This illustrates the role of chemotherapy in rhabdomyosarcoma along with brief description of pathology, staging etc.

1. Chemotherapy in Childhood
Rhabdomyosarcoma: A brief
review
DR SAMEER RASTOGI
ASSISTANT PROFESSOR,
MEDICAL ONCOLOGY DEPARTMENT
AIIMS, NEW DELHI

2. Histologic subtypes
 Embryonal – Predominantly males
Peak incidence 0-4 years
57% of all in SEER database
 Alveolar -- Doesn’t vary by gender
Constant for all ages
23% of patients in SEER database
 Others -- Pleomorphic/ anaplastic – 30-50 years of age
worse prognosis
Embryonal
Spindle cell
Botryoidal ---obsolete1
Classic
Solid variant
WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Pre

4. Risk factors for Rhabdomyosarcoma
 Li fraumeni syndrome
 NF1
 Costello syndrome
 Beckwith Wiedmann syndrome
 Noonan’s syndrome
 High birth weight and large gestational age are associated with increased
incidence of embryonal rhabdomyosarcoma

5. Prognostic factors
 Age 1-9 years have best prognosis
 Intergroup rhabdomyosarcoma trial
 5 year FFS – 57% for patients younger than 1 year
- 87% for patients 1 to 9 years
- 68% for older than 10 years

6. Prognostic factors
 Poor outcome in infants
 Don’t receive adjuvant radiation due to concern/ bias about high incidence of
late side effects1
 ? Poorly tolerant for chemotherapy &dose frequently reduced2
 Older children
 Vcr and dactinomycin have upper limit for the dose and the neurotoxicity
1.Rhabdomyosarcoma in Infants Less than One Year of Age: A Report from the Children’s Oncology Group. Ca
2.Age is a risk factor for chemotherapy-induced hepatopathy with vincristine, dactinomycin, and cyclophosph

7. Prognostic factors
 Adolescents: A report from the AIEOP (Italian) Soft Tissue Sarcoma
Committee suggests that adolescents may have more frequent
unfavorable tumor characteristics, including alveolar histology, regional
lymph node involvement, and metastatic disease at diagnosis, accounting
for their poor prognosis.
Rhabdomyosarcoma in adolescents: a report from the AIEOP Soft Tissue Sarcoma Committee. Cancer 118 (3): 821-7

8. Prognostic Factors
 Site
 Size of the tumor
 Grouping
 Histology – Alveolar vs Embryonal
 Molecular testing
 Metastasis
 Lymph node involvement – l. N sampling depending upon the risk
https://www.cancer.gov/types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq#sect

9. Questions ?
 Is staging work up mandatory for all patients
 Role of molecular testing – established or theoretical
 Risk group guided treatment
 VAC (A – Actinomycin D) ? (what about others? )
& Dose of cyclophosphamide ? 2.2 vs 1 gm/m2
 Newer strategies for escalation or de escalation
 Non metastatic
 Metastatic

10. Staging Work up
 Local Imaging – MRI or CT scan
 CT Chest
 Bone Scan
 Bone marrow Aspirate and biopsy (usually bilateral)
 CSF if parameningeal ..

11. Background
 IRS I – 3 out of 500 patients had isolated bone marrow metastasis.1
 IRS IV – 12 out of 901 with no other site of disease have isolated BM mets.
2
 COG suggested BMBx and Bone scans are not needed in one-third of
patients
1. Ruymann et al. Bone Marrow Metastases at Diagnosis in Children and Adolescents With Rhabdomyosarcoma. IRS committee
Cancer 53.368-373, 1984.
2. Breneman et al. Prognostic Factors and Clinical Outcomes in Children and Adolescents With Metastatic
Rhabdomyosarcoma—A Report From the Intergroup Rhabdomyosarcoma Study IV. JCO 21.78-84,2003

12.  1687 patients who had undergone this staging (Pooled on Intergroup
studies and COG studies)

13. JCO 2013.

14. Questions ?
 Is staging work up mandatory for all patients
 Role of molecular testing – established or theoretical
 VAC (A – Actinomycin D) ? (what about others? )
 How important is risk grouping guided treatment?
 Dose of cyclophosphamide ? 2.2 vs 1 gm/m2
 Newer strategies for escalation or de escalation
 Non metastatic
 Metastatic

15. Role of molecular testing in
rhabdomyosarcoma
 LOH 11p in ERMS 1
 ARMS shows two distinct set of translocation2
 Both RT PCR and FISH are used for detection of these translocation (highly
concordant3)
 Minimally diagnostic (but existent) but mainly prognostic information
1. Parham DM, Barr FG. Classification of rhabdomyosarcoma andits molecular basis. Adv Anat Pathol. 2013;2:387---97.
2. Bilar et al. ARMS: origin and prognostic implications of molecular findings. Bol Med Hosp Infant Mex. 2016;73(6):405
3. PAX-FOXO1 Fusion Status Drives Unfavorable Outcome for Children With RMS: A COG Report. PBCR. 2015

