Rhabdomyosarcoma

Updated by Vinita Takiar

BACKGROUND

What are the 3 most commonly tested rhabdomyosarcoma (RMS) cases on the radiation oncology oral boards?

Bladder (trigone), parameningeal (PM), and orbit

What are the 2 incidence age peaks of RMS and their associated histologies?

2–6 yo (embryonal) and 15–19 yo (alveolar)

What is the estimated overall annual incidence of RMS in the U.S.?

350 cases/yr of RMS in the U.S., 3% of all childhood cancers (#1 soft tissue sarcoma)

What are the most common sites of RMS? List them in order of approximate frequency in %.

Most common sites of RMS:

1. H&N 40% (PM 25%, orbit 9%, non-PM 6%)

2. GU 30%

3. Extremity 15%

4. Trunk 15%

What are the most common sites of mets?

Bone, BM, and lung

What % of pts present with mets? What types are prone to have hematogenous mets?

15% of pts present with mets. The prostate, trunk, and extremities are prone to hematogenous mets.

What is the most common origin of RMS?

Mesenchymal stem cells. Sporadic RMS is the most common.

What genetic syndromes are associated with RMS?

Genetic syndromes: Beckwith-Wiedemann syndrome (BWS), Li Fraumeni, NF-1, Costello syndrome, and Noonan syndrome

What are the 4 major histologies of RMS and their associated subtypes (if any)? Which is most common?

Major histologies of RMS and subtypes:

1. Embryonal (classic, spindle cell, and botryoid) (Most common: 60%)

2. Alveolar

3. Pleomorphic

4. Undifferentiated

What genetic change is associated with embryonal RMS?

LOH 11p15.5 (embryonal) is associated with IGF2 gene deletion, seen in BWS; also, abnormalities in chromosomes 2, 8, 12, and 13 are associated with MYCN, MDM2, CDK4, CDKN2A (p16), CDKN2B, and TP53 genes.

What translocations are associated with alveolar RMS? What are the genes involved in the fusion?

Alveolar RMS is associated with t(2;13) (70%) and t(1;13) (20%). Genes involved are PAX3 or PAX7 with FOX01 (also known as FKHR).

Which is the most common histology of RMS in infants? Young children? Adolescents? Adults?

Most common RMS histology (by age group):

Infants: botryoid

Young children: embryonal

Adolescents: alveolar

Adults: pleomorphic

Which histologies are most commonly associated with each organ site (H&N, GU, extremities/trunk)?

Most common RMS histologies (by site):

H&N: embryonal

GU: botryoid

Extremities/Trunk: alveolar

What is the most important cytogenetic tumor marker for RMS?

MyoD (and other myogenic proteins: actin, myosin, desmin, myoglobin)

What is the DDx for small round blue cell tumors of childhood?

Medulloblastoma, rhabdomyosarcoma, leukemia/lymphoma, Ewing sarcoma, retinoblastoma, neuroblastoma, Wilms tumor

List the histologies of RMS in terms of prognosis from best to worst.

1. Spindle cell and botryoid

2. Classic embryonal

3. Alveolar

4. Undifferentiated

What are the ~5-yr OS rates for each of the histologic subtypes?

∼5-yr OS (by histology):

Botryoid: 95%

Spindle cell: 88%

Embryonal: 66%

Alveolar: 54%

Undifferentiated: 40%

Which sites require LND b/c of a high propensity for LN mets? What is the risk of LN mets for these sites?

The following sites are associated with >20% LN mets rate and thus require LND:

Paratesticular (PrT): (only if >10 yo)

Bladder: pelvic

H&N: nasopharynx (NPX), LND typically not done for NPX

Extremities: upper extremity (UE) (axillary) and lower extremity (LE) (inguinal/femoral) (La TH et al., IJROBP 2011)

Which International Rhabdomyosarcoma Study (IRS) called for routine LN sampling in RMS of the extremity?

