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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

Marie-Cécile Le Deley, Thierry Leblanc, Akthar Shamsaldin, Marie-Anne Raquin, Brigitte Lacour, Danièle Sommelet, Agnès Chompret, Jean-Michel Cayuela, Chantal Bayle, Alain Bernheim, Florent de Vathaire, Gilles Vassal, Catherine Hill

From the Biostatistics and Epidemiology Unit, the Radiophysics Unit, the Department of Pediatric Oncology, the Department of Medicine, the Hematology Unit, and the Cytogenetics Laboratory, Institut Gustave-Roussy, Villejuif; the Pediatric Hematology Unit and the Hematology Laboratory, Hôpital Saint-Louis, Paris; INSERM Unit 521, Villejuif; and the Registre Lorrain des Cancers de l’Enfant, Nancy, France.

Address reprint requests to Marie-Cécile Le Deley, MD, Service de Biostatistique et d’Epidémiologie, Institut Gustave Roussy, rue Camille Desmoulins, 94805 Villejuif Cedex, France; email: le_deley{at}igr.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To estimate the risk of secondary leukemia as a function of the dose of epipodophyllotoxins and anthracyclines.

Methods: We conducted a case-control study of the risk of secondary leukemia or myelodysplasia after a solid tumor in childhood within the Société Française d’Oncologie Pédiatrique, including 61 patients with leukemia matched with 196 controls. The characteristics of the first cancer, the patient’s family history of cancer, and the treatment (type, cumulative dose of chemotherapy, schedule of etoposide administration, and radiation dose delivered to active bone marrow) were compared in the two groups.

Results: Only two factors were found to increase the risk of leukemia in multivariate analysis, namely, the type of the first tumor, with an excess risk in patients with Hodgkin’s disease (relative risk 6.4; 95% confidence interval [CI], 1.6 to 24) or osteosarcoma (relative risk 5; 95% CI, 1.3 to 19), and exposure to epipodophyllotoxins and anthracyclines. The risk of leukemia increased regularly with the cumulative dose of etoposide. In summary, patients who received between 1.2 and 6 g/m² of epipodophyllotoxins or more than 170 mg/m² of anthracyclines had a seven-fold higher risk (95% CI, 2.6 to 19) compared with patients who received lower doses or none of these drugs. The risk of leukemia in patients who received more than 6 g/m² of epipodophyllotoxins was multiplied by 197 (95% CI, 19 to 2,058). The risk of leukemia was not increased by exposure to alkylating agents or radiotherapy.

Conclusion: 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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
EPIPODOPHYLLOTOXINS ARE increasingly used to treat cancer, with various dose regimens and schedules. In particular, continuous or semicontinuous etoposide administration is used for refractory and advanced-stage malignancies in both adults and children.^1–5 The outstanding efficacy of etoposide in this setting may result in its use in less advanced disease, yet little is known of its long-term unwanted effects, especially its leukemogenicity. Available data indicate an excess risk of leukemia among patients treated in childhood with high cumulative doses of epipodophyllotoxins administered weekly or twice weekly as compared with every other week,⁶ but the relationship is not clearly established.^6–8 Secondary leukemias have also been described after treatment with anthracyclines,^9–19 but the level of risk associated with these drugs is poorly documented.

We report the results of a case-control study of secondary leukemia that evaluated the risk associated with epipodophyllotoxins and anthracyclines as a function of the dose of these drugs. It is the first case-control study that evaluated the risk associated with continuous or semicontinuous etoposide.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Leukemia Patients
The patients studied had secondary leukemia or myelodysplasia and had been treated before age 18 years for a solid malignancy, including non-Hodgkin’s lymphoma, or for Langerhans cell histiocytosis.

In December 1996, a questionnaire was sent to all investigators of the Société Française d’Oncologie Pédiatrique and to all French regional cancer registries with a request to identify cases of leukemia or myelodysplasia diagnosed in patients treated for a first malignancy after 1980. All new leukemia patients were registered prospectively between January 1997 and June 1999.

We reviewed both the characteristics of the first and second neoplasms and the results of all tests done on bone marrow aspirates and biopsy specimens to verify the diagnosis of secondary leukemia or myelodysplasia. We also subjected all available frozen samples to Southern blotting to detect mixed-lineage leukemia gene (MLL) rearrangements, except in patients with t(9;11)(p21;q23) or t(11;19)(q23;p13) translocation. Sixty-seven patients with secondary leukemia or myelodysplasia were identified. Four patients were excluded from the analysis because the secondary malignancy was considered likely to be a relapse (three patients with initial non-Hodgkin’s lymphoma and one patient with probable misdiagnosed chloroma); another two patients were excluded because they developed iso(12p) leukemia after primary germ cell tumors—these tumors were considered to arise from the same progenitor cell.^20,21

Thirty-two (52%) of the 61 patients included in the analyses were males. Median age at diagnosis of the first tumor was 7.8 years (range, 0 to 17 years). The median interval between diagnosis of the first tumor and the onset of leukemia or myelodysplasia was 3.4 years (range, 0.8 to 12.8 years).

