What is the role for adjuvant systemic therapy for adults with BSTT?

From Cancer Guidelines Wiki

Introduction

For many years surgery has been the primary treatment modality of patients with apparently localised bone and soft tissue sarcoma. Evidence has emerged of improved outcomes when sarcoma care is concentrated in referral centres specialising in these rare tumours. [1] Multidisciplinary teams including surgeons, pathologists, medical and radiation oncologists, and imaging experts have evolved in these specialist centres and commonly paediatric and AYA (Adolescent and Young Adult) oncologists, and psychosocial services are included. These specialist centres are increasingly engaged in clinical research including familial and molecular investigations, clinical trials and supportive care studies.

Chemotherapy is now playing an increasing role in the management of high grade localised sarcomas, not only as adjuvant therapy after surgical resection, but also as initial therapy (neoadjuvant) for large high-grade sarcomas in which radical surgery and/or radiation treatment is contraindicated. Several new drugs have been found to be active in sarcomas of different types, and the integration of these agents into care is the subject of current investigation. The range of sarcoma types in which chemotherapy is sometimes effective has increased and is not restricted to sarcomas diagnosed in children.

Chemotherapy can be considered either as systemic adjuvant treatment with the primary goal of treating microscopic disease at the time of initial presentation, or as a complement to local treatment by surgery or radiation. In the latter setting, the goal of chemotherapy is to ‘downstage’ the tumour enabling surgery or radiation to achieve local disease control sometimes with reduced morbidity. Tumour shrinkage or percentage necrosis after pre-operative chemotherapy may also provide important prognostic information, enabling informed treatment decisions after completion of local treatment.

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Sarcoma types

Traditionally sarcomas are divided into those arising in bone or soft tissues. This subdivision is now better informed by immune-histochemical and molecular analysis, and these studies will likely guide treatment selection in the future. Some literature considers sarcomas by their primary site and then by histological type. Commonly the outcomes of children with sarcomas are considered separately from the same histological types in older people.

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Bone sarcomas

The classification of bone sarcomas used most commonly in reports of treatment trials is the following:

  • Osteosarcoma
  • Ewings sarcoma
  • Chondrosarcoma
  • Malignant fibrous histiocytoma
  • Spindle cell sarcomas


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Soft tissue sarcomas

The classification of soft tissue sarcomas used most commonly in reports of treatment trials is the following:

  • Soft tissue sarcomas
  • Embryonal rhabdosarcoma
  • Synovial sarcoma
  • Leiomyosarcoma
  • Malignant fibrous histiocytoma (now undifferentiated pleomorphic sarcoma)
  • Myxoid liposarcoma
  • Liposarcoma


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Evidence summary and recommendations

Bone sarcomas

Osteosarcoma

Evidence summary Level References
In general chemotherapy is administered before and after surgery, but formal proof is lacking that pre-operative chemotherapy predicts survival. II [2]
The extent of histological response to pre-operative chemotherapy predicts survival. II [2]
Altering post-operative chemotherapy in poor responders to pre-operative chemotherapy has not been shown to improve outcomes.

Ifosfamide and etoposide are active drugs in osteosarcoma, but their individual or combined contribution to outcomes compared to cisplatin, doxorubicin and high dose methotrexate regimens is not established.

II [3]
Intra-arterial chemotherapy compared to intravenous administration has not been shown to improve outcome. II [2]
Evidence-based recommendationQuestion mark transparent.png Grade
Curative treatment of high-grade osteosarcoma comprises chemotherapy and surgery.
B
Evidence-based recommendationQuestion mark transparent.png Grade
Pre-operative chemotherapy for high-grade osteosarcoma including cisplatin, doxorubicin and in selected patients high-dose methotrexate, improves outcomes compared to regimens omitting high-dose methotrexate.
C

Malignant fibrous histiocytoma of bone

Evidence summary Level References
Doxorubicin and cisplatin pre-operative chemotherapy caused a good pathologic response (>90% necrosis) in 42% of assessable patients.

Those with a good pathologic response had longer survival times and time to disease progression than did those with a poor response.

