Radiation Oncology/Rhabdomyosarcoma

Epidemiology

• 350 children per year in US
• Most common soft tissue sarcoma of childhood
• 2/3 occur <6 years, second peak mid-teen
• Clinical presentation depends on site, but frequently an asymptomatic mass
• Most common locations are H&N, GU, and extremities
• Local spread along fascial and muscle planes
• LN+ in 15%, incidence varies by subsite (ocular 1%, paratesticular 25%)
• DM+ in 15% at diagnosis, commonly lung, bone marrow, bone
• Li-Fraumeni syndrome: multiple tumors in siblings/relatives of children with RMS (adrenal, GBM, lung, breast, sarcomas)

Histology

• Myogenic precursor markers on IHC (actin, myosin, desmin, myoglobin, myoD, Z-band protein)
  • MyoD drives cells to myogenic lineage differentiation, and also stops cell replication. MyoD MAb available for diagnosis
• Two very distinct histologies and behavior patterns
• Embryonal (includes botyroid ERMS and spindle cell ERMS)
  • diploid to hyperploid DNA
  • no consistent transclocations identified, but loss of heterozygosity at 11p15.5
  • predominately in infants/young childern
  • frequently H&N, GU location
  • considered to have favorable prognosis
• Alveolar
  • tetraploid DNA
  • translocations: t(2,13) PAX3-FKHR and t(1,13) PAX7-FKHR gene fusion, which regulates neuromuscular development
  • N-myc amplification (unlike embryonal)
  • predominately older childern
  • predominately extremities, trunk, and retroperitoneum
• Undifferentiated
  • diffuse cell population of primitive, noncommitted mesenchymal cells
  • primarily a diagnosis of exclusion

Superior prognosis:

• Botyroid ERMS (6%) - 5-yr OS 95%
  • "grape like." Occurs in mucosa-lined organs -- bladder, vagina, nasopharynx, middle ear, biliary tree. Generally localized and non-invasive.
• Spindle cell ERMS (3%) - 5-yr OS 88%
  • Most common site is paratesticular.

Intermediate prognosis:

• Embryonal (59%) - 5-yr OS 66%
  • Orbit, GU, H&N
  • Blastemal mesenchymal cells. Resembles normal skeletal muscle of 7-10 wk old fetus. Often with LOH 11p15.5.

Poor prognosis:

• Alveolar (32%) - 5-yr OS 54%
  • Extremities, Trunk, Retroperitoneal
  • Line connective tissue septa reminescent of alveoli. Resemble normal skeletal muscle of 10-20 wk old fetus. t(2;13) or t(1;13). Frequent n-myc amplification.
• Undifferentiated (1%) - 5-yr OS 40%

Prognostic factors

• Primary site - determines resectability (and thus IRS grouping)
• Tumor size (<5 or >5 cm)
• Lymph node involvement - +LN associated with more advanced primary
• Histology
• Complete resection

Staging and grouping

TNM Staging:

• T1 - Confined to anatomic site of origin
  • T1a - <= 5 cm
  • T1b - > 5 cm
• T2 - Extension beyond site of origin
  • T2a - <= 5 cm
  • T2b - > 5 cm

• N-stage: N0 or N1
• M-stage: M0 or M1

IRS Staging Classification (pre-treatment): (IRS-IV)

Stage	Sites	TNM	5-yr OS
Stage 1	Favorable sites: Orbit, H&N (excluding parameningeal), GU (non-bladder, non-prostate), Biliary tract	any size, N0 or N1	90%
Stage 2	Unfavorable sites: Parameningeal H&N, GU (Bladder/Prostate,) Extremity, Other (trunk, retroperitoneum, etc.)	<=5cm and N0	85%
Stage 3	Unfavorable sites: Same as Stage 2	>5cm or N+	70%
Stage 4	All	M1	30%

• Parameningeal H&N sites include: (IMMNNPPP) - Infratemporal fossa, Middle ear, Mastoid region, Nasal cavity, Nasopharynx, Paranasal sinus, Pterygopalatine fossa, +/- parapharyngeal region (sometimes included). Mnemonic is "I make money nuking numerous pediatric patients."

