الله الله بسم بسمالرحيم الرحيم الرحمن الرحمن

NEW STANDARD OF NEW STANDARD OF NEOADJUVANT AND NEOADJUVANT AND

ADJUVANT ADJUVANT CHEMOTHERAPY IN CHEMOTHERAPY IN

OSTEOGENIC SARCOMAOSTEOGENIC SARCOMA

Sarcomas are cancers derived from Sarcomas are cancers derived from primitive mesenchymal cells. primitive mesenchymal cells.

They can originate from bone or They can originate from bone or soft tissue and vary in terms of soft tissue and vary in terms of

biological behavior, response to biological behavior, response to different treatment modalities and different treatment modalities and

prognosis.prognosis. Untreated they run an aggressive Untreated they run an aggressive

course with local & also systemic course with local & also systemic disease progression.disease progression.

ClassificationClassification

Current histopathologic Current histopathologic classification of bone neoplasms is classification of bone neoplasms is

based on the putative cell of origin. based on the putative cell of origin. Malignant tumors may arise from Malignant tumors may arise from any cellular constituent present in any cellular constituent present in

bone.bone. osteogenic (osteosarcoma)osteogenic (osteosarcoma)

chondrogenic (chondrosarcoma)chondrogenic (chondrosarcoma)

ClassificationClassification

hematopoietic (multiple myeloma, hematopoietic (multiple myeloma, lymphoma)lymphoma)

vascular (angiosarcoma, vascular (angiosarcoma, hemangioendothelioma, hemangioendothelioma, leiomyosarcoma)leiomyosarcoma)

lipogenic (liposarcoma)lipogenic (liposarcoma) neurogenic (neurofibrosarcoma, neurogenic (neurofibrosarcoma,

chordoma)chordoma) and histiocytic and fibrohistiocytic and histiocytic and fibrohistiocytic

(MFH, Ewing’s sarcoma) elements. (MFH, Ewing’s sarcoma) elements.

OsteosarcomaOsteosarcoma Osteosarcomas occur in all age groups Osteosarcomas occur in all age groups

but have a bimodal age distribution; but have a bimodal age distribution; 75% occur in patients younger than age 75% occur in patients younger than age 20. 20.

In adolescence, about half of them arise In adolescence, about half of them arise in the metaphysis around the knee, in the metaphysis around the knee, either in the distal femur or proximal either in the distal femur or proximal tibia. These are the sites of greatest tibia. These are the sites of greatest skeletal growth activity. skeletal growth activity.

In persons over age 25, the incidence in In persons over age 25, the incidence in flat bones and longflat bones and long bones is almost bones is almost equalequal..

PathogenesisPathogenesis UnknownUnknown

Modal incidence correlates with rapid Modal incidence correlates with rapid bone growthbone growth

Radiation exposureRadiation exposure

Cancer survivorsCancer survivors

RetinoblastomaRetinoblastoma

Major sites of origin of osteosarcomas. The numbers are approximate percentages.

ClassificationClassification

Clinical PresentationClinical Presentation

Painful mass arising from bonePainful mass arising from bone

Sudden #of the boneSudden #of the bone Metastisize early in evolutionMetastisize early in evolution

20% clinically detectable mets at dx20% clinically detectable mets at dx

OsteosarcomaOsteosarcoma

Grossly, osteosarcomas are Grossly, osteosarcomas are bulky tumors that are gritty, bulky tumors that are gritty, gray-white, and often gray-white, and often contain areas of hemorrhage contain areas of hemorrhage and cystic degeneration. The and cystic degeneration. The formation of bone by the formation of bone by the tumor cells is characteristic tumor cells is characteristic of osteosarcomaof osteosarcoma. .

Osteosarcoma of the upper end of the tibia. The tan-white tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and formed soft tissue masses on both sides of the bone.

OsteosarcomaOsteosarcoma

Radiographs of the Radiographs of the primary tumor usually primary tumor usually show a large, destructive, show a large, destructive, mixed lytic and blastic mixed lytic and blastic mass. The tumor mass. The tumor frequently breaks through frequently breaks through the cortex and lifts the the cortex and lifts the periosteum, resulting in periosteum, resulting in reactive periosteal bone reactive periosteal bone formation. The triangular formation. The triangular shadow between the cortex shadow between the cortex and raised ends of and raised ends of periosteum is known periosteum is known radiographically as radiographically as CodmanCodman triangletriangle and is and is characteristic, but not characteristic, but not diagnostic of this tumor.diagnostic of this tumor. Distal femoral osteosarcoma with prominent bone formation

extending into the soft tissues. The periosteum, which has been lifted, has laid down a proximal triangular shell of reactive bone known as a Codman triangle (arrow).

