NCG BST GUIDELINES

National Cancer Grid

Management of Bone and Soft Tissue Tumors

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Index

S.No TOPIC Page Number 1 Evaluation of suspected bone 3

2 Evaluation of suspected soft tissue sarcoma 4

3 Evaluation of suspected metastatic bone 5 disease

4 Osteosarcoma 6

5 Ewing’s Sarcoma 9

6 Chondrosarcoma 12

7 Extremity Soft Tissue Sarcoma 14

8 Surveillance in 17

9 Appendix 1: Principles of Management 18

10 Appendix 2: References 25

11 Appendix 3: Imaging 31

12 Appendix 4: Biopsy for Surgeons 35

13 Appendix 5: Biopsy for Pathologists 36

14 Appendix 6: Chemotherapy for bone and soft 41 tissue sarcomas 15 Appendix 7: Radiation for bone and soft tissue 47 sarcomas

Note: The guidelines have two components, Essential and optional. All work-up unless specified otherwise is Essential. Optional where applicable has been specified.

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EVALUATION OF SUSPECTED BONE SARCOMA

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EVALUATION OF SUSPECTED SOFT TISSUE SARCOMA

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EVALUATION OF SUSPECTED METASTATIC BONE DISEASE

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OSTEOSARCOMA

Symptoms – swelling & pain

Detailed clinical history

Clinical diagnosis

Workup for diagnosis Basic imaging (local & chest x-ray) & routine blood investigations (Essential)

Local 3D imaging - MRI (with contrast) of entire bone with adjoining joints (Essential) OR - Local imaging - X ray and Dynamic Contrast MRI with Diffusion (Optimal) Additional serological investigations (alkaline phosphatase and lactate dehydrogenase) (Essential)

Clinico- radiological diagnosis

Biopsy (core needle biopsy preferred) (Essential) (Appendix 4 for principles of biopsy)

Histopathological diagnosis (Use of Immunohistochemistry where applicable- Optional)

Workup for Staging (NCCT scan chest & Bone scan) (Essential) Or - (Optional -F18 PET/EDF PET -with breath hold chest CT Scan)

Non-metastatic Osteosarcoma Metastatic Osteosarcoma

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OSTEOSARCOMA NON-METASTATIC PRESENTATION Multiagent neoadjuvant chemotherapy (NACT) (Cisplatin, Adriamycin, / HD-MTX-3 drugs combination is preferable) (Essential) (MAP / IAP Regimen)

Evaluation for local therapy (reimaging with MRI recommended) (Essential)

Limb sparing surgical resection possible with adequate oncologic margins

Yes No

Limb sparing surgery Extremity Lesion Centro Axial Lesion

Evaluation of margins and Amputation Definitive radiotherapy (Essential) Proton beam therapy (Optional)

If positive margins to consider additional local therapy Adjuvant chemotherapy (Essential)

Surveillance

 MAP regimen should only be administered in centers with adequate facility for monitoring Methotrexate levels.

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OSTEOSARCOMA-METASTATIC AT PRESENTATION

Isolated Pulmonary Multiple Bilateral Non pulmonary or both (Oligometastatic - and/or Deemed inoperable less than 4, UL)

Chemotherapy (Essential) (as for non-metastatic disease)

Evaluation for response / restaging

No progression of disease Progression of disease Consider or treatment with Inoperable Palliative intent

Local control and metastasectomy (as for non-metastatic disease) (Essential)

Adjuvant chemotherapy (Essential)

Surveillance

 May consider palliative chemotherapy with 2 agents (cisplatin & ) to avoid toxicity and palliative radiotherapy for relieving pain.

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EWING SARCOMA

Symptoms – swelling & pain

Detailed clinical history

Clinical diagnosis

Workup for diagnosis Basic imaging (local & chest x-ray) & routine blood investigations (Essential)

Local 3D imaging - MRI (with contrast) of entire bone with adjoining joints (Essential) OR - Local imaging - X ray and Dynamic Contrast MRI with Diffusion (Optimal) Additional serological investigations (alkaline phosphatase and lactate dehydrogenase) (Essential)

Clinico-Radiological diagnosis

Biopsy (core needle biopsy preferred) (Essential) (Appendix 4 for principles of biopsy)

Histopathological diagnosis with IHC (Essential) AND Molecular Pathology (Optional)

Workup for Staging Non-Contrast Computed Tomography of Chest AND Bone Scan AND Bone Marrow Aspiration (2 sites-Bilateral) (Essential) OR FDG PET Scan with Breath Hold CT Chest (Essential) OR Non-Contrast Computed Tomography of Chest AND MRI Whole Body (Optional -special situations like pregnancy)

Non-metastatic Ewing’s sarcoma Metastatic Ewing’s sarcoma

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EWING’S SARCOMA - NON-METASTATIC AT PRESENTATION

Multiagent induction chemotherapy for at least 9 weeks prior to local therapy (Essential) VAC/IE ( + doxorubicin + alternating with ifosfamide + ) or VIDE (vincristine + ifosfamide + doxorubicin + etoposide) (Essential) (Appendix 6 for principles of chemotherapy)

Evaluation for local therapy between week 9 and 12 (reimaging with local Xray and MRI)

Limb sparing surgical resection possible with adequate oncologic margins

Yes No

Surgery Extremity Lesion Centro Axial Lesion

Definitive RT vs. Ablative surgery Definitive radiotherapy (Discuss with patient and multidisciplinary team)

Evaluation of margins and necrosis Maintenance chemotherapy (Essential)

Consider additional local therapy if positive margins (Discuss with patient and multidisciplinary team)

Indications for post-operative RT Adjuvant RT to be strongly considered in -(Appendix 7) (Essential)  Sites- Spinal/ Paraspinal / pelvic location (Difficult to achieve adequate margins due to complex anatomy)  Large tumor volume >300 cc  Pathological fracture Negative Margins Positive margins > 90 % necrosis No adjuvant RT Adjuvant RT

< 90 % necrosis Discuss in multidisciplinary Adjuvant RT

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clinic (MDJC)

EWING’S’S SARCOMA – METASTATIC AT PRESENTATION

Isolated Pulmonary Multiple Non pulmonary or both Pulmonary and non-pulmonary (Bone / Bone marrow)

Induction chemotherapy (as for non-metastatic disease) (Essential)

Evaluation for response / restaging (Essential)

No progression of disease Progression of disease Consider treatment with Palliative intent

Local control (as for non-metastatic disease) and Metastasectomy and / or Lung Bath (radiotherapy) (Appendix 7) (Essential)

Maintenance chemotherapy (Essential)

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CHONDROSARCOMA

Symptoms – swelling & pain

Detailed clinical history

Clinical diagnosis

Workup for Diagnosis Basic imaging (local & chest x-ray) & routine blood investigations (Essential)

Local 3D imaging - MRI (with contrast) of entire bone with adjoining joints (Essential) OR - Local imaging - X ray and Dynamic Contrast MRI with Diffusion (Optimal)

Clinico- radiological diagnosis

Biopsy (core needle biopsy preferred) (Essential) (Appendix 4 for principles of biopsy)

Histopathological diagnosis

Workup for Staging (Local X ray & MRI & CT scan chest Bone scan – Optional in primary cases)

Non-metastatic chondrosarcoma Metastatic chondrosarcoma

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CHONDROSARCOMA - NON-METASTATIC AT PRESENTATION

Limb sparing surgical resection possible with adequate oncologic margins

Yes No

Limb sparing surgery Extremity Lesion Centro Axial Lesion

Evaluation of margins Amputation Definitive Radiation (Essential) Proton beam (Optional) If positive margins to consider additional local therapy

CHONDROSARCOMA-METASTATIC AT PRESENTATION

Isolated Pulmonary Non pulmonary or both

Local control (as for non-metastatic disease) Consider treatment with palliative intent and metastasectomy (Essential)

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EXTREMITY SOFT TISSUE SARCOMA

Symptoms – swelling & pain

Detailed clinical history and examination

Clinical diagnosis

Workup for Diagnosis Basic imaging (local & chest x-ray, local MRI) & routine blood investigations (Essential)

Clinico- radiological diagnosis

Biopsy (core needle biopsy preferred) (Essential)

Histopathological diagnosis

Workup for Staging (Local X ray & MRI NCCT scan chest & USG abdomen pelvis/groin/neck / axilla) (Essential)

Non- metastatic soft tissue sarcoma Metastatic soft tissue sarcoma

- Tumors referred after prior excision with inadequate or unknown margins need to be considered for re excision with similar guidelines as primary tumors

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EXTREMITY SOFT TISSUE SARCOMA – NON-METASTATIC AT PRESENTATION

Evaluation for local therapy

Limb sparing surgical resection possible with adequate oncologic margins

Yes No

Discuss role of preoperative radiotherapy and/or chemotherapy (Depends on tumor site / size / histology)

Reevaluate clinically and with imaging if limb sparing surgical resection possible with adequate oncologic margins

Limb sparing surgery

Yes No If surgical margins positive - consider re excision

Limb sparing surgery Amputation

 All upfront resectable cases should be evaluated for feasibility of intra-operative interstitial brachytherapy.

