ewings sarcoma management chemotherapy trials
TRANSCRIPT
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Ewing’s Sarcoma Management
Parag royDept of radiotherapy
Lok nayak hopital
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Introduction• Identified in 1921 by James Ewing• Ewing’s Sarcoma Family of tumors:• Ewing’s sarcoma (Bone –87%) • Extraosseous Ewing’s sarcoma (8%)• Peripheral PNET(5%) • Askin’s tumor
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Cytogenetics• Consistent cytogenetic abnormality, t(11;22)(q24;q12) present in 90-95%
resultant fusion gene is EWS/FLI-1• Also seen:• t(21;22)(q22;q12) 5-10% EWS/ERG• t(7;22) and t(17;22) the remainder EWS/ETV1 and EWS/E1AF respectively• t(1;16)(q21;q13) present along with t(11;22)
• The c-myc protooncogene is frequently expressed in Ewing’s. • CD 99 ( MIC2)• PAS +ve
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Routes of spread• Direct extension into adjacent bone or soft tissue.• Metastases generally spread through bloodstream• 25% present with metastatic disease• Lungs (38%)• Bone (31%)• Bone Marrow (11%)
• Nearly all pts. have micromets at diagnosis, so all Need chemo.
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Primary tumor (T)TX Primary tumor cannot be assessedT0 No evidence of primary tumorT1 Tumor 8 cm or less in greatest dimensionT2 Tumor more than 8 cm in greatest dimensionT3 Discontinuous tumors in the primary bone siteRegional lymph nodes (N)NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasisNote: Because of the rarity of lymph node involvement in bone sarcomas, the designation NX may not be appropriate and cases should be considered N0 unless clinical node involvement is clearly evident.Distant metastasis (M)M0 No distant metastasisM1 Distant metastasisM1a LungM1b Other distant sites
AJCC Staging (7th Ed. 2010) Bone Tumor
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IAT1 N0 M0 G1,2 low grade, GX
IBT2 N0 M0 G1,2 low grade, GXT3N0 M0 G1,2 low grade, GX
IIAT1 N0 M0 G3, 4 high grade
IIBT2 N0 M0 G3, 4 high grade
III T3 N0 M0 G3, 4IVA Any T N0 M1a any GIVB Any T N1 any M any G
Any T any N M1b any G
StageHistologic Grade (G)GX Grade cannot be assessedG1 Well differentiated — Low GradeG2 Moderately differentiated — Low GradeG3 Poorly differentiatedG4 Undifferentiated
Note: Ewing's sarcoma is classified as G4.
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CONSORT
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Disease factors Favorable prognosis Unfavorable prognosisSite Distal extremity (tibia,
fibula, radius, ulna, hands, feet)
Central lesions (especially pelvic bones) less favorable: proximal extremity (humerus, femur), ribs
Size <8 cm in greatest diameter or <200 mL estimated volume
Larger tumors
Soft tissue extension
Absence of radiographically identifiable soft tissue extension
Presence of soft tissue extension by radiograph or significant extension by computed tomography
Extent of disease
Localized Metastatic
Site of Metastasis
Lung Bone / bone marrowBoth Lung and Bone
Response to CT Responsive Unresponsive
Prognostic Factors
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Treatment
• Chemotherapy: control of Micro/Macro metastasis
• Surgery: local control where possible
• Radiotherapy: local control where surgery not possible or Incomplete
Multidisciplinary
approach
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General Management• Effective local and systemic chemotherapy (CT) necessary for
cure.• Induction chemotherapy preferred over starting the systemic
and local therapy• Advantage of this approach:• Evaluation of effectiveness of the regimen• Decreases the vol. of primary tumor for surgery or RT• Some bone healing occurs during CT, diminish the risk of pathological
fracture
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Induction Chemother
apy
Local Control• Surgery• Radiotherapy
Maintenance• Chemotherap
y
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Chemotherapy
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Chemotherapy
• All patients require chemotherapy• Induction chemotherapy• Maintenance chemotherapy
• Effective chemotherapy has improved local control rates achieved with radiation to 85-90%
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First-line therapy• Primary/ neoadjuvant/ adjuvant therapy• VAC/IE (vincristine, doxorubicin, and cyclophosphamide alternating with
ifosfamide and etoposide)• VAI (vincristine, doxorubicin, and ifosfamide)• VIDE (vincristine, ifosfamide, doxorubicin, and etoposide)
