ADVANCES IN RADIOTHERAPY AND TARGETED AGENTS TO …€¦ · OF EXTREMITY AND BODYWALL. None...

Dian Wang, MD., Ph.D.

Professor of Radiation Oncology

Adjunct Professor of Urology

Rush University Medical Center

ADVANCES IN RADIOTHERAPY

AND TARGETED AGENTS TO

TREAT SOFT TISSUE SARCOMA

OF EXTREMITY AND BODYWALL

None

Conflict of Interest

PRESENTED BY: DIAN WANG, MD., PH.D., RUSH UNIV. MED. CENTER

LEARNING OBJECTIVES

PRESENTED BY: DIAN WANG, MD., PH.D., RUSH UNIVERSITY MEDICAL CENTER

Following this presentation, the participant should have improved knowledge of:

•Advances in Radiation Therapy (RT) technology for the treatment of soft tissue sarcoma (STS)

•Evidence to support adjunctive RT for STS including both pre- and post – operative RT

•Recent combination studies on RT and targeted agents for STS

SOFT TISSUE SARCOMA


Annual incidence: approximately15000

Author Lower Extr Upper Extr H & N Trunk*

Abbas et al 1981 81 42 24 90

Potter el al 1985 152 59 12 84

Torosian et al 1988 208 81 21 182

Lawrence el al 1987 2110 594 406 1440

MDACC 1965-1987 340 136 66 158

TOTAL 2891 (46%) 912 (15%) 529 (8%) 1954 (31%)

*about ½ are retroperitoneal


• Many Types!

• ~25 major categories of

malignant/borderline STS

• ~60 types when all

subcategories are

considered

• ~>300 synonyms for these

60 types!

• Grade is Critical!

• A Major Factor in Staging

• Strongly Correlates with

Metastatic Risk

• Some Histologic Types

Almost Always Low Grade

• Some Histologic Types

Almost Always High Grade

HISTOPATHOLOGY AND GRADE


A group of heterogeneous soft tissue malignancy

that is mainly arising from embryonic

mesodermal origin

SOFT TISSUE SARCOMAS

2018 AJCC STAGING SYSTEM, 8TH ED

• Grade: WD (G1), MD (G2), PD (G3)

• Size: T1≤ 5 cm, T2 > 5 cm, T3 > 10 cm, T4 >15 cm

• Extent: Nodes (N0-1) and Distant mets (M0-1)

• Variables not accounted for: Location, histology

stage

IA T1;N0;M0;G1

IB T2, T3, T4; N0; M0; G1

II T1;N0;M0; G2/3

IIIA T2;N0M0;G2/3

IIIB T3,T4;N0;M0;G2/3


CATES AJCC 8TH ED

N1 or M1

QUESTION 1

When compared to staging soft tissue sarcoma in

the AJCC 7th edition, staging in the AJCC 8th

edition NO LONGER includes the following:

A. T1-4 is based on tumor size

B. T1-4 is based on tumor depth

C. Grade is important

D. N1 or M1 is equally considered for stage IV

PRESENTED BY:

Is N1 Vs M1 Different?

Ashamalla et al 2019

NCDB database 2004-2014: of 82,987, 55,417 met inclusion criteria

PRESENTED BY: DIAN WANG

Conclusion

Ashamalla et al 2019

In adult STS, including those of the trunk and

extremity, OS is superior with N1M0 compared

with N0-1M1 disease. These results suggest

that the AJCC 8th edition grouping of N1 and

M1 patients into stage IV may obscure the

more favorable prognosis of patients with

N1M0 disease.

