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Radiation Therapy As A Component of Multidisciplinary Sarcoma Management PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Radiation Therapy As A Component of Multidisciplinary Sarcoma Management" by Matt Spraker, MD, PhD.

This medical PowerPoint presentation tells us how radiation therapy is an important component of multidisciplinary sarcoma management. Sarcoma is a type of cancer that arises from the connective tissues of the body, such as bone, muscle, and cartilage. Radiation therapy is the use of high-energy radiation to kill cancer cells or shrink tumors.

In the case of sarcoma, radiation therapy is used in several ways. It may be used before surgery to shrink the tumor and make it easier to remove, or after surgery to kill any remaining cancer cells. In some cases, radiation therapy may be used alone as a primary treatment for sarcoma.

Radiation therapy can be delivered in several ways, including external beam radiation therapy, brachytherapy, and proton therapy. External beam radiation therapy is the most common type of radiation therapy for sarcoma. It involves directing high-energy radiation from a machine outside the body to the tumor and surrounding tissue. Brachytherapy involves placing radioactive sources inside the body, close to the tumor, to deliver radiation directly to the cancer cells. Proton therapy is a type of external beam radiation therapy that uses high-energy proton beams to treat the cancer.

Radiation therapy can have side effects, such as skin irritation, fatigue, and nausea. However, these side effects can often be managed with medications and supportive care. The benefits of radiation therapy in treating sarcoma can outweigh the risks of side effects, especially when used as part of a multidisciplinary treatment plan.

In summary, radiation therapy is an important component of multidisciplinary sarcoma management. It can be used before or after surgery, or as a primary treatment for sarcoma. Different types of radiation therapy can be used, and side effects can be managed with appropriate care. Working with a team of specialists, including radiation oncologists, medical oncologists, and surgeons, can provide the best outcomes for patients with sarcoma.

Tags : Radiation Therapy, Multidisciplinary Sarcoma Management, Sarcoma, cancer, Orthopaedic Surgery, Orthopaedic Surgery PowerPoint presentation

Published on : Jun 23, 2023 | Views : 830 | Downloads : 3

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Slide 1-

Instructions for Use of These Slides The purpose of these slides is to serve as a resource that any radiation oncologist can use when speaking about the role of radiation therapy in treating sarcoma The target audience is residents/fellows in the fields of surgery, medical oncology, pathology and radiology However, any user is welcome to format the slides as needed to fit your target audience Please ask attendees to complete either the pre-test or post-test so that we can assess the effectiveness of the slides. If you make significant changes to the content of the slides for your presentation, we prefer that you use the pre-test only. Pre-test link: https://redcap.link/sarcoma_pre1 Post-test link: https://redcap.link/sarcoma_post1 Primary Author: Matt Spraker, MD, PhD (@SprakerMDPhD) Peer Reviewers: Sabin B. Motwani, MD, Arash Naghavi, MD, MS, Stephen Rosenberg, MD Additional Support: The ASTRO Communications Committee and ARRO Communications Subcommittee Last updated in September 2020 – newer data may impact the accuracy of the content of these slides
Slide 2-

Radiation Therapy As A Component of Multidisciplinary Sarcoma Management
Slide 3-

Learning Objectives Understand the presentation and initial work up of sarcomas Understand how radiotherapy is used in the treatment of sarcomas Explore the current open trials evaluating radiotherapy in sarcomas
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Preamble to “Sarcoma” Sarcomas are a rare group of cancers, 13,000+ estimated new cases in 2020 Sarcomas are highly heterogeneous More than 100 subtypes Indolent (ex. Desmoid) to aggressive (ex. Angiosarcoma) behavior Many locations: 59% - extremity, 18% torso/chest wall, 17% retroperitoneum, 9% head and neck Sarcoma is hard to diagnose, benign soft tissue masses are 100x more common
Slide 5-

Outline to Slides Diagnosing and Staging Sarcoma Extremity Sarcoma Retroperitoneal Sarcoma Desmoid Tumors Palliative Radiation and SBRT Current Cooperative Group Trials for Sarcoma NOT covered: Ewing’s sarcoma, rhabdomyosarcoma and many rare types
Slide 6-

