Risk of Secondary Leukemia After a Solid Tumor in Childhood According to the Dose of Epipodophyllotoxins and Anthracyclines: A Case-Control Study by the Société Française d’Oncologie Pédiatrique

Deley, Marie-Cécile Le; Leblanc, Thierry; Shamsaldin, Akhtar; Raquin, Marie-Anne; Lacour, Brigitte; Santini, Daniele; Chompret, Agnès; Cayuela, Jean‐Michel; Bayle, C; Bernheim, Alain; Vathaire, Florent de; Vassal, Gilles; Hill, Catherine

doi:10.1200/jco.2003.04.100

Cited by 199 publications

(149 citation statements)

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“…The relatively high incidence of second malignancy in patients treated for an osteosarcoma is a matter of concern, as documented by several authors in previous reports 5,14,17,[37][38][39][40] . The design of the present dose-dense induction chemotherapy (including alkylating agents, cisplatin, and doxorubicin), its use of etoposide in phr patients, and the impact, if any, of hematologic growth factors 40 may contribute to the development of secondary hemopathy 38 .…”

Section: Total Patients (N) (%) (N) (%) (N) (%) (N) (%)mentioning

confidence: 79%

“…The design of the present dose-dense induction chemotherapy (including alkylating agents, cisplatin, and doxorubicin), its use of etoposide in phr patients, and the impact, if any, of hematologic growth factors 40 may contribute to the development of secondary hemopathy 38 . However, more than 150 patients have been recruited into other trials based on the same api-ai regimen in locally advanced soft-tissue sarcoma 41 and the Ewing family of tumours 42 , and no second malignancy has been reported to date in those populations.…”

Section: Total Patients (N) (%) (N) (%) (N) (%) (N) (%)mentioning

confidence: 99%

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Intensive Induction Chemotherapy without Methotrexate in Adult Patients with Localized Osteosarcoma: Results of the Institut Gustave-Roussy Phase II Trial

et al. 2010

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Purpose: To improve outcomes in localized osteosarcoma and to reduce the duration of preoperative chemotherapy, we conducted a phase ii trial assessing the efficacy of an intensive protracted regimen without methotrexate (API-AI regimen) in adolescent and adult patients with newly diagnosed disease. Patients and Methods: Induction chemotherapy consisted of 2 cycles (4 courses) of doxorubicin 60 mg/m2 (days 1 and 15), cisplatin 100 mg/m2 (day 1), and ifosfamide 5 g/m2 (days 2 and 15). The primary endpoint was good histologic response [GHR (≤5% identifiable tumour cells)]. Results: From March 1993 to March 2000, 32 patients [median age: 21 years (range: 15–49 years)] were administered 126 induction courses. The median time between chemotherapy courses was 15 days (range: 12–32 days). All but 3 patients underwent conservative surgery. Toxicity was mainly hematologic, with febrile neutropenia occurring in 35% of patients and grades 3–4 thrombocytopenia in 35%. The GHR rate was 47%. The median follow-up was 64 months (range: 30–115 months). The 5-year event-free and overall survivals were 65% [95% confidence interval (CI): 48–79%] and 69% (95% CI: 50–83%) respectively. Two secondary hematologic malignancies occurred: 1 acute myelocytic leukemia (M5) in a poor responder with concomitant relapse, and 1 myelodysplastic syndrome in a patient achieving GHR. Conclusions: Despite hematologic toxicity, the results observed with the API-AI regimen compare favourably with those observed during previous induction chemotherapy containing methotrexate in adult patients and the pediatric population treated at our institution. These promising results have to be validated by an ongoing national multicentre trial coordinated by the French Sarcoma Group.

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Section: Total Patients (N) (%) (N) (%) (N) (%) (N) (%)mentioning

confidence: 79%

Section: Total Patients (N) (%) (N) (%) (N) (%) (N) (%)mentioning

confidence: 99%

Intensive Induction Chemotherapy without Methotrexate in Adult Patients with Localized Osteosarcoma: Results of the Institut Gustave-Roussy Phase II Trial

et al. 2010

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“…The total amount of etoposide did not contribute to 19), and exposure to epipodophyllotoxins or anthracyclines. 71 An increased incidence of AML was found in children with non-testicular germ cell tumors after chemo-radiotherapy, with a cumulative incidence at 10 years of 1.0% for patients treated with chemotherapy and of 4.2% for patients treated with combined chemotherapy and radiotherapy. 72 No cases of leukemia were found in patients treated with radiotherapy only.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O N © F E R R A mentioning