MANAGEMENT OF LOCALIZED, EXTREMITY STS -

MODALITIES


• Surgery

• Radiation

• Chemotherapy: Role Still Debated

• Neoadjuvant

• Concurrent or interdigitated

• Adjuvant

SURGICAL OPTIONS


amputation

Compartmental

resection

Wide resection

Marginal

resectionIntra-capsular

excision

Generally

Unnecessary

Standard of care in combination

with RT

Usually

Inadequate

SARCOMA RADIOTHERAPY

ACCUMULATED EVIDENCE SUPPORTING

PERIOPERATIVE RT

• Landmark Studies supporting postop RT

• Rosenberg et al., Ann Surg 1982

• Pisters et al., JCO 1996

• Yang et al., JCO, 1998

• Landmark Studies supporting preop RT

• O’Sullivan et al., Lancet 2002

• O’Sullivan et al., Cancer 2013

• Wang et al., JCO 2015

PREOP VS. POSTOP RT


• Preop and postop RT are options for extremity STS

• Preop RT associated with acute wound complications

• IMRT, especially pre-op, significantly reduces late morbidity (joint stiffness, lymphedema, fibrosis et al)

• Smaller RT volume and reduced RT dose

• Might facilitate resection and reduce the risk for tumor seeding during the surgery

• Reserve Resection & postop RT

• Uncertain histology after initial biopsy if info critical for systemic treatment

• Lower extremity STS in pts with co-morbidities, at high risk for wound complications poor healing.

• Very small tumor & expectation that No RT will be required

QUESTION 2

The DRAWBACK for preoperative radiation for

extremity soft tissue sarcoma, when compared to

postoperative radiation, is the following:

A. More LATE toxicities such as fibrosis, joint stiffness,

and lymphedema.

B. Higher radiation dose.

C. Larger radiation target volumes.

D. More ACUTE wound complications.

T1 T2

CONVERSION OF PSEUDOCAPSULE TO REAL CAPSULE AFTER PRE RT


T1 T2T1T2

T2T1

MRI STS, pre-RT (left), post-RT (right)

PREOP RT TARGET VOLUME DEFINITIONS

PRESENTED BY:

TARGET DEFINITIONS FOR PRE-OP RT OF

EXTREMITY STS

• WANG D, Bosch W, Roberge D, et al. IJROBP 81(4), e525-8. 2011.

• RTOG Website Core lab Contouring Atlas

• WANG D, Bosch W, Kirsch D, et al. IJROBP 81(5), e775-780, 2011.

• Bahig H, Roberge D, Bosch W…..Wang D. IJROBP 2013 Jun 1; 86(2):298-303. doi: 10.1016/j.ijrobp.2013.01.032. Epub 2013 Mar 6. PMID:23474110

• Li XA, Chen X, Zhang Q, Kirsch DG, ………Wang D. PRO, 2015

GTV: MRI T1 or CT with contrast (MRI preferred)

CTV: For T2G2-3, GTV plus 1.5 cm radial margin and 3 cm

longitudinal margin, CTV is required to cover suspicious

peritumor edema.

For others, GTV plus 1 cm radial margin and 2 cm

longitudinal margin, CTV is required to cover suspicious

peritumor edema.

PTV: 0.5 cm with daily IGRT vs. 1.5 cm without daily IGRT

QUESTION 3 In RTOG 0630 (phase II image guided radiotherapy of

extremity soft tissue sarcoma), the recommended

definitions for GTV, CTV and PTV for large high-grade

tumor includes the following:

A. The GTV is defined as the gross tumor volume noted on

physical exam.

B. The CTV is an expansion of the GTV using the following

dimensions: 1.5 cm radial and 3 cm superior and inferior.

C. The CTV is and expansion of the GTV using the

following dimensions: 2 cm radial and 4 cm superior and

inferior.

D. The PTV is 10 mm expansion of the CTV when daily

pretreatment IGRT is used.

TARGET DEFINITIONS:

REPRESENTATIVE GTV, CTV, PTV


Wang D et al., ASCO Expert

Education Book 2014

GTV→←CTV

Wang et al. RTOG Website Core lab Contouring Atlas for soft tissue sarcoma

TARGET DEFINITIONS FOR POST-OP RT OF

EXTREMITY STS

• Haas RLM, DeLaney TF, O'Sullivan B, Keus RB, LePechoux C, Poulsen JP, Seddon B,

Fairchild A, Wang D. Radiotherapy in the management of extremity soft tissue sarcomas:

Why, when, and where? IJROBP 2012, 84(3): 572-80 . PMID:22520481.