Differential DiagnosisDifferential Diagnosis

Giant Cell TumorGiant Cell Tumor Aneursymal Bone CystAneursymal Bone Cyst EwingsEwings OsteoblastomaOsteoblastoma MetastasisMetastasis LymphomaLymphoma

The prognosis has improved greatly The prognosis has improved greatly during the past decades with the use during the past decades with the use

of multiagent chemotherapy, with the of multiagent chemotherapy, with the improvement of diagnostic improvement of diagnostic

technologies such as CT scans and technologies such as CT scans and MRI, and with a more aggressive MRI, and with a more aggressive

surgical approach. surgical approach. 61 % event free survival at 6 years for 61 % event free survival at 6 years for

adjuvant treated patients and 11 % adjuvant treated patients and 11 % event free survival at 6 years for event free survival at 6 years for

patients treated with surgery alone.patients treated with surgery alone.

•Although the incidence of local recurrence is low, microscopic

dissemination is likely to be present in 80% of patients at the time of diagnosis, leading to distant metastases, mostly in

the lungs and bones, within the first 6–12 months.

Surgical excision is the mainstay of Surgical excision is the mainstay of treatment for patients with low-grade treatment for patients with low-grade sarcomas. For high-grade tumors, sarcomas. For high-grade tumors, multimodality therapy is indicatedmultimodality therapy is indicated..

For high-grade sarcomas, preoperative For high-grade sarcomas, preoperative multiagent chemotherapy (3 to 4 cycles) multiagent chemotherapy (3 to 4 cycles) is followed by surgical extirpation of the is followed by surgical extirpation of the primary tumorprimary tumor

Standard of CareStandard of Care

ChemotherapyChemotherapy

Best protocol is subject of ongoing Best protocol is subject of ongoing trialstrials

DrugsDrugs DoxorubicinDoxorubicin CisplatinCisplatin IfosfamideIfosfamide MethotrexateMethotrexate CyclophosphamideCyclophosphamide

Induction ChemotherapyInduction Chemotherapy

Arose in conjunction with Arose in conjunction with development of limb sparing development of limb sparing surgerysurgery

Increase survivalIncrease survival

prognosticprognostic

Early trials incorporated high doses of Early trials incorporated high doses of methotrexate, given weekly for 4 methotrexate, given weekly for 4 weeks with leucovorin rescue, prior to weeks with leucovorin rescue, prior to surgery. surgery.

Subsequent modifications included Subsequent modifications included the incorporation of bleomycin, the incorporation of bleomycin, dactinomycin (Cosmegen), and dactinomycin (Cosmegen), and cyclophosphamide into the regimen, cyclophosphamide into the regimen, with the further addition of with the further addition of doxorubicin. doxorubicin.

ConsiderationsConsiderations

Surgeon: I got it allSurgeon: I got it all Oncologist: the surgeon got all Oncologist: the surgeon got all

that he or she could seethat he or she could see Patient: what are my chances?Patient: what are my chances?

The European Osteosarcoma The European Osteosarcoma Intergroup (EOI) reported no Intergroup (EOI) reported no

difference in histopathologic response difference in histopathologic response to preoperative chemotherapy and to preoperative chemotherapy and

overall survival in patients randomized overall survival in patients randomized to receive a two-drug regimen with to receive a two-drug regimen with

doxorubicin and cisplatin or a complex doxorubicin and cisplatin or a complex multidrug protocol containing multidrug protocol containing

doxorubicin, cisplatin, and high-dose doxorubicin, cisplatin, and high-dose methotrexate among other agents.methotrexate among other agents.

European Osteosarcoma European Osteosarcoma Intergroup Study IIntergroup Study I

Bramwell et al. JCO 1992.

DOX/DDP

HDMTX/DOX/DDP

Overall Survival

Giving cisplatin intra-arterially did Giving cisplatin intra-arterially did not lead to improved results in a not lead to improved results in a prospective trial of Cooperative prospective trial of Cooperative

Osteosarcoma Study Group.Osteosarcoma Study Group.