IRS-IV (Neville HL et al., J Pediatr Surg 2000): 139 extremity pts, 76 patients had surgical LN evaluation; of the 10% who were cN+, 50% were pN+; of those cN0, 17% were pN+.

What are considered nonregional mets/LNs for various sites (UE, LE, pelvic organs [PrT, vagina, uterus])?

Non regional LN stations by primary site:

UE: scalene node

Pelvic (PrT/vagina/uterus): inguinal

Retroperitoneal (RP): para-aortic (PrA) (except if immediately adjacent)

LE: iliacs/PrA

What are the 4 favorable organ sites and their ∼3-yr OS rate?

Favorable organ sites:

1. Orbit

2. Non-PM H&N

3. Nonprostate/bladder GU

4. Biliary

The ∼3-yr OS is 94%.

What is the estimated 3-yr OS for RMS arising from unfavorable sites (PM H&N, prostate, bladder, extremities/trunk)?

For unfavorable sites, overall ∼3-yr OS is 70%.

What are the PM H&N sites?

PM H&N sites:

Middle ear

Mastoid

Nasal cavity

Nasopharynx

Infratemporal fOssa

Pterygopalatine fOssa

Paranasal sinuses

Parapharyngeal space

(Mnemonic: MMNNOOPP)

What are the non-PM H&N sites?

Scalp, cheek, parotid, oral cavity, oropharynx, and larynx

WORKUP/STAGING

List the general workup for RMS.

RMS workup: H&P, basic labs (CMP, CBC, lactate dehydrogenase [LDH]), EUA, CT/MRI primary, CT chest/abdomen, bone scan, BM Bx, and primary site core Bx/incisional Bx; PET/CT may be useful in determining extent of Dz

What specific workup studies are needed for PM RMS?

PM RMS workup: MRI brain, CSF cytology (neuroaxial MRI if +)

What specific workup studies are needed for bladder RMS?

Bladder RMS workup: EUA and cystoscopy

Summarize the TNM criteria for RMS.

T1: confined to anatomic site of origin

T1a: ≤5 cm

T1b: >5 cm

T2: extension or fixed to adjacent tissue

T2a: ≤5 cm

T2b: >5 cm

N1: regional node involvement

M1: DM

Summarize the preop staging of RMS.

Stage I: favorable site (any T, any N, M0)

Stage II: unfavorable site, T1a or T2a (≤5 cm), N0, M0

Stage III: unfavorable site, T1b or T2b (>5 cm), and/or N1, M0

Stage IV: M1

Summarize the postop grouping for RMS.

Group I: R0 resection, localized Dz

Group II: R1 resection and/or resected +LN

Group III: R2 (both primary and +LN) or Bx only

Group IV: DM

Most RMS pts present with what group of Dz?

Most (∼50%) present with group III Dz.

Define the risk groups for RMS (based on IRS-VI).

Low risk (5-yr OS 90%–95%): nonmetastatic, embryonal, and

a. favorable site all groups or

b. unfavorable site groups I–II

Intermediate risk:

a. nonmetastatic, group III embryonal, unfavorable site (5-yr OS 70%–85%) or

b. nonmetastatic unfavorable histology (UH), any site (5-yr OS 55%–60%)

High risk: all metastatic Dz, including 2–10 yo embryonal (5-yr OS 25%–35%)

TREATMENT/PROGNOSIS

What is the Tx paradigm for RMS?

The Tx for RMS in the IRS studies varies based on site, histology, and tumor size.

RMS Tx paradigm: generally, max safe resection (or Bx alone) → chemo +/– RT (timing of CRT depends on risk groupings)

What chemo regimens are commonly used in RMS?

Vincristine/Actinomycin D/Cytoxan (VAC) and vincristine/actinomycin D (VA) are commonly used.

Ifosfamide/etoposide (IE) is also used in subsets of RMS.

How does age factor into the prognosis of metastatic embryonal RMS?