Diagnosing and staging sarcoma
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Features of a “Bump” That is a Sarcoma 526 patients who presented to a “lumps and bumps” clinic (UK) Prognostic features for a malignant lesion: Size > 5 cm (< 5cm best indicator of benign “bump”) Report of increasing size (increasing size best indicator of “malignancy”) Pain Deep location Johnson et al., Am R Coll Surg Engl, 2001
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Imaging Workup of STS MRI of primary tumor required for extremity/superficial trunk T1-weighted with and without contrast and T2-weighted sequences CT of the chest without contrast CT of the chest, abdomen, and pelvis with contrast for retroperitoneal sarcoma Many institutions utilize PET/CT for staging Eary et al., CCR, 1998, 2000
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PET Signal and Grade Tumor FDG metabolic rate and SUV associated with grade in STS and bone sarcoma PET/CT used to target a biopsy of suspected high-grade components of heterogeneous STS (ex. Dedifferentiated liposarcoma) Eary et al., CCR, 1998, 2000
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Workup and Diagnosis Biopsy is required before any therapy International Guidelines recommend multidisciplinary evaluation prior to any therapy Due to rarity, misdiagnosis and unplanned procedures are common! Gundle et al., JCO, 2018
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Biopsy and Pathology Incisional biopsy is the historical standard, but CT-guided core needle biopsy is now commonly used 97% sensitive for malignancy (vs benign) and 86% accurate for grade FNA is not sufficient for histotype diagnosis, but may be useful in diagnosing recurrence Expert pathologist review IS REQUIRED as histotyping is increasingly driving therapeutic decision making Strongly consider sending slides for review at a high-volume center Strauss et al., J Surg Onc, 2010
Slide 12-

AJCC 8th Edition Staging T-staging N-staging | N0 vs N1 Mstaging | M0 vs M1 Note: Staging also includes FNCLCC grade (1-3) Differentiation Mitotic Count Necrosis
Slide 13-

Need to discuss with a radiation oncologist? Not routinely Always Yes, probably Extremity
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Extremity and Superficial Trunk Sarcomas Why are extremity and superficial trunk or “chest wall” grouped? Similar prognostic factors and outcomes in numerous case series Grouped by AJCC and NCCN Extremity/Chest Wall Treatment Pathways Low-grade – managed with surgery alone in most cases (not further discussed) Small (<5 cm), high-grade Large, high-grade (high-risk) Unresectable
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Evolution of Radiotherapy Use in STS Limb-sparing surgery + Radiation offers similar outcomes to amputation
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N=43; median follow up 4 years, 8 mos No difference in QoL 5 year DFS: 78% (amp) vs 71% (sx-rt), p=0.75 5 year OS: 88% (amp) vs 83% (sx-rt), p=0.99 Trend toward worse LR: 0 (amp) vs 3 (sx-rt), p=0.06 2/3 LR recurrences also had DM P=0.75 Rosenberg et al., Ann Surg, 1982
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Evolution of Radiotherapy Use in STS Limb-sparing surgery + Radiation offers similar outcomes to amputation Limb-sparing surgery + Radiation offers better outcomes than limb-sparing surgery alone Rosenberg et al., Ann Surg., 1992 | 5 yr local control: 71% vs 78% Yang et al., JCO, 1998 | 10 yr local control: 100% vs 81%
Slide 18-

”…although post-op RT is highly effective at preventing LRs, selected patients with extremity STS may not require adjuvant XRT after LSS” Randomized study of limb-sparing surgery with or without radiation High-grade sarcomas (N=91) | RT + Chemo versus Chemo alone Low-grade sarcomas (N=50) | RT versus observation Median follow up of 9.6 years Improved local control with RT versus no RT (both p<0.05) No difference in distant metastasis or overall survival (75%) Worse QoL noted with RT (ROM, stiffness, edema)
Slide 19-

Poor QoL After Radiotherapy? Although field sizes cannot be quoted for different tumors, the field, in our opinion, should allow at least a 10 cm margin both proximally and distally to the tumor mass for the initial field, even for low grade tumors Tepper et al., IJROBP, 1981 Fields in then Fields now
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Modern Radiotherapy Fields are Smaller Pre-operative radiotherapy, smaller fields are safe Local recurrence rates only 7-11% Late grade 2+ toxicity rates only 10-14% Persistent wound healing toxicity rates of 30-37% in the pre-operative setting
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Prognostic Factors for Recurrence Large retrospective studies define independent risk factors for local recurrence, PFS and OS Prognostic factors for LR (MSKCC nomogram) Age >50 years (RR 1.6) Presenting with LR (RR 2.0) Positive margins (RR 1.8) Fibrosarcoma histology (RR 2.5) MPNST (RR 1.8) Cahlon et al., Ann Surg, 2012
Slide 22-

