Adjuvant Radiotherapy for Pediatric and Young Adult Nonrhabdomyosarcoma Soft-Tissue Sarcoma

doi:10.1016/j.ijrobp.2010.05.005

International Journal of Radiation OncologyBiologyPhysics

Volume 81, Issue 1, 1 September 2011, Pages 150-157

https://doi.org/10.1016/j.ijrobp.2010.05.005 Get rights and content

Purpose

To evaluate the prognostic factors, outcomes, and complications in patients aged ≤30 years with resectable nonrhabdomyosarcoma soft-tissue sarcoma treated at the University of Florida with radiotherapy (RT) during a 34-year period.

Methods and Materials

A total of 95 pediatric or young adult patients with nonrhabdomyosarcoma soft-tissue sarcoma were treated with curative intent with surgery and RT at the University of Florida between 1973 and 2007. The most common histologic tumor subtypes were synovial sarcoma in 22 patients, malignant fibrous histiocytoma in 19, and malignant peripheral nerve sheath tumor in 11 patients. The mean age at RT was 22 years (range, 6–30). Of the 95 patients, 73 had high-grade tumors; 45 had undergone preoperative RT and 50 postoperative RT. The prognostic factors for survival, local recurrence, and distant recurrence were analyzed.

Results

The median follow-up was 7.2 years (range, 0.4–30.5). The actuarial 5-year local control rate was 88%. A microscopically negative margin was associated with superior local control. Although 83% of local recurrence cases initially developed in the absence of metastases, all patients with local failure ultimately died of their disease. The actuarial estimate of 5-year overall survival and disease-free survival was 65% and 63%, respectively. Of all the deaths, 92% were disease related. An early American Joint Committee on Cancer stage, tumor <8 cm, and the absence of neurovascular invasion were associated with superior disease-free survival. The National Cancer Institute Common Toxicity Criteria, version 3, Grade 3-4 treatment complication rate was 9%. No secondary malignancies were observed.

Conclusion

In the present large single-institution study, we found positive margins and locally advanced features to be poor prognostic factors for both local progression and survival. The results from the present study have helped to characterize the therapeutic ratio of RT in pediatric and young adult sarcoma patients and have provided a basis for identifying high-risk patients for whom treatment intensification might be justified.

Introduction

Sarcomas are rare in the pediatric population. The 500 children diagnosed with nonrhabdomyosarcoma soft-tissue sarcoma (NRSTS) each year in the United States represent only 4% of all malignant tumors in the pediatric population (1). Most pediatric soft-tissue sarcomas are rhabdomyosarcomas (2); however, 40% of children <5 years and 77% aged 15–19 years will have NRSTS (1). This group of tumors comprises many different histologic types. Most common in pediatric and young adult patients are malignant fibrous histiocytoma/pleomorphic sarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and fibrosarcoma (3). Because these entities are so rare in young patients, our knowledge of their natural history and appropriate treatment is limited. Prospective randomized studies are scarce, and most have been designed to answer questions regarding systemic therapy. The standard of care for local management has been surgical excision, and the optimal role of adjuvant radiotherapy (RT) is unclear.

The purpose of the present study was to evaluate the prognostic indicators, outcomes, and complications in pediatric and young adult patients with NRSTS treated at the University of Florida with adjuvant RT.

Section snippets

Methods and Materials

Using an institutional review board-approved protocol, we retrospectively reviewed the charts of 95 patients aged ≤30 years who presented to the University of Florida with a tissue diagnosis of NRSTS and had been treated curatively between 1973 and 2007. All patients had undergone RT at our institution, and most had also undergone surgery at the University of Florida. Patients treated with surgery alone were not included in the present study. Patients who underwent RT alone for macroscopic

Local control

Of the 95 patients, 12 developed local recurrence. The median interval to local failure was 0.9 year (range, 0.2–7.4). The LC rate at 5 and 15 years was 88% and 86%, respectively (Fig. 1). All but one recurrence occurred within the first 2 years. Of the patients with local recurrence, 83% developed the recurrence in the absence of metastatic disease. On univariate analysis, a negative microscopic margin was associated with a statistically significant improvement in LC (Table 1). On multivariate

