Evidence Based Questions

Question 1

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

Answer 1

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

Question 2

IRS-I: What did it answer?

Answer 2

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 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.

Question 3

IRS-II: What did it answer?

Answer 3

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).

Question 4

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

Answer 4

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

Question 5

IRS-III: What did it answer?

Answer 5

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.

Question 6

Who did not get RT in IRS-III?

Answer 6

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

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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 + Adr/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%).

Question 9

IRS-IV: What did it answer?

Answer 9

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).

Question 10

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

Answer 10

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 wk 9 except at day 0 for SC compression and wk 1 for high-risk PM (direct intracranial extension, base of skull invasion, CN palsy).

Question 11

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

Answer 11

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.

Question 12

What was the purpose of COG-D9602?

Answer 12

To determine whether the lowest risk pts 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)

Question 13

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

Answer 13

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.

Question 14

What did the results of COG-D9602 demonstrate?

Answer 14

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)

Question 15

What RT doses were used in COG-D9602?

Answer 15

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

Question 16

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

Answer 16

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

Question 17

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

Answer 17

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

Question 18

What is the timing of RT in IRS-V?

Answer 18

Low risk: wk 3

Intermediate risk: wk 12

High risk: wk 15

Question 19

What is the timing of RT in COG-D9602?

Answer 19

Low risk: wk 13

Intermediate risk: wk 4

High risk: wk 20

Question 20

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

Answer 20

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

Question 21

What is the dose for CG-I with FH?

Answer 21

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

Question 22

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

Answer 22

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

Question 23

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

Answer 23

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.

Question 24

Under what circumstances should RT be interrupted?

Answer 24

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.

Question 25

How do you treat PA nodes (if +)?

Answer 25

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

Question 26

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

Answer 26

95% IDL covers <90% PTV but b/t 90% and 100% CTV, or >110% PTV

Question 27

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

Answer 27

95% IDL covering <90% of CTV

Question 28

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

Answer 28

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

Question 29

PT RMS arises from where?

Answer 29

PT RMS arises from the distal spermatic duct.

Question 30

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

Answer 30

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

Question 31

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

Answer 31

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

Question 32

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)?

Answer 32

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.

Question 33

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

Answer 33

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)

Question 34

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

Answer 34

2–3 wks: 1.8 Gy

>3 wks: 3.6 Gy

<2 wks: no change in dose

Question 35

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

Answer 35

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.

Question 36

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?

Answer 36

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

Question 37

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

Answer 37

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

Question 38

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

Answer 38

At the discretion of the RT oncologist. At the JHH, 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.

Question 39

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

Answer 39

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

Question 40

For what RMS tumor sites would LND be recommended?

Answer 40

LND is recommended for the following RMS tumor sites:

1. GU (PrT/bladder) (pelvic and P-A)
2. Extremities/Trunk (axillary, inguinal)

Question 41

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

Answer 41

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

Question 42

What did the IRS studies show?

Answer 42

The Intergroup Rhabdomyosarcoma Study Group (IRSG) was formed in 1972 to investigate the biology and treatment of RMS and undifferentiated sarcoma (UDS); it was merged into the Children’s Oncology Group (COG) in 2000. They led a series of protocols (IRS I-V) that have dictated RMS management with a rise in OS seen for all pts from ~50% to >70%.

Question 43

List conclusions for Maurer, IRS-I (Cancer 1988, PMID 3275486).

Answer 43

• 5-yr OS for all Groups I-IV was 55%.
• For favorable histology (FH) Group 1, RT not needed if giving 2 years of VAC. However, benefit to RT for FFS and OS seen in Group I, unfavorable histologies (UH; e.g., alveolar and undifferentiated).24
• Primary tumors of orbit and GU tract had best prognosis compared to retroperitoneum with worst prognosis.
• Limited RT volumes (GTV + 2 cm) outcomes similar to big fields such as whole muscle bundle RT.

Question 44

List conclusions for Maurer, IRS-II (Cancer 1993, PMID 8448756).

Answer 44

• 5-yr OS for all Groups I-IV was 63%, significant improvement from IRS-I (55%; p < .001).
• 5-yr OS for all nonmetastatic pts was 71%, significant improvement from IRS-I of 63% (p = .01).
• LC improved for >40 Gy (93% LC) for orofacial and laryngopharyngeal sites.25
• Cyclophosphamide not needed in FH Group I/II.