• UK 2006: Randomized trial of Volume of post-operative

radiotherapy given to adult patients with eXtremity soft tissue

sarcoma (VORTEX)

PRIMARY ENDPOINT: LIMB FUNCTIONALITY AND LOCAL

RECURRENCE

STS

Conventional two-phase RT 66 Gy/33 fx

(Control arm, 200 pts)

Single phase to only phase-2 volume of

control arm 66 Gy/33 fx (tailored field, 200pts) resection

COMBINATION OF NEW AGENTS AND

MODERN RT TO TREAT STS

FUTURE PRIORITY


STRATEGIC VISION OF NCI-NRG ONCOLOGY

SARCOMA WORKING GROUP

Wong P….Wang D. JNCI 2014

COG-NRG PAZOPANIB SOFT TISSUE SARCOMA

TRIAL


• Pazopanib: Inhibitor of

VEGF receptors 1-3,

PDGF alpha and beta,

and cKIT

ARST1321: Pazopanib Neoadjuvant Trial In Non-

Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A

Phase II/III Randomized Trial of Preoperative

Chemoradiation or Preoperative Radiation +/- Pazopanib

PALETTE: PHASE IIIR MET STS

PRESENTED BY:

Van Der Graaf WT, Lancet 2012


FIRST EVER COLLABORATIVE STUDY CO-

DEVELOPED, WRITTEN AND CONDUCTED BY BOTH A

PEDIATRIC AND ADULT CANCER COOPERATIVE

GROUP

30Aaron Weiss

PURPOSE

• To improve treatment for intermediate and high

risk NRSTS by adding pazopanib to standard

therapy

• Highest risk patients with chemosensitive histologies: preop chemo RT

+/- pazopanib

• Intermediate to high risk patients not receiving chemotherapy: preop RT

+/- pazopanib

• A unique opportunity to advance treatment of

pediatric and adult NRSTS and collect large

specimens for biomarker/gene profiling

SCHEMA


Chemotherapy cohort

“chemosensitive” STS

Non-chemotherapy cohort

“Non chemosensitive” STS

PRIMARY OBJECTIVES

• Determine feasibility of pazopanib + radiation or chemoradiation

(phase II)

• Compare rates of complete pathologic response in patients

receiving radiation or chemoradiation ± pazopanib (phase II)

3

3Aaron Weiss

PREOPERATIVE CHEMORADIATION +/-

PAZOPANIB IN NON-RHABDOMYOSARCOMA

SOFT TISSUE SARCOMA (NRSTS): A

REPORT FROM CHILDREN'S ONCOLOGY

GROUP (COG) AND NRG ONCOLOGY

Aaron R. Weiss1, Yen-Lin Chen1, Thomas Scharschmidt1, Yueh-Yun Chi, Jennifer O. Black, Julie

Fanburg-Smith, Eduardo Zambrano, Edwin Choy, Jessica L. Davis, Mark Kayton, Lynn Million, Scott

H. Okuno, Andrew Ostrenga, R. Lor Randall, Joel Sorger, Jing Tian, Stephanie A. Terezakis, Douglas

S. Hawkins2, Sheri L. Spunt2, Dian Wang2

Oral presentation iat 2019 ASCO

1Study Co-Chairs 2Study Co-Senior Leadership

Pathologic Response at Week 13 Regimen A (n=42) Regimen B (n=39) p-value

≥ 90% 14 (58.3%) 4 (22.2%) 0.021

< 90% 10 (41.7%) 14 (77.8%)

1Chi-square test

DISEASE RESPONSE

Aaron WeissCorrelation of Pathologic Necrosis with Survival Outcome: pending

Regimen A: Preop ChemoRT + Pazopanib

Regimen B: Preop ChemoRT

WANG ET AL. ASCO 2017

Key Scientific Findings

pCR is associated with improved

survival outcomes in STS pts treated

with either neoadjuvant RT or CT-RT

from long-term update of these two

multicenter prospective studies

Local failure rate was 0% in pts with

pCR vs. 5-year 11.7% and 9.1% for

pts with <pCR in 9514 and 0630,

respectively.