A recent randomized controlled trial A recent randomized controlled trial by the European Osteosarcoma by the European Osteosarcoma

Intergroup failed to achieve a survival Intergroup failed to achieve a survival advantage for adding G-CSF to advantage for adding G-CSF to

doxorubicin and cisplatindoxorubicin and cisplatin

European Osteosarcoma European Osteosarcoma Intergroup IIIIntergroup III

Lewis et al. JNCI, 2007

• No difference in disease-free and overall survival─ Higher rate of greater than 90% necrosis in dose intensive arm

Poor respondersPoor responders Patients with poor tumor response may Patients with poor tumor response may

represent 30%–60% of the population represent 30%–60% of the population with extremity osteosarcoma. For these with extremity osteosarcoma. For these patients, more effective treatment patients, more effective treatment regimens, such as dose intensification regimens, such as dose intensification using growth factors and stem-cell using growth factors and stem-cell support, and newer agents need to be support, and newer agents need to be evaluated.evaluated.

Alternative approachesAlternative approaches One alternative approach to One alternative approach to

neoadjuvant therapy is adjuvant neoadjuvant therapy is adjuvant therapy. therapy.

A randomized study of the Pediatric A randomized study of the Pediatric Oncology Group (POG) demonstrated Oncology Group (POG) demonstrated

no detectable difference in EFS no detectable difference in EFS whether chemotherapy was offered whether chemotherapy was offered

before or after surgery.before or after surgery.

The feasibility of safely performing limb-The feasibility of safely performing limb-salvage surgery in these patients, salvage surgery in these patients, however, has not been studied directly. however, has not been studied directly.

Additionally, intra-arterial delivery of Additionally, intra-arterial delivery of cytotoxic agents has shown no specific cytotoxic agents has shown no specific survival benefit but provides increased survival benefit but provides increased concentration of chemotherapy to the concentration of chemotherapy to the primary tumor, which may impact primary tumor, which may impact favorably on the extent of the resection favorably on the extent of the resection for patients undergoing limb-salvage for patients undergoing limb-salvage surgery surgery

ImmunotherapyImmunotherapy

A recent investigation found evidence A recent investigation found evidence of a survival advantage in of a survival advantage in osteosarcoma patients who suffer osteosarcoma patients who suffer postoperative infections.postoperative infections.

The production of tumor-specific The production of tumor-specific humoral & cellular immune responses humoral & cellular immune responses to osteosarcoma has been previously to osteosarcoma has been previously recognized, prompting interest in the recognized, prompting interest in the potential role of immunotherapy in potential role of immunotherapy in osteosarcomaosteosarcoma

ImmunotherapyImmunotherapy

Muramyl Tripeptide Phosphatidyl Muramyl Tripeptide Phosphatidyl Ethanolamine Ethanolamine

InterferonsInterferons Inhaled GM-CSFInhaled GM-CSF TrastuzumabTrastuzumab 105AD7 vaccine 105AD7 vaccine

Background of MTP-PEBackground of MTP-PEMTP-PE MTP-PE Biological response modifier developed Biological response modifier developed

by Ciba-Geigy in 1980sby Ciba-Geigy in 1980s Fully synthetic lipophilic derivative of Fully synthetic lipophilic derivative of

Mycobacterium cell walls.Mycobacterium cell walls. Delivered to macrophages stimulates Delivered to macrophages stimulates

tumoricidal activitytumoricidal activity Clinical development for osteosarcoma Clinical development for osteosarcoma

based on activity in animal models based on activity in animal models

COG Phase III StudyCOG Phase III Study

Meyers et al. JCO, 2005.

GPG Phase III StudyGPG Phase III Study

Meyers et al. JCO, 2005.

Event-free Survival

• 3-year EFS─ 71% Standard chemotherapy arm─ 68% MTP + standard chemotherapy─ 61% Ifosfamide + standard chemotherapy─ 78% Ifosfamide + MTP + standard chemotherapy

InterferonsInterferons

IFNs exert a direct inhibitory effect against IFNs exert a direct inhibitory effect against several tumor types several tumor types in vitroin vitro, including , including osteosarcomaosteosarcoma..