Prognostic Factors for OS Multicenter effort to create two, externally validated nomograms for OS and DMFS Created the Sarculator App Now includes externally validated dynamic nomogram to predict survival for patients in surveillance up to 3 years Callegaro et al., eClin Med, 2019 Callegaro et al., Lancet Oncol, 2017
Slide 23-

Small, High-grade Sarcomas For stage II (T1G2-3) tumors, surgery + radiation is generally recommended Select patients may receive surgery alone based on prospective data De novo T1 G2-3 STS resected with a minimum 1 cm margin** 5 year and 10 year local recurrence rates of 7.9% and 10.6% Note 10-year local recurrence rate for high grade STS is 16.7% If positive margin present, re-resection is required if feasible with low morbidity Pisters et al., Ann Surg, 2007
Slide 24-

Resectable, High-risk (T2-4 G2-3) Sarcomas Treated with surgery with pre- or post-operative radiotherapy Compared in NCIC SR2 Randomized Trial Pre-op 50 Gy in 25 fractions (N=94) versus Post-op 60-66 Gy in 30-33 fractions (N=96) Powered to detect a decrease in wound complication rate for pre-operative radiotherapy from 30%, stopped early for higher rate No difference in local/regional recurrence, PFS or OS Symptom profile differed considerably O’Sullivan et al., Lancet, 2002
Slide 25-

Pre- vs Post-operative EBRT Pre-operative radiotherapy had a higher wound complication rate Overall rate pre vs post: 35% vs 17% Location dependent Upper extremity pre vs post: 6% vs 0% Lower extremity pre vs post: 35% vs 25% Bias toward secondary closure with pre-op (did not affect complications) Post-operative radiotherapy had a higher radiation toxicity rate Grade 2+ radiation dermatitis pre vs post: 36% vs 68% Higher grade 2+ late toxicity rate, which is associated with worse QoL O’Sullivan et al., Lancet, 2002 Davis et al., JCO, 2002 Davis et al., Radiother and Oncol, 2005
Slide 26-

IMRT vs 3-D CRT Retrospective data shows improved toxicity and LC with IMRT versus 3-D CRT 5yr LC: 94% vs 85%, p=0.05 Radiation dermatitis(Grade 2+) : 32% vs 49%, p=0.002 Edema: 8% vs 15%, p=0.05 IMRT supported by single arm phase II study from Toronto 30% wound complication rate versus 43% historical control (NS) Lower rates of re-operation Low rates of flap closure 4 year local failure rate = 7% O’Sullivan et al., Cancer, 2013 Folkert et al., JCO, 2014
Slide 27-

Daily Imaging is the Standard of Care RTOG 0630 was a single arm study of pre-op radiotherapy with small fields 1.5 cm radial, 2-3 cm proximal/distal, most using 0.5 cm PTV Estimated that a 1.5 cm PTV would be needed without daily imaging Li et al., PRO, 2016
Slide 28-

Hypofractionation for Extremity/Superficial Trunk Sarcoma Numerous hypofractionation strategies have been employed, recent studies include: UCLA 6 Gy x5 | Kalbasi et al., Clin Can Res, 2019 Polish 5 Gy x5| Kosela-Patercyzk et la., EJSO, 2014 OHSU 3.5 Gy x8 (high-risk with ifosfamide) | Lu et al., Ann Surg Onc, 2018 Surgery within 1 week of completion of RT Wound comp rate = 32%, Late tox rate = 15% Local recurrence = 19% Polish prospective trial of 5 Gy x5 using 3-D CRT First prospective study For an excellent review of hypofractionation see Haas et al. Radioth and Oncol, 2016
Slide 29-