>10 yo is worse than <10 yo (EFS 14% vs. 47%).

What factors make PM RMS high risk?

Subarachnoid space involvement with skull base erosion, CN palsy, intracranial extension; DFS 51% vs. 81% (without risk factors)

What is the seminal trial that 1^st supported the use of chemo for RMS?

Heyn RM et al. (Cancer 1974): VA chemo vs. nothing after surgery improved OS.

IRS-I: What did it answer?

Group I: favorable histology (FH); RT not needed

Group II: RT + VA × 1 yr (no need for Cytoxan)

Groups III–IV: RT + VAC × 2 yr (no Adriamycin [Adr] needed)

DM is more common than LF.

No dose response for RT; no difference in RT field size (large = involved field):

PM RMS ↑ CNS relapse if certain high-risk features are present.

IRS-II: What did it answer?

Group I: VA × 1 yr same as VAC × 2 yrs (except in UH)

Group II: RT + VA × 1 yr same as RT + VAC + 1 yr (except in UH, use VAC + RT).

Groups III–IV: no benefit adding Adr to VAC + RT (except in UH).

Better PM outcomes than IRS-I with prophylactic WBRT for high-risk pts.

Chemo alone for special pelvic sites with VAC is not adequate (bladder preservation only 22% b/c of inadequate response).

According to IRS I–II analysis, which RMS site was shown to carry the highest risk for LN mets?

The prostate (∼40% with LN+ Dz) was shown to have the highest risk for LN mets.

IRS-III: What did it answer?

Groups I–II UH: better with vincristine/Adriamycin/cyclophosphamide (VAdrC) alternating with VAC + RT, than RT + VA or VAC.

Groups II–III favorable site: VA + RT adequate

Groups II–III unfavorable site and group IV FH/UH: VAC + RT; no benefit adding Adr

WBRT prophylaxis did not reduce CNS relapse.

There was an improved bladder preservation rate and OS in the multimodality Tx of special pelvic sites.

Who did not get RT in IRS-III?

Group I FH and group III special pelvic sites (if CR after chemo) did not get RT.

In IRS-III, the OS was mainly driven by what groups of pts?

Groups I–II UH getting VAdrC alternating with VAC and group III FH special pelvic sites

What did IRS-III demonstrate about the Tx of special pelvic sites?

Pelvic site I (bladder dome, vagina, uterus): VAdrC alternating with VAC × 2 yrs → second-look surgery (SLS) at 20 wks → if PR, then RT at wk 20 + Adriamycin/etoposide × 2 cycles; if CR, no RT and continue chemo.

Pelvic site II (bladder neck/trigone, prostate): VAdrC alternating with VAC × 2 yrs → RT (wk 6) → SLS at 20 wks.

Bladder preservation rate 60% vs. 25% (IRS-I–II) and better OS rate (83% vs. 72%).

IRS-IV: What did it answer?

IRS-IV focused on improving outcome for group III: utility of adding IE to VAC, and bid RT (1.1 Gy bid to 59.4 Gy) vs. conventional RT (1.8–50.4 Gy).

Conventional once daily RT remains standard.

VAC remains standard, even for the alveolar type.

However, for group IV, VAC + IE is standard (IE vs. vincristine/melphalan).

What trial utilized WBRT prophylaxis for high-risk PM RMS, and how did it differ from other IRS trials?

IRS-II–III, with whole brain to 30 Gy with intrathecal chemo, all started day 0. IRS-IV started day 0 but did not treat the whole brain—just to tumor + 2-cm margin on day 0.

For IRS-IV, RT started week 9 except at day 0 for spinal cord compression and week 1 for high-risk PM (direct intracranial extension, base of skull invasion, CN palsy).

What did Wolden et al. data show about the importance of RT in clinical group (CG)-I UH RMS?

Wolden et al. ( JCO 1999) analyzed IRS-I–III, RT vs. no RT in CG-I pts: showed only a trend to improved FFS and no OS with RT in FH; however, in CG-I UH, RT improved FFS and OS.