IRS Grouping (after resection):

Group	Status
Group I	completely resected
Group II	microscopic residual disease, or resected LN+
Group III	gross residual disease
Group IV	distant mets

Risk stratification

EMB = Embryonal, Botryoid, or Spindle cell
ALV = Alveolar or undifferentiated

• Low risk:
  • EMB Stage 1 (favorable site), Group I-III (non-metastatic)
  • EMB Stage 2-3 (unfavorable site), Group I-II (R0, R1, or LN+)

• Intermediate risk:
  • EMB Stage 2-3 (unfavorable site), Group III (gross disease)
  • ALV Stage 1-3 (any alveolar)

• High risk:
  • Metastases (Stage 4, Group IV)

Treatment

• Prior to 1970, RMS was treated with surgery alone or RT alone and had poor outcomes (OS <25%). Only exception was orbit and GU
• Series of trials: Intergroup Rhabdomyosarcoma Study Group IRS I-IV, V ongoing
• Risk adapted therapy based on: tumor size, site, histology, residual disease after surgery, LN involvement, distant mets, and patient age (see above)
  • 5-year OS improved from IRS-I 55% to IRS-II 63% to IRS-III/IV 71%
• Recommend treating all patients on protocol

IRS Trials

• IRSG-D9602 (1997-2004) - non-randomized.
  • Purpose: to decrease toxicity by reducing RT doses and eliminating cyclophosphamide.
  • Subgroup A (lowest risk) - (embryonal, stage 1, group I/IIA; stage 1, group III orbit; or stage 2, group I) -- received VA (vincristine, dactinomycin)
  • Subgroup B - (embryonal, stage 1, group IIB/C; stage 1, group III non-orbit; stage 2, group II; stage 3, group I/II) -- received VA + cyclophosphamide
  • 342 pts (264 in subgroup A, 78 in subgroup B). Patients in group II or III received RT. Dose reduction of 36 Gy vs 41.4 Gy (in stage 1, group IIA), compared with IRS-IV; or 45 Gy (in group III orbit) vs 50-59 Gy, compared with IRS-IV.
  • 2011 PMID 21357783 (Median f/u 5.1 yrs) -- "Results of the Intergroup Rhabdomyosarcoma Study Group D9602 Protocol, Using Vincristine and Dactinomycin With or Without Cyclophosphamide and Radiation Therapy, for Newly Diagnosed Patients With Low-Risk Embryonal Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children's Oncology Group." (Raney RB, J Clin Oncol. 2011 Feb 28. [Epub ahead of print])
    • 5-yr FFS 89% for subgroup A, 85% subgroup B. 5-yr FFS 81% (stage 1, group IIA), 86% (group III orbit)
    • Conclusion: Compared with historical controls (in IRS-III/IV, 5-yr FFS 83% and OS 95%), FFS and OS rates were similar compared with pts on IRS-III, but were lower than pts on IRS-IV receiving VA + cyclophosphamide. FFS rates were similar among subgroups A and B.

• IRS-IV (1991-1997)
  • Randomized. 883 patients with non-metastatic RMS after surgery. Treatment by tumor site, Group (1-3), and Stage (I-III)
  • CG III RT: conventional (50.4/28) vs. hyperfractionated (59.4/54 in 1.1 Gy BID). Also, WBRT omitted for all parameningeal unless CSF involvement documented
  • 2001 PMID 11408506 -- "Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease." (Crist WM, J Clin Oncol. 2001 Jun 15;19(12):3091-102.)
    • 3-year OS: 86%
    • CG III: HF-RT comparable to conventional RT
    • VAC and VAI or VIE equally effective
    • Embryonal RMS benefited from intense chemo, no difference for alveolar/undifferentiated
    • Prognostic subgroups developed (see above)

• IRS III (1984-1991)
  • Randomized. 1062 previously untreated patients. Treatment by clinical group (I-IV), histology (favorable-unfavorable), and site
  • RT: none in CG I favorable, CG I unfavorable and CG II 41.4 Gy, CG III 41.4 Gy if <5cm and <6 years, 50.4 Gy if >5cm or >6 years
  • 1995 PMID 7884423 -- "The Third Intergroup Rhabdomyosarcoma Study." (Crist W, J Clin Oncol. 1995 Mar;13(3):610-30.)
    • 5-year OS: 71% (compared with 62% in IRS II). 5-year PFS 65% (compared with 55% in IRS II)
    • CG I favorable: VA alone as good as VAC. 5-year PFS 83%
    • CG II favorable (excluding orbit, head, paratesticular): VA + RT comparable to VAD + RT
    • CG III (excluding orbit, head): intensive chemo better than VAC or VAC-VADRC. 5-year PFS 62%
    • CG III (bladder, vagina, pelvis): much better outcome due to early RT, with better bladder salvage (60% vs. 25%)
    • CG IV: no benefit from aggressive therapy
    • Whole brain RT omitted for parameningeal tumors with nerve palsy or base of skull erosion - risk of CNS relapse comparable