Brachytherapy Brachytherapy includes low-dose rate (LDR), pulsed dose rate (PDR), high-dose-rate (HDR), and intra-operative radiotherapy (IORT) LDR (40-200cGy/hour) vs HDR (>1200cGy/hour) Adjuvant monotherapy or boost after EBRT Useful for re-irradiation American Brachytherapy Society publishes detailed guidance ABS Consensus Statement for Sarcoma Brachytherapy |Naghavi et al. ABS 2017| HDR brachytherapy delivered via temporary catheters placed after resection of STS
Slide 30-

Randomized Trial of Adjuvant Brachytherapy Randomized trial (N=126) at MSKCC from 1982-1987 Patients with de novo sarcoma s/p oncologic resection enrolled LDR via Ir-192, GTV prior plus 2 cm, 42-46 Gy over 4-6 days At 5 years, brachy versus no brachytherapy: Local control: 82 vs 67% (p<0.05) Benefit limited to high-grade tumors but studyunderpowered to address this subgroup Benefit unclear with positive margins No difference in DM, OS
Slide 31-

Case Examples of Radiotherapy Use for Resectable STS Pre-operative IMRT: large, high-grade sarcoma of the proximal upper extremity Post-operative IMRT: large, high-grade sarcoma of the thigh, smoker, co-morbid uncontrolled diabetes Peri-operative re-irradiation with IORT or brachytherapy: localized recurrence of a small, high-grade myxofibrosarcoma of the calf Pre-operative or post-operative proton therapy: history of prostate cancer, now with a resectable radiation-associated sarcoma of pelvic floor musculature
Slide 32-

Unresectable Sarcomas If tumor cannot be resected with acceptable functional outcomes, there are a range of options: Induction therapy Definitive radiation or chemoradiation Amputation with planned prosthesis Induction therapy can include: Chemotherapy and/or radiotherapy (used as previously discussed) Chemoradiation therapy | 50 Gy in 25 fractions with adriamycin and ifosfamide
Slide 33-

Basis for Chemoradiation for Sarcoma Old strategy for high-risk sarcoma with good success but high toxicity RTOG 9514 tested interdigitated chemoRT with Mesna (M), Adriamycin (A), Ifosfamide (I) and Dacarbazine (D) Very high-risk group eligible (high grade, tumor > 8 cm) 5 year local and distant failure rates only 22% and 28% respectively RT 22 Gy/11 fx MAID Surgery RT 16 Gy (if + margin) MAID
Slide 34-

Definitive Radiation for Unresectable Sarcomas Supported by retrospective studies Studies primarily used 3-D CRT, high-dose fields more conformal today Radiation dose to >63 Gy associated with good control Excellent outcomes also seen with 60 Gy RT + ifosfamide 5 year LC 60% versus 20% Estimated 5 year LC 70% Eckert et al., Rad Onc, 2010 Kepka et al., IJROBP, 2012
Slide 35-

High-dose RT for Sarcoma of Spine Phase II study of patients with spine sarcoma with extraosseous extension or paraspinal sarcomas Patients treated with a mix of 3-D conformal, IMRT and passive-scattered proton therapy Shrinking fields treated to high dose with excellent local control Chen et al., Spine, 2013 Kabolizadeh et al., IJROBP, 2017
Slide 36-

High-dose RT for Sarcoma of Spine Age 16+, spine/paraspinal sarcomas, surgery and RT recommended N=50, median follow up 7.3 years 5 year LC: 85.4%, improved for: Primary vs local recurrence R0 vs other Grade 3-4 toxicity approx. 20% at 10 years See Chowdhry et al., Radiother and Oncol, 2016 for a detailed analysis of spinal cord toxicity Kabolizadeh et al., IJROBP, 2017
Slide 37-

Retroperitoneal Sarcoma
Slide 38-

RP Sarcoma Basics Relatively asymptomatic, often present large (median >15 cm) Mix of histologies: 60% liposarcoma, 20% leiomyosarcoma, 20% other Liposarcoma versus Leiomyosarcoma Gronchi et al., Ann Surg, 2016 Stoechle et al., Cancer, 2001
Slide 39-

Diagnostic Challenges in RP Sarcoma Biopsy prior to resection is strongly recommended (TARPSWG) Can be high grade discordance between biopsy and resection (>30%) Image-guided biopsy improves accuracy Solid portion PET avid portion Tirotta et al., Ann Surg Onc, 2020
Slide 40-