17. Translocation in alveolar
rhabdomyosarcoma
 Not yet incorporated in risk grouping though COG trials are accruing
based upon this translocation
 Should be done whenever feasible

18. Questions ?
 Is staging work up mandatory for all patients
 Role of molecular testing – established or theoretical
 Risk grouping guided treatment
 VAC (A – Actinomycin D) ? (what about others? )
& Dose of cyclophosphamide ? 2.2 vs 1 gm/m2
 Newer strategies for escalation or de escalation
 Non metastatic
 Metastatic

19. Staging and Risk grouping
 Complex.
 Assigning a Stage: Determined by primary site, tumor size (widest
dimension), and presence or absence of regional lymph node and/or
distant metastases.
 Assigning a Group: Determined by status of the initial surgical
resection/biopsy, with pathologic assessment of the tumor margin and of
lymph node involvement, before the initiation of therapy.
 Assigning a Risk Group: Determined by Stage, Group, and histology.

20. Term Definition
Favourable site Orbit, non parameningeal head and neck,
genitourinary other than bladder, prostate and
kidney
Biliary tract
Unfavourable site Any other site
T1 Confined to organ or tissue of origin
T2 Beyond organ or tissue of origin
A Tumor ≤5 cm in maximum dimension.
B Tumor >5 cm in maximum dimension.
N0 No clinical regional lymph node involvement.
N1 Clinical regional lymph node involvement.
NX
Regional lymph nodes not examined; no
information.
M0 No metastatic disease.

21. Stage
Stage Site of
tumor
T staging Tumor size Regional
lymph nodes
Metastatasis
1 Favourable site T1 or T2 Any size N 0 or N1 or
Nx
M0
2 Unfavourable
site
T1 or T2 a, ≤5 cm N0 or Nx M0
3 Unfavourable
site
T1 or T2 a, ≤5 cm N1 M0
b, >5 cm N0 or N1 or Nx
4 Any site T1 or T 2 Any size N0 or N1 or Nx M1

22. Group
I Approximately 13%
Localized tumor, completely removed with microscopically clear
margins and no regional lymph nodes .
II Approximately 20%
Localized tumor, completely removed with: (a) microscopic residual
disease; (b) regional disease with involved, grossly removed regional
lymph nodes; or (c) regional disease with involved nodes, grossly
removed but with microscopic residual and/or histologic
the most distal node from the primary tumor.
III Approximately 48%
Localized tumor, incompletely removed with gross, residual disease
after: (a) biopsy only or (b) subtotal resection.
IV Approximately 19%
Distant metastases present at diagnosis. This category includes: (a)
radiographically identified evidence of tumor spread or (b) positive
tumor cells in cerebral spinal fluid, pleural or peritoneal fluids, or
implants in these regions.

23. STS – COG Risk group classification
Histology Stage Group
Low Risk Embryonal 1 I, II, III
Embryonal 2,3 I, II
Intermediate Risk Embryonal 2,3 III
Alveolar 1,2,3 I, II, III
High Risk Embryonal or
alveolar
4 IV

24. 25%
21%
54%
Risk Group percentages
n ERMS favourable site all, n ERMS
unfavourable site but completely
resected
n ARMS all, n ERMS unfavourable site
and unresected
Metastatic

25. Questions ?
 Is staging work up mandatory for all patients
 Role of molecular testing – established or theoretical
 Risk grouping guided treatment
 VAC (A – Actinomycin D) ? (what about others? )
& Dose of cyclophosphamide ? 2.2 vs 1 gm/m2
 Newer strategies for escalation or de escalation
 Non metastatic
 Metastatic

26. Multidisciplinary management
 Primary care physician.
 Pediatric surgeon.
 Radiation oncologist.
 Pediatric oncologist and hematologist.
 Pediatric radiologist.
 Rehabilitation specialist.
 Pediatric nurse specialist.
 Social workers.
 Psychologist.

27. Intergroup rhabdomyosarcoma study
group
 IRS-I,1972 to 1978
 IRS-II, 1978 to 1984
 IRS-III, 1984 to1991
 IRS-IV, 1991 to 1997

28. The Second and Third intergroup RMS
study
 ADR failed to benefit patients with group III or IV disease in IRS-II1
 Children with favorable histology tumors in group II did not clearly benefit
from the addition of ADR to a regimen of VA2
The dose of Cyclophosphamide used in IRS III was
1gm/m2
1. Intergroup study group II. 1993
2.Third Rhabdomyosarcoma intergroup study. JCO 1995

29. IRS IV
 The main objective was to improve the outcome of children with local or
regional RMS who can’t be readily cured with surgery and VCR and
Actinomycin D
 It was always believed that ifosfamide would be better in pediatric sarcoma
 Data with ifosfamide and etoposide in patients refractory to
cyclophosphamide based protocol
Journal of Clinical Oncology, Vol 18, No 12 (June), 2000: pp 2427-