Indications for post-operative radiotherapy (Appendix 7) (Essential) - All high grade lesions - All recurrent lesions - Low grade lesions if deep seated /or ≥ 5cm /or margin close or positive

Chemotherapy may be offered to patients with high grade lesions > 5cm or recurrent lesions after discussion in multidisciplinary clinic. Ifosfamide and doxorubicin combination is preferred (Appendix 6) (Essential)

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EXTREMITY SOFT TISSUE SARCOMA – METASTATIC AT PRESENTATION

Complete resection possible at all sites

Yes No

Discuss in multidisciplinary clinic Consider treatment with palliative intent

Local control (as for non-metastatic disease) and metastasectomy (Essential)

Indications for radiotherapy and chemotherapy as for non-metastatic disease (Essential)

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SURVEILLANCE IN SARCOMAS

Follow up Strategy

During postoperative period patient attends rehabilitation services for physiotherapy

Follow up every 6 months for the first 5 years (Essential)

Or Every 3 months for first 2 years, every 6 months for next 3 years (optional) (Clinical evaluation, Radiological evaluation, Functional evaluation)

Annual follow up after 5 years (Essential) (Clinical evaluation, Radiological evaluation, Functional evaluation)

 Clinical evaluation - Examination of local area.  Radiological evaluation - X-ray of the local part and Chest X-ray is done at every follow up. CT scan of chest may be considered every 6 months for first 2 years. (optional)  Functional evaluation - using special scores like MSTS Score etc.

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Appendix – 1 Principles of management of sarcomas

General Principles -

Sarcomas are rare cancers that originate from transformed cells of mesenchymal origin. Sarcomas are connective tissue tumors and arise commonly from bones, muscles, tendons, cartilage, nerves, fat and blood vessels of the appendicular skeleton, but they can also arise from other areas of the body. There are more than 50 types of sarcomas and can be grouped into two main types a) Bone sarcomas and b) Soft tissue sarcomas (STS). Sarcomas account 12-15%& 1-2% of all cancers in the pediatric and adult population respectively. Outcomes for patients with sarcomas has improved significantly over the past 3 to 4 decades due to advances in diagnostic radiology, pathology, chemotherapy, , and improvement in surgical techniques including the availability of micro-vascular tissue transfers, improvements in prosthetic design and availability of bone auto-allografts.

Any suspicious lesion (see below) in the bone or soft tissue should be referred to a specialized sarcoma care unit for better outcomes.

When to suspect sarcoma

a) BONE SARCOMA: Commonest presenting symptoms of bone sarcomas: non- mechanical pain and a palpable mass arising from bone. This needs evaluation by a biplanar plain radiograph. Features suggestive (but not diagnostic) of bone sarcoma are:  Bone destruction and/or pathological fracture  New bone formation  Periosteal reactions  Soft tissue mass b) SOFT TISSUE SARCOMA: Any soft tissue lump greater than 5cmsand located deep to the deep fascia should be regarded as soft tissue sarcoma unless proved otherwise. Most STS present as painless progressive swelling.

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Biopsy: All patients with a suspected sarcoma must undergo complete local imaging (as per guidelines) before biopsy. Ideally, biopsies should be performed at the center where definitive treatment is planned, alternatively, it can be done by a clinician trained in performing biopsies and who understands the principles of limb salvage surgery. Core needle biopsy is the gold standard for most cases (Essential). Additional studies like immunohistochemistry, cytogenetic, and molecular studies are desirable in some sarcomas like Ewing’s sarcoma and STS (Optional). A poorly performed biopsy may not only fail to provide the correct diagnosis but may lead the subsequent surgery being more extensive, thus making the limb salvage surgery difficult and can impact survival negatively. Once the diagnosis of sarcoma has been established (Appendix 4/5), they should be treated at a specialized in sarcoma center by a multidisciplinary team (MDT). Staging work up: All malignant musculoskeletal tumors should undergo staging investigation to assess the extent of disease spread in the body. Imaging with radiographs in two perpendicular planes with MRI to evaluate local extent of the disease.  Osteosarcoma and chondrosarcoma are staged with non-contrast CT scan (NCCT) of the chest and a bone scan. (Essential)  Ewing’ sarcoma requires bone marrow- aspiration & biopsy from two different sites in addition to NCCT chest and a bone scan. (Essential)  Optional: PET scan with a breath-hold CT scan of chest is an alternative and may obviate the need of invasive bone marrow biopsies.  STS Staging - Local imaging to be performed prior to doing a biopsy (Essential). MRI with contrast is recommended in all cases (Essential). NCCT chest for metastatic workup is advised (Essential). Ultrasonography of regional lymph node basin may be done, particularly for angiosarcoma, synovial sarcoma, rhabdomyosarcoma, epithelioid sarcoma and clear cell sarcomas. (Optional)  Additional imaging to be considered based on histology are as follows (Essential) i) MRI whole spine: Myxoid/round cell liposarcoma

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ii) Contrast CT scan of abdomen and pelvis: Myxoid/round cell liposarcoma, epithelioid sarcoma, angiosarcoma, leiomyosarcoma. iii) MRI brain: Alveolar soft part sarcoma and angiosarcoma iv) Contrast CT scan of the Pelvis: Lower extremity well differentiated liposarcoma.  The F18 FDG PET CT scan with a breath hold CT of the chest may be used for metastatic workup but is not cost effective and yet not recommended as standard of care (Optional) Treatment: Sarcomas are best treated by a multidisciplinary team comprising of a core team of musculoskeletal oncologist-surgeon, medical oncologist, radiation oncologist, radiologist and a pathologist. Cross consultations with other disciplines like thoracic surgery, GI surgery, plastic surgery, and rehabilitation medicine are essential to provide optimum oncological and functional outcomes. Treatment is planned as per guidelines and patients are reassessed periodically at different stages of treatment. Further details: Sections on Osteosarcoma, Chondrosarcoma, Ewing’s sarcoma and Soft tissue sarcoma A.) SURGERY: Goal of surgery is to achieve adequate oncologic clearance with optimal function. Decision on type of surgical procedure is multifactorial and varies on case to case basis, dependingon factors like patient’s age, tumor site, size, extent, response to neoadjuvant treatment, socio-economic factors, surgeon’s expertise etc. Resected specimens need to be evaluated for adequacy of surgical margins (Quantitative and Qualitative margins) and percentage necrosis (when neoadjuvant chemotherapy has been administered). (Appendix 4/5) B.) CHEMOTHERAPY: Multiagent chemotherapy is the standard of care in osteosarcoma and Ewing’s sarcoma. (Appendix 6). (Essential) C.) RADIOTHERAPY: Osteosarcoma and chondrosarcoma are relatively radioresistant tumors. Radiotherapy has a definite role in the management of Ewing’s sarcoma and high-grade soft tissue sarcoma. (Appendix 7)

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Surveillance:

Optimum surveillance is essential to diagnose local and/or distant relapse. A surveillance visit usually entails clinical and radiological examination. This helps to assess oncological and functional outcomes. Most recurrences occur in the first 2-3 years and decreases over time and these tumors are generally followed up to 10 years. Intense follow up may be required for first 5 years. Intensity of surveillance and interval between visits may vary based on risk stratification and Institutional protocols. Standard follow-up investigations include a detailed clinical history and examination, radiographs/ ultrasonography/ MRI of affected region with chest radiographs or CT scans. Visits are usually planned every 3 to 6 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. PRINCIPLES OF TREATMENT

Bone Sarcomas -  Baseline assessment of renal, cardiac and auditory function - (CBC, RFT, LFT, SE, ECHO, ECG, GFR, Audiomety.  Counselling for Sperm banking for male patients of reproductive age while using ifosfamide.  Fertility specialist consultation for female patients should be considered.  Utmost care should be taken to avoid a pathological fracture; weight bearing precautions and splintage should be advised wherever deemed necessary. Presence of pathological fracture, either at presentation or during neoadjuvant chemotherapy may increase the risk of local and systemic recurrence and negatively impacts survival. Internal fixation of pathological fracture through a sarcoma should not be done; the limb should be splinted, and neoadjuvant chemotherapy started. Performance of limb can be attempted in a very carefully selected subset of these patients without increased risk of local recurrence or death, taking into account factors like histopathology, severity of fracture, degree of displacement, response to chemotherapy, fracture union and response to neo adjuvant chemotherapy. Ewing sarcoma patients with pathological fractures require post-operative radiotherapy after limb salvage.

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 All patients should be re-evaluated clinically before each cycle of chemotherapy Patients with disease progression during chemotherapy are at increased for local and systemic failure.  Patients with disease progression during chemotherapy are at increased risk for local and systemic failure. o Local progression alone: Early definitive local therapy should be considered: May result in amputation. o Systemic progression during chemotherapy: These patients can be considered for best supportive care  Adjuvant radiation where indicated should be advised. (Appendix 7)  All patients considered for surgery should undergo evaluation with a contrast MRI, MRI should include entire length of the affected bone. Limb salvage surgery with wide margins and a functional limb is preferred.  Type of local therapy (Amputation vs Limb Salvage Surgery) to be decided based on factors like local extent of tumor, involvement of adjacent structures, biopsy tracts, pathological fracture, any prior surgical procedures, vascular-nerve-soft tissue involvement, progression on chemotherapy etc.  Type of limb salvage to be based on skeletal maturity, location of tumor (intercalary/trans-articular/extra-articular). Reconstructive techniques to be based on availability of resources and expertise.  Plastic and vascular surgeons to be involved in surgical planning for reconstruction as indicated.  In Ewing sarcoma, the decision on the choice of local therapy should follow an MDT discussion, and a detailed discussion with the patient/parents. Patients having metastases at presentation should have a systemic evaluation at the time of local therapy, in the form of a whole-body PET CT / NCCT chest as applicable. (Essential)  Osteosarcoma metastatic at presentation (oligometastatic) and deemed treatable: Treatment practices as to the timing of surgery for primary and metastasis vary depending on a) institutional protocol and b) patient and disease factors.

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 Management of recurrent Osteosarcoma needs to take into account the timing of recurrence / metastases, number of metastases, and site of metastases. Each case needs to be discussed in aMDT. (Appendix 6)  Complete removal of all metastases must be attempted. No clear benefit of second line chemotherapy in isolated local recurrences. Patients with distant metastasis with more than 18-month DFI may be benefitted. These patients must be evaluated on case by case basis in multi-disciplinary team. (Appendix 6). Non operable metastases are treated with palliative intent treatment/ best supportive care.  Oligometastatic Ewing’s sarcoma (only pulmonary or isolated bone metastasis) at presentation is treated with curative intent. These patients are re-evaluated after induction chemotherapy with relation to local and systemic staging (Essential).  Metastasectomy after completion of surgery of primary and all chemotherapy is an acceptable alternative (Optional).  Lung bath is an essential component in the management of pulmonary metastasis in Ewing’s sarcoma (Essential).  Chondrosarcomas are radiotherapy resistant and chemotherapy resistant tumors, hence surgical excision remains the mainstay of treatment.  Dedifferentiated chondrosarcomas may receive multiagent chemotherapy like high- grade Osteosarcoma (Essential).  Mesenchymal chondrosarcoma may receive multiagent chemotherapy like Ewing’s sarcoma (Essential).  It may be safe to treat extremity grade I (low grade) chondrosarcomas with intralesional curettage without increasing the risk for local or metastatic recurrence.  Osteosarcomas diagnosed as low grade on initial biopsy (parosteal / low grade intramedullary) are treated with wide excision only. If after definitive surgery a high- grade component is identified they receive multiagent adjuvant chemotherapy (Essential).  Periosteal osteosarcomas are currently treated similar to high-grade osteosarcomas.

 For relapsed Ewing’s Sarcoma, salvage therapy to be considered, if relapse occurs 12 months after completion of maintenance chemotherapy. Treatment of relapse

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should be decided in a MDT based on time of relapse, site(s) of relapse, prior treatment and performance status. SOFT TISSUE SARCOMA

 Type of local therapy (Amputation vs Limb Salvage Surgery) to be decided based on factors like local extent of tumor, involvement of adjacent structures, biopsy tracts, pathological fracture, any prior surgical procedures, vascular-nerve-soft tissue involvement, progression on chemotherapy.

 Plastic and vascular surgeons to be involved in surgical planning for reconstruction as indicated.

 The surgical specimen should be evaluated jointly by the surgeon and pathologist to evaluate margin status, preferably immediately after surgery.

 Radiation therapy should be considered for all high-grade tumours, tumours >5 cms, recurrent tumours and tumours with close/positive margins. Radiotherapy may be administered as intraoperative brachytherapy or external beam radiotherapy or a combination both (Essential). Radiotherapy may be delivered either as pre or postoperative radiotherapy depending on surgeon/institution preference. (Appendix 7)

 Currently there is inadequate evidence to recommend adjuvant chemotherapy as standard for all adult soft tissue sarcoma patients. It may be considered in a select population of high-grade extremity sarcoma, > 5 cm or recurrent high-grade tumours using doxorubicin alone or a combination of doxorubicin plus ifosfamide after discussion in multidisciplinary clinic. Any potential benefits should be considered in the context of the short and long-term toxicities of chemotherapy. (Appendix 6)

 Management of metastatic STS, needs to take into account the timing of recurrence/metastases, number of metastases, and site of metastases. All cases should be discussed in MDT. Complete removal of all metastases must be attempted.  Second line chemotherapy may be considered on case by case basis after discussion in MDT (Optional).

 Non-operable recurrences are treated with palliative intent treatment/ best supportive care.

 Palliative radiotherapy may be required for disease or pain control. Palliative chemotherapy/ should be decided in a multidisciplinary clinic with careful selection of agents to have minimum side effect and better quality of life.