Question 45

List conclusions for Crist, IRS-III (JCO 1995, PMID 7884423).

Answer 45

• 5-yr OS for all Groups I-IV was 71%, significantly better than IRS-II (p < .001).
• Group 1, UH benefitted with addition of RT.
• For PM H&N with CN palsy or BOS erosion, limited RT volumes as good as WBRT. WBRT still used for intracranial extension.

Question 46

List conclusions for Breneman, IRS-IV (JCO 2003, PMID 12506174; Crist JCO 2001, PMID 11408506).

Answer 46

• For Group III disease, no benefit to hyperfractionated regimen (59.4 Gy with 1.1 Gy BID) over conventional regimen of 50.4 Gy in 1.8 Gy/fx.
• No benefit to VAI or VIE over VAC for nonmetastatic disease.
• Group IV pts with ≤2 metastatic sites had improved 3-yr OS and FFS on MVA (p = .007 and .006, respectively).

Question 47

List conclusions for Raney, IRS-V (JCO 2011, PMID 21357783).

Answer 47

• Reduced RT doses (36 Gy for microscopic disease [Stage 1/Group IIa] and 45 Gy for Group III orbit primaries if cyclophosphamide is included in systemic therapy) do not compromise local control.
• Inclusion of an alkylating CHT agent (cyclophosphamide or ifosfamide) may be important for FFS.

Question 48

When should RT be initiated?

Answer 48

RT timing has varied by protocol and risk group through the years. On the most recent COG protocols, low-risk pts start week 13, intermediate-risk week 4, and high-risk week 20. Metastatic sites may be treated at the end of CHT. Pts with cord compression, visual loss, or intracranial extension should be treated right away, on day 0 per high-risk COG ARST 0431 protocol. Analysis from IRS II-IV showed reduced local failure if RT started within 2 weeks versus >2 weeks for pts with meningeal impingement (18% vs. 33%, p = .03) and intracranial extension (16% vs. 37%, p = .07). A recent analysis from Spaulding et al. demonstrated similar clinical outcomes for pts with cranial nerve palsy or skull base erosion treated with immediate versus delayed RT; thus, it is fine to treat pts with these high-risk features at a later date (week 20 per COG ARST 0431) but treat pts with intracranial extension on day 0.

Question 49

What is the benefit of RT and in whom is RT required?

Answer 49

There are no good prospective randomized data. RT is currently indicated for all pts except embryonal tumors after gross total resection. Wolden et al. reviewed pts treated on IRS I-III and showed that pts with alveolar/undifferentiated histology after GTR (Group I) have improved FFS and OS with the addition of RT. Further, when comparing outcomes between IRS IV and MMT-89 (contemporary European International Society of Pediatric Oncology Malignant Mesenchymal Tumor study that attempted to avoid RT and radical surgery as much as possible by giving more CHT as necessary), RT appears to have significant benefits in LC, EFS, and OS.

Question 50

Is there a benefit to proton therapy in RMS?

Answer 50

The rationale is to reduce late effects and is permitted on ongoing RMS trials. Small series demonstrating dosimetric advantages have been published for orbit, parameningeal, and bladder/prostate sites. There are concerns regarding increased neutron dose associated with proton technology, and longer follow-up is necessary to evaluate safety and efficacy.

Question 51

What is the incidence and age distribution of rhabdomyosarcoma?

Answer 51

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, accounting for 3% to 4% of all cases of childhood cancer, with approximately 350 new cases per year in the United States. This tumor is more common in males, and 60% occur in patients under the age of 10 years.

Pappo, AS, Russell, HV, Komguth, DG, et al. Cancers of childhood. In: DeVita, V, Hellman, S, Rosenberg, SA, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia, PA: Wolters Kluwe Health Lippincott Williams & Wilkins; 2008:2043-2083.

Question 52

What are the most common sites, and which are favorable for rhabdomyosarcoma?

Answer 52

The most common sites are head and neck (40%: subdivided into parameningeal 25%, orbit 9%, and nonparameningeal 6%), genitourinary 30%, extremity 15%, and trunk 15%. Favorable sites include the orbit, head and neck (excluding parameningeal), genitourinary (nonbladder and nonprostate) and biliary tract.

