Abstract
Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma and 5-year overall survival exceeds 70%. With more long-term survivors, it is critical to understand the frequency of late events, including recurrence, second malignant neoplasm, and death, occurring 5 years after diagnosis, and the variables associated with these events. We report late events in patients enrolled on Intergroup Rhabdomyosarcoma Study Group and Children’s Oncology Group trials from 1997–2013 including D9602, D9803, D9802, ARST0331, ARST0431, ARST0531, and ARST08P1. A late event occurred in 2.9% of 5-year event free survivors supporting guidelines to limit surveillance for these events to 5 years from diagnosis.
Keywords: Rhabdomyosarcoma, late events
Introduction
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. After 30 years of cooperative group trials, the 5-year overall survival of pediatric RMS treated with multimodality regimens exceeds 70%1. With an increasing number of long-term survivors, it is critical to understand the frequency and etiology of late events, including recurrence, second malignant neoplasm (SMN), and death, occurring more than 5 years after diagnosis. Recent trials including D9602, D9803, D9802, ARST0331, ARST0431, ARST0531, and ARST08P1, have focused on lowering the burden of therapy in low-risk disease, optimizing local control approaches, and intensifying treatment in high-risk disease2–9. Characterizing late events on these trials is essential to provide counseling regarding long-term surveillance of pediatric RMS survivors. The objectives of this study were to determine the prevalence of late events, identify clinicopathologic variables associated with late events, and compare these findings to older pediatric RMS cohorts.
Methods
Using the Children’s Oncology Group (COG) database, we reviewed the records of children with pediatric RMS treated on Intergroup Rhabdomyosarcoma Study Group (IRSG) and Children’s Oncology Group (COG) trials from 1997–2013, including D9602 (1997–2004), D9803 (1999–2005), D9802 (1999–2004), ARST 0331 (2004–2011), ARST0531 (2006–2012), ARST0431 (2006–2008), and ARST08P1 (2010–2013). We identified all patients alive and event-free at 5 years from study entry and evaluated late events. An event was defined as disease recurrence, development of SMN, or death from any cause. Patients who had a first event, were censored, or were lost to follow-up before 5 years were excluded from the analysis. Patients with more than one late event were evaluated as experiencing two or more events. Clinicopathologic variables in these patients are summarized using frequency and percentage. Cumulative incidence of late events at 10 years are estimated using Nelson-Aalen method and compared using the Gray test.
Results
A total of 2,157 patients were enrolled on D9602, D9803, D9802, ARST0331, ARST0431, ARST0531, and ARST08P1 between 1997 and 2013. Of these, 1,037 patients were event-free with available follow-up data at 5 years from study entry and eligible for the analysis (Supplemental Figure 1). A late event was identified in 30 patients (2.9%) of whom 14 had recurrent RMS, 14 had SMN, and 2 died. The estimated cumulative incidence was 1.35% for recurrence, 1.35% for SMN, and 0.19% for death as a first event at 10 years from study entry. Cause of death for 1 patient treated on D9803 was cor pulmonale attributed to Cyclophosphamide-induced lung injury. Cause of death for the second patient was not reported. Median follow-up time of patients eligible for the analysis was 8 years (5–14.75 years) and 219 patients (21%) were lost to follow-up after 5 years from study entry.
Table 1 describes the clinicopathologic features of patients with a late event. Median time to first late event was 5.7 years for recurrent RMS, 7.4 years for SMN, and 9.4 years for death. Histology in 28 patients was embryonal (n=17, 61%), alveolar (n = 4, 14%), botryoid (n = 4, 14%), and spindle cell (n=3, 11%). The majority of patients (n=15, 54%) had unfavorable primary tumor sites. Sixteen patients (53%) had tumors > 5 cm. Of the 14 patients with a late recurrence, most (n=10, 71.4%) had Group III or IV disease. Ten recurrences were characterized, most (n=8, 80%) were local, and of those local recurrences, 50% had received radiotherapy as part of their initial treatment.
TABLE 1.