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Appendix – 2

REFERENCES Osteosarcoma

 Briccoli A, Rocca M, Salone M, Guzzardella GA, Balladelli A, Bacci G. High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005. Surg. Oncol. 2010 Dec;19(4):193-9.  Anninga KJ, GelderblomH,FioccoM.Chemotherapeutic adjuvant treatment for osteosarcoma: Where do we stand? European Journal of Cancer 2011;Volume 47, Issue 16, Pages 2431–2445.  Bone Sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow up. Annals of Oncology2014 Sep; 25(3):113-123.  Bielack S, Kempf-Bielack B, Schwenzer D, Birkfellner T et al. Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients. KlinPadiatr. 1999 Jul-Aug; 211(4):260-70.  Kawaguchi N, Ahmed AR, Matsumoto S, Manabe J, Matsushita Y. The concept of curative margin in surgery for bone and soft tissue sarcoma. Clin OrthopRelat Res. 2004 Feb; (419):165-72.  Zhang Q, Niu XH, Cai YB, Hao L, Ding Y. Prognostic factors for the local recurrence of osteosarcoma in extremities treated with combined therapy. ZhonghuaWaiKeZaZhi. 2007 Aug 15; 45(16):1114-7.  Bacci G, Ferrari S, Bertoni F, et al.: Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the IstitutoOrtopedico Rizzoli according to the IstitutoOrtopedico Rizzoli/Osteosarcoma- 2 protocol:an updated report. J Clin Oncol 2000; 18:4016–4027.  Okada K, Frassica FJ, Sim FH, Beabout JW, Bond JR, Unni KK. Parosteal osteosarcoma. A clinicopathological study. J Bone Joint Surg Am. 1994Mar; 76(3):366-78.  Grimer RJ, Bielack S, Flege S, et al. Periosteal osteosarcoma--a European review of outcome. Eur J Cancer. 2005;41(18):2806-2811.  Hawkins DS, Rajendran JG, Conrad EU, et al. Evaluation of chemotherapy response in pediatric bone sarcomas by F-18 FDG PET. Cancer 2002 Jun;94:3277- 3284.  Scully SP, Ghert MA, Zurakowski D, Thompson RC, Gebhardt MC. Pathologic fracture in osteosarcoma: prognostic importance and treatment implications. J Bone Joint Surg Am 2002; 84: 49-57.  Picci P, Sangiorgi L, Rougraff BT, Neff JR, Casadei R, Campanacci M. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J Clinical Oncol 1994;12(12):2699-2705.  Puri A, Gulia A, Hawaldar R, Ranganathan P, Badwe RA. Does intensity of surveillance affect survival after surgery for sarcomas? Results of a randomized noninferiority trial. Clin OrthopRelat Res. 2014;472(5):1568–1575. doi: 10.1007/s11999-013-3385-9

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 Kager L, Zoubek A, Potschger U et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003 May; 21: 2011–2018.  Kempf-Bielack B, Bielack SS, Jurgens H et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005 Jan; 23: 559–568.  van Dalen EC, van As JW, de Camargo B: Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane Database Syst Rev (5):CD006325, 2011.  Lewis IJ, Nooij MA, Whelan J, et al; MRC BO06 and EORTC 80931 collaborators; European Osteosarcoma Intergroup. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007;99(2):112–128.  Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet. 1997;350(9082):911–917.  Winkler K, Beron G, Delling G. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol. 1988;6(2):329–337.  Marina NM, Smeland S, Bielack SS, et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EUARMOS-1): an open-label, international, randomized controlled trial. Lancet Oncol. 2016;17:1396-408.  Van Winkle P, Angiolillo A, Krailo M, et al. Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children’s Cancer Group (CCG) experience. Pediatr Blood Cancer. 2005;44(4):338–347.  Saylors RL 3rd, Stine KC, Sullivan J, et al; Pediatric Group. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol. 2001;19(15):3463–3469.  Goodrin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-doseifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol. 2002;20(2):426-33. http://www.ncbi.nlm.nih.gov/pubmed/11786570.

Ewing’s Sarcoma

 Quartuccio N, Fox J, Kuk D, Wexler LH, Baldari S, Cistaro A, Schöder H. Pediatric Bone Sarcoma: Diagnostic Performance of (18)F-FDG PET/CT Versus Conventional Imaging for Initial Staging and Follow-Up. AJR Am J Roentgenol. 2015 Jan;204(1):153-60.  Bruget E, Nesbit M, Garnsey L, et al. Multimodal therapy for management of non pelvic, localized Ewing’s’s sarcoma of bone: a long term follow up of the first intergroup study. J Clin Oncol 1990;8,1664-74

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 Granowetter L, Womer R, Devidas M, et al. Dose intensified compared with standard chemotherapy for nonmetastatic Ewing’ssarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol 2009; 27:2536-41  Indelicato DJ, Keole SR, Shahlaee AH, Shi W, Morris CG, Marcus RB Jr. Definitive radiotherapy for ewing’stumors of extremities and pelvis: long-term disease control, limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys. 2008 Nov 1; 72(3):871-7.  Bacci G, Longhi A, Briccoli A, et al. The role of surgical margins in treatment of Ewing’s’s sarcoma family tumors: Experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol BiolPhys 2006; 65:766–772.  Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing’stumors: Results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol BiolPhys2003;55:168–177.  Paulussen M, Ahrens S, Craft AW et al. Ewing’s'stumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s's Sarcoma Studies patients.JClinOncol. 1998 Sep; 16(9):3044-52.  Pinkerton CR, Bataillard A, Guillo S et al. Treatment strategies for metastatic Ewing’s'ssarcoma.Eur J Cancer. 2001 Jul; 37(11):1338-44.  Dirksen U, Brennan B, Le Deley MC, et al. High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing’s Sarcoma With Pulmonary Metastases: Results of the European Ewing’s Tumour Working Initiative of National Groups, 99 Trial and EWING’S 2008. J Clin Oncol. 2019;37(34):3192-3202.  Chin M, Yokoyama R, Sumi M, et al. Multimodal treatment including standard chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for the Ewing’s sarcoma family of tumors in Japan: Results of the Japan Ewing’s Sarcoma Study 04. Pediatr Blood Cancer. 2020;67(5):e28194.  Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer. 2006;47(1):22–29.  Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H. Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer. 2006;47(6):795–800.  Casey DA, Wexler LH, Merchant MS, et al. Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009;53(6):1029–1034.

Chondrosarcoma

 Gulia A, Kurisunkal V, Puri A, Purandare N, Gupta S, Rangarajan Drm V. Is Skeletal Imaging Essential in the Staging Workup for Conventional Chondrosarcoma? [published online ahead of print, 2020 Jun 10]. Clin Orthop Relat Res. 2020;10.1097/

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 Lee FY, Mankin HJ, Fondren G, Gebhardt MC, Springfield DS, Rosenberg AE, Jennings LC. Chondrosarcoma of bone: an assessment of outcome. J Bone Joint Surg Am. 1999 Mar; 81(3):326-38.  Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P. Clinical outcome of central conventional chondrosarcoma. J Surg Oncol. 2012 Dec; 106(8):929-37.  Leddy LR, Holmes RE. Chondrosarcoma of bone. Cancer Treat Res.2014; 162:117- 30.  Bindiganavile S, Han I, Yun JY, Kim HS. Long-term Outcome of Chondrosarcoma: A Single Institutional Experience. Cancer Res Treat. 2015 Oct; 47(4):897-903. Epub 2015 Feb 12.  Frezza AM, Cesari M, Baumhoer D, et al. Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. Eur J Cancer. 2015;51(3):374-381. doi:10.1016/j.ejca.2014.11.007  Terlizzi M, Le Pechoux C, Salas S, et al. Postoperative Radiation Therapy in Patients with Extracranial Chondrosarcoma: A Joint Study of the French Sarcoma Group and Rare Cancer Network. Int J Radiat Oncol Biol Phys. 2020;107(4):726- 735. doi:10.1016/j.ijrobp.2020.03.041.  Nakayama R, Hayakawa K, Kobayashi E, et al. What Factors Are Associated with Treatment Outcomes of Japanese Patients with Clear Cell Chondrosarcoma? Clin Orthop Relat Res. 2020;10.1097/CORR.  Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta-analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Ann Surg Oncol. 2011 Jun;18(6):1705-9. Soft Tissue Sarcoma  Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy; Ann Surg. 1982; 196(3):305-15.  Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998; 16(1):197-203.  O'Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002; 359 (9325):2235-41.  Pervaiz N, Colterjohn N, Farrokhyar F et al. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer 2008; 113: 573–581.  Gronchi A, Frustaci S, Mercuri M et al. Short, full-dose adjuvant chemotherapy in high-risk adult soft tissue sarcomas: a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group. J Clin Oncol 2012; 30: 850-856.  Woll PJ, Reichardt P, Le Cesne A et al. EORTC Soft Tissue and Bone Sarcoma Group and the NCIC Clinical Trials Group Sarcoma Disease Site Committee. Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 2012; 13: 1045-1054.