What was the purpose of COG-D9602?

To determine whether the lowest risk patients from IRS-III and IRS-IV (localized, grossly resected, or gross residual [orbit only]) embryonal RMS could be treated with reduced toxicity by reducing RT dose and eliminating cyclophosphamide. (Raney RB et al., JCO 2011)

What are the 2 subsets of low-risk pts on COG-D9602?

Subsets of low-risk pts on COG-D9602:

Subset A (treated with VA + RT on IRS-III–IV): stage 1, CG-I–II, orbit CG-III, stage 2, CG-I–II. Now treated with VAC × 4 cycles (reduced chemo) → 4 cycles VA + RT.

Subset B (treated with VAC + RT on IRS-III–IV): stage 1, CG-III (nonorbit), stage 3 CG-I–II. Now treated with VAC × 4 cycles (reduced chemo) → 12 cycles VA + RT.

What did the results of COG-D9602 demonstrate?

5-yr FFS rate (88%) and OS rate (97%) were similar to comparable IRS-III pts, even with lower RT doses but were worse than comparable IRS-IV pts receiving VA + cyclophosphamide. (Raney RB et al., JCO 2011)

What radiation doses were used in COG-D9602?

Dose depended on clinical group (extent of surgery) and LN positivity. After resection, pts with microscopic residual and uninvolved LN received 36 Gy. Involved LN: 41.4–50.4 Gy. Orbital primary: 45 Gy. (Breneman J et al., IJROBP, 2012)

What are the major study questions for intermediate-risk pts in COG-ARST0531?

VAC vs. VAC alternating with vincristine/irinotecan (VI); timing of RT (wk 4 vs. wk 10, IRS-IV)

What are the major study questions for high-risk pts in COG-ARST0431?

VAC alternating with IE using interval dose compression; ability to improve LC in metastatic RMS by using VI with RT.

What is the timing of RT in IRS-V?

Low risk: wk 3

Intermediate risk: wk 12

High risk: wk 15

What is the timing of RT in COG-D9602?

Low risk: wk 13

Intermediate risk: wk 4

High risk: wk 20

What were the secondary objective questions for RT in COG-D9602?

Whether 36 Gy is adequate for N0, R1 and if 45 Gy is adequate for orbital RMS.

What is the dose for CG-I with FH?

0 Gy. No RT is required for CG-I with FH.

What study provided the rationale for reduced RT doses of 36 Gy in IRS-V– COG-D9602?

MSKCC retrospective review (Mandell L et al., JCO 1990): in only 32 CG-II pts, no difference in LC between <40 Gy vs. >40 Gy.

All pts with initial nodal involvement, regardless of response to induction therapy or SLS, must get what?

RT to 41.4 Gy if R0-R1 resected; all gross or suspected gross Dz treated to 50.4 Gy.

RT is NEVER omitted for node+ Dz.

Under what circumstances should RT be interrupted?

ANC <750 μL or Plt <75 K, and if uncontrolled infection or Hgb <10. RT is restarted after these are normalized; if a low blood count is a problem, chemo should be withheld or modified until RT is completed.

How do you treat PA nodes (if +)?

AP/PA to 36 Gy → boost to 50.4 Gy with off-cord technique, IMRT, or protons (allowed on COG studies).

What is defined as a minor deviation of an RT plan?

95% IDL covers <90% PTV but between 90% and 100% CTV, or >110% PTV

What is defined as a major deviation of an RT plan?

95% IDL covering <90% of CTV

What % of CG-III pts get a GTR at SLS?

25% of CG-III pts get a GTR at SLS.

PT RMS arises from where?

PT RMS arises from the distal spermatic duct.

Which RMS tumors have a better prognosis: hyperdiploid or diploid?