• IRS II (1978-1984)
  • Randomized. 999 previously untreated patients. Treatment by clinical group (I-IV), histology (favorable-unfavorable), and site
  • RT Dose escalation (CG I no RT, CG II 40-45 Gy, CG III and <5cm and <6 years 40-45 Gy, CG III and >5 cm or >6 years 50-55 Gy). WBRT if parameningeal tumors with nerve palsy, base of skull erosion, or intracranial extent
  • 1993 PMID 8448756 -- "The Intergroup Rhabdomyosarcoma Study-II." (Maurer HM, Cancer. 1993 Mar 1;71(5):1904-22.)
    • 5-year OS: 62% (compared with 55% in IRS I)
    • CG I (excluding extremity alveolar): VA comparable to VAC. Alveolar had high rate of relapse
    • CG II: intensive VA comparable to repetitive-pulse VAC
    • CG III (excluding pelvic): VAC comparable to VDC-VAC
    • Whole brain RT improved meningeal recurrence and increased survival in high risk patients with parameningeal sites (67% vs. 45% in IRS-I)
    • CG IV: no benefit over IRS-I

• IRS I (1972-1978)
  • Randomized. 686 previously untreated patients. Minimum F/U 7 years
  • 1988 PMID 3275486 -- "The Intergroup Rhabdomyosarcoma Study-I. A final report." (Maurer HM, Cancer. 1988 Jan 15;61(2):209-20.)
    • 5-year OS: 55%, after relapse 32% at 1 year. Risk of DM much greater than LR
    • CG I: VAC, no benefit to RT. Subsequent analysis showed benefit in alveolar or undifferentiated histology.
    • CG II: No difference between VA + RT or VAC + RT
    • CG III and IV: No difference between VAC + RT or VACD + RT. 5-year OS CG III 52% vs. CG IV 20%
    • No dose-response relationship 40-60 Gy
    • No difference in RT to whole muscle bundle vs. tumor + margin only
    • Parameningeal sites with high risk factors (palsy, erosion of base of skull, etc) had high incidence of CNS relapse

Surgery

• Only ~20% of patients can undergo R0 resection, and another 20% can undergo compromised R1 resection
• Trend toward less aggressive surgical resection and more reliance on chemo-RT
• Normal margin of 5mm typically required (Perez 5th edition) to be considered complete excision

Radiotherapy

General:

• RMS infiiltrates along tissues planes, and may extend beyond obvious visible margins
• Treat pre-chemo, pre-surgery tumor volume. 2 cm margin is sufficient (per IRS-IV)
• For parameningeal sites, treatment of adjacent meninges can prevent meningeal relapse
• Elective LN irradiation not neccesary if clinically negative and will be treated with chemotherapy (Perez 5th ed)
• Hyperfractionated BID RT does not improve outcomes in a randomized setting
• Timing: Low risk - week 3 of chemo. Intermediate risk - week 12 of chemo. High risk - week 15 of chemo. Immediately for locally advanced cranial parameningeal disease.

IRS-V (ongoing):

• low risk disease
  • complete resection, SM- = no RT
  • microscopic SM+ and LN- = 36 Gy
  • microscopic SM+ and LN+ = 41.1 Gy
  • orbital primary with residual gross disease = 45 Gy
  • non-orbital primaries with residual gross disease = 50.4 Gy
• intermediate risk disease
  • complete resection, SM- = 36 Gy
  • miscroscopic SM+ = 41.4 Gy
  • gross residual disease = 50.4 Gy

• RT guidelines
  • CTV = pre-chemo GTV + 1.5 cm
  • PTV = CTV + institutional margin (0.3 - 0.5 cm)
  • Since this margin (1.8 - 2cm) is larger than the original IRS margin (2cm from block, which translates to effective 1.5cm due to penumbra), next generation of protocols will have CTV - PTV expansion of 1.5 cm
  • Start time: Day 0 if intracranial extension, week 3 for low risk, week 12 intermediate risk, week 15 high risk

Chemotherapy

• Chemotherapy is used for all patients
• Non-metastatic: VAC (vincristine, actinomycin D, cyclophosphamide)
• Metastatic: Currently using "up-front window" approach:
  • Test 1-2 agents for 1-2 cycles during 6 weeks
  • If they respond, add to standard VAC + XRT

• Topotecan
  • Metastatic disease: highly active
• Melphalan
  • Metastatic disease: inferior survival compared to IE
• Ifosfamide/Etoposide
  • Recurrent disease: active
  • Local disease: comparable outcome VAC vs. VAI vs. VIE, but toxicity and logistics better for VAC
• Cisplatin/Etoposide
  • No benefit VAC/dox/cisplatin and VAC/dox/cisplatin/etoposide vs. VAC alone
• Doxorubicin
  • No benefit VAC/dox vs. VAC alone
• Base chemotherapy is VAC (vincristine, actinomycin D, cyclophosphamide)

