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Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

picture - Introduction

Introduction

  • Expert Center

  • MultiDisciplinary Team

These ESMO–EURACAN Clinical Practice Guidelines cover STSs (Soft Tissue sarcomas).
Soft tissue and Visceral sarcomas (including embryonal, alveolar rhabdomyosarcomas and Extraskeletal osteosarcoma) gather over 150 histological entities, with even more molecular subsets, characterised by a low to very low incidence in all countries.

GISTs are covered by ESMO–EURACAN Clinical Practice Guidelines on Gastrointestinal stromal tumours

Extraskeletal Ewing and Ewing-like sarcoma are covered by ESMO–PaedCan–EURACAN Clinical Practice Guidelines on bone sarcomas.

In general, the same principles apply to children and adults for these tumors.

Adult STS pathological subtypes occurring in adolescents should be managed the same way as in adult patients, though the same histotype might display clinical peculiarities when occurring at different ages.

  • Multidisciplinary approach by sarcome expert  in a Multi disciplinary Team is mandatory in all cases.
  • Management of STS should be carried out in reference centres for sarcomas and/or within reference networks

see page on reference networks and centres

Referral of all patients with a lesion suspected to be a sarcoma would be recommended.
This would mean referring all patients with an unexplained deep mass of soft tissues, or with a superficial lesion of soft tissues having a diameter of ≥5 cm.
picture - Diagnosis

Diagnosis

  • Expert Center

  • Standard Treatment

  • MultiDisciplinary Team

  • Pathological diagnosis should be made according to the most recent WHO classification
  • Appropriate imaging assessment can include: MRI, standard radiographs, CT, ultrasound (followed by CT or MRI).
  • The standard approach to diagnosis requires a biopsy, usually with multiple core needle biopsies, carried out by a surgeon or a radiologist after multidisciplinary discussion, as needed, within reference centres.

Standard management of local/locoregional

  • Standard Treatment

  • Surgery

  • Radiation Therapy

Surgery is the standard treatment of all patients with an adult type, localised STS – see figure 1

It must be carried out by a surgeon specifically trained in the treatment of this disease. see page on reference networks and centres

The standard surgical procedure is a wide excision with negative margins (absence of residual tumour, R0) [II, A]

Describing  accurately the quality of resection (fragmentation, bleeding, R0, R1, R2)

The surgical report should provide details on preoperative and intraoperative diagnosis; surgical conduct, including possible contaminations (i.e. it should mention whether the tumour was opened and was ‘seen’ during the excision, etc.); and surgical actual completeness vis-a-vis planned quality of margins.

The pathology report after definitive surgery should mention the tumour status: intact or not, margin description, margin status (assessment of margins made in collaboration with the surgeon).

Pathological response of the tumour to neoadjuvant treatment when relevant.

Reoperation in reference centres if the resection was not done as per standard.

It must be considered and discussed in a specialized  MDT in the case of R1 resections (microscopic tumour at the margin), if adequate margins can be achieved without major morbidity, taking into account tumour extent and tumour biology.

It is mandatory for R2 surgery, possibly following preoperative treatments if adequate margins cannot be achieved

RT will follow marginal or R1–R2 excisions, if these cannot be rescued through re-excision, tailoring the decision depending on further considerations, including impact on future surgeries.

The typical wide excision is followed by radiotherapy as the standard treatment.

Applies to high-grade (G2–3), deep, ≥5 cm lesions [II, B].

Dose and timing according to wound complications analysis.

Exceptions may be made after multidisciplinary discussion considering several variables such as the anticipated incidence of wound complications.

The main advantage of preoperative radiotherapy is that, with prolonged follow-up, late morbidity (fibrosis, bone fracture, etc.) is lower, translating into improved long-term functional outcome and quality of life (QoL).

drawing about Standard management of local/locoregional

Management of local/locoregional

  • Specific Treatment

  • MultiDisciplinary Team

  • Radiation Therapy

  • Chemotherapy

  • Surgery

  • Chemo-hyperthermia

Adjuvant chemotherapy is not standard treatment in adult-type STS.

It can be proposed as an option to the high-risk individual patient [II, C]

There are randomized evidence of the efficacy of neoadjuvant chemotherapy

Anthracyclines plus ifosfamide for at least 3 cycles is an option in the high-risk individual patient [II, B]

Randomized evidence of efficacy in high-risk extremity and superficial trunk STS ‘fit’ patients.