Hyperdiploid (found in embryonal histologies) vs. diploid (in alveolar histologies)

Based on a review of IRS-III data, where do failures mostly occur after Tx? What is the #1 prognostic factor for LF?

LF > DM. LN positivity is the biggest predictor for LF.

What evidence supports the use of ≤40 Gy in the management of CG-II RMS (and therefore the rationale for a test dose of 36 Gy in COG-D9602)?

St. Jude data (Regine WF et al., IJROBP 1995) suggest that for the 24 CG-II pts in this study, the LC rate with <40 Gy (89%) was not statistically different from ≥40 Gy (100%).

MSKCC data (Mandell L et al., JCO 1990): 32 CG-II pts treated with various doses also found that the LC for doses <40 Gy was equivalent to doses ≥40 Gy.

What evidence is there to support IMRT for H&N RMS (as endorsed by IRS-VI)?

Wolden et al. reviewed 28 pts (21 PM) treated with IMRT. A 1.5-cm margin was used, with a median dose of 50.4 Gy. There was excellent LC (95%) despite reduced margins used, min late toxicity, and comparable acute toxicity. (IJROBP 2005)

In IRS-V, what additional dose must be given if Tx is delayed by 2–3 wks? How about >3 wks? If <2 wks?

2–3 wks: 1.8 Gy

>3 wks: 3.6 Gy

<2 wks: no change in dose

What 3 issues must be considered when treating an extremity site?

Considerations when treating an extremity site:

1. Evaluate the need to radiate regional nodes.

2. Include scars/drains in the field.

3. Try to spare a strip of skin or portion of the joint/epiphyses.

If a CR is obtained after induction chemo with a group III, N0 embryonal tumor of the vagina, cervix, and uterus, what RT dose would you use?

No RT if CR! These are “special sites.”

What dose of RT would you give for a pt with stage III, group I embryonal RMS? How about alveolar RMS?

No RT for ALL embryonal group I pts (stages I–III). For UH group I pts, 36 Gy RT is given.

If a pt is high risk (i.e., metastatic), should the mets be treated as well as the primary with RT?

At the discretion of the radiation oncologist. At the Johns Hopkins Hospital, the preference is to treat the primary and let the pt finish chemo; if the pt responds to chemo, then mets are treated with RT. Consider treating the mets concurrently with the primary if not too large a BM volume is irradiated.

For what 2 sites of the H&N would you not recommend primary resection?

The orbit and PM sites are not recommended for primary resection.

For what RMS tumor sites would LND be recommended?

LND is recommended for the following RMS tumor sites:

1. GU (PrT/bladder) (pelvic and PA)

2. Extremities/Trunk (axillary, inguinal)

What are 2 favorable prognostic factors in pts with CG-IV RMS?

Per IRS-IV, ≤2 metastatic sites and embryonal histology were associated with better OS. (Breneman JC et al., JCO 2003)

TOXICITY

Per COG-D9602, what is the dose constraint for the whole kidney?

The dose constraint for the whole kidney is 19.8 Gy.

What is the max allowed dose to the whole liver?

The max dose to the whole liver is 23.4 Gy.

Per COG-D9602, what is the dose limit to the chiasm?

The dose limit to the chiasm is 46.8 Gy.

What is the max allowed dose to the whole heart? Whole abdomen/pelvis?

The max dose to the whole heart is 30.6 Gy. The max dose to the whole abdomen/pelvis is 24 Gy (at 1.5 Gy/fx).

What is the dose limit to the lungs, if less than half of the combined lung volume is in the PTV?

In this situation, the dose limit to the lung is 15 Gy (in 1.5 Gy/fx).

What is a major side effect of VAC besides myelosuppression?

Veno-occlusive Dz of the liver

Related posts:

Optic Pathway Glioma Plasmacytoma/Multiple Myeloma Hodgkin Lymphoma Arteriovenous Malformation Mycosis Fungoides Early-Stage (I–II) Breast Cancer

Stay updated, free articles. Join our Telegram channel

Join