The Cooperative German/Austrian The Cooperative German/Austrian Osteosarcoma Study Group (COSS)-80 Osteosarcoma Study Group (COSS)-80

investigation randomized osteosarcoma investigation randomized osteosarcoma patients to either receive or not receive 22 patients to either receive or not receive 22

weeks of IFN maintenance therapy after weeks of IFN maintenance therapy after the completion of chemotherapy. the completion of chemotherapy.

Administered twice weekly for 18 weeks Administered twice weekly for 18 weeks and once daily for another 4 weeks, IFN and once daily for another 4 weeks, IFN

was found to confer no survival advantage.was found to confer no survival advantage.

InterferonsInterferons

Pegylated IFN-α2b is incorporated into the Pegylated IFN-α2b is incorporated into the ongoing The European and American ongoing The European and American Osteosarcoma Study Group (EURAMOS) 1 Osteosarcoma Study Group (EURAMOS) 1 intergroup study of resectable osteosarcoma intergroup study of resectable osteosarcoma tumors. Patients who experience a favorable tumors. Patients who experience a favorable histological response after neoadjuvant histological response after neoadjuvant MAP therapy as measured by less than 10% MAP therapy as measured by less than 10% viable tumor will be randomized to receive viable tumor will be randomized to receive or not to receive 75 weeks of weekly or not to receive 75 weeks of weekly subcutaneous IFN-α 2b after the completion subcutaneous IFN-α 2b after the completion of adjuvant MAP therapy. of adjuvant MAP therapy.

Muller et al, Muller et al, Acta Oncol; Acta Oncol;

2005.2005.

Inhaled GM-CSFInhaled GM-CSF

GM-CSF is capable of activating GM-CSF is capable of activating numerous components of the immune numerous components of the immune system including neutrophils, system including neutrophils, macrophages, lymphocytes, and macrophages, lymphocytes, and natural killer cells.natural killer cells.

These immunostimulatory effects These immunostimulatory effects confer an antitumor effect in confer an antitumor effect in numerous cancer typesnumerous cancer types..

Inhaled GM-CSFInhaled GM-CSF

A Phase II study is being carried out by A Phase II study is being carried out by the Children's Oncology Group (COG), the Children's Oncology Group (COG), investigating the effect of inhaled GM-investigating the effect of inhaled GM-CSF in osteosarcoma patients with CSF in osteosarcoma patients with pulmonary relapse. If favorable pulmonary relapse. If favorable therapeutic effects are confirmed, therapeutic effects are confirmed, inhaled GM-CSF may be an attractive inhaled GM-CSF may be an attractive agent in patients with pulmonary agent in patients with pulmonary metastasis or as a prophylactic metastasis or as a prophylactic measure in patients at high risk of measure in patients at high risk of relapse. relapse.

TrastuzumabTrastuzumab

HER-2 expression has been associated HER-2 expression has been associated with a poor histologic response to with a poor histologic response to neoadjuvant chemotherapy and neoadjuvant chemotherapy and decreased EFS in osteosarcoma decreased EFS in osteosarcoma patients. A study of trastuzumab, a patients. A study of trastuzumab, a HER-2 monoclonal antibody, in HER-2 monoclonal antibody, in osteosarcoma tumors with HER-2 osteosarcoma tumors with HER-2 amplification has recently been amplification has recently been completed by the COG, but results from completed by the COG, but results from the study have yet to be publishedthe study have yet to be published

Investigational Cytotoxic Investigational Cytotoxic Chemotherapy Chemotherapy

GemcitabineGemcitabine

DocetaxelDocetaxel

TopotecanTopotecan

PemetrexedPemetrexed

Investigational Cytotoxic Investigational Cytotoxic ChemotherapyChemotherapy

Synergistic cytotoxicity with sequential Synergistic cytotoxicity with sequential treatment of soft tissue & bone treatment of soft tissue & bone sarcomas with gemcitabine followed by sarcomas with gemcitabine followed by docetaxel has been demonstrated . docetaxel has been demonstrated .

This regimen resulted in an overall RR This regimen resulted in an overall RR of 43% in multiple types of soft –tissue of 43% in multiple types of soft –tissue sarcomas, osteosarcomas & Ewing’s sarcomas, osteosarcomas & Ewing’s sarcoma at the university of Michigan sarcoma at the university of Michigan Comprehensive Cancer center.Comprehensive Cancer center.

Leo et al, JCO; Leo et al, JCO; 2004.2004.