In 34 patients, the second malignancy was acute myeloblastic leukemia, with the following subtypes: M1 in three patients, M2 in seven patients, M3 in two patients, M4 in nine patients, M5 in 11 patients, and M6 and M7 in one patient each. Nineteen patients had myelodysplasia or a myeloproliferative syndrome, which subsequently transformed in 10 patients. Eight patients had acute lymphoblastic leukemia (ALL). All of these diagnoses are thus referred to as leukemia.

Among the 55 patients with cytogenetic or molecular biology investigations, 17 patients had rearrangements involving 11q23, four patients had translocations involving 21q22, and 11 patients had total or partial deletions of chromosome 5 or 7. In addition, there were two t(15;17)(q22;q21), one inv(16)(p13;q22), and two t(9;22)(q34;q11) translocations.

Controls
The controls were patients treated for solid tumors or Langerhans cell histiocytosis who did not subsequently develop leukemia. This analysis is based on 196 controls; 15 leukemia patients had four controls, 44 leukemia patients had three controls, and two leukemia patients had two controls. The control patients were matched for sex, age at initial diagnosis, date of diagnosis, and hospital (when possible); the follow-up period for each control was at least as long as the interval between diagnosis of the primary tumor and the onset of leukemia in the matched patient. They were not matched for type of first tumor because it would preclude the study of type of first tumor as a risk factor. Matching on date of diagnosis, age at diagnosis, and type of first tumor might also result in similarity in treatment. Demographic characteristics of leukemia patients and controls are described in Table 1.

On the basis of available data in the medical files, family histories of cancer were classified as major risk (Li-Fraumeni syndrome, neurofibromatosis including sporadic cases, or one cancer occurring before age 45 years in a first-degree relative), minor risk (cancer before age 45 years in a second- or third-degree relative), or no familial risk.

Estimation of Radiation Doses
When external radiation therapy was administered, the doses received at 91 points of the skeleton were estimated from treatment sheets, control, and simulatory x-ray films by using a computer program described elsewhere (Dos-EG; Institut Gustave-Roussy, Villejuif, France).^22,23 The mean radiation dose received by active bone marrow was computed as a weighted mean of the doses received at these points, using published age-dependent weights.²⁴ In the only patient treated with ¹⁹²Ir wires, the doses delivered to the 91 skeletal points were calculated manually using the method employed by the ICTA computer program (Institut Gustave-Roussy) to calculate distant doses in brachytherapy.²⁵

Quantification of Chemotherapy
Information on the chemotherapy received by each patient was obtained from medical records, medical prescriptions, pharmacy delivery lists, and daily nursing records. For each cytotoxic drug and for each cycle, the dose was recorded together with the patient’s weight and height at the time. The total dose of each cytotoxic drug per unit body-surface area was computed.

Because of the small number of patients and the diversity of drugs used (36 different agents), we pooled drugs belonging to the same pharmacologic group, converting the dose of each individual drug into the dose of a reference drug, on the basis of either dose equivalence in terms of hematologic toxicity or substitution rules (Table 2). This method is based on the assumption that the leukemogenic potencies of agents within each group are proportional to their acute hematologic toxicity. Because of the uncertainty surrounding the relative leukemogenicity of alkylating agents, we also used the sum of milligrams per meters squared of all alkylating agents, the sum of millimoles per meters squared, and the sum of scores as defined by Tucker et al²⁶ to combine exposures.

Statistical Analysis
Leukemia patients and controls were compared by means of multiple conditional logistic regression methods,²⁷ using the PH-REG procedure of the SAS software system (SAS Institute, Cary, NC). Nested models were compared using two-sided likelihood-ratio tests. To estimate the relation between the dose of chemotherapy or radiotherapy and the risk of leukemia, we calculated the relative risk of leukemia for patients in each third or quartile of the dose distribution compared with patients who had not been exposed to the drug or to radiation therapy. These subgroups (thirds, quartiles) were then pooled to obtain a simpler classification of the population without significantly reducing the likelihood of the multivariate model. This simplification of the model was necessary for the assessment of the effect of the exposure to multiple drugs simultaneously. The stability of the final model was studied according to the type of leukemia, first by excluding all ALL patients (analysis on 53 myeloid leukemia patients matched with 171 controls) and last by restricting analysis to the patients with a translocation defined as either a rearrangement involving 11q23 or a translocation involving 21q22, a t(15;17)(q22;q21), an inv(16)(p13;q22), or a t(9;22)(q34;q11) (analysis on 26 leukemia patients matched with 84 controls).

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Table 3 summarizes the results of univariate and multivariate analyses of the characteristics of the first cancer, the patient’s family history of cancer, and treatments.

Radiotherapy was not associated with a significant excess risk of leukemia, and there was no increase in the risk as the average radiation dose received by active bone marrow increased (data not shown).

The risk of leukemia increased with the use of chemotherapy. Almost all of the patients who received chemotherapy were given several drugs: 71% received at least four cytotoxic agents, and 9% received 10 or more cytotoxic agents.