Leiomyosarcoma, myxoid/round cell

liposarcoma, and myxofibrosarcoma

are associated with better OS while

liposarcoma/myxofibrosarcoma are

associated with better DFS

A PHASE IB TRIAL OF NEOADJUVANT AMG-232

CONCURRENT WITH PREOPERATIVE RADIOTHERAPY IN

WILD-TYPE P53 SOFT TISSUE SARCOMA

Meng Welliver MD, Ph.D., Peter Houghton Ph.D., David Kirsch MD, Ph.D., Gary Schwartz, MD, Raphael Pollock MD, Ph.D., John Kane, MD, Steve Jiang, Ph.D., Brian Van Tine MD, Ph.D, Jeffrey

Sklar, MD, Ph.D, Michelle Rudek, Pharm.D., Ph.D., Paul Wakely, MD, Qiang Zhang, Ph.D., Dian Wang, MD, Ph.D.

NCI-NRG Study Protocol (PTMA AWARD)

Trino S et al. Front. Pharmacol., 2016

P53-MDM2 Pathway

MDM2 inhibitors

( Nutlin-3A, AMG232,

RG7388)

PRECLINICAL DATA: MDM2 INHIBITORS POTENTIATE RT IN (A) P53

WT RH18 EMBRYONAL RHABDOMYOSARCOMA XENOGRAFTS

PHELPS, D. ET AL PEDIATR BLOOD CANCER 2015

PI: MENG WELLIVER AND CO-PI DIAN WANG, NRG DT 001

HYPOTHESIS AND OBJECTIVES:

• Biologic Hypothesis: AMG-232 and radiotherapy will have additive or synergistic anti-tumor

activity in p53 WT STS.

• Clinical Hypothesis: Preoperative AMG-232 +radiotherapy is safe/well tolerated and shows

preliminary efficacy in STS.

• Primary objectives:

• To evaluate the safety and tolerability of AMG-232 in combination with standard-dose

radiotherapy in STS in two separate cohorts;

• To determine the MTD/RP2D of AMG-232 in combination with radiotherapy.

• DLT includes all grade 3-5 toxicities up to 4 weeks after AMG-232+RT treatment.

• Secondary Objectives:

• To determine % necrosis and pCR in final surgical resection specimen;• To determine % LC, PFS and OS at 2 years;• To determine PD effects of AMG-232 when combined with radiotherapy by

assessing serial serum Macrophage Inhibitory Cytokine (MIC)-1 levels; • To correlate AMG-232 exposure-response relationships (PD, toxicity, and

efficacy).

SARC83

PRESENTED BY:

CONCLUSIONS


• Perioperative RT is required for many soft tissue sarcoma of extremity

• Both preop RT and postop RT are equivalent in clinical outcomes

• Preop RT, esp. IG-IMRT late toxicities, but acute wound complications mainly in low extremity

• Co-administration of angiogenesis inhibitor Pazopanib enhances pCR rate in patients with high grade STS treated with neoadjuvant chemoRT

• Correlation of pCR with survival outcomes: pending

• Future priority on RT for STS: Identification of new targeted agents in combination with modern RT

• Participation in the clinical studies such as NRG DT 001b STS trial is highly recommended.

ACKNOWLEDGEMENTS


• NRG/RTOG

• NRG/RTOG Sarcoma Working Group

• RUMC Sarcoma Program

PRESENTED BY:

Thank you!


RETROPERITONEAL SARCOMA: EVOLVING ROLE OF RADIATION?

Krisha Howell, MD

Fox Chase Cancer Center

Philadelphia, PA

ACRO 28h 2020

CONFLICTS OF INTEREST

• Employment – Spouse: Medtronic

• Stock: Medtronic

• Introduction – Soft Tissue Sarcoma• Introduction – Retroperitoneal Sarcoma

• Staging• Histology• Pathology• Question #1

• Treatment Support• Radiation • Question #2• Chemotherapy

• Radiation Guidance• Current Interests/Advancements

OVERVIEW

POLL – QUESTION #1

• How many retroperitoneal sarcomas do you see in consultation for radiation therapy in a year?