Mutilating surgery may be needed in some cases.

  • Options for limb-preserving surgery include:
    • chemotherapy and/or radiotherapy [III, A],
    • or isolated hyperthermic limb perfusion with tumour necrosis factor-alphaþmelphalan [III, A],
    • or regional hyperthermia combined with chemotherapy [I, B]

For sensitive histological types of regional lymph node metastases, surgery through wide excision, coupled with adjuvant radiotherapy and adjuvant chemotherapy is the standard treatment.
They are rare and constitute an adverse prognostic factor in adult-type STSs.

Chemotherapy may be administered as preoperative treatment, at least in part.

Indication of adjuvant radiotherapy should be reserved for specific case.

The increase in local control should be balanced against.

Regional hyperthermia and isolated limb perfusion are options to combine with other modalities [III, A].

Localised, clinically unresectable STS : Figure 2

Management of advanced/metastatic disease

  • MultiDisciplinary Team

  • Surgery

  • Chemotherapy

  • The decision making should always be multidisciplinary.
Main criteria are presentation, localisation, resectability, and histology
Evaluated with Abdominal CT scan, bone scan and (FDG)-PET

See Figure 3 and 4.

Surgery is used when possible
Metachronous (disease-free interval ≥ 1 year), resectable lung metastases without extrapulmonary disease are managed with surgery as standard treatment, if complete excision of all lesions is feasible [IV, B]

Chemotherapy may be added to surgery as an option, taking into account the prognostic factors.

Chemotherapy combinations are used depending on the case.

Standard chemotherapy is based on anthracyclines as the first-line treatment [I, A]. Multi-agent chemotherapy with adequate-dose anthracyclines plus ifosfamide may be the treatment of choice, particularly in subtypes sensitive to ifosfamide, when a tumour response is felt to be potentially advantageous and patient PS is good [I, B]

The combination of doxorubicin with an anti-PDGFRA agent, olaratumab, is option [II, Cb; ESMO-MCBS v1.1 score: 4]

Gemcitabine/docetaxel combination is not generally recommended as a first-line therapy for advanced STS patients [I, D]

Imatinib is standard medical therapy for those rare patients with dermatofibrosarcoma protuberans [III, A]

Trabectedin is an option for second line and beyond [I, B] and is approved for advanced previously treated STS

Pazopanib is an option in non-adipogenic STS [I, B]

Regorafenib is an option (not approved by FDA and EMA) in doxorubicin-pretreated advanced, non-adipogenic STS patients [II, C].

Eribulin is an option in patients with liposarcomas and LMS [II, A; ESMO-MCBS v1.1 score: 4]

The combination of dacarbazine and gemcitabine or gemcitabine/docetaxel is an option in doxorubicin-pretreated patients [II, B]

There is evidence of activity of several molecular targeted agents.

mTOR inhibitors in malignant PEComas [IV, C];

Crizotinib in inflammatory myofibroblastic tumours associated with ALK translocations [IV, C];

Sunitinib and cediranib in alveolar soft part sarcoma, where the molecular target is as yet unclear [IV, C]; and Sunitinib in solitary fibrous tumours [IV, C]

NTRK inhibitors in  sarcomas progressing after standard treatment and  bearing  translocations involving  on of the  3NTRK genes

  • Active systemic therapies must be considered in progressing advanced STS patients
  • Radiotherapy should be used as a palliative resource in all cases as appropriate to the clinical need.

Follow up

  • Routine follow up policy based on malignancy grade and risk assessment
  • High risk – relapse in 2-3 years – follow
    • every 3-4 months for 2-3 years
    • twice a year for 2-3 more years
    • Once a year after
  • Low risk – later relapses – follow
    • Every 4-6 months for 3-5 years (X Rays or CT longer intervals possible)
    • Once a year after
  • Relapses often to the lungs with no symptoms when surgery still an option
    • Clinical assessment and chest X rays
    • No benefit for MRI and CT

Special presentation and entities

Retroperitoneal sarcomas : referred to reference centers forsarcomas centre

  • Functional assessment of contralateral kidney is necessary
  • No transperitoneal, no open or laparoscopic biopsies
  • Surgery « en bloc » with adherent structure
  • Postoperative/adjuvant EBRT after complete gross resection not advised
  • Brachitgerapy and intraoperative radiotherapy not advised