confidence: 99%

Therapy-related leukemia and myelodysplasia: susceptibility and incidence

Leone¹,

Pagano²,

et al. 2007

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Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is an increasingly recognized treatment complication in patients treated with radiotherapy or chemotherapy for previous hematologic malignancies or solid tumors. Distinct clinical entities have been described according to the primary treatment, corresponding to defined genetic lesions. Chromosome 7 and/or 5 losses or deletions are typical of alkylating agent-induced AML, while development of t-AML with balanced translocations involving chromosome bands 11q23 and 21q22 has been related to previous therapy with drugs targeting DNA-topoisomerase II. In addition, anti-metabolites, and in particular the immunosuppressant azathioprine, have been shown to induce defective DNA-mismatch repair. This could promote survival of misrepaired cells giving rise to the leukemic clone. Individual predisposing factors, including polymorphisms in detoxification and DNA repair enzymes have been identified. Their combination may significantly increase the risk of t-MDS/AML. Among patients with hematologic malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased risk of t-MDS/AML, particularly when receiving MOPP-based, and escalated BEACOPP regimens, and when alkylators are combined with radiotherapy. Patients with Hodgkin's and non-Hodgkin's lymphoma are at highest risk when total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation therapy. The addition of granulocyte-colony-stimulating factor and radiotherapy plays a significant role in t-AML following treatment of children with acute lymphoblastic leukemia. In non-hematologic malignancies, treatment for breast cancer and germcell tumors has been associated with a 1-5% lifetime risk of both lymphoid as well as myeloid leukemia. In all cases the risk of t-MDS/AML drops sharply by 10 years after treatment.Key words: susceptibility, therapy-related, AML, MDS. Established genetic factors alone explain approximately 5% of all cancers, the remainder can be attributed to environmental carcinogens, tobacco smoke, dietary costituents, pollutants, drugs, radiation, and infectious agents that act in conjunction with both genetic and acquired susceptibility.1 Yet, the role of exogenous factors is not always so evident. Apart from radiotherapy and chemotherapy, which are recognized as the most frequent causes of secondary malignant neoplasms, therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndromes (t-MDS) account for 10-20% of all cases of AML.2 In the GIMEMA registry, the incidence of AML occurring as a second malignancy was about 5%, but this registry includes only patients in whom treatment is feasible.3 The high incidence of t-AML has been attributed to the increasing use of cytotoxic drugs causing DNA damage, and to the longer survival of many treated patients. Yet, only a minimal proportion of subjects exposed present with a secondary leukemia, indicating that an important role is played by the susceptibility of hemato...

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“…4,5 Another secondary hematological malignancy is late-onset acute myeloid leukemia (AML), which is a dose-dependent late effect of treatment with alkylating agents and is classically preceded by myelodysplastic syndrome (MDS) with loss or deletion of chromosome 5 or 7. 6,7 Childhood cancer survivors can also develop AML or MDS after treatment with growth factors (GFs), in combination with etoposide, anthracyclines, and radiotherapy. However, it is difficult to distinguish the contribution of GF versus intensified therapy and the effect of intensity 8 or cumulative doses of chemotherapy 9,10 in the development of secondary hematological malignancies.…”

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confidence: 99%

Secondary hematopoietic malignancies in survivors of childhood cancer

Rihani

Bazzeh

Faqih

et al. 2010

Cancer

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BACKGROUND: Studying secondary hematological malignancies in a large cohort of patients can help predict risks and trends associated with current therapies. METHODS: The authors analyzed data from the Surveillance, Epidemiology, and End Resultsecondary 9 (SEER-9) database on patients with a primary malignancy (diagnosed before the age of 20 years) between 1973 and 2005 who developed a secondary hematological malignancy. Primary cancer and histological subtype, incidence, risk factors, outcomes, and changes in risk patterns of secondary hematological malignancies were analyzed for 1973 to 1985, 1986 to 1995, and 1996 to 2005. Standardized incidence ratios (SIRs) of observed to expected cancers were calculated. RESULTS: Of 34,867 patients with a histology-confirmed primary malignancy, 111 developed secondary hematological malignancies (median, 44 months). Lymphoma was the commonest primary cancer (n ¼ 47). The main histological subtype of secondary hematological malignancy was acute myeloid leukemia (AML) (49%), which had the shortest median latency time and the worst 5-year survival (18% AE 5.3%; P ¼.044). Secondary Hodgkin lymphoma had the best 5-year survival (83% AE 15%). The 5-year overall survival for patients with secondary hematological malignancies was 31% AE 4.7%. The risk of secondary AML steadily increased from 1986 to 2005, whereas SIRs for acute lymphoblastic leukemia did not change over time. Non-Hodgkin lymphoma, the second most common secondary hematological malignancy, occurred at a median of 112 months, and its risk steadily increased over time periods. CONCLUSIONS: Childhood cancer survivors are at increased risk of developing secondary hematological malignancies, particularly secondary AML. This risk has continued to rise even in recent years, emphasizing the need to study other factors contributing to secondary hematological malignancies and closely monitor these patients. Cancer 2010;116:4385-94.

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Risk of Secondary Leukemia After a Solid Tumor in Childhood According to the Dose of Epipodophyllotoxins and Anthracyclines: A Case-Control Study by the Société Française d’Oncologie Pédiatrique

Abstract: Both epipodophyllotoxins and anthracyclines increase the risk of secondary leukemia. The current challenge is to minimize the mutagenic effects of these drugs by diminishing cumulative doses without losing the therapeutic benefits.

Cited by 199 publications

References 45 publications

Intensive Induction Chemotherapy without Methotrexate in Adult Patients with Localized Osteosarcoma: Results of the Institut Gustave-Roussy Phase II Trial

Intensive Induction Chemotherapy without Methotrexate in Adult Patients with Localized Osteosarcoma: Results of the Institut Gustave-Roussy Phase II Trial

Therapy-related leukemia and myelodysplasia: susceptibility and incidence

Secondary hematopoietic malignancies in survivors of childhood cancer

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