Retroperitoneal Sarcoma Therapy Surgical resection is the cornerstone of therapy Often includes resection of involved visceral organs (mean 1-2) Positive margins are common Adjuvant radiotherapy and chemotherapy are controversial Radiotherapy is delivered before or perioperatively with brachytherapy Post-op radiotherapy is strongly discouraged except in select cases
Slide 41-

Surgical Resection of RP Sarcoma Complicated resections, best outcomes at high-volume centers Significant (but acceptable) serious toxicity at high volume centers Grade 3 13% | Grade 4 5% | Grade 5 2% R1, R2 resection, and tumor spill strongly associated with poor survival Bonvalot et al., JCO, 2009 Gronchi et al., Ann Surg, 2016 “Compartmental resection” associated with best disease control + survival Radiotherapy may benefit most in expected close/+margin resections
Slide 42-

Radiotherapy in RP Sarcoma Most studies have given pre-operative radiotherapy with or without perioperative brachytherapy Generally, 45-50 Gy with 10-12 Gy brachytherapy (catheter, IORT) ACOSOG Z9031 prospectively tested pre-op IMRT with IORT 5 year local recurrence and overall survival 26% and 72% respectively
Slide 43-

IMRT or Proton Therapy with SIB Modern approach uses 25 fraction EBRT with SIB 50 Gy in 25 fractions with SIB to high-risk CTV of 57.5 Gy (Tzeng et al., 2006) High-risk CTV must be defined with surgeon High variability between Rad Oncs (Baldini et al., Ann Surg Onc, 2015) Multicenter phase I/II trial seeking to escalate dose to high-risk CTV with IMRT or protons (NCT01659203)
Slide 44-

The STRASS Trial Randomized trial of pre-op RT (50.4 Gy with IMRT) + surgery versus surgery alone N=266, de novo RP sarcoma of any histology, deemed resectable Primary endpoint composite ARFS Radiographic local progression during RT (this was later changed)* Radiographic distant progression during RT Peritoneal metastasis found at surgery Macroscopic residual disease left in at surgery Local relapse *At the first unplanned interim sensitivity analysis, outcome was changed so that local progression on RT was not considered progression if R0/R1 resection possible A second unplanned interim sensitivity analysis defined no event if the surgery was R0/R1 despite local progression on radiotherapy OR medically unfit according to the surgery operability criteria
Slide 45-

The STRASS Trial Similar outcome in both groups (no RT vs RT) 3 yr ARFS: 58.7% vs 60.4% 3 yr modified ARFS: 58.7% vs 66% Fit for surgery only: 62.2% vs 71.3% Liposarcoma subgroup: 60.4% vs 71.6% 3 year OS: 84.6% vs 84% Important critiques: lower dose RT, high rate of protocol violations/toxicity, confusing composite endpoint Possible benefit in certain patients with liposarcoma, but longer follow-up is required Conventional pre-op RT (50 Gy) should not be offered on a routine basis
Slide 46-

Desmoid tumor
Slide 47-

Desmoid Tumor Basics Rare cancers, 3% of soft tissue tumors Most are sporadic, but 5-15% of desmoids due to FAP or Gardner Sx Can be associated with high-estrogen states, such as pregnancy 10-15% can regress spontaneously, no OB complications reported in literature Some may be driven by APC gene and beta-catenin mutations (Wnt pathway) Cleveland Clinic Staging System Quintini et al., Ann Surg, 2012
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Therapy for Desmoid Tumors Treatment highly individualized, multidisciplinary management strongly recommended Many can be managed with active surveillance On diagnosis On progression NCCN Soft Tissue Sarcoma v.2.2020
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Therapy for Desmoid Tumors Desmoid Tumor Foundation international consensus document: Excellent literature review Treatment guidelines https://dtrf.org/consensus-paper/
Slide 50-

Sorafenib for Desmoid Tumors Double-blind phase III multicenter trial 87 patients with inoperable or recurrent/progressive desmoid Sorafenib 400 mg daily versus placebo (with cross-over at progression) Primary end point: PFS Objective response rate 33%, median time to response 9.6 mos 47% grade 3+ toxicity (rash, fatigue, GI) Gounder et al., NEJM, 2018
Slide 51-