Uterine sarcomas

  • Diagnosis : carefully excluding epithelial component (pathology review)
  • En bloc resection : no procedures resulting in potential cell spillage
  • Standard treatment is « en bloc » total hysterectomy for all uterine LMSs, ESSs and localised UESs
  • Bilateral salpingo-oophorectomy debated
  • Lymphadenectomy, radiotherapy, chemotherapy, adjuvant hormonal not standard
    • Specific cases to be discussed multidisciplinary

Desmoid-type fibromatosis : initial watchful waiting policy for non life threatening lesions upon monitoring by expert centers

  • MRI monitoring of potentially life-threatening extra-abdominal locations and intra-abdominal desmoids
  • If progressing multidisciplinary decision case
  • Treatment options : radiotherapy, NSAIDS, hormonal treatment (antioestrogens), cytotoxics , VEGFR2 inhibitors (sorafenib, pazopanib)

Breast sarcomas : referred to sarcomas unit

  • Multidisciplinary decision case by case
  • Breast-conserving surgery possible in specific clinical presentations or histotypes
  • Mastectomy advised for angiosarcomas
  • Chemotherapy recommandations : same as for STS

Credits

Citation

Casali PG, Abecassis N, Aro HT, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up [published correction appears in Ann Oncol. 2018 Oct 1;29(Suppl 4):iv268-iv269] [published correction appears in Ann Oncol. 2018 Oct;29 Suppl 4:iv268-iv269]. Ann Oncol. 2018;29(Suppl 4):iv51-iv67. doi:10.1093/annonc/mdy096

Authors

P. G. Casali1, N. Abecassis2, S. Bauer3, R. Biagini4, S. Bielack5, S. Bonvalot6, I. Boukovinas7, J. V. M. G. Bovee8, T. Brodowicz9, J. M. Broto10, A. Buonadonna11, E. De Àlava10, A. P. Dei Tos12, X. G. Del Muro13, P. Dileo14, M. Eriksson15, A. Fedenko16, V. Ferraresi17, A. Ferrari18, S. Ferrari19, A. M. Frezza1, S. Gasperoni20, H. Gelderblom21, T. Gil22, G. Grignani23, A. Gronchi1, R. L. Haas24, A. Hannu25, B. Hassan26, P. Hohenberger27, R. Issels28, H. Joensuu29, R. L. Jones30, I. Judson31, P. Jutte32, S. Kaal33, B. Kasper27, K. Kopeckova34, D. A. Krákorová35, A. Le Cesne36, I. Lugowska37, O. Merimsky38, M. Montemurro39, M. A. Pantaleo40, R. Piana41, P. Picci19, S. Piperno-Neumann6, A. L. Pousa42, P. Reichardt43, M. H. Robinson44, P. Rutkowski37, A. A. Safwat45, P. Schöffski46, S. Sleijfer47, S. Stacchiotti48, K. Sundby Hall49, M. Unk50, F. Van Coevorden51, W. Van der Graaf30, J. Whelan52, E. Wardelmann53, O. Zaikova54 & J. Y. Blay55, on behalf of the ESMO Guidelines Committee and EURACAN*


*Correspondence to: ESMO Guidelines Committee, ESMO Head Office, Via Ginevra 4, 6900 Lugano, Switzerland. E-mail: clinicalguidelines@esmo.org

†Approved by the ESMO Guidelines Committee and EURACAN: December 2017.

Pictures

References
[1]Brierley JD, Gospodarowicz MK, Wittekind C (eds). TNM Classification of Malignant Tumours, 8th edn. Oxford: John Wiley & Sons, Inc. 2016.

[2] Cherny NI, Dafni U, Bogaerts J et al. ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol 2017; 28: 2340–2366, https://doi.org/10.1093/annonc/mdx310

[3]Schoffski P, Chawla S, Maki RG et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016; 387: 1629–1637, https://doi.org/10.1016/S0140-6736(15)01283-0

[4]By permission of the Infectious Diseases Society of America (Clare A. Dykewicz, Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients, Clinical Infectious Diseases, Volume 33, Issue 2, 15 July 2001, Pages 139–144, https://doi.org/10.1086/321805).

Other references available in the complete guideline available here: https://www.annalsofoncology.org/article/S0923-7534(19)31692-8/pdf

Patient’s typology

Child
Teenager
Adult