Clinicopathologic variables in patients with late events
| Late Recurrence (n=14) | Late SMN (n=14) | Late Death (n=2) | No Event (n=1,007) | |
|---|---|---|---|---|
| Time To Event (years) | ||||
| Mean | 6.4 | 7.6 | 9.4 | N/A |
| Median | 5.7 | 7.4 | 9.4 | N/A |
| Range | 5.0, 11.3 | 5.1, 11.0 | 7.9, 11.0 | N/A |
| Age (years), n (%) | ||||
| <1 | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 37 (3.7%) |
| 1–9 | 13 (92.9%) | 12 (85.7%) | 2 (100.0%) | 706 (70.1%) |
| ≥10 | 1 (7.1%) | 2 (14.3%) | 0 (0.0%) | 264 (26.2%) |
| Gender, n (%) | ||||
| Male | 8 (57.1%) | 10 (71.4%) | 0 (0.0%) | 628 (62.4%) |
| Female | 6 (42.9%) | 4 (28.6%) | 2 (100.0%) | 379 (37.6%) |
| Histology, n (%) | ||||
| Alveolar | 2 (14.3%) | 2 (14.3%) | 0 (0.0%) | 197 (19.6%) |
| Embryonal | 8 (57.1%) | 8 (57.1%) | 1 (50.0%) | 523 (51.9%) |
| Botryoid | 3 (21.4%) | 1 (7.1%) | 0 (0.0%) | 121 (12.0%) |
| Not otherwise specified | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 29 (2.9%) |
| Spindle cell | 1 (7.1%) | 2 (14.3%) | 0 (0.0%) | 121 (12.0%) |
| Other | 0 (0.0%) | 1 (7.1%) | 0 (0.0%) | 2 (0.2%) |
| Mixed RMS | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 13 (1.3%) |
| Unknown | 0 (0.0%) | 0 (0.0%) | 1 (50.0%) | 1 (0.1%) |
| Primary Site, n (%) | ||||
| Unfavorable | 8 (57.1%) | 6 (42.9%) | 1 (50.0%) | 452 (44.9%) |
| Favorable | 5 (35.7%) | 8 (57.1%) | 0 (0.0%) | 532 (52.8%) |
| Other | 1 (7.1%) | 0 (0.0%) | 0 (0.0%) | 22 (2.2%) |
| Unknown | 0 (0.0%) | 0 (0.0%) | 1 (50.0%) | 1 (0.1%) |
| Size, n (%) | ||||
| ≤5 cm | 8 (57.1%) | 6 (42.9%) | 0 (0.0%) | 627 (62.3%) |
| >5 cm | 6 (42.9%) | 8 (57.1%) | 2 (100.0%) | 380 (37.7%) |
| Tumor Invasiveness, n (%) | ||||
| T1 | 8 (57.1%) | 10 (71.4%) | 0 (0.0%) | 686 (68.1%) |
| T2 | 6 (42.9%) | 4 (28.6%) | 1 (50.0%) | 319 (31.7%) |
| Unknown | 0 (0.0%) | 0 (0.0%) | 1 (50.0%) | 2 (0.2%) |
| Nodal Involvement, n (%) | ||||
| N0 | 11 (78.6%) | 12 (85.7%) | 1 (50.0%) | 848 (84.2%) |
| N1 | 3 (21.4%) | 1 (7.1%) | 0 (0.0%) | 145 (14.4%) |
| Unknown | 0 (0.0%) | 1 (7.1%) | 1 (50.0%) | 14 (1.4%) |
| Group, n (%) | ||||
| I | 2 (14.3%) | 1 (7.1%) | 0 (0.0%) | 230 (22.8%) |
| II | 2 (14.3%) | 2 (14.3%) | 0 (0.0%) | 190 (18.9%) |
| III | 6 (42.9%) | 9 (64.3%) | 0 (0.0%) | 520 (51.6%) |
| IV | 4 (28.6%) | 2 (14.3%) | 1 (50.0%) | 66 (6.6%) |
| Unknown | 0 (0.0%) | 0 (0.0%) | 1 (50.0%) | 1 (0.1%) |
| Stage, n (%) | ||||
| 1 | 6 (42.9%) | 6 (42.9%) | 0 (0.0%) | 523 (51.9%) |
| 2 | 2 (14.3%) | 1 (7.1%) | 0 (0.0%) | 165 (16.4%) |
| 3 | 2 (14.3%) | 5 (35.7%) | 0 (0.0%) | 251 (24.9%) |
| 4 | 4 (28.6%) | 2 (14.3%) | 1 (50.0%) | 67 (6.7%) |
Among the 14 patients with a late SMN, there were 16 SMNs with 12 solid and 4 hematologic malignancies including myelodysplastic syndrome and acute myeloid leukemia. Solid malignancies included mucoepidermoid carcinoma, thyroid carcinoma, basal cell carcinoma, osteosarcoma, undifferentiated sarcoma, anaplastic astrocytoma, pontine glioma, and Sertoli-Leydig cell tumor. Five (41.7%) of the solid malignancies occurred in the radiation field of the primary tumor. Nearly one-third of patients with late SMN (n=4, 28.6%) had a known cancer predisposition syndrome including Li-Fraumeni, DICER1, and Gorlin syndrome. Of the 3 patients with a known cancer predisposition syndrome who developed a solid SMN, 1 patient developed an SMN in the radiation field of the primary tumor.
