of sarcoma in the wall of the stomach or bowel [3]. If it has not spread, it is removed by surgery; if the risk of it coming back is high, 3 years of imatinib tablets after surgery helps people live longer [35]. If it has spread, imatinib often controls it for years, but it must be taken without stopping, because the disease usually returns when the drug is stopped [31, 32].
How long should imatinib be taken?
What is the survival rate for osteosarcoma?
Is sarcoma hereditary?
Most sarcomas are not inherited [4], but the risk is higher with some inherited conditions such as Li-Fraumeni syndrome and neurofibromatosis type 1 [4]. If you had a sarcoma at a young age and several relatives were diagnosed young with breast cancer, sarcoma or a brain tumour, ask about genetic counselling [1]. Read more: Is cancer hereditary?
Evidence and recent advances (for physicians)
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Referral and centralised care
NICE NG12: in adults, an urgent direct-access ultrasound for an unexplained lump that is increasing in size; a suspected cancer pathway referral if the ultrasound suggests soft tissue sarcoma or is uncertain and clinical concern persists; and a suspected cancer pathway referral if an X-ray suggests the possibility of bone sarcoma. In children and young people, a very urgent direct-access X-ray for unexplained bone swelling or pain and a very urgent ultrasound for an unexplained lump that is increasing in size; with suggestive or uncertain findings, a very urgent referral (appointment within 48 hours) [13].
ESMO: referral to a reference centre should happen at the clinical diagnosis of a suspected sarcoma, i.e. all unexplained deep soft tissue masses and superficial lesions of 5 cm or more in diameter; management in sarcoma reference centres or tertiary paediatric oncology centres as appropriate for age [III, A] [1]. For bone sarcoma, the initial work-up (history, examination, imaging and biopsy) should be done at a reference centre [IV, B] [2].
Evidence: in the NETSARC national registry (35,784 patients; 29,497 incident patients, 33.7% operated on in a NETSARC centre), surgery at a reference centre was associated with better local relapse-free, event-free and overall survival (HR for overall survival 0.681; P less than 0.001); presentation to a specialised tumour board without surgery at a reference centre was an adverse factor for overall survival [15]. As the network grew (43,975 patients, 2010–2020), overall survival improved nationwide, biopsy before surgery rose from 62.9% to 72.6%, R0 resection at first surgery from 36.1% to 46.6%, and R2 fell from 10.9% to 7.9% [16]. In a Swedish population-based series (375 patients), local recurrence was 45% in patients not referred, 24% in those referred after initial surgery or incisional biopsy and 18% in those referred before any surgical procedure [4].
- Preoperative hypofractionation, radiotherapy combined with immunotherapy or targeted therapy, and histotype-specific dose tailoring are promising but should not enter routine practice until more evidence is available [19].
- ESMO's table of agents active in selected subtypes includes PD-1/PD-L1 inhibitors in alveolar soft part sarcoma (response rate 32% to 36%) and tazemetostat in epithelioid sarcoma (response rate 15%); these have not entered standard practice or are not approved in all European countries, so individual shared decisions are needed [1].
- Adjuvant imatinib for longer than 3 years is being tested in randomised trials [3].
- In relapsed bone sarcoma, data on cabozantinib and regorafenib are still preliminary and not standard [2].
Scientific evidence
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Key studies
6 itemsDoxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial
One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor
Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial
Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors
Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial
Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group
Clinical guidelines
3 itemsSoft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up
Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up
Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up
References
58 referencesShow all references, 9 with a study cardClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
- 1Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up(☆)
- 2Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up
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- 12Kaposi Sarcoma Treatment (PDQ®)–Patient Version
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- 21A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma
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- 29Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
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- 33Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial
- 34One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial
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- 57EURAMOS-1: A Randomized Trial of the European and American Osteosarcoma Study Group to Optimize Treatment Strategies for Resectable Osteosarcoma Based on Histological Response to Pre-operative Chemotherapy (NCT00134030)
- 58NEUPOGEN (filgrastim) injection: Prescribing Information
This page is based on reputable scientific sources and was last updated on 28 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.
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