• 1. > 25 a year

• 2. 10 - 25 a year

• 3. 5 - 10 a year

• 4. 1 - 5 a year

• 5. never

INTRO – SOFT TISSUE SARCOMAS

• Soft-tissue tumors are mesenchymal neoplasms that can arise anywhere in the body

• Retroperitoneal sarcomas occur deep in the abdomen and pelvis, behind the peritoneum

Gray’s Anatomy, Plate 1126

D.S. Strayer Rubin’s Pathology Ch 30, 2020

INTRODUCTION – RETROPERITONEAL SARCOMA

• Retroperitoneal sarcomas (RPS) have a risk of local recurrences (LR).

• Extrapolating from extremity data, RT is employed to limit LR.

HD Suit et al. Cancer. 1975;35(5):1478RD Lindberg. Cancer. 1981;47(10):2391.

T Category T Criteria

TX Cannot be assessed

T0 No evidence of primary tumor

T1 Tumor <5cm in greatest dimension

T2 Tumor > 5cm - <10cm

T3 Tumor >10cm - <15cm

T4 Tumor >15cm

Nodal Disease:N0 vs N1

Metastatic Disease:M0 vs M1

Primary Tumor:

Grade Grade Definition

GX Cannot be assessed

G1 Total differentiation, mitotic count & necrosis score of 2 or 3

G2 Total differentiation, mitotic count & necrosis score of 4 or 5

G3 Total differentiation, mitotic count & necrosis score of 6, 7, or 8

Group Staging dependent on both T, N, M and GradeAJCC manual 8th ed. Retroperitoneal sarcoma

0

100

200

300

400

500

600

700

FibrosarcomaLeiomyosarcomaLiposarcomaMPNSTUPSMyxofibrosarcomaSynovial SarcomaGIST

Brennan at al. 2013

PATHOLOGY – RETROPERITONEAL SARCOMA

• Common histologies:• Liposarcoma: All types may show lipoblasts

• Well-differentiated liposarcoma (WD)/Atypical lipomatous tumor (ALT)

• Dedifferentiated liposarcoma

• Pleomorphic liposarcoma

• Myxoid- (inclusive of round-cell) liposarcoma

• Leiomyosarcoma• Undifferentiated Pleomorphic Sarcoma (UPS)/Undifferentiated or

Unclassified SarcomasDS Strayer. Rubin’s Pathology Ch 30, 2020CDM Fletcher. WHO Classification, 2013

Well-differentiated liposarcoma (WD):A locally aggressive neoplasm composed of mature adipocytic proliferation with variation in cell size and at least focal nuclear atypia in adipocytes and stromal cells.

100x 400x

Lipoma-like appearance

Fibrous bands with atypical hyperchromatic cells

Source: Dr. Jian Fu, FCCC

Dedifferentiated liposarcoma: WD liposarcoma showing progression, either in the primary or in a recurrence, to (usually non-lipogenic) sarcoma of variable histological grade. In most cases there is substantial amplification of MDM2. A well-differentiated component may not be identifiable. Rarely, the high-grade component may be lipogenic.

100x 400x


Leiomyosarcoma: Malignant neoplasm showing pure smooth-muscle differentiation. Common location is the retroperitoneum. May arise in large blood vessels, most commonly the inferior vena cava.


Leiomyosarcoma 400x- intersecting

fascicles of spindle cells

- Tumor necrosis- Increased mitotic

activity

RETROPERITONEAL SARCOMA

• Well-differentiated liposarcoma and G1- G2 de-differentiated liposarcoma, the 2 most common histological subtypes originating at this site, predominantly fail locally

• High grade dedifferentiated liposarcoma and leiomyosarcoma are characterized by a high metastatic risk, which portends a dismal prognosis, with a risk of death of > 70% at 5 yrs

MCB Tan. Ann Surg 2016; 263: 593A Gronchi. Ann Surg 2016; 263: 1002

RECAP:

A dedifferentiated liposarcoma (DDLPS):Has the histological hallmark of a transition from ALT/well-differentiated liposarcoma to non-lipogenic sarcoma, which, in most cases, is of high grade. In addition, DDLPS most often has ring or giant marker chromosomes wherein MDM2 is consistently amplified and over-expressed.

