Second malignancies after treatment for Ewing’s sarcoma: a report of the CESS-studies

doi:10.1016/S0360-3016(98)00228-4

International Journal of Radiation OncologyBiologyPhysics

Volume 42, Issue 2, 1 September 1998, Pages 379-384

Presented at the Annual ASTRO Meeting 1997, Orlando, FL.

https://doi.org/10.1016/S0360-3016(98)00228-4 Get rights and content

Abstract

Purpose: During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing’s sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing’s Sarcoma Studies CESS 81 and CESS 86.

Materials and Methods: From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing’s sarcoma trials CESS 81 (recruitment period 1981–1985) and CESS 86 (1986–1991). The systemic treatment in both studies consisted of a four-drug-regimen (VACA = vincristine, actinomycin D, cyclophosphamide, and adriamycin; or VAIA = vincristine, actinomycin D, ifosfamide, and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36–46Gy (n = 274), or definitive radiotherapy with 46–60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years.

Results: The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing’s sarcoma and the diagnosis of the SM was 17–78 months for the four AMLs, 96 months for the MDS and 82–136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clincal remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1% (3/328) of all deaths in the CESS-studies.

Conclusions: The risk of leukemia after treatment for Ewing’s sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5% after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.

Introduction

The use of radiation therapy for the treatment of pediatric malignancies has decreased over past decades. This can be attributed in part to recent advances in chemotherapy and surgery which have reduced the need for definitive or adjuvant radiotherapy. A major concern, which has led to a restrictive use of radiotherapy, however, is the fear of radiation-induced second malignancies (SM). A very high frequency of radiation-induced osteosarcomas exists in patients with retinoblastoma, especially bilateral retinoblastoma 1, 2, 3, 4. This can be attributed to the defect in the Rb-suppressor gene in this disease. However, an elevated risk of SM in irradiated patients has recently been reported in several types of malignancies including leukemias, lymphomas, and most pediatric solid tumors 2, 3, 5, 6, 7. Ewing’s sarcoma patients are probably at higher risk for developing second cancers than pediatric patients with other malignancies (2).

Most reports on SM include patients who have been treated more than 20 years ago. During the past two decades, however, major changes in treatment protocols have occurred. The radiation treatment volume is smaller now than in the 1970s, the treatment techniques have improved, and the total dose is now lower than 60 Gy; in most cases in the range of 45– 55 Gy. These changes may reduce the risk of SM-induction by radiotherapy. On the other hand, the intensity of chemotherapy has increased over the past years. Chemotherapy, especially the use of alkylating agents, is known to contribute to the induction of leukemias, and also seems to increase the risk of bone sarcomas in irradiated patients 2, 4

The following article is the first analysis of the multicentric CESS-studies on this topic, and focuses on the frequency of second tumors in cured Ewing’s sarcoma patients. The treatment results of these studies have been published 8, 9.

Section snippets

Study protocols

The multicentric Cooperative Ewing’s Sarcoma Studies (CESS) started in 1981. The first study, CESS 81, recruited patients from 1981 through 1985, and the second study, CESS 86, from 1986 through 1991. The second study included a more intense chemotherapy and an altered fractionation schedule in radiotherapy which was piloted in a phase II-protocol (CESS 86-P) in 1985. These two studies, including the pilot protocol, form the basis of the following analysis.

The treatment protocol and the results

Second malignancies

Eight second malignancies have been observed to date. A detailed description is given in Table 2. One additional case of a benign neurinoma has been reported, but this patient will not be considered in this analysis.

Five out of eight SM were acute myelogenic leukemias (n = 4) or myelodysplastic syndrome (MDS, n = 1). The four AML occurred 17–78 months after diagnosis. Three patients with AML have died from rapid progression, the fourth is living with AML and has also progressive metastases of

Discussion

In this analysis, a low risk of second malignancies has been observed; moreover, the risk of dying from a SM was less than 1% over the entire observation period. Although the follow-up period is relatively short with regard to the induction of SMs and especially sarcomas, extremely high frequencies of SM seem unlikely even with prolonged follow-up. Five out of eight SMs were secondary leukemias. All of them occurred within the first 8 years after diagnosis and at least three of them were

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Cited by (100)

Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors
2019, International Journal of Radiation Oncology Biology Physics
Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS).
We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n = 757) and ES (n = 314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8 Gy vs <55.8 Gy) × disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS.
The median follow-up for surviving patients was 97 months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8 Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P = .015), and there was a significant radiation dose × disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; P_interaction < .001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8 Gy radiation therapy to the pelvis or spine was 5.0% (95% CI, 0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS.
Patients with osteosarcoma and ES receiving ≥55.8 Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.
Secondary Acute Leukemia in Sarcoma Patients: A Population-Based Study
2018, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
In addition these patients are often young and, with advancements in therapies, usually can expect to be cured of their primary disease, thus are at risk for late effects over longer intervals. Multiple prior institutional studies have reported on secondary leukemia in the sarcoma population but have focused on the role of systemic therapy, including chemotherapy and granulocyte-colony stimulating factor in leukemogenesis (13, 22-24). One prior SEER study examining the risk of therapy-related AML in patients treated with chemotherapy found that these patients had a 4.7-fold increased risk of AML as compared with the general population.
To compare rates of secondary acute leukemia between sarcoma patients and the general population, using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry, and to examine whether various patient, tumor, and treatment factors were associated with development of a secondary acute leukemia.
Patients with a primary diagnosis of connective tissue malignancy between 1973 and 2008 in the SEER database were included. Multivariable competing risk analysis was used to determine risk factors associated with subsequent development of acute leukemia. Using observed-to-expected ratios, we compared incidence rates of secondary acute leukemia between sarcoma patients and the general population.
A total of 72,945 patients were identified, with median follow-up of 131 months. On multivariable competing risk analysis, factors associated with increased risk of secondary acute leukemia included receipt of radiation therapy (hazard ratio [HR] 1.67, P=.02), distant disease (HR 2.67, P=.004), male gender (HR 1.53, P=.03), year of diagnosis (HR 0.98, P=.049), and Ewing sarcoma histology (HR 9.95, P < .0001) and osteosarcoma histology (HR 5.06, P=.0001). The observed-to-expected ratio for development of a secondary acute leukemia was 3.67 (95% confidence interval [CI] 1.95-6.28), 3.41 (95% CI 2.73-4.20), and 1.6 (95% CI 1.38-8.19) for acute lymphocytic leukemia, acute myeloid leukemia, and acute monocytic leukemia, respectively. The 10-year cumulative incidence of secondary acute leukemia for patients who did and did receive radiation therapy was 0.3% versus 0.1% (P=.02).
Patients treated for sarcoma, in particular those with Ewing sarcoma and osteosarcoma histology, seem to have a higher incidence of secondary acute leukemia as compared with the general population. Treatment factors including radiation therapy and chemotherapy seem to play a role in this increased risk, although the absolute incidence nevertheless remains very small.
Ewing's sarcoma of the maxillofacial region in Greek children: Report of 6 cases and literature review
2018, Journal of Cranio-Maxillofacial Surgery
The rarity of Ewing's sarcoma (ES) in the maxillofacial region of children, coupled with the technical challenge of resection and associated functional and cosmetic impairment has resulted in deficient data regarding the optimal local control of the disease.
To describe our experience in the management of primary maxillofacial ES in children, focusing on the therapeutic modalities for local control of the disease.
Single institution observational study.
This is a single institution review of patients, treated between 2007 and 2016.
Six primary maxillofacial ES were treated according to the EURO-EWING 99 protocol, consisting of a uniform chemotherapy regimen, combined selectively with surgery and radiotherapy as local treatment. Patients' mean age was 9.42 years (range 6–12.5 years). One patient initially suffered from metastasis and succumbed to the disease; another refused further treatment following chemotherapy and was lost to follow-up. Four patients underwent surgery and adjuvant radiotherapy successfully. At a mean follow-up of 3.78 years relapse-free and overall survival rates were 60% and 80% respectively. The aesthetic and functional outcome was satisfactory in all treated patients.
In eligible cases the combination of chemotherapy with surgery and adjuvant radiotherapy results in optimal oncological and functional outcome for children with ES of the maxillofacial region. Metastasis and poor response to chemotherapy are the most important adverse prognostic factors.
Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children
2018, Hematology: Basic Principles and Practice
Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children
2017, Hematology: Basic Principles and Practice
Interinstitutional patient transfers between rapid chemotherapy cycles were feasible to utilize proton beam therapy for pediatric Ewing sarcoma family of tumors
2018, Reports of Practical Oncology and Radiotherapy
Citation Excerpt :
Hematological malignancies are known risks of cyclophosphamide, etoposide, and doxorubicin exposure. The risk of secondary malignancy after standard treatments for ESFT has been reported; the incidence ranges from 1% to 15%, including both solid and hematological malignancies, depending on the type and cumulative dose of chemotherapy, as well as the type and dose of radiation therapy and the duration of follow-up.23–28 In these reports, hematological malignancies tended to occur more often than solid tumors as secondary malignancies.
To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology.
The treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy.
Clinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed.
Fifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively.
Although the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT.
Multidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events.

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¹: Herbert Jürgens is the study coordinator of the Cooperative Ewing’s Sarcoma Studies.

View full text

Clinical InvestigationsSecond malignancies after treatment for Ewing’s sarcoma: a report of the CESS-studies

Abstract

Introduction

Section snippets

Study protocols

Second malignancies

Discussion

Second primary tumors following radiotherapy for childhood cancer

Int J Radiat Oncol Biol Phys

Radiotherapy, alkylating agents, and the risk of bone cancer after childhood cancer

J Natl Cancer Inst

Second malignant neoplasms in childrenAn update from The Late Effects Study Group

J Clin Oncol

Bone sarcomas linked to radiotherapy and chemotherapy in children

N Engl J Med

Second malignant neoplasms in children treated for rhabdomyosarcoma

J Clin Oncol

Second malignant neoplasms after cancer in childhood or adolescence

Br Med J

The incidence of second neoplasms following megavoltage radiation for pediatric tumors

Cancer

Clinical Investigations
Second malignancies after treatment for Ewing’s sarcoma: a report of the CESS-studies