Tumor size ≥5 cm, advanced group, and advanced stage were predictive of a late event on a univariate analysis. Group and stage were significantly associated with late recurrence with an estimated cumulative incidence of 8.1% (p=0.0124) for patients with Group IV or Stage 4 disease. There was a non-significant trend towards increased rates of late SMN in patients with tumors ≥5 cm with a cumulative incidence of 4.2% (p=0.0560) (Supplemental Table 1).
Discussion
This analysis demonstrates that children with RMS treated with contemporary protocols who remain event-free for 5 years after study entry have a low risk (2.9%) of late events. The probability of a late event in our series was lower when compared to the late event analysis of IRSG III-IV10. This difference may be due to efforts in contemporary protocols to further refine risk stratification and individualize therapies. The most common late events in our analysis, recurrence and SMN, reflects a similar distribution of late events in the IRSG III-IV analysis and a report by the Italian Cooperative Group11. There were fewer late deaths in our analysis that may reflect the lower burden of therapy in low risk disease or optimization of supportive care measures. Median time to late event was comparable to the IRSG III-IV analysis10. Most patients with a late event were 1–9 years at time of initial RMS diagnosis. The lower rate of clinical trial enrollment and higher incidence of attrition in the adolescent and young adult patient population may confound these findings12.
Our analysis determines that late recurrences are rare and consistent with the report from Childhood Cancer Survivor Study among patients with soft tissue sarcoma13. This supports current recommendations to limit surveillance for recurrence to 5 years from diagnosis. In addition, outcomes are not superior in patients with relapse detected by surveillance14–15. The cumulative incidence of late SMN is comparable to analyses reporting late SMNs in 1.8–2.3% of childhood RMS survivors16–17. The cumulative incidence of late SMN was higher in patients diagnosed with RMS between 1–9 years aligned with data suggesting the risk of SMN is age-dependent and highest among young children18. Nearly half of solid SMNs occurred in the radiation field similar to previous reports18. Further long-term studies are needed to investigate the impact of conformal radiotherapy on the risk of late SMN. Our report also highlights the prevalence of cancer predisposition syndromes in patients with RMS and SMN. Cancer predisposition has been reported in 7.3% of newly diagnosed patients with fusion negative RMS19–20. Goudie et al provides recommendations for screening patients for cancer predisposition at diagnosis of RMS, and several authors have provided guidelines for predisposition-specific surveillance21–23.
There are several limitations of our report. The small number of patients with a late event limits the extent of statistical analysis. We are likely underestimating the cumulative incidence of a late event, in particular SMN, since median follow-up time was 8 years and SMNs may develop thereafter. The percentage of patients susceptible to SMN may be underreported since not all patients with SMN were screened for cancer predisposition.
