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 children 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 children 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 foetus. Often with LOH 11p15.5. Poor prognosis: Alveolar (32%) - 5-yr OS 54% Extremities, Trunk, Retroperitoneal Line connective tissue septa reminiscent of alveoli. Resemble normal skeletal muscle of 10-20 wk old foetus. 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 OSStage 1Favorable sites:Orbit, H&N (excluding parameningeal), GU (non-bladder, non-prostate),Biliary tractany size, N0 or N190%Stage 2Unfavorable sites: Parameningeal H&N,GU (Bladder/Prostate,) Extremity,Other (trunk, retroperitoneum, etc.)<=5cm and N0 85%Stage 3Unfavorable sites:Same as Stage 2 >5cm or N+ 70%Stage 4AllM130% Parameningeal H&N sites include: (IMMNNPPP) - Infratemporal fossa, Middle ear, Mastoid region, Nasal cavity, Nasopharynx, Paranasal sinus, Pterygopalatine fossa, +/- parapharyngeal region (sometimes included). Alternate (MMNNOOPP) - Middle ear, Mastoid region, Nasal cavity, Nasopharynx, Infratemporal fOssa, Pterygopalatine fOssa, Paranasal sinus, +/- parapharyngeal region (sometimes included) IRS Grouping (after resection): Group StatusGroup I SM-, localized diseaseGroup IIA SM+Group IIB LN+ (resected)Group IIC IIA & IIBGroup III gross residual diseaseGroup 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: (1) decrease toxicity by reducing RT doses(2) eliminate cyclophosphamide in lowest-risk patients. 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). No RT for Group I pts. Pts in group II-III received RT. In patients with stage I, group IIA disease, dose was reduced to 36 Gy (41.4 Gy in IRS-IV). For those with group III orbit disease, dose was reduced to 45 Gy (50-59 Gy in IRS-IV). 2011 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 Apr 1;29(10):1312-8) 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 to IRS-III including those with reduced RT doses, but inferior to IRS-IV pts with 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 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 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 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 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 infiltrates 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 necessary if clinically negative and will be treated with chemotherapy (Perez 5th ed) Hyperfractionated BID RT does not improve outcomes in a randomized setting Timing (newly-revised): Low risk - week 13 of chemo. Intermediate risk - week 4 of chemo. High risk - week 20 of chemo. Day 0 for documented intracranial extension. IRS-V (ongoing): low risk disease complete resection, SM- = no RT microscopic SM+ and LN- = 36 Gy microscopic SM+ and LN+ = 41.4 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 13 for low risk, week 4 intermediate risk, week 20 high risk (primary site) and week 47 (metastases) 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) 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) 19204197 -- "Treatment of nonmetastatic cranial parameningeal rhabdomyosarcoma in children younger than 3 years old: results from international society of paediatric 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 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 asymmetry) Conclusion: Outstanding local control despite reduced margin IRS II-IV, 2004 (1978-1997) 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