Pappo, AS, Russell, HV, Komguth, DG, et al. Cancers of childhood. In: DeVita, V, Hellman, S, Rosenberg, SA, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia, PA: Wolters Kluwe Health Lippincott Williams & Wilkins; 2008:2043-2083.

Question 53

What is the grouping system for rhabdomyosarcoma?

answer

Answer 53

Clinical grouping is a surgical-pathologic staging system that depends on the surgical resectability of the disease and the presence or absence of metastases:

Group I: R0 resection, localized disease

Group II: R1 resection and/or resected with positive lymph nodes

Group III: R2 (both primary and positive lymph nodes) or biopsy only

Group IV: Distant mets

The grouping and staging systems, in addition to histologic subtype, should be used to stage patients with pediatric rhabdomyosarcoma because therapy and outcome closely depend on the variables outlined by each system.

Pappo, AS, Russell, HV, Komguth, DG, et al. Cancers of childhood. In: DeVita, V, Hellman, S, Rosenberg, SA, eds. Cancer: Principles and Practice of Oncology. 8th ed. Philadelphia, PA: Wolters Kluwe Health Lippincott Williams & Wilkins; 2008:2043-2083.

Question 54

What is the benefit of RT for unfavorable histology in rhabdomyosarcoma?

Answer 54

Based on IRS I-III, patients in clinical group I with unfavorable histology who received RT had improved failure-free survival and overall survival. In IRS-I and II, patients with alveolar or undifferentiated histologies who received RT compared to those who did not receive RT had improved 10-year failure-free survival rates (73% vs. 44%, p = .03) and overall survival rates (82% vs. 52%, p = .02). In IRS-III, these patients also experienced improved 10-year FFS (95% vs. 69%, p = .01) and overall survival (95% vs. 86%, p = .23).

Wolden, SL, Anderson, JR, Crist, WM, et al. Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol. 1999;17:3468-3475.

Question 55

How should orbital rhabdomyosarcoma be treated?

Answer 55

Primary surgery is not recommended for the orbit, and treatment should consist of chemotherapy and radiation. The radiation dose is 45 Gy to the tumor volume plus margin taking into consideration doses delivered to the lens, lacrimal gland, cornea, retina, optic nerve, bony structures, and brain. The volume does not need to include the entire orbit if the tumor is small. Treatment with the eye open to avoid bolus effect of the lids, unless the lids are involved, may be preferred. Notably, a recent publication suggests that 45 Gy may not be sufficient if there is less than a CR to chemotherapy, in which case 50.4 Gy may be preferred.

Ermoian, RP, et al. 45 Gy is not sufficient radiotherapy dose for Group III orbital embryonal rhabdomyosarcoma after less than complete response to 12 weeks of ARST0331 chemotherapy. Pediatr Blood Cancer. May 26, 2017;64(9)

Question 56

What is the surgical management of paratesticular rhabdomyosarcoma?

Answer 56

Paratesticular rhabodmyosarcoma should be resected via radical inguinal orchiectomy and resection of the spermatic cord. Additionally, ilsilateral retroperitoneal lymph node dissection should be performed in all boys age 10 or older and in boys of any age with suspicious radiographic lymph nodes.

MacDonald, SM, Friedmann, AM, Tarbell, NJ, et al. Rhabdomyosarcoma. In: Halperin, E, Constine, L, Tarbell, N, et al., eds. Pediatric Radiation Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:204-229.

Question 57

Which patients need radiotherapy after an R0 resection? What doses are used for R1, positive lymph nodes, and gross residual disease?

Answer 57

While embryonal histology can be observed after gross total resection, alveolar patients should be treated to 36 Gy. After an R1 resection, all patients should get 36 Gy. If lymph nodes are positive, the dose is 41.4 Gy. Gross disease is treated to 50.4 Gy, except in orbital tumors with a CR to chemotherapy for whom 45 Gy is likely sufficient.

MacDonald, SM, Friedmann, AM, Tarbell, NJ, et al. Rhabdomyosarcoma. In: Halperin, E, Constine, L, Tarbell, N, et al., eds. Pediatric Radiation Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:204-229.