Discussion

A paucity of outcome data addressing multimodality local therapy in pediatric and young adult NRSTS patients is available. In the largest single-institution series to date, Spunt et al. (8) analyzed 121 pediatric patients with NRSTS who underwent surgical resection with or without RT between 1969 and 1996 from St. Jude's hospital. The 5-year rate of local recurrence was 13%. Local recurrence was associated with microscopically positive margins, an intra-abdominal primary tumor, and the lack of

Conclusion

Our study has contributed to understanding the expected outcomes of pediatric and young adult NRSTS patients treated with surgery and RT for local therapy. Furthermore, our study has provided a basis for identifying high-risk patients for whom treatment intensification might be justified. The priority in local management is to obtain function-preserving wide local excision. When complete excision is not achieved, patients are at an increased risk of local failure and death from the local

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Cited by (11)

Synovial sarcoma in children and adolescents
2016, Bulletin du Cancer
Les synovialosarcomes (SS) sont des tumeurs mésenchymateuses malignes rares rencontrées chez l’adolescent et l’adulte jeune. Il existe une signature génomique pathognomonique présente dans 90 à 95 % des cas, correspondant aux réarrangements moléculaires entre SYT-SSX1 ou SYT-SSX2 et permettant de confirmer le diagnostic histologique. En pédiatrie, il s’agit le plus souvent d’une tumeur de haut grade survenant au niveau des extrémités, localisée, sans extension ganglionnaire ni métastase. Les données cliniques, radiologiques, morphologiques et cytogénétiques semblent identiques chez l’enfant et l’adolescent, mais le pronostic est habituellement meilleur en période pré-pubertaire avec 84 % de survie à 5 ans versus 60 % chez l’adolescent. Même si la stratégie globale de prise en charge des SS reste basée sur le contrôle tumoral local associant chirurgie ± radiothérapie, les modalités thérapeutiques médicamenteuses diffèrent entre les équipes pédiatriques et d’adultes, avec une utilisation plus fréquente de la chimiothérapie chez l’enfant et l’adolescent, basée sur une assez bonne chimio-sensibilité documentée à cet âge. L’évaluation précise des facteurs pronostiques (taille tumorale, site primitif, stade postopératoire) permet d’établir un programme thérapeutique adapté à la gravité tumorale selon une approche multimodale. Ainsi, les résultats récents de l’étude pédiatrique prospective européenne EpSSG NRSTS 05 font-ils état d’une survie à 5 ans > 90 % pour les patients présentant une tumeur localisée. Les découvertes génétiques somatiques récentes relancent le débat sur une stratégie adaptée à la biologie tumorale des SS. Au vu des faibles chiffres d’incidence, cette stratégie thérapeutique adaptée ne peut être envisagée que dans le cadre d’une étude prospective de l’ensemble des patients européens.
Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumor affecting children, adolescents, and young adults. Cytogenetically, more than 90% of SS is characterized by the t(X;18)(p11.2;q11.2), translocation resulting in two chimeric fusion genes SYT-SSX1 and SYT-SSX2, confirming histological diagnosis. Pediatric SS arises most often in soft tissues of the extremities (66% of cases), and is a localized tumor without spreading to regional lymph nodes (96% of cases) nor to metastatic sites (94% of cases). Although clinical and radiologic presentation, histologic analysis and tumor biology appear similar in pediatric and adolescent SS, outcome seems better in children than in adolescents, respectively 84% vs 60% of 5 years overall survival (OS). If complete resection is the gold standard in SS, other therapeutic modalities differ between pediatric and adult populations, considering SS as an intermediate chemosensitive tumor more frequently by pediatric oncologists. Prognostic factors evaluation (tumor size, site of primary and IRS group) is necessary to establish optimal treatment strategies, with multimodal therapeutic approach in children and adolescents. Thus, recent results about the European prospective EpSSG NRSTS 05 study for children and adolescent patients with localized SS showed a 5 years OS > 90%. Moreover, recent somatic genetic data about SS open the debate on an appropriate strategy based and stratified on tumor genomic. Multinational prospective pediatric, adolescent and young adult study is necessary to improve optimal and appropriate approach in this rare tumor.