Radiotherapy for Desmoid Tumor Radiotherapy (RT): Definitive or neoadjuvant/adjuvant RT Preferred dose is 50-56 Gy in 1.8-2 Gy fractions Addition of RT likely does not improve local control when resected with negative margins, BUT… Close/positive margins: Surgery +RT > Surgery alone 5y LC: Surgery + RT = RT alone (75-85%) Surgical management of desmoids requires consideration of extent of the tumor, symptom burden from the tumor, and potential morbidity of surgery and is best handled by a surgeon experienced in management of these tumors Radiotherapy for intra-abdominal desmoid tumor should be avoided Ballo et al., JCO, 1999 Sherman et al., IJROBP, 1990
Slide 52-

Radiotherapy for Desmoid Tumor Strong evidence for age disparity in local control Not RT-related, seen in surgical series No obvious connection to tumor mutational status Strong motivation to save RT as a “last resort” in young patients! Bishop et al., IJROBP, 2018
Slide 53-

Radiotherapy use in metastatic sarcoma
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Radiotherapy for Oligometastatic Disease Retrospective data supports use of ablative therapy for patients with sarcoma and 1-5 metastasis Local therapies should be selected via multi-disciplinary discussion Surgery SBRT IR ablation Falk et al., Clin Oncol, 2015
Slide 55-

SBRT in Metastatic Sarcoma Growing excitement for SBRT in (oligo)metastatic disease Numerous case series show SBRT is safe and effective for sarcoma lung metastases Lung mets: many consider BED >100 (a/b 10) (Navarria et al., 2015), but doses as low as 50Gy/10fractions provide >90%LC (Lindsay et al., 2018) EQD2 ≥50Gy considered ablative(Falk et al., 2015) BED (a/b 10) >48 associated with 2 year local control of spine sarcoma (66 vs 20%) (Bishop et al., 2017) BED (a/b 4) >=50 associated with improved pain relief in sarcoma (Tween et al 2019) Local control 80-90+% at 1-2 years Mehta et al., Sarcoma, 2013 Navarria et al., Eur J Cancer, 2015 Baumann et al., JSO, 2016
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Chemoradiotherapy in Metastatic Sarcoma TRASTS - Phase I/II prospective study of Trabectadin and Radiotherapy Eligibility: Metastatic STS progressed on 1 line of chemotherapy Trabectadin 1.5 mg/m2 with radiotherapy 30 Gy in 10 fractions 60% ORR (central review), median PFS of 9.9 months Up to 40% grade 3-4 hem toxicity Good option to start/continue chemo or for multiple mets Beware: no OS data, no QoL data Martin-Bronto et al., JAMA Onc, 2019
Slide 57-

MultiCenter “National” studies of radiation for sarcomas
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Sarc 032 – randomized phase II study of adding immunotherapy Extremity and “Limb girdle”/shoulder eligible Histology restricted: pleomorphic sarcoma, undifferentiated sarcoma, myxofibrosarcoma NRG DT-001 – phase I-II study of adding AMG-232 Extremity and Retroperitoneal Cohorts Genotype-directed therapy Randomized: RT  Surgery RT + Pembro  Surgery  Pembro Single arm, dose escalation of drug: If wild-type p53  stay on drug If mutant p53  stop drug
Slide 59-

MGH SIB for RP Sarcoma – phase I-II study of image-guided IMRT or IMPT dose-escalationResectable RP sarcoma eligible Pre-op radiotherapy to 50.4 Gy in 28 fractions with SIB to high-risk CTV defined by Rad Onc and Surgeon Dose escalation: 57.5 Gy --> 63 Gy in 28 fractions 63 Gy in 28 fractions deemed safe
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Supplemental Slides
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Hypofractionation Using 30 Gy in 5 Fractions UCLA – single-arm phase II study of adult patients with STS planning neoadjuvant RT then surgical resection Radiotherapy 30 Gy in 5 fractions daily, fields per RTOG 0630 Primary endpoint: grade ≥ 2 radiation-associated tox (i.e. fibrosis, lymphedema) 2 year local recurrence: 5.7% Grade 2 dermatitis: 8% Grade 2 late tox: 16% No grade 3 or greater toxicities No significant decline in TESS or MSTS Results Kalbasi et al., Clin Can Res, 2016
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Wound Complications Associated with Pre-op RT Kalbasi et al., Clin Can Res, 2016