30. IRS IV
 VAI vs VAC vs VIE (A stands for Actinomycin D)
 Cyclophosphamide dose in IRS IV was raised from 1gm/m2 to 2.2 gm/m2
(Equivalent oxazophorines doses)
 IRS III vs IRS IV to answer optimal cyclophosphamide dose (cross trial)
 IRS IV to tell the optimal drug cyclophosphamide vs ifosfamide
Journal of Clinical Oncology, Vol 18, No 12 (June), 2000: pp 2427-2

31. Journal of Clinical Oncology, Vol 18, No 12 (June), 2000: pp

32. Results from IRS IV study
Journal of Clinical Oncology, Vol 18, No 12 (June), 2000: pp 2427-2434

33. Results from IRS IV study
 Cross trial comparison of post hoc subsets of IRS III and IV NOT FAIR
 3 year FFS for intermediate risk improved in Embryonal RMS (IRS III -72%
vs IRS IV 78%)
 Still the verdict on cyclophosphamide dose is not solved but future trials
are using 1.2 gm/m2 only
 No Difference between VAC vs VAI and VIE statistically
Journal of Clinical Oncology, Vol 18, No 12 (June), 2000: pp 2427-2434

34. Questions ?
 Is staging work up mandatory for all patients
 Role of molecular testing – established or theoretical
 Risk grouping guided treatment
 VAC (A – Actinomycin D) ? (what about others? )
& Dose of cyclophosphamide ? 2.2 vs 1 gm/m2
 Newer strategies for escalation or de escalation
 Non metastatic
 Metastatic

35. D 9803 – Addition of topotecan to VAC
 Background – Phase 2 window studies RR to Topotecan was 46-50%1,2
 Hypothesis - substitution of topotecan for dactinomycin in approximately
half the t/t cycles would improve the outcome of patients with
intermediate-risk RMS.
 Randomized Control trial in intermediate risk – VAC vs VAC/ VTC
1. Journal of Clin Oncol 19:213-219, 2001
2. J Clin Oncol 22: 1398– 1403,2004

36. J Clin Oncol 27:5182-5188.

37.  De-escalation strategy
 High risk of infertility with cyclophosphamide and other complications in
long term
 Low risk divided in to 2 groups
J Clin Oncol 29:1312-1318. 2011

38. Histology Stage Group
Low Risk
(25%)
Embryonal 1 I, II, III
Embryonal 2,3 I, II
Site Size Group Nodes
N0 = absence of nodal spread.
Favorable Any (stage 1) I, IIA N0
Orbital Any (stage 1) I, II, III N0
Unfavorable ≤5 cm (stage 2) I N0
J Clin Oncol 29:1312-1318. 2011

39. D 9602 protocol
 Objectives –
 To estimate FFS rates of patients in subgroup A after VA chemotherapy for
45 weeks plus RT
 To estimate FFS rates of patients in subgroup B after VAC chemotherapy
for 45 weeks plus RT
J Clin Oncol 29:1312-1318. 2011

40.  The goal of Children’s Oncology Group ARST0331 for subset 2 low-risk
patients was to reduce the total cumulative cyclophosphamide dose
without compromising FFS.
Waterhouse et al. Cancer 2017. Published online

41. Waterhouse et al. Cancer 2017. Published online

42. Waterhouse et al. Cancer 2017. Published online

43.  Pooled data from 9 studies in Europe and Americas
 N= 788 patients
 3 year OS was 34% and Event Free survival was 27%
Oberlin et al. Journal of Clinical Oncology 26, no. 14 (May 2008) 2384-2389.

44. High risk group
(Oberlin risk factors):
 Age at diagnosis younger than 1 year or 10 years and older.
 Unfavorable primary site (all sites that are not orbit, nonparameningeal
head and neck, genitourinary tract other than bladder/prostate, and biliary
tract).
 Bone and/or bone marrow involvement.
 Three or more different metastatic sites or tissues.
The EFS rate at 3 years depended upon the number of
adverse prognostic factors
The EFS rate was 50% for patients without any of
these adverse prognostic factors.
The EFS rates were 42% - with 1
18% for patients with 2
12% for patients with 3
5% for patients with 4
Oberlin et al. Journal of Clinical Oncology 26, no. 14 (May 2008) 2384-2

45. Background
Very poor outcome in this group
Irinotecan and Vcr have been very effective in phase 2 window studies
Ifosfamide and Etoposide are as effective as VAC
Irinotecan can work as radiosensitizer as well
J Clin Oncol 34:117-122. © 2015 by American Society of Clinical Onco

47. 3 year EFS
=38%
J Clin Oncol 34:117-122. © 2015 by American Society of Clinical Onco

48. J Clin Oncol 34:117-122. © 2015 by American Society of Clinical Oncolog

49. Questions ?
 Is staging work up mandatory for all patients
 Role of molecular testing – established or theoretical
 Risk grouping guided treatment
 VAC (A – Actinomycin D) ? (what about others? )
& Dose of cyclophosphamide ? 2.2 vs 1 gm/m2
 Newer strategies for escalation or de escalation
 Non metastatic
 Metastatic