TREATMENT

Source: Dr. Jeffrey Farma, FCCC

TREATMENT - RADIATION

• Preop RT for RPS is well tolerated

KS Mak. PRO 2016 Sept-Oct 6(5):360

STRASS I

STRASS I - STUDY DESIGN

266 patients accrued

During or after surgery

STRASS I –PRIMARY ENDPOINT:ABDOMINAL RECURRENCE FREE SURVIVAL

(ARFS)

STRASS 1 – PRIMARY ENDPOINTARFS

Median f/u 43 mos

STRASS I –PRIMARY ENDPOINT:ABDOMINAL RECURRENCE FREE SURVIVAL

(ARFS)

STRASS I – ARFS: IDMC SENSITIVITY ANALYSIS

Median f/u 43 mos

Local progression on RT NOT regarded as a primary endpoint event for the patients who subsequently achieve a complete

surgical resection

STRASS I – IDMC SENSITIVITY ANALYSIS: LIPOSARCOMA SUBGROUP

Median f/u 43 mos

RECAP:

With a median follow up of 43 months, the primary endpoint tested in STRASS I:

Was not significant for the primary endpoint, abdominal recurrence free survival (ARFS), although on further subgroup sensitivity analysis, ARFS was significantly better after preoperative RT in the liposarcoma subgroup.

POLL – QUESTION #2

• Do you routinely consider chemotherapy for retroperitoneal sarcomas?

• 1. yes

• 2. no

• 3. I don’t know

CHEMOTHERAPY SENSITIVITIES

VERY SENSITIVERhabdomyosarcoma

Synovial sarcomaAngiosarcoma

Myxoid liposarcoma

LOW SENSITIVITYExtra skeletal myxoid chondrosarcoma

FibrosarcomaEpithelioid sarcoma

Malignant peripheral nerve sheath tumorHemangiopericytoma/solitary fibrous

tumor

AVERAGE SENSITIVITYLeiomyosarcoma

High grade undifferentiated sarcomaDediff/pleomorphic liposarcomaDesmoplastic round cell tumor

RESISTANTGIST

Alveolar soft part sarcomaClear cell sarcoma

TREATMENT - CHEMOTHERAPY?

STRASS 2: RANDOMIZED PHASE III STUDY OF NEOADJUVANT CHEMO FOLLOWED BY SURGERY

VS SURGERY ALONE FOR HIGH RISK RETROPERITONEAL SARCOMA

• Systemic chemo has the potential to address the metastatic risk and improve relapse free survival and overall survival

• The neoadjuvant setting is preferable as it allows assessment of drugefficacy, immediately address the systemic risk, and study tumor biology

STRASS 1 & STRASS 2 SUMMARY

• "STRASS [1] included all "adult-type" primary RPS, without distinguishing those with a high loco-regional risk from those with a more pronounced systemic risk. This is the main reason why the study failed to show a benefit of neoadjuvant radiation in the whole RPS family" - STRASS 2

CONTOURING AND TREATMENT RECOMMENDATIONS

ADVANCES IN RADIATION OF RETROPERITONEAL SARCOMAS

ADVANCES IN RADIATION OF RETROPERITONEAL SARCOMAS

• Trial NCT01659203/Mass Gen’l Hospital: Phase I/II Trial of Pre-Operative Image Guided Intensity Modulated Proton Radiation Therapy (IMPT) or Photon (IMRT) With Simultaneously Integrated Boost to the High Risk Margin for Retroperitoneal Sarcomas

• Boosting the region of proposed positive/close surgical margins.

https://clinicaltrials.gov/show/NCT01659203

THANK YOU

• Fox Chase Cancer Center Sarcoma Group:

• Dr. Margaret von Mehren

• Dr. Jeffrey Farma

• Dr. Jian Fu

• Dr. Sanjay Reddy

• Dr. Stephanie Greco

• Dr. John Abraham

ADDITIONAL REFERENCES:

• Question #1:AJCC manual 8th ed.• Question #2:

• 1. A. Paolo Dei Tos. Bone and Soft Tissue Pathology: Ch 4 – Adipocytic Tumors, Elsevier 2010, pgs 97-118.