Conclusions
Children with RMS treated with contemporary protocols who remain event-free for 5 years after study entry have a low risk (2.9%) of late events. Our data justifies discontinuation of surveillance for recurrence after 5 years from diagnosis. For patients who develop late SMN, consider germline genetic evaluation if not already performed.
Supplementary Material
Acknowledgements
We acknowledge the support from the National Institutes of Health with NCTN Operations Center Grant U10CA180886, NCTN Statistics & Data Center Grant U10CA180899, and St. Baldrick’s Foundation.
Abbreviations:
- RMS
Rhabdomyosarcoma
- OS
Overall survival
- SMN
Second malignant neoplasm
- IRSG
Intergroup Rhabdomyosarcoma Study Group
- COG
Children’s Oncology Group
Footnotes
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of Interest Statement
The authors have no conflicts of interest to disclose.
References
- 1.Skapek SX, Ferrari A, Gupta AA, et al. Rhabdomyosarcoma. Nat Rev Dis Primer. 2019;5(1):1–19. 10.1038/s41572-018-0051-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Beverly Raney R, Walterhouse DO, Meza JL, et al. 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. J Clin Oncol. 2011;29(10):1312–1318. 10.1200/JCO.2010.30.4469 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Arndt CAS, Stoner JA, Hawkins DS, et al. Vincristine, Actinomycin, and Cyclophosphamide Compared With Vincristine, Actinomycin, and Cyclophosphamide Alternating With Vincristine, Topotecan, and Cyclophosphamide for Intermediate-Risk Rhabdomyosarcoma: Children’s Oncology Group Study D9803. J Clin Oncol. 2009;27(31):5182–5188. 10.1200/JCO.2009.22.3768 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Walterhouse DO, Pappo AS, Meza JL, et al. Shorter-Duration Therapy Using Vincristine, Dactinomycin, and Lower-Dose Cyclophosphamide With or Without Radiotherapy for Patients With Newly Diagnosed Low-Risk Rhabdomyosarcoma: A Report From the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol. 2014;32(31):3547–3552. 10.1200/JCO.2014.55.6787 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Walterhouse DO, Pappo AS, Meza JL, et al. Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. Cancer. 2017;123(12):2368–2375. 10.1002/cncr.30613 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Casey DL, Chi YY, Donaldson SS, et al. Increased Local Failure for Patients with Intermediate-Risk Rhabdomyosarcoma on ARST0531: A Report from the Children’s Oncology Group. Cancer. 2019;125(18):3242–3248. 10.1002/cncr.32204 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hawkins DS, Chi YY, Anderson JR, et al. Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J Clin Oncol. 2018;36(27):2770–2777. 10.1200/JCO.2018.77.9694 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Weigel BJ, Lyden E, Anderson JR, et al. Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J Clin Oncol. 2015;34(2):117–122. 10.1200/JCO.2015.63.4048 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Malempati S, Weigel BJ, Chi YY, et al. The Addition of Cixutumumab or Temozolomide to Intensive Multiagent Chemotherapy Is Feasible but Does Not Improve Outcome for Patients with Metastatic Rhabdomyosarcoma: A Report from the Children’s Oncology Group. Cancer. 2019;125(2):290–297. 10.1002/cncr.31770 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Sung L, Anderson JR, Donaldson SS, Spunt SL, Crist WM, Pappo AS. Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. Eur J Cancer. 2004;40(12):1878–1885. 10.1016/j.ejca.2004.04.005 [DOI] [PubMed] [Google Scholar]
- 11.Bisogno G, Pastore G, Perilongo G, et al. Long-term results in childhood rhabdomyosarcoma: A report from the Italian cooperative study RMS 79. Pediatr Blood Cancer. 2012;58(6):872–876. 10.1002/pbc.23292 [DOI] [PubMed] [Google Scholar]