Non-rhabdomyosarcoma soft tissue sarcomas in children: A surveillance, epidemiology, and end results analysis validating COG risk stratifications
2015, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Critical data regarding surgical margins, systemic therapy, radiation dose and schedule, treatment intent, and performance status likely influenced this selection bias. As an example, multiple series have shown that negative margins are strongly associated with improved survival outcomes in pediatric NRSTS, and many of these patients do not receive radiation therapy (10, 24, 25). Conversely, positive margins are often an indication for adjuvant radiation therapy, yet these patients fare much worse.
Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of sarcomas that encompass over 35 histologies. With an incidence of ∼500 cases per year in the United States in those <20 years of age, NRSTS are rare and therefore difficult to study in pediatric populations. We used the large Surveillance, Epidemiology, and End Results (SEER) database to validate the prognostic ability of the Children's Oncology Group (COG) risk classification system and to define patient, tumor, and treatment characteristics.
From SEER data from 1988 to 2007, we identified patients ≤18 years of age with NRSTS. Data for age, sex, year of diagnosis, race, registry, histology, grade, primary size, primary site, stage, radiation therapy, and survival outcomes were analyzed. Patients with nonmetastatic grossly resected low-grade tumors of any size or high-grade tumors ≤5 cm were considered low risk. Cases of nonmetastatic tumors that were high grade, >5 cm, or unresectable were considered intermediate risk. Patients with nodal or distant metastases were considered high risk.
A total of 941 patients met the review criteria. On univariate analysis, black race, malignant peripheral nerve sheath (MPNST) histology, tumors >5 cm, nonextremity primary, lymph node involvement, radiation therapy, and higher risk group were associated with significantly worse overall survival (OS) and cancer-specific survival (CSS). On multivariate analysis, MPNST histology, chemotherapy-resistant histology, and higher risk group were significantly poor prognostic factors for OS and CSS. Compared to low-risk patients, intermediate patients showed poorer OS (hazard ratio [HR]: 6.08, 95% confidence interval [CI]: 3.53-10.47, P<.001) and CSS (HR: 6.27; 95% CI: 3.44-11.43, P<.001), and high-risk patients had the worst OS (HR: 13.35, 95% CI: 8.18-21.76, P<.001) and CSS (HR: 14.65, 95% CI: 8.49-25.28, P<.001).
The current COG risk group stratification for children with NRSTS has been validated with a large number of children in the SEER database.
Anticipated intraoperative electron beam boost, external beam radiation therapy, and limb-sparing surgical resection for patients with pediatric soft-tissue sarcomas of the extremity: A multicentric pooled analysis of long-term outcomes
2014, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
To the date it is not yet completely clear which NRSTS patients with resectable disease will fail locally and thus might particularly benefit from the addition of radiation therapy (2). It is known from retrospective single-institution studies that for completely resected tumors the width of a clear surgical margin influences the local recurrence rate (23, 24). Spunt et al (23) retrospectively reviewed the St. Jude Children's Research Hospital experience of 125 pediatric NRSTS and reported after a median follow-up of 9.2 years 5-year survival and DFS rates of 89% and 77%.
To perform a joint analysis of data from 3 contributing centers within the intraoperative electron-beam radiation therapy (IOERT)-Spanish program, to determine the potential of IOERT as an anticipated boost before external beam radiation therapy in the multidisciplinary treatment of pediatric extremity soft-tissue sarcomas.
From June 1993 to May 2013, 62 patients (aged <21 years) with a histologic diagnosis of primary extremity soft-tissue sarcoma with absence of distant metastases, undergoing limb-sparing grossly resected surgery, external beam radiation therapy (median dose 40 Gy) and IOERT (median dose 10 Gy) were considered eligible for this analysis.