CamptothecinsCamptothecins

A Phase II study of topotecan in A Phase II study of topotecan in combination with cyclophosphamide combination with cyclophosphamide led to a partial response in two of 18 led to a partial response in two of 18

and stable disease in five of 18 and stable disease in five of 18 relapsed or refractory osteosarcoma relapsed or refractory osteosarcoma

patients. All other osteosarcoma patients. All other osteosarcoma patients experienced progressive patients experienced progressive

disease.disease.

PemetrexedPemetrexed

By inhibiting multiple folate-dependent By inhibiting multiple folate-dependent enzymes, the antimetabolite pemetrexed has enzymes, the antimetabolite pemetrexed has

drawn attention as a promising osteosarcoma drawn attention as a promising osteosarcoma therapy. therapy.

Pemetrexed has demonstrated synergism with Pemetrexed has demonstrated synergism with other chemotherapies such as platinum agents other chemotherapies such as platinum agents

and gemcitabine.and gemcitabine. However, a recent However, a recent in vitroin vitro study utilizing study utilizing

human osteosarcoma cell lines demonstrated human osteosarcoma cell lines demonstrated an inferior response to pemetrexed compared an inferior response to pemetrexed compared

to MTX when the agents were used individually.to MTX when the agents were used individually.[39] Hence, the value of pemetrexed may be in [39] Hence, the value of pemetrexed may be in the context of a multidrug regimen rather than the context of a multidrug regimen rather than

as a monotherapyas a monotherapy

BisphosphanatesBisphosphanates Many solid tumors, including Many solid tumors, including

osteosarcoma, express tumor-osteosarcoma, express tumor-specific antigens on their surface, specific antigens on their surface, representing targets for immune representing targets for immune

effector T cells.effector T cells. At present, a Phase III study is in At present, a Phase III study is in

progress in France, evaluating the progress in France, evaluating the impact of zoledronic acid as adjuvant impact of zoledronic acid as adjuvant

therapy to chemotherapy and therapy to chemotherapy and surgery on EFS in pediatric and surgery on EFS in pediatric and

adult patientsadult patients. .

Emerging Directed Emerging Directed Therapies Therapies

An evolving understanding of An evolving understanding of osteosarcoma biology will likely play a osteosarcoma biology will likely play a significant role in the development of significant role in the development of novel therapeutics. novel therapeutics.

Promising therapies targeted at Promising therapies targeted at molecules critical to the pathogenesis of molecules critical to the pathogenesis of osteosarcoma tumors are currently under osteosarcoma tumors are currently under investigation. investigation.

These molecular targets include IGF1R, These molecular targets include IGF1R, mTOR,, and HSP90 molecular chaperonemTOR,, and HSP90 molecular chaperone..

Side–effects of Side–effects of chemotherapychemotherapy

The most frequent chemotherapy related The most frequent chemotherapy related complications include complications include infections,mucositis, impaired renal infections,mucositis, impaired renal function(tubular damage due to function(tubular damage due to ifosfamide & glomerular dysfunction ifosfamide & glomerular dysfunction caused by cisplatin), hearing loss, caused by cisplatin), hearing loss, neuropathy and cardiomyopathy.neuropathy and cardiomyopathy.

Close monitoring during chemotherapyis Close monitoring during chemotherapyis mandatotrymandatotry

Long-term follow up is required not only Long-term follow up is required not only to monitor remission status but also to to monitor remission status but also to screen for and manage late effectsscreen for and manage late effects

Take home messageTake home message

Osteosarcoma is most commonly Osteosarcoma is most commonly observed during the adolescent observed during the adolescent

growth spurt, as well as at the site of growth spurt, as well as at the site of pre-existing lesions such as Paget's pre-existing lesions such as Paget's

disease and bone infarctsdisease and bone infarcts

Take home messageTake home message The combination of high-dose The combination of high-dose

methotrexate, doxorubicin, and cisplatin, methotrexate, doxorubicin, and cisplatin, with or without ifosfamide, is widely used, with or without ifosfamide, is widely used,

however, clinical trials remain the however, clinical trials remain the standard of carestandard of care..

Many of the immunotherapy agents Many of the immunotherapy agents currently under investigation are currently under investigation are

theorized to be the most useful in the theorized to be the most useful in the setting of minimal residual disease. setting of minimal residual disease.

The impact of these agents in the The impact of these agents in the future remains under investigation future remains under investigation