IV [4]
Evidence-based recommendationQuestion mark transparent.png Grade
As for osteosarcoma, doxorubicin and cisplatin are indicated for malignant fibrous histiocytoma of bone.
D


High-grade spindle cell sarcomas of bone other than osteosarcoma or malignant fibrous histiocytoma

Evidence summary Level References
Pre-operative doxorubicin and cisplatin prior to resection in twenty patients caused a good histological response in two specimens. IV [5]
Evidence-based recommendationQuestion mark transparent.png Grade
As for osteosarcoma, doxorubicin and cisplatin are indicated for high-grade spindle cell sarcomas of bone and malignant fibrous histiocytoma.
D


Ewings sarcoma

Evidence summary Level References
All current trials of treatment employ pre-operative chemotherapy for three to six cycles followed by local therapy by surgery and/or radiotherapy to the primary site and this approach achieves five year-survival rates of 60% plus in those with localised disease compared to historical survival rates of 10% with surgery or radiotherapy alone. II [6]
Cycles of chemotherapy administered every two weeks are more effective than chemotherapy administered every three weeks. II [6]
Evidence-based recommendationQuestion mark transparent.png Grade
Curative treatment of Ewings sarcoma comprises of a combination of chemotherapy and surgery and/or radiotherapy.
B


Soft Tissue Sarcomas

Evidence summary Level References
Post-operative chemotherapy with doxorubicin in localised resectable soft tissue sarcoma reduces distant and overall recurrence OR 0.7 (95% CI 0.56-0.82; p=0.0001). The OR for doxorubicin combined with ifosfamide was 0.56 (95% CI 0.36-0.85; p=0.01) in favour of chemotherapy. I [7]
Subsequent to the meta-analysis above, a large randomised controlled trial was published favouring no chemotherapy over adjuvant chemotherapy in terms of five-year overall survival rate, and demonstrated no difference between groups in terms of overall survival and relapse-free survival. II [8]
Evidence-based recommendationQuestion mark transparent.png Grade
The use of post-operative chemotherapy in adult type soft tissue sarcomas is not the current standard of care.
D


Evidence summary Level References
Three cycles of full dose pre-operative epirubicin, ifosfamide and GCSF were not inferior to five cycles. II [9]
Post-operative chemotherapy was associated with improved relapse free survival only in patients <30 years. III-3 [10]
Evidence-based recommendationQuestion mark transparent.png Grade
The use of pre-operative chemotherapy in adult type soft tissue sarcomas is not the standard of care.
D


Practice pointQuestion mark transparent.png

Patients considered for chemotherapy should be referred for clinical trial participation.

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Issues requiring further clinical research

Future studies should focus on larger grade III and extremity sarcomas.

References

  1. National Institute for Health and Clinical Excellence. Improving Outcomes for People with Sarcoma. NICE 2006 Mar Abstract available at http://www.nice.org.uk/nicemedia/pdf/SarcomaFullGuidance.pdf.
  2. 2.0 2.1 2.2 Bacci G, Ferrari S, Tienghi A, Bertoni F, Mercuri M, Longhi A, et al. A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity. Eur J Surg Oncol 2001 Feb;27(1):98-104 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11237499.
  3. Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival--a report from the Children's Oncology Group. J Clin Oncol 2008 Feb 1;26(4):633-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18235123.
  4. Bramwell VH, Steward WP, Nooij M, Whelan J, Craft AW, Grimer RJ, et al. Neoadjuvant chemotherapy with doxorubicin and cisplatin in malignant fibrous histiocytoma of bone: A European Osteosarcoma Intergroup study. J Clin Oncol 1999 Oct;17(10):3260-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10506628.
  5. Nooij MA, Whelan J, Bramwell VH, Taminiau AT, Cannon S, Hogendoorn PC, et al. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study. Eur J Cancer 2005 Jan;41(2):225-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15661546.
  6. 6.0 6.1 Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 2012 Nov 20;30(33):4148-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23091096.
  7. Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008 Aug 1;113(3):573-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18521899.
  8. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, et al. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 2012 Oct;13(10):1045-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22954508.
  9. Gronchi A, Verderio P, De Paoli A, Ferraro A, Tendero O, Majò J, et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Ann Oncol 2012 Oct 30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23110811.
  10. Kasper B, Ouali M, van Glabbeke M, Blay JY, Bramwell VH, Woll PJ, et al. Prognostic factors in adolescents and young adults (AYA) with high risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62771 and 62931. Eur J Cancer 2012 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22975215.

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Appendices

Further resources