• Primary therapy for metastatic disease at initial presentation• VAdriaC (vincristine, doxorubicin, and cyclophosphamide)• VAC/IE• VAI• VIDE
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Second-line therapy • Relapsed/refractory or metastatic disease• Cyclophosphamide and topotecan• Irinotecan ± temozolomide• Ifosfamide (high dose) ± etoposide• Ifosfamide, carboplatin, and etoposide• Docetaxel and gemcitabine• Decetaxel and irinotecan
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NCCN Guidelines Version 2.2016 Ewing’s Sarcoma Family of Tumors
PRESENTATION WORKUP PRIMARY RESTAGE TREATMENT
Ewing’s sarcoma family of tumors
•History and physical•MRI ± CT of primary site•Chest CT• PET scan and/or bone scan•Bone marrow biopsy and/or screening MRI of spine and pelvisd•Cytogenetics and/or molecular studiese (may require re-biopsy)•LDH• Fertility consultation should be considered
Multiagent chemotherapyf (category 1) for at least12 weeks prior to local therapyh
localized diseaseRestage with:•Chest imaging• Imaging of primary site•Consider PET scan or bone scang
For patients withmetastatic diseaseRestage with:•Chest imaging• Imaging of primary site•Consider PET scan or bone scang
Repeat other abnormal studies
Response
Progressive disease
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NCCN Guidelines Version 2.2016 Ewing’s Sarcoma Family of Tumors
Stable/improved disease following response to primary treatment
Progressive disease following primary treatment
LOCAL CONTROL THERAPY
Wide excisionborDeinitive RTl and chemotherapyorAmputationb in selected cases
Positive marginsNegative marginsi
ADJUVANT TREATMENT/ ADDITIONAL THERAPYContinue chemotherapyf,j
(category 1) followed by RTl orRTl and chemotherapyf,j (category 1, for chemotherapy)Chemotherapyf,j (category 1)
Postoperative chemotherapy,f consider RTl depending on margin status
SURVEILLANCE
• Physical exam, imaging of primary site and chest every2–3 mo• CBC and other laboratory studies as indicated• Increase intervals for physical exam, imaging of chest, and primary site after 24 mo and annually after 5 y (category 2B) (indeinitely)• Consider PET scan or bone scang
PROGRESSIVE DISEASE/RELAPSE
Early relapse
Late relapsek
Chemotherapyf,k±RTl
Consider RTl and/or surgery to primary site for local control or palliation
Chemotherapyf orBest supportive care
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IESS-1
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• 193 patients • randomized to 3 arms • vincristine, actinomycin-D,cyclophosphamide (VAC), adriamycin
(Regimen I); • VAC alone (Regimen II); • VAC and bilateral pulmonary irradiation (Regimen III).
• All patients received radiation therapy to local site.• Local control was achieved in 96% of the patients in Regimen
I, and 86% of the patients in both Regimens II and III.
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• Local control was same (92%) for tumors treated with whole bone RT vs 5cm free margin around the lesion• Local control was 79% when <5m margin was taken• Bilateral pulmonary irradiation- lowering the incidence of lung
mets from 38 to 28%. • Lung metastases were similarly decreased (10%) when
adriamycin was added to VAC chemotherapy.
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IESS-II: Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II.
• 214 patients • Adriamycin, cyclophosphamide, vincristine, and dactinomycin by either a
high-dose intermittent method (treatment [trt] 1) or a moderate-dose continuous method (trt 2) similar to the four-drug arm of IESS-I• The overall outcome was significantly better on trt 1 than on trt 2• Treatment failure for both treatment groups was the development of
metastatic disease (lung)• High-dose intermittent of VACA and 3 week cycle has better outcome
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INT-0099
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INT-0099• Definitive role of IE was proved in this North American Intergroup trial INT-
0091.• vincristine, doxorubicin, and cyclophosphamide (VDC) or VDC cycles alternating
every 3 weeks with IE cycles. • Duration -49 weeks• Actinomycin-D substituted once patients received that cumulative doxorubicin
dose (>375mg/m2)• 518 eligible patients were randomized, 398 of whom had localized disease • Among patients with localized disease, there was a statistically significant
difference in 5-year event-free survival (54% for VDC versus 69% for VDC/IE arm).• Now VDC/IE as a new North American standard of care for patients with newly
diagnosed localized Ewing sarcoma.