Specific Subsets

Clinical Group I (complete resection)

• IRS-I/II/III, 1999 (1972-1991) PMID 10550144 -- "Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III." (Wolden SL, J Clin Oncol. 1999 Nov;17(11):3468-75.)
  • Retrospective analysis of IRS-I to IRS-III protocols. 439 patients with completely resected RMS (Group I), treated with VAC +/- dox/cisplatin. 19% received RT
  • 10-year outcomes: OS 89%, FFS 79%. Failures: 6% local, 6% regional, 7% distal
  • ERMS: no difference in OS, trend to benefit for FFS
  • ARMS/undifferentiated:
    • IRS I/II: 10-year OS RT+ 82% vs. RT- 52% (SS), 10-year FFS 73% vs. 44% (SS)
    • IRS III: 10-year OS RT+ 95% vs. RT- 86% (NS), 10-year FFS 95% vs. 69% (SS)
  • Conclusion: Patients with Group I embryonal RMS have excellent prognosis without RT; alveolar RMS outcomes substantially improved with RT

Head & Neck

• 35% of RMS patients (15% parameningeal, 10% orbit, 10% other)
• Majority are unresectable (CG III) at diagnosis
• Orbit and non-parameningeal sites have high cure rates
• Parameningeal sites (see above) have worse control
  • Bad prognostic factors: base of skull erosion, intracranial extension, cranial nerve palsy, primary location in paranasal sinuses or pterygoid/infratemporal fossa
  • Local failure in IRS-IV was 16%, with DM 11%
  • Local failure from MSKCC series was 5%, and 0% in CG I-III as reported in IRS-IV

• SIOP MMT 89 & 95 1989-2003) PMID 19204197 -- "Treatment of nonmetastatic cranial parameningeal rhabdomyosarcoma in children younger than 3 years old: results from international society of pediatric oncology studies MMT 89 and 95." (Defachelles AS, J Clin Oncol. 2009 Mar 10;27(8):1310-5. Epub 2009 Feb 9.)
  • Prospective. 59 children, cranial parameningeal RMS. Goal to avoid RT if CR after chemo
  • Outcome: 5-year EFS if RT used 59% vs. if no RT used 28% (SS). Only 12% ultimately cured without RT
  • Conclusion: Despite concerns about late effects, cure of PM RMS remains unlikely without RT

• MSKCC, 2005 PMID 15817347 -- "Intensity-modulated radiotherapy for head-and-neck rhabdomyosarcoma." (Wolden SL, Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1432-8.)
  • Retrospective. 28 patients (21 parameningeal, 3 orbital, 4 other), treated with IMRT. 89% Group III disease, 71% intracranial extension . Median tumor size 5.2 cm. RT median dose 50.4 Gy (30-55.8), 1.5 cm margin (1cm CTV + 0.5 PTV). No boost.
  • 3-year OS: 65%, 3-year FFF 95% locally (100% for Groups I-III), 90% regional LN, 88% CNS, 80% distal sites. Alveolar RMS significantly worse
  • Toxicity: acute comparable to IRS trials, late was mild (1 cataract, 1 GH deficiency, 1 mild facial asymetry)
  • Conclusion: Outstanding local control despite reduced margin

• IRS II-IV, 2004 (1978-1997) PMID 15234036 -- "Influence of radiation therapy parameters on outcome in children treated with radiation therapy for localized parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Study Group trials II through IV." (Michalski JM, Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1027-38.)
  • Retrospective. 595 patients with PM-RMS registered. 95% with Group III disease. RT varied per protocol (40, 50.4, 59.4 BID). 21% patients (40% on IRS-II) received WBRT
  • 5-year OS: 73%. 5-year LF: 17%
  • Intracranial extension: increased 24% to 41% with cross-sectional imaging
  • Timing of RT:
    • Meningeal impingement: <2 weeks after chemo 18% LF vs. >2 weeks 33% (SS)
    • Intracranial extension: <2 weeks after chemo 16% LF vs. >2 weeks 37% (NS, p=0.07)
    • Cranial nerve palsy/ base of skull bone erosion: <2 weeks after chemo 21% LF vs. >2 weeks 30% (NS)
    • If no signs of meningeal impingement: no difference in LF if RT start earlier/later than 10 weeks
  • RT Dose
    • Large (>=5 cm) tumors: <47.5 Gy LF 35% vs. >47.5 Gy 15%. Small tumors no difference
    • WBRT no impact on LR or CNS failure