• 2. J.D.R. Reimann and C.D.M. Fletcher. The Molecular Basis of Cancer (4th Ed.): Ch 44 - Soft Tissue Sarcomas, Elsevier 2015, pg 609 – 620.

• 3. D.M. Fletcher, K. Krishnan Unni, F. Mertens. WHO Classification: Tumours of Soft Tissue and Bone. IARC Press: Lyon 2013

• Question #3: Source: ASCO slides – STRASS 1

QUESTIONS FOR CME CREDIT:

Which statement is true in regards to staging (per AJCC Manual v.

8th ed, 2017) of retroperitoneal sarcomas:

1. The current AJCC staging manual generalizes all sarcomas sites into 1 staging system.

2. Retroperitoneal staging does NOT include grade in the group staging.

3. The manual lumps abdominal and thoracic visceral organ sarcomas with that of

retroperitoneal sarcomas.

4. The staging system breaks up the T-stage of the sarcoma based upon size of greatest

dimension (every 5cm increments from </= 5cm for T1 up to >15cm for T4). *

Harvard Medical School

RADIATION THERAPY FORSOFT TISSUE SARCOMAS

Thomas F. DeLaney, M.D. Chief, Sarcoma Service, Department of Radiation OncologyAssociate Medical Director, Francis H. Burr Proton Therapy CenterMassachusetts General HospitalAndres Soriano Professor of Radiation OncologyHarvard Medical School


DISCLOSURES

Author/editor: Elsevier (honorarium); UpToDate (honoraria), Inc; Wolters, Kluwer Health, Inc., (royalties)

Educational Conference Speaker: AO Spine (honorarium)

Educational Video Speaker: Oakstone Medical Publishing (honoraria)

Consulting: RBC Consulting(honorarium); Gerson Lehman (honoraria)

Medical Advisory Board: Chordoma Foundation (no remuneration)


TAKE AWAY LESSONS: EXTREMITY STS

• Pre-Op RT preferred for upper extremity lesions• Postop RT preferred for myxofibrosarcomas• Lower extremity

• Balance higher rate of acute wound healing complications vs lower risk of late effects with preop RT

• Preop RT target volumes per RTOG 0630 guidelines• GTV defined on the T1, post-gado images• If G2, 3, T >8 cm: CTV 1.5 cm radial, 3 cm prox/distal to GTV +

edema• Others: CTV 1 cm radial, 2 cm prox/distal to GTV + edema• PTV expansion 0.5 cm if using image guidance


TAKE AWAY LESSONS: EXTREMITY STS

• Preop RT target volumes• Subcutaneous tissue overlying tumor deep to the

fascia is not target• Princess Margaret reduced acute wound healing

complications when they were able to spare flap of tissue overlying the target (Griffin et al, IJROBP 2007)

• Adjuvant systemic therapy for high risk patients• Between a fielder’s choice and a single

• New agents being tested included pazopanib, AMG-232 (MDM2 inhibitor, pembrolizumab (immune checkpoint inhibitor)


Toronto Preop/Postop 50 Gy Study


HISTOLOGY-DRIVEN RADIATION TREATMENT

• DOREMY Study: DOSE REDUCTION OP PREOPERATIVE RADIOTHERAPY IN MYXOID LIPOSARCOMAS

• Phase II Study• Reduction of preoperative radiotherapy from 50 Gy/25 fractions

(standard) to 36 Gy/18 fractions.• Primary endpoint: pathologic response• Target accrual : 80 patients