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 Blackmon SH, Shah N, Roth JA et al. Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long-term survival. Ann ThoracSurg 2009; 88: 877-884.  Pfeifer JD, Hill DA, O'Sullivan MJ, Dehner LP. Diagnostic gold standard for soft tissue tumours: morphology or molecular genetics?. Histopathology. 2000;37(6):485-500. doi:10.1046/j.1365-2559.2000.01107.  Zagars GK, Ballo MT, Pisters PW, Pollock RE, Patel SR, Benjamin RS. Surgical margins and reresection in the management of patients with soft tissue sarcoma using conservative surgery and radiation therapy. Cancer. 2003;97(10):2544- 2553. doi:10.1002/cncr.11367.  Naghavi AO, Fernandez DC, Mesko N, et al. American Brachytherapy Society consensus statement for soft tissue sarcoma brachytherapy. Brachytherapy. 2017;16(3):466-489. doi:10.1016/j.brachy.2017.02.004.  Coens C, van der Graaf WT, Blay JY, et al. Health-related quality-of-life results from PALETTE: A randomized, double-blind, phase 3 trial of versus placebo in patients with soft tissue sarcoma whose disease has progressed during or after prior chemotherapy-a European Organization for research and treatment of cancer soft tissue and bone sarcoma group global network study (EORTC 62072). Cancer. 2015;121(17):2933-2941. doi:10.1002/cncr.29426.  Eary JF, O'Sullivan F, Powitan Y, et al. Sarcoma tumor FDG uptake measured by PET and patient outcome: a retrospective analysis. Eur J Nucl Med Mol Imaging. 2002;29(9):1149-1154. doi:10.1007/s00259-002-0859-5.  Gortzak E, Azzarelli A, Buesa J, et al. A randomised phase II study on neo- adjuvant chemotherapy for 'high-risk' adult soft-tissue sarcoma. Eur J Cancer. 2001;37(9):1096-1103. doi:10.1016/s0959-8049(01)00083-1  Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350:1647-54, 1997  Judson I, Verweij J, Gelderblom H, et al: Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic  soft-tissue sarcoma: A randomised controlled phase 3 trial. Lancet Oncol 15:415- 423, 2014  Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, et al. and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Oncol.  Van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double- blind, placebo-controlled phase 3 trial. Lancet. 2012; 379: 1879-1886.  Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma after Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2015.  Schöffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or

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leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016; 387: 1629-1637.

Radiology

 Costelloe CM, Madewell JE. Radiography in the initial diagnosis of primary bone tumors. American Journal of Roentgenology. 2013 Jan;200(1):3-7.  Rana RS, Wu JS, Eisenberg RL. Periosteal reaction. American Journal of Roentgenology. 2009 Oct;193(4): W259-72.  http://www.radiologyassistant.nl/en/p494e15cbf0d8d/bone-tumor-systematic- approach-and-differential-diagnosis.html.  Helms C.A.: Fundamentals of skeletal radiology. 3rd edition 2004.WB Saunders Philadelphia (PA).  Unni K.K., Inwards C.Y.: Dahlin’s bone tumors.6th edition 2010. Lippincott Philadelphia  Kricun M.E.: Radiographic evaluation of solitary bone lesions.Orthop Clin North Am 1983; 14: pp. 39-64  Miller T.T.: Bone tumors and tumorlike conditions: analysis with conventional radiography.Radiology 2008; 246: pp. 662-674.  Madewell J.E., Ragsdale B.D., Sweet D.E.: Radiologic and pathologic analysis of solitary bone lesions. Part I: internal margins.Radiol Clin North Am 1981; 19: pp. 715- 748.  Hwang S., Panicek D.M.: The evolution of musculoskeletal tumor imaging.Radiol Clin North Am 2009; 47: pp. 435-453.  O’Donnell P.: Evaluation of focal bone lesions: basic principles and clinical scenarios.Imaging 2003;15: pp. 298-323.  Cerase A., Priolo F.: Skeletal benign bone-forming lesions.Eur J Radiol 1998; 27: pp. S91-S97.  Geirnaerdt M.J., Hermans J., Bloem J.L., et. al.: Usefulness of radiography in differentiating enchondroma from central grade 1 chondrosarcoma.AJR Am J Roentgenol 1997; 169: pp. 1097-1104.  Brien E.W., Mirra R.J., Kerr R.: Benign and malignant cartilage tumors of bone and joint: their anatomic and theoretical basis with an emphasis on radiology, pathology, and clinical biology.Skeletal Radiol 1997; 26: pp. 324-353.  Stacy G.S., Mahal R.S., Peabody T.D.: Staging of bone tumors: a review with illustrative examples.AJR Am J Roentgenol 2006; 186: pp. 967-976.  Morrison W.B., Zoga A.C., Daffner R.H., et. al.: Primary bone tumors.ACR Appropriateness criteria. 2009.American College of RadiologyReston (VA): pp. 1-6.

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Appendix - 3

Imaging Evaluation of Bone and Soft Tissue Tumors

Imaging modalities include –

 Radiographs  Magnetic Resonance Imaging (MRI)  Computed Tomography (CT) Scan  Bone scan  Positron Emission Tomography (PET) / PET- CT

Radiograph –

Radiographs are easily available, inexpensive and are the first line of imaging in evaluation of the bone (Essential). Absolutely benign lesions on radiographs do not require additional work up, rest will require further imaging work up. Radiographs can be evaluated and in reported as per below reported format.

Radiographic approach to bone tumors

Radiograph quality - Acceptable / Not acceptable (whether/not joints proximal and distal to the lesion included in the lesion) Age: Skeletal maturity: Mature/immature Location: Epiphysis/Metaphysis/Diaphysis/combination of these Relationship to the bone: Central/eccentric/juxtacortical/juxtaarticular(does juxtaarticular lesion cross the joint) Lesion type: Lytic/sclerotic; Dimensions: Distance from nearest surgical landmark (distance from proximal and distal articular surface, landmarks like greater or lesser tronchanter): Matrix: Osseous/Chondroid/Ground glass/indeterminate If lytic, zone of transition: Narrow/Wide Cortex: Intact/Expanded/Breached Periosteum: Interrupted/uninterrupted

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Uninterrupted Periosteal reaction: Solid/Unilaminar/Buttress Interrupted periosteal reaction: Multilaminar (onion skin type)/Sunburst/Codman's triangle In immature skeleton, relationship to physis: Uninvolved/crossed Extraosseous soft tissue: Present/Absent Number of lesion: Solitary lesion/polyostotic disease Skip Lesions: Yes/no and their number/s

IMPRESSION: ………………………………………………………………………………………………………………………

Magnetic Resonance Imaging (MRI) –

Further evaluation of aggressive bone tumours will often require MR imaging (Essen tial)and is preferred over CT scan (Optional). The indications of doing MRI include further characterization of -

 Radiographically indeterminate lesion  Aggressive bone lesions  Normal radiograph with persistent localized symptoms.

MR imaging is superior in depiction of locoregional anatomic detail, detecting marrow- based skip lesions apart from characterizing the bone lesions and generally preferred over CT and radionuclide studies, like bone and PET scan.

MRI can be evaluated and in reported as per below reported format.

Bone Tumor MRI Evaluation and Reporting Format

 History of previous therapy or intervention, if any  Technique:  Radiographic findings:  Findings:

 Whether full bone is covered or not  If Implant in situ - MARS protocol

 PRIMARY TUMOR:  Location: Which bone and Epi/Meta/Dia; within bone: Intramedullary, Juxtamedullary, Cortical, Juxta-Cortical  Morphology: expansile/non-expansile, mention fluid-fluid levels  Cortical Breach: present/absent  Soft tissue component: present/absent.

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 T2:hyper/iso/hypo  T1: hyper/iso/hypo  Diffusion restriction: present/absent  PC Enhancement with/without dynamics: if Dynamic type of enhancement curve  Measurement of the soft tissue: AP x TS x CC cm  Craniocaudal extent of the marrow involvement: cm  Distance from proximal joint or other major bony landmark: if applicable  Distance from distal joint: if applicable  Physeal plate involvement:  Reaching upto articular surface:  Joint Involvement:  Presence of necrosis:  Presence of haemorrhage:  Presence of cystic areas:  Neurovascular bundle Relationship:  SKIP LESIONS AND OTHER LESIONS:  Lymphadenopathy - Present / Absent, Local / Distant  Other Incidental Findings:  Comparison with prior study:

 Impression: …………………………………………………………………………………………….