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INT-0099 conclusion
Addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma,
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INT-0154
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INT-0154• Children’s Oncology Group (COG) has sought to intensify the VDC/IE regimen. • INT-0154 was a randomized trial for newly diagnosed localized Ewing sarcoma. • They were randomly assigned to receive standard doses of VDC/IE over 48
weeks or a dose-intensified regimen of VDC/IE over 30 weeks. • All patients received same cumulative doses of chemotherapy • A total of 478 eligible patients were randomized. • 231 patients received the standard regimen; 247 patients intensified regimen. • The 5-year event-free survival (EFS) and overall survival rates for all eligible
patients were 71.1% and 78.6%
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INT-0154 conclusionThere was no statistically significant difference in event-free survival between the standard arm and the experimental arm, demonstrating that higher-dose therapy did not improve outcomes.(p=.54)
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COG protocol: AEWS-0031
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COG protocol: AEWS-0031• This trial sought to intensify therapy not by dose escalation,
but rather by decreasing the interval between chemotherapy cycles (interval compression)• Standard and intensified treatment were to chemotherapy
every 21 and 14 day• A total of 568 eligible patients were randomized. • Patients randomized to the interval-compressed arm had a
significantly greater 5-year event-free survival (73% versus 65% for patients randomized to the standard arm with p=0.048).
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AEWS-0031 conclusion
• Chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.
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EICESS-92
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EICESS-92•Standard-risk patients (localized tumors, volume 100 mL) and high-risk disease (volume 100 mL or metastases )•3-year EFS rates were 73% and 74%, respectively, for VACA and VAIA in SR group•Cyclophosphamide has the same efficacy with increased toxicity•The 3-year EFS rate was not significantly different between the two treatment groups (52% and 47%, respectively, for EVAIA and VAIA) in HR group•However addition of etoposide was associated with a greater survival benefit in the subgroup of patients without metastases (P = .18) than in those with metastases (P = .84)
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EURO-EWING 99
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EURO-EWING 99
•To improve the poor prognosis of patients with primary disseminated multifocal Ewing sarcomas (PDMES) with a dose-intense treatment concept. •six courses of VIDE and one course of VAct-DI, local treatment (surgery and/or RT), and High Dose Therapy/Stem Cell Transplant •After a median follow-up of 3.8 years, the EFS and OS rates at 3 years 27% and 34% •Patient’s age, tumor volume, and extent of metastatic spread were identified as relevant risk factors in multivariate analysis•The outcome of patients with and without HDT/SCT was not performed because of the bias introduced early in the non-transplant group (82% of patients without HDT/SCT died after a median time of 1 year).
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Relapsed or Refractory Disease•About 30% to 40% of patients with ESFT experience recurrence (local and/or distant) and have a very poor prognosis. •Favorable prognostic factors-longer time to first recurrence , Late relapse (2 years or more from the time of original diagnosis), lung-only metastases, •Adverse prognostic factors- early relapse (less than 2 years from the time of original diagnosis) with metastases in lungs and/or other sites, recurrence at local and distant sites, elevated LDH •The probability of 5-year post-relapse survival was 50% and 13%, respectively, for patients with local and distant relapse. •The probability of 5-year post-relapse survival was also significantly higher for patients with late relapse than for those with early relapse
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Relapsed or Refractory Disease•Docetaxel in combination with gemcitabine was found to be well tolerated, resulting in an overall objective response rate of 29% in children and young adults •Topoisomerase I inhibitors (topotecan and irinotecan) in combination with cyclophosphamide and temozolomide •54 patients with relapsed or refractory Ewing’s sarcoma, cyclophosphamide and topotecan induced responses in 44% of patients (35% of patients had complete response and 9% had partial response) •Recurrent or progressive Ewing’s sarcoma, irinotecan and temozolomide resulted in an overall objective response rate of 63%. •Combination therapy with vincristine, irinotecan, and temozolomide also appears to be active and well-tolerated in patients with relapsed or refractory Ewing’s sarcoma, with an overall response rate of 68.1%.
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Duration of Chemotherapy
• Induction Multiagent chemotherapy for at least 12-18 weeks prior to local therapy.• Maintenance (adjuvant chemotherapy) with or without
Radiotherapy is recommended following local control treatment and the duration of chemotherapy should be between 28 and 49 weeks depending on the type of regimen and the dosing schedule (category 1 evidence)
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Recurrent/ Refractory ESFT
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Recurrent/Refractory ESFT
• Patients aged <30 years with ESFT, who failed ≥ third-line therapy were eligible• Enrolled 9 patients• Overall median PFS was 2.2 months (range: 0.5-16.9 months). • All nine patients had grade 4 neutropenia (100%); grade 3 diarrhea or
grade 2/3 neuropathy each occurred in two patients• The Doce+Ireno combination may be effective and tolerable for patients
with heavily pre-treated ESFT.