- 12.Puthenpura V, Ji L, Xu X, Roth ME, Freyer DR, Frazier AL, Marks AM, Pashankar FD. Loss to follow-up of minorities, adolescents, and young adults on clinical trials: A report from the Children’s Oncology Group. Cancer. 2023. May 15;129(10):1547–1556. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Wasilewski-Masker K, Liu Q, Yasui Y, et al. Late Recurrence in Pediatric Cancer: A Report From the Childhood Cancer Survivor Study. JNCI J Natl Cancer Inst. 2009;101(24):1709–1720. 10.1093/jnci/djp417 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Lin JL, Guillerman RP, Russell HV, Lupo PJ, Nicholls L, Okcu MF. Does Routine Imaging of Patients for Progression or Relapse Improve Survival in Rhabdomyosarcoma? Pediatr Blood Cancer. 2016. Feb;63(2):202–5. [DOI] [PubMed] [Google Scholar]
- 15.Vaarwerk B, Mallebranche C, Affinita MC, van der Lee JH, Ferrari A, Chisholm JC, Defachelles AS, De Salvo GL, Corradini N, Minard-Colin V, Morosi C, Brisse HJ, McHugh K, Bisogno G, van Rijn RR, Orbach D, Merks JHM. Is surveillance imaging in pediatric patients treated for localized rhabdomyosarcoma useful? The European experience. Cancer. 2020. Feb 15;126(4):823–831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Heyn R, Haeberlen V, Newton WA, et al. Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol. Published online September 21, 2016. 10.1200/JCO.1993.11.2.262 [DOI] [PubMed] [Google Scholar]
- 17.Sung L, Anderson JR, Donaldson SS, Spunt SL, Crist WM, Pappo AS. Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. Eur J Cancer. 2004;40(12):1878–1885. 10.1016/j.ejca.2004.04.005 [DOI] [PubMed] [Google Scholar]
- 18.Archer NM, Amorim RP, Naves R, et al. An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population-Based Evidence for a Cancer Predisposition Syndrome? Pediatr Blood Cancer. 2016;63(2):196–201. 10.1002/pbc.25678 [DOI] [PubMed] [Google Scholar]
- 19.Li H, Sisoudiya SD, Martin-Giacalone BA, et al. Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children’s Oncology Group. JNCI J Natl Cancer Inst. 2021;113(7):875–883. 10.1093/jnci/djaa204 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Pinto N, Hawkins DS. Second Malignant Neoplasms in Rhabdomyosarcoma: Victims of Our Own Success or an Underlying Genetic Predisposition Syndrome? Pediatr Blood Cancer. 2016;63(2):189–190. 10.1002/pbc.25776 [DOI] [PubMed] [Google Scholar]
- 21.Goudie C, Coltin H, Witkowski L, Mourad S, Malkin D, Foulkes WD. The McGill Interactive Pediatric OncoGenetic Guidelines: An approach to identifying pediatric oncology patients most likely to benefit from a genetic evaluation. Pediatr Blood Cancer. 2017;64(8):e26441. 10.1002/pbc.26441 [DOI] [PubMed] [Google Scholar]
- 22.Kratz CP, Achatz MI, Brugières L, Frebourg T, Garber JE, Greer MC, Hansford JR, Janeway KA, Kohlmann WK, McGee R, Mullighan CG, Onel K, Pajtler KW, Pfister SM, Savage SA, Schiffman JD, Schneider KA, Strong LC, Evans DGR, Wasserman JD, Villani A, Malkin D. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin Cancer Res. 2017;23(11):38–45. 10.1158/1078-0432.CCR-17-0408 [DOI] [PubMed] [Google Scholar]
- 23.Schultz KAP, Williams GM, Kamihara J, Stewart DR, Harris AK, Bauer AJ, Turner J, Shah R, Schneider K, Schneider KW, Carr AG, Harney LA, Baldinger S, Frazier AL, Orbach D, Schneider DT, Malkin D, Dehner LP, Messinger YH, Hill DA. DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies. Clin Cancer Res. 2018;24(10):2251–2261. 10.1158/1078-0432 [DOI] [PMC free article] [PubMed] [Google Scholar]
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