 MRI findings consistent/inconsistent with radiographic findings of______ Most likely diagnosis ± differential diagnosis

Computed Tomography - CT scan has a limited value in diagnosis and evaluating the local extent of the disease. It is more useful in evaluation of distant spread of the disease like to lung and lymph nodes (Essential). The indications are -  Staging for pulmonary metastasis in both bone and soft tissue sarcomas  Diagnosing osteoid osteoma  Patients with metallic implants  Patients with contraindication to MRI  Characterization of equivocal chondroid lesions  Characterization of lesion on complex anatomical locations line vertebrae.  Cortical involvement in some soft tissue lesions in close proximity with bone

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Bone Scan -

Radionuclide bone scan do not aid diagnosis of bone tumours, however remains the primary imaging examination to screen for skeletal metastases (Essential). In pregnant patients instead of skeletal scintigraphy whole-body MR imaging can be done for the search of skeletal metastasis.

PET Scan - PET scan is helping in staging sarcomas. FDG or F-18 PET scan are utilized. (Optional) The indications are limited and would include:  Staging and post-treatment evaluation of patients with osteosarcoma and Ewing sarcoma  Identifying higher metabolic sites in negative biopsies for higher diagnostic yield  Evaluation of patients with equivocal cartilage lesions in some settings

 Identifying areas of sarcomatous change in the borderline cartilaginous tumours.

 Evaluation of suspected metastatic bone disease myeloma or lymphoma. The use of FDG PET or PET/CT in the initial staging can lead to treatment optimisation particularly in Ewing’s sarcoma patients due to the superiority of FDG PET in detecting bone lesions ove a bone scan however in OGS patients, there is only little impact of FDG-PET on therapy planning because bone scan seems to be equally suited to detect skeletal involvement.

FDG PET/CT is useful in detecting recurrence at the primary site and is often complementary to other imaging modalities.

Like malignant lesions, infective pathologies and benign tumours can also show increased standard uptake values (SUVs), hence the reliability in differentiation is always a question, though it may be helpful in some cases.

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Appendix - 4

Algorithm for performing biopsy in musculoskeletal lesions

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APPENDIX - 5 Pathology Reporting formats Bone Tumor Pathology Reporting Format

Name: …………………Hospital no: ………………Report no: ……………… Grossed by: ……………… Reported by: ……………… Consultant: ……

CLINICAL INFORMATION Symptoms: Duration of illness: Treatment history: or none Others: Eg. H/o injury etc. Exact Site: Location of Tumour: Type: Superficial / Deep. Clinical Tumour size: Radiology findings Bone involved: Location of Tumor: Epiphysis/Metaphysis/Diaphysis Superficial / Deep Extent of lesion: Narrow zone/Wide zone Type of lesion: Lytic/Sclerotic/ Mixed Cortical destruction and Soft tissue involvement GROSS DESCRIPTION Type of Specimen: Core Needle biopsy, Curettage, Excisional biopsy, Amputation, Not specified. Site: Epiphysis/apophysis, metaphysis, diaphysis (drop down); cortex, medulla, surface, joint, soft tissues, cannot be determined

Exact Tumor size: __x__x__(cm). Gross margins (applicable in resection specimens). Anterior, posterior, superior, inferior, lateral, medial, Closest margin (unoriented resection): HISTOLOGY Histologic Subtype (According to WHO Classification of Bone Tumours): ______,

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Mitotic count _____ per 10 hpf; Necrosis: present (less than 50%, 50% and more), absent. Histological Grade (For Sarcoma): I, II, III. Low-grade, high-grade. Lymphovascular invasion: present, absent. Microscopic margins (in case of resection specimens) Margin status cannot be ascertained. Percentage necrosis (post chemotherapy treated resection specimens): Less than 90 % (Poor), ≥ 90 %(Good) in cases of High-grade osteosarcoma and Ewing’s sarcoma [Optional] Lymph nodes if any: Involved………………. Not involved……………. Skip lesions: Metastasis: Nil/ Lung/Other sites Ancillary Studies: Recommended/ Not Recommended Type of tests: (Interphase cytogenetics) FISH test EWSR1, etc. Molecular by RT-PCR: EWS-FLI1, EWS-ERG, etc SYT-SSX, SYT-SSX1, SYT-SSX2, EWS-WT1, PAX3-FKHR, PAX7-FKHR. TNM Tumour Stage: T/N/M (to type) / Cannot be ascertained. Type of Resection: R0 / R1 / R2 Additional Comment: ………………………………………………………………………………………………. Signature: Registrar: Consultant: Date: …………………………………………………………………………………………………………………………………………………… TNM STAGING Primary tumor (T): Tx: Cannot be assessed Stage IA T1a N0,NX M0 Low grade T0: No primary tumor T1: ≤ 8cm, a: superficial b: deep T1b N0,NX M0 Low grade T2: > 8cm, a: superficial b: deep Stage IB T2a N0,NX M0 Low grade Regional lymph nodes (N): T2b N0,NX M0 Low grade Nx: Cannot be assessed N0: Negative Stage IIA T1a N0,NX M0 High grade N1: Positive T1b N0,NX M0 High grade Distant metastasis (M): M0: No metastasis Stage IIB T2a N0,NX M0 High grade M1: Distant metastasis Stage III T2b N0,NX M0 High grade

Stage IV Any T N1 M0 Any grade

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Soft Tissue Tumor Pathology Reporting Format

Name: …………………Hospital no: ……………… Report no: ……………… Grossed by:……Reported by:………………Consultant:…………

CLINICAL INFORMATION Exact Site: Location of Tumour: Superficial / Deep: Clinical Tumour size: Duration of illness: Treatment history: GROSS DESCRIPTION Type of Specimen: Needle core biopsy / Incisional biopsy / Excisional biopsy / Amputation

Exact Tumor size: __x__x__(cm). HISTOLOGY Histologic Subtype (According to WHO Classification of Soft Tissue Tumours): ______, exact type cannot be ascertained. Mitotic count _____ per 10 hpf; Necrosis is seen (less than 50% / 50% and more) / not seen. Histological Grade (For Sarcoma): Lymphovascular invasion is seen / not seen / cannot be ascertained. Microscopic margins ______Margin status cannot be ascertained. Ancillary Studies: Recommended/ Not Recommended ______Cytogenetics (FISH test): Specify Molecular (RT PCR): Specify TNM Tumour Stage: / Cannot be ascertained. Type of Resection: R0 / R1 / R2 Additional Comment: …………………………………………………………………………………………._

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Signature: Registrar: Consultant: Date: ......

TNM STAGING

Primary tumor (T): Stage IA T1a N0,NX M0 Low grade Tx : Cannot be assessed T1b N0,NX M0 Low grade T0 : No primary tumor T1 : ≤ 5cm, a: superficial b: deep Stage IB T2a N0,NX M0 Low grade T2 : > 5cm, a: superficial b: deep T2b N0,NX M0 Low grade Regional lymph nodes (N): Nx : Cannot be assessed Stage IIA T1a N0,NX M0 High grade N0 : Negative T1b N0,NX M0 High grade N1 : Positive Stage IIB T2a N0,NX M0 High grade Distant metastasis (M): M0: No metastasis Stage III T2b N0,NX M0 High grade M1: Distant metastasis Stage IV Any T N1 M0 Any grade Tumour site: Superficial: Defined as above fascia. This includes Any dermal T Any and N M1 subcutaneous Any grade Deep: Defined as below fascia. This includes Fascial, Subfascial, Intramuscular, Mediastinal, Intra-abdominal, including Retroperitoneal, Head and Neck. Histologic Grading: System used: French Federation of Cancer Centres Sarcoma Group (FNCLCC) Grade 1 (Total Scores = 2-3), Grade 2 (Scores 4-5), Grade 3 (Scores 6-8) (i) Tumor Differentiation Score: (1-3): Well-differentiated liposarcoma 1 Myxoid liposarcoma 2 Round cell liposarcoma 3 Pleomorphic liposarcoma 3 Dedifferentiated liposarcoma 3 Fibrosarcoma 2 Myxofibrosarcoma (malignant fibrous histiocytoma [MFH]) 2 Storiform MFH (sarcoma, not otherwise specified [NOS)] 3 MFH, pleomorphic type (patternless pleomorphic sarcoma) 3

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Giant cell and inflammatory MFH (pleomorphic sarcoma, NOS, with giant cells or inflammatory cells) 3 Well-differentiated leiomyosarcoma 1 Conventional leiomyosarcoma 2 Poorly differentiated / pleomorphic / epithelioid leiomyosarcoma 3 Biphasic / monophasic synovial sarcoma 3 Poorly differentiated synovial sarcoma 3 Pleomorphic rhabdomyosarcoma 3 Mesenchymal chondrosarcoma 3 Extra-skeletal osteosarcoma 3 Ewing’s sarcoma / Primitive neuroectodermal tumor 3 Malignant rhabdoid tumor 3 Undifferentiated sarcoma 3 (ii) Mitosis (Score): (1-3) 0-9/10 high power field (hpf) =1, 10-19/10 hpf =2, ≥ 20/10hpf =3 (iii) Necrosis (Percentage) (Score): (0-2) Defined as coagulative tumor necrosis in untreated specimens (chemo or radio) 0 = No necrosis, 1= <50% tumor necrosis, 2=> 50% tumor necrosis Grade 1 = Low Grade. Grades 2 and 3 = High Grade.