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Targeted Therapy
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Surgery
• Wide excision should achieve histologically negative surgical margins.• Negative surgical margins optimize local tumor control.• Local tumor control may be achieved by either limb-sparing resection
or limb amputation (individualized for a given patient).• Expendable bone (fibula, rib, clavicle)• Limb-sparing resection is preferred to optimize function if reasonable
functional expectations can be achieved.
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• Definitive Radiation Therapy:• Tumors where Resection is Impossible • For skull, face, vertebra, or pelvic primary• where only an intra-lesional resection is achievable• Patient with poor Surgical risk• Patient refusing surgery
• Note: Surgery is the preferred arm where wide or marginal resection is possible
Indications for RT: After induction chemotherapy
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• Pre-operative Radiation Therapy• Indicated when narrow resection margins are expected• Principle : To sterilize the tumor compartment before surgery & to
potentially reduce the risk of dissemination during surgery• Local recurrence with pre-op RT <5%
EI-CESS-92 : Schuck et al – IJROBP-1998 & 2003
Cont…
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• Post-operative Radiation Therapy
• For gross or microscopic positive margin• For marginal Resection• For wide-resection with Poor Histological response to Neo-adjuvant
Chemotherapy (>10% viable tumor cells in the specimen)
Based on CESS-81, CESS-86, EICESS-92 Studies : Schuck et al,IJROBP-1998 & 2003
Cont…
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Thank you
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Definitive RT
•no randomized trials that have directly compared Radiotherapy to surgery for local control of Ewing’s sarcoma.•Should start by week 12 of VAC/IE chemotherapy or week 18 of VIDE chemotherapy•Treatment volumes and doses:•45 Gy to initial GTV•Cone-down (CD) to cover original bony extent + a total of 55.8 Gy to
postchemotherapy volume (GTV2) •Consider increasing boost dose to a total of 59.4 Gy for chemotherapy
response <50%•Preoperative RT• for marginally resectable tumors and is given concurrently with consolidation Chemo• Treatment volumes and doses: 36–45 Gy for initial GTV + 2 cm
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• 30-40% of patients develop relapse with <20% survival
• Early relapse – less than 2 years:• Consider Changing Chemotherapy
• Late relapse – more than 2 years:• Continue the previously used chemotherapy
Relapse
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Survival
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Postoperative RT
• Should begin within 60 days of surgery and is given concurrently with consolidation chemotherapy• Treatment volumes and doses:•R0 resection: Consider treatment for poor histologic response
even if margins are adequate (45 Gy to GTV2 equivalent volume •R1 resection: 45 Gy GTV2 equivalent volume •R2 resection: 45 Gy to GTV2 equivalent volume followed by CD to
residual disease plus a total of 55.8 Gy to GTV2
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Palliative RT• Hemithorax Irradiation• Should be considered for chest wall primaries with pleural involvement• 15–20 Gy folowed by CD to primary site (final dose based on resection margins)• Treatment of Metastatic Disease• Whole-lung irradiation following completion of chemotherapy/metastasectomy• 15 Gy (1.5 Gy/fx) for patients <14 years• 18 Gy for patients >14 years• Current Children's Oncology Group (COG) study stratiies age below or above 6
years (12 vs. 15 Gy)
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Chemotherapy
• First Line therapy:• VAC/IE • Vincristine 2.0 mg/m2 on D1• Adriamycin 75 mg/m2 on D1• Cyclophosphamide 1.2 gm/m2 on D1• Ifosphamide 1.8 gm/m2 on D1-5• Etoposide 100 mg/m2 on D1-5
• **Substitute adriamycin with dactinomycin (1.2 mg/m2 on D1) after 375 mg/m2
• VAI (Vincristine, Adriamycin, Ifosphamide)• VIDE ( Vincristine, ifosphamide, Doxorubicin, Etoposide)
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Chemo
• Adjuvant chemotherapy following wide excision or amputation is recommended for all patients regardless of surgical margins. The panel strongly recommends that the duration of chemotherapy following wide excision should be between 28 and 49 weeks depending on the type of regimen and the dosing schedule (category 1).200-202 The addition of postoperative RT to chemotherapy is recommended for patients with positive or very close surgical margins {nccn2016)