Prospective Hypofractionated Pre-op Radiotherapy for Extremity/Truck STS

• 272 pts Warsaw, Poland (1/2006-6/2011)• 5 Gy x 5 fx preop->Surgery 3-7 days after RT• Neoadjuvant chemoRx in high risk pts (61 – 22.4%)• LC 81%: worse size > 10 cm, G3, R1• ChemoRx no significant impact on OS• 114 patients (42%) had Rx toxicity, most with

tumors located on lower limbs. 7% (21) of pts required surgery for Rx of complications

Kosella-Paterczyk et al., Eur J Surg Oncol. 2014 Dec;40(12):1641-7


IMRT vs. Brachytherapy• MSKCC - Retrospective• 134 pts with soft tissue sarcoma

– 71 pts postop brachy (45 Gy) (1995-2003)

– 63 pts IMRT pre or postop (50-63Gy) (2002-2006)

• More IMRT pts had <1 mm margins, large tumors (>10 cm), and bone or nerve stripping/resection

• 5 yr Local control: 92% (IMRT) vs. 81% (brachy), p=0.04

• Multivariate: IMRT retained significance as independent predictor of improved LC

Alektiar et al, Cancer, 2011


Pooled multicenter analysis: 259 patientsR0: 71% R1: 29% 5 year LC: 86%

Limb preservation and good functional outcome were achieved in 95% and 81% of patients.


Stereotactic Body Radiotherapy for Lung Metastases from Sarcomas

• 52 pts: SBRT 50 Gy in 5 fractions• Local control 82% at 3 years• Median overall survival

– 2.1 years (0.8 to 15 years) SBRT versus 0.5 for no SBRT

– Consider for pts who are not surgical candidates, have had prior surgery, or decline surgery

• ---Dhakal et al, IJROBP 2011


RETROPERITONEAL SARCOMA• Only proven treatment modality for RPS is surgery

– Local control only ~50% at 5 years with surgery•Hard to achieve (-) margins: Tumor size and adjacent organs• Compartmental resection may reduce LR to 30-40% (Bonvalot 2009)

• Local recurrence more common with liposarcoma• If RT to be used, should be done pre-op• STRASS I study suggests potential benefit for preop RT

for patients with liposarcoma– STRASS II study to assess role of chemoRx for high grade

dediff liposarcoma and leiomyosarcoma


If RT is to be used, preoperative RT is preferred

MSKCC: No Impact of (+) Margins on RPS LR• 2084 pts who underwent sarcoma resection at MSKCC

– (+) margins: RPS: 45% Head/Neck: 30% Extremity 19%– Risk for local recurrence: RPS: HR=3.1 (highest risk), P<.001– For the majority of sarcoma anatomic sites and histologies, (+) margins

were a significant risk factor for local recurrence (LR)

• 229 pts with retroperitoneal sarcomas• No significant difference in risk of LR with (+) margins

– Relative risk of LR only 1.2 with (+) vs (-)…p> 0.05 (NS)• This suggests that although margins were nominally (-) in 55% of

patients, many may have had undetected (+) margins.Stojadinovic A et al, Ann Surg 2002:235;424-34

Local Control, STS, all sites, (+) margins, by RT Dose

86% at 5 years

66% at 5 years


RPS Dose-escalated, Dose-Painted Pre-op RT

Patients with retroperitoneal

sarcoma

IMRT/IMPT 50.4 Gy/ 28 fx to Lower

Risk CTV1

SIB 60.2/61.6/63 Gy/ 28 fx to high risk CTV2

margins

Resection 4-8 weeks after IMRT/IMPT

Phase I/II Preop Intensity Modulated Photons (IMRT)

Phase I/II Preop Intensity Modulated Protons (IMPT)

for Retroperitoneal Sarcoma:

Neoadjuvant chemoRxallowed

Phase I IMPT Cohort66 y.o. female with grade 2/3 dedifferentiated liposarcoma; NED 58 months after start of intensity modulated proton RT

CTV1 50.4 GyRBE,CTV2 63 GyRBE/28 fx

ADVANCES IN RADIOTHERAPY AND TARGETED AGENTS TO …€¦ · OF EXTREMITY AND BODYWALL. None...

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