After a median follow-up of 66 months (range, 4-235 months), 10-year local control, disease-free survival, and overall survival was 85%, 76%, and 81%, respectively. In multivariate analysis after adjustment for other covariates, tumor size >5 cm (P=.04) and R1 margin status (P=.04) remained significantly associated with local relapse. In regard to overall survival only margin status (P=.04) retained association on multivariate analysis. Ten patients (16%) reported severe chronic toxicity events (all grade 3).
An anticipated IOERT boost allowed for external beam radiation therapy dose reduction, with high local control and acceptably low toxicity rates. The combined radiosurgical approach needs to be tested in a prospective trial to confirm these results.
Pulmonary metastasectomy in pediatric/adolescent patients with synovial sarcoma: An institutional review
2013, Journal of Pediatric Surgery
Citation Excerpt :
Many reports that have evaluated the role of metastasectomy in pediatric/adolescent patients with NRMS have analyzed an aggregate patient population with different primary histologies. For instance, four recently published adult and pediatric series examining pulmonary metastasectomy for metastatic STS evaluated a total of 301 patients, of which only 12% had SS [2,10–12]. In this retrospective review, our aim was to identify prognostic factors, best surgical approach, and survival outcomes for pediatric and adolescent patients with SS who underwent surgical resection for confirmed pulmonary metastasis at Memorial Sloan-Kettering Cancer Center between June 1971 and May 2011.
Synovial sarcoma (SS) often metastasizes to the lung; however, the indications for and outcomes of pulmonary metastasectomy have not been evaluated in pediatric/adolescent patients.
The records of pediatric patients (age < 22 years) with pathologically confirmed SS and pulmonary metastasis treated between June 1971 and May 2011 at our institution were retrospectively reviewed for the number and type of surgical metastasectomies, tumor characteristics, and survival outcomes.
Forty-one patients (mean age: 15.9 years) were identified and 31 (76%) underwent at least one metastasectomy. Seventy-two resections (range, 1–8/patient) were performed. Two- and 5-year survival rates after metastasis diagnosis were 65% and 24% for patients who underwent metastasectomy. Patients who did not undergo a metastasectomy survived no more than 2 years from the diagnosis of pulmonary disease (P < 0.001). Longer time to progression after primary tumor resection (> 1 year) and complete resection of pulmonary disease correlated with greater OS (P = 0.02 and P < 0.001, respectively). Palliative debulking did not improve OS. Survival was unaffected by tumor histological subtype, bilateral pulmonary disease, number of surgical resections, or number and size of resected metastatic lesions.
Pulmonary metastasectomy may be associated with improved survival in pediatric/adolescent patients with SS and pulmonary metastases if complete resection is achieved.
High expression of ACKR1 predicts a good prognosis and suppresses sarcoma cell progression via regulating the tumor immune microenvironment
2024, Journal of Applied Genetics
The non-rhabdomyosarcoma soft tissue sarcomas, desmoid tumor and osteosarcoma
2018, Pediatric Oncology

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Clinical InvestigationAdjuvant Radiotherapy for Pediatric and Young Adult Nonrhabdomyosarcoma Soft-Tissue Sarcoma

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Methods and Materials

Local control

Discussion

Conclusion

J Pediatr

Am J Otolaryngol

National Institutes of Health publication No. 99-4649: Cancer incidence and survival among children and adolescents: United States SEER Program 1975–199 5

Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: A Pediatric Oncology Group study

Med Pediatr Oncol

Pediatric nonrhabdomyosarcoma soft tissue sarcomas

Oncologist

Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: Formulation of a simplified system for grading

Mod Pathol

Nonparametric estimation from incomplete observations

J Am Stat Assoc

Regression models and life tables—Series B (methodological)

J R Stat Soc

Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue sarcoma: An analysis of 121 patients treated at St Jude Children's Research Hospital

J Clin Oncol

Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity

J Clin Oncol

Clinical Investigation
Adjuvant Radiotherapy for Pediatric and Young Adult Nonrhabdomyosarcoma Soft-Tissue Sarcoma