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APPENDIX - 6 Chemotherapy for Bone and Soft Tissue Tumors Bone Sarcoma Background Chemotherapy is an important component of the management of bone tumors. Chemotherapy can be given with curative intent or used in the palliative setting for symptom control. The choice of chemotherapy regimen will depend on the tumor histology, disease stage, patient’s performance status, organ function, available infrastructure, and associated comorbidities. Pre-requisites before administration of chemotherapy. It is important to clinically examine the patient and perform laboratory tests before the administration of chemotherapy. The chemotherapy should be administered under the supervision of a qualified medical oncologist. All cases should be discussed in the multidisciplinary tumor board including a surgical oncologist and radiation oncologist before starting treatment. Regimen for Osteosarcoma First-line treatment: The following regimens are commonly used in the neoadjuvant, adjuvant and palliative setting (Essential) 1. Cisplatin and doxorubicin (cisplatin and doxorubicin) 2. Ifosfamide, doxorubicin and cisplatin (IAP regimen) 3. Methotrexate, doxorubicin and cisplatin regimen (MAP)

It is important to ensure adequate intravenous hydration in patients receiving chemotherapy for osteosarcoma as cisplatin and methotrexate are nephrotoxic.

Regimen [reference} Schedule Cisplatin + doxorubicin Days 1–3: Doxorubicin 25mg/m2/day IV over 2 hours, plus Day 1: Cisplatin 100mg/m2 IV over 3 hours Repeat cycle every 3 weeks for 6 cycles.

MAP (high-dose Neoadjuvant (week 1-10/2 cycles) methotrexate + cisplatin Cisplatin 120 mg/m² (4 h infusion of 60 mg/m² per day for 2 + doxorubicin) days) and doxorubicin 37·5 mg/m² per day on days 1 and 2 as 4-hour infusion (on weeks 1 and 6). This is followed by high- dose methotrexate 12 g/m² over 4 h (maximum dose 20 gm) with hyper-hydration, alkalinisation, and standard leucovorin rescue at a dose of 15 mg/m² starting 24–48 h from methotrexate infusion and continuing until methotrexate

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concentration was less than 0·1 μM (weeks 4, 5, 9, and 10). Surgery: week 11 Adjuvant chemotherapy (week 12-29/4 cycles) Cisplatin 120 mg/m² (4 h infusion of 60 mg/m² per day for 2 days) (on week 12 and 17). Cisplatin is capped at a cumulative dose of 480 mg/m2 Doxorubicin 37·5 mg/m² per day on days 1 and 2 as 4-hour infusion (on week 12, 17, 22 and 26). High-dose methotrexate 12 g/m² over 4 h (maximum dose 20 gm) with hyper-hydration, alkalinisation, and standard leucovorin rescue at a dose of 15 mg/m² starting 24–48 h from methotrexate infusion and continuing until methotrexate concentration was less than 0·1 μM (weeks 15, 16, 20, 21, 24, 25, 28, 29). Note: Pegfilgrastim 6 mg is given on the day after completing doxorubicin infusion. Patients treated with amputation restart chemotherapy 3 to 5 days after surgery; patients who undergo limb salvage or rotation plasty restart chemotherapy 10 to 21 days after surgery. Ifosfamide, Adriamycin Ifosfamide 1.3 gm/m2 day 1,2 and 3 and Cisplatin (IAP) Adrimaycin 50 mg/m2 day 1 Cisplatin 100 mg/m2 divided over day 1-3

 The treating medical oncologist will decide on the dose and schedule based on the patient's needs. The above regimens are for guidance purposes only.  The above regimens are also used in patients with metastatic disease.  All the above regimens require growth factor support and routine monitoring of hemogram and biochemical parameters as per institutional policy.

Salvage/Second-line chemotherapy Second-line chemotherapy for patients with relapsed/refractory disease is given below (Essential). There is evidence from retrospective studies that multi-agent chemotherapy is associated with better survival than with single-agent chemotherapy. Patients who relapse within 12 months to 18 months of completion of treatment don’t respond well to chemotherapy.

Regimen Schedule Gemcitabine + docetaxel Days 1 and 8: Gemcitabine 675mg/m2 IV, plus Day 8: Docetaxel 75–100mg/m2 IV. Repeat cycle every 3 weeks for up to 13 cycles (median 4 cycles).

Carboplatin + ifosfamide + Days 1 and 2: Carboplatin 400mg/m2/day IV, plus etoposide Days 1–5: Ifosfamide 1,800mg/m2/day IV + mesna +

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etoposide 100mg/m2/day IV. Repeat cycle every 3 weeks for up to 12 cycles

Cyclophosphamide + topotecan Days 1–5: Cyclophosphamide 250mg/m2 IV over 30 minutes Days 1–5: Topotecan 0.75mg/m2 IV over 30 minutes Repeat cycle every 3 weeks for 12–14 cycles.

Ifosfamide (high dose) ± Days 1–5: Ifosfamide 1,800mg/m2/day IV + mesna, plus etoposide Days 1–5: Etoposide 100mg/m2/day IV. Repeat every 3 weeks for 12 cycles.

 Not in order of preference. The treating medical oncologist will decide on the dose and schedule based on the patient's needs. The above regimens are for guidance purposes only.  Any drug which was/ were not used in first-line settings can be used in a second-line setting.

Chemotherapy for Ewing’s Sarcoma First-line non-metastatic disease (Neoadjuvant/Adjuvant) (Essential)

Regimen [reference] Schedule VAC/IE (vincristine + Alternating VAC and IE cycles doxorubicin + VAC cycles cyclophosphamide Day 1: Vincristine 2 mg/m2 (max 2mg) IV over 5-10 minutes alternating with Day 1: Doxorubicin 75mg/m2 IVP or ifosfamide + etoposide) 1250mcg/m2 IVP (Substitute for doxorubicin when cumulative lifetime doxorubicin dose of 375mg/m2 has been met) Day 1: Cyclophosphamide 1200mg/m2 IV over 60 minutes + Mesna IE cycles Days 1-5: Ifosfamide 1800 mg/m2 IV over 3 hours + Mesna Days 1-5: Etoposide 100mg/m2 IV over 60 minutes Repeat each cycle every 2 weeks or 3 weeks for 17 cycles

VIDE (vincristine + Day 1: Vincristine 1.5 mg/m2 (max 2mg) IV push over 5-10 ifosfamide + doxorubicin minutes + etoposide) Days 1-3: Ifosfamide 3g/mg2 IV continuous infusion over 1-3 hours + Mesna (give concurrently with ifosfamide) Days 1-3: Doxorubicin 20mg/m2 IV continuous infusion over 4 hours or Dactinomycin 500mcg/m2 IV (Substitute for doxorubicin when cumulative lifetime doxorubicin dose of 375mg/m2 has been met) Days 1-3: Etoposide 150mg/m2 IV over 1 hour

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Repeat cycle every 3 weeks for up to 6 cycles

First-line treatment metastatic disease Patients receiving treatment with palliative intent can be given VAC every 3 weeks up to 6- 12 cycles. Patients receiving treatment with curative intent can be treated with VAC/IE as for non-metastatic disease. (Essential)

Second-line treatment for relapsed/refractory disease (Essential)

Regimen [reference] Schedule Cyclophosphamide + Days 1–5: Cyclophosphamide 250mg/m2 IV over 30 minutes topotecan Days 1–5: Topotecan 0.75mg/m2 IV over 30 minutes Repeat cycle every 3 weeks for 12-14 cycles

Irinotecan ± Days 1–5: Temozolomide 100mg/m2/day orally, plus temozolomide Days 1–5 and 8–12: Irinotecan 10–20mg/m2/day IV at least 1 hour after temozolomide. Repeat cycle every 3 or 4 weeks.

Docetaxel + gemcitabine Days 1 and 8: Gemcitabine 675mg/m2 IV, plus Day 8: Docetaxel 75–100mg/m2 IV. Repeat cycle every 3 weeks for up to 13 cycles (median 4 cycles).

Note: not in order of preference Soft Tissue Sarcoma Available evidence from meta-analysis and randomized controlled trials suggests that adjuvant chemotherapy improves relapse free survival, data on overall survival however is conflicting.

Modalities of delivering chemotherapy Neoadjuvant chemotherapy - NACT can be given in borderline resectable tumors with chemo sensitive histologies. It may help to shrink the tumor and may increase resectability. The responses are unpredictable. This may be combined with preoperative RT but toxicities are higher. All such cases should be discussed in MDJC and patient selection should be done carefully. Adjuvant chemotherapy – Adjuvant chemotherapy should be considered in STS post-surgery if it is >5cm and high grade and deep seated in chemo-sensitive histologies like leiomyosarcoma, synovial sarcoma, myxoid liposarcoma, myxofibrosarcoma, pleomophic undifferentiated sarcoma and can be avoided in histologies like clear cell sarcoma, alveolar soft part sarcoma. However, in fewer histologies like MPNST, epitheloid sarcoma it can be

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Advanced, Unresectable or Metastatic Disease.

First Line - Single agent chemotherapy (doxorubicin, ifosfamide, dacarbazine, epirubicin) or doxorubicin-based combination chemotherapy (with dacarbazine/ifosfamide) have been wide used for advanced, unresectable or metastatic STS. Other agents like gemcitabine, docetaxol, vilnorebine and temozolamide have also been evaluated in clinical trials. Single agent chemotherapy may be considered for other patients to avoid toxicity. (Essential)

After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology. Second Line Therapy– (optional) Second line therapy after first line therapy favours histology directed approach. Pazopanib, Trabectedin and Eribulin are mainly used agents. Other drugs used as second line therapy - paclitaxel for angiosarcoma, propanolol for angiosarcoma, sorafenib for desmoid tumors and for INI negative epitheloid sarcoma. Similarly, ALK inhibitors like crizotinib are effective in ALK positive IMFT and various anti angiogenic agents like are effective in advanced ASPS. Summary of drugs and doses in localized and advanced STS

Regimen Doses Histology specific approval Ifosfamide and Ifosfamide(with mesna) 9 gm/m2 None doxorubicin Doxorubicin 75mg/m2 Divided over 3 or 5 days with GCSF prophylaxis every 21 days Single agent 75mg/m2 every 21 days none doxorubicin Pazopanib 800mg per day orally Non adipocytic Administer on an empty stomach at least 1 sarcoma hour before or 2 hours after a meal Trabectedin 1.5mg/m2 iv over 24 hours every 21 days Liposarcoma and (Premedicate with dexamethasone 20 mg to leiomyosarcoma prevent hepatotoxicity)

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Eribulin 1.4mg/m2 iv D1 and D8 every 21 days Liposarcoma

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Appendix - 7 Radiotherapy for Bone and Soft Tissue Tumors Bone Sarcomas Ewing’s Sarcoma - Adjuvant Radiotherapy (Essential) Radiotherapy doses and technique 1. Margin negative R0 resection: 45Gy/25#s over 5 weeks (essential) 2. Positive margin: R1 resection - 50.4Gy/28#s over 6 weeks, R2 resection - 55.8Gy/31#s over 6.5 weeks (essential). 3. Target volumes should encompass the tumor bed along with margins for the microscopic disease. Scar and the drain site need not be chased. Tailored portals for all patients (essential). IMRT +/- IGRT can be used (optional). Definitive Radiotherapy (Optional) RT is preferred over surgery as local treatment for tumors presenting with metastatic disease (RT for primary as well as metastatic sites) Radiotherapy doses and technique 1. 55.8Gy/31#s over 6 weeks (essential) 2. Target volumes should encompass the gross tumor (GTV) with margin for microscopic disease (CTV). 3. Tailored portals for all patients (essential). IMRT +/- IGRT can be used (optional). 4. Adaptive RT may be considered if required (optional). 5. Concurrent CTRT protocol to be used while on RT. Lung bath (Essential) The recommended dose for lung bath is 12.6Gy/7#s over 10 days with tailored portals (essential). RT in metastatic disease RT may be preferred local treatment (for primary as well as the metastatic sites) in oligometastatic cases (Optional). RT doses are same as that of non-metastatic cases. Hypofractionated RT can be considered for skeletal metastatic sites. Patients with disseminated disease or with multiple bony metastasis should be treated with palliative intent (Optional).

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Palliative RT RT can be used for palliation of symptomatic sites (primary or metastatic or both) with dose fractionation depending upon tolerance and response (Optional). Osteosarcoma and Chondrosarcoma - Radiotherapy doses and technique 1. Definitive RT up to doses of >70Gy@ 1.8-2Gy/# to be considered (essential). 2. Conformal portals, adaptive planning and image guidance is recommended (essential). 3. Select cases to be considered for particle beam therapy (optional).

Soft Tissue Sarcomas Radiotherapy reduces local recurrences and may have an impact on the overall survival in STS. Intra operative interstitial brachytherapy should be considered for extremity STS, wherever feasible. Adjuvant Radiotherapy (Essential)

Indications of adjuvant RT 1. High grade tumors 2. Tumors>/= 5 cms 3. Close or positive margins 4. Recurrent tumors Radiotherapy doses and technique 1. Margin negative: 60Gy/30#s over 6 weeks with phased portals (Ph-1 50Gy/23#s followed by Ph-2 with shrinking portals 10Gy/5#s) essential 2. Positive margin: To add a boost of 6-10Gy for microscopic/ gross positive margins to the above planned dose. 3. Target volumes should encompass the tumor bed along with margins for the microscopic disease. Scar and the drain site need not be chased. Tailored portals for all patients (essential). IMRT +/- IGRT can be used (optional). 4. Attempt should be made to spare around 1.5 - 2.0cm of limb circumference as well as reduce doses to uninvolved bone/ joint and minimize hotspots on the skin and subcutaneous tissues (essential). 5. Radio-opaque clips placed during surgery help in defining the tumor bed.(optional) 6. Adjuvant chemotherapy if planned, to be considered after completion of RT. 7. Brachytherapy dose: 36Gy/9#s @ 400cGy per dose, twice a day.

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Preoperative radiotherapy (Optional to Adjuvant radiotherapy)

To be considered for marginally/borderline resectable cases. Radiotherapy doses and technique 1. 50Gy/25#s over 5 weeks (essential) 2. Target volumes should encompass the tumor (GTV) with a 2 cms margin for microscopic disease (CTV). 3. Tailored portals for all patients (essential). IMRT +/- IGRT can be used (optional). 4. Adaptive RT may be considered if required (optional). 5. Neo-adjuvant chemotherapy if planned, to be considered either before starting RT or after completion of RT.

Definitive Radiotherapy (Optional) To be considered for select cases with unresectable/ inoperable tumors. Doses up to 70Gy @ 1.8-2Gy/# to be considered. Conformal portals, adaptive planning and image guidance can be considered. Palliative RT (Optional) RT can be used for palliation of symptomatic sites (primary or metastatic or both) with dose fractionation depending upon tolerance and response. They may help decreasing pain, temporarily arresting tumor growth or to achieve haemostasis.

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