Table 4 shows the risk of leukemia associated with each pharmacologic group. In univariate analysis, the risk of leukemia was associated with epipodophyllotoxins, anthracyclines, and alkylating agents. However, only epipodophyllotoxins and anthracyclines remained significantly associated with an increased risk of leukemia after adjustment for the exposure to the other types of drugs.

View larger version (15K): [in this window] [in a new window]   Fig 1. Relative risk (RR) of leukemia according to the dose of epipodophyllotoxins. The adjusted relative risks were estimated using a model that included the type of the first tumor (osteosarcoma, Hodgkin’s disease, others) and the anthracycline dose (0 to 170 mg/m2 or 170 mg/m2).

Thus, in the multivariate analysis (Table 6), only two factors were found to increase the risk of leukemia: the type of primary tumor (an excess risk was associated with Hodgkin’s disease [relative risk, 6.4; 95% CI, 1.6 to 24] and osteosarcoma [relative risk, 5; 95% CI, 1.3 to 19]) and exposure to DNA topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines). The risk of leukemia in patients who received more than 170 mg/m² of anthracyclines or between 1.2 and 6 g/m² of epipodophyllotoxins was multiplied by seven (95% CI, 2.6 to 19) relative to patients who received lower doses or none of these drugs (reference group). The risk of leukemia in patients who received more than 6 g/m² of epipodophyllotoxins was multiplied by 197 (95% CI, 19 to 2,058) relative to the reference group. Owing to the small size of this group (only 11 patients and three controls), the 95% CI of this estimation is large, but its lower boundary is high.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
We found that the risk of secondary leukemia following treatment for a primary solid tumor depended both on the type of the primary cancer and on exposure to DNA topoisomerase II inhibitors. The risk increased regularly with the cumulative dose of epipodophyllotoxins, with a high risk in patients who received more than 6 g/m². Exposure to moderate or high doses of anthracyclines ( 170 mg/m²) was associated with a similar risk to that observed after moderate doses of epipodophyllotoxins (between 1.2 and 6 g/m²). There was no excess risk associated with alkylating agents or radiotherapy.

We cannot translate directly the relative risks into a range of absolute risks because there is no national registry for pediatric solid tumors in France. However, the cumulative risk of secondary leukemia in our pediatric population may be of the same order of magnitude as that in patients with testicular germ cell tumors;²⁸ that is, 0.5% at cumulative doses of less than 2 g/m² and 2.6% at cumulative doses exceeding 2 g/m² (median 5 g/m²).

Our investigation confirms, in a larger population, the results of the only other case-control study evaluating the risk of leukemia as a function of the epipodophyllotoxin dose and controlling for other risk factors (relative risk 2.6, 6.6, and 17.1 after exposure to 1 to 750, 751 to 1,200, and > 1,200 mg/m² of epipodophyllotoxins, respectively).²⁹ This latter study, with 26 patients, was also based on a pediatric population, but the frequency of epipodophyllotoxin use and the cumulative doses were much lower than in our study; only 2% of controls received more than 1.2 g/m² of epipodophyllotoxins compared with 26% of controls in our series. However, the Cancer Therapy Evaluation Program⁸ identified 17 cases of leukemia in a cohort of 2,291 patients receiving epipodophyllotoxins. A higher risk of leukemia was found among patients assigned to a protocol including less than 1.5 g/m² of epipodophyllotoxins than in patients assigned to protocols with higher doses. The authors’ conclusion was that factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Indeed, risk factors such as alkylating agent and anthracycline administration were not taken into account.

It is important to evaluate the risk of leukemia according to the schedule of epipodophyllotoxin administration. The schedules compared in the study by Pui et al⁶ (weekly or twice-weekly v every-other-week administration) were not used in our series. We could not distinguish the effect of the dose from the effect of the schedule in multivariate analysis because these factors were strongly associated. Thus, the median cumulative dose of epipodophyllotoxins was equal to 1,915 mg/m² (range, 290 to 9,870 mg/m²) in patients who received only sequential courses, whereas it was 17,400 mg/m² (range, 3,425 to 51,310 mg/m²) in those who received continuous or semicontinuous etoposide. However, it is important to note the relatively low risk after sequential courses of administration because this is the primary schedule used for newly diagnosed patients.

We have observed a high risk of leukemia after continuous etoposide administration. Few cases of secondary leukemia had previously been reported after such therapy.^30–36 This may partly be the results of the generally short survival of patients receiving such therapy, especially when they are adults; in our series, the median survival time of the 16 patients who received continuous or semicontinuous etoposide was 2.4 years after the beginning of this therapy.

Cases of leukemia have been reported after treatment with anthracyclines,^9–19 but the risk is generally considered relatively low. In the case-control study published by the Late Effect Study Group in 1987,²⁶ the risk of leukemia was found to increase with the dose of doxorubicin, but the trend was not statistically significant, possibly because of the small number of patients (only seven of 25 leukemia patients and six of 90 controls received doxorubicin). Our study shows that the risk of leukemia after moderate or high doses of anthracyclines ( 170 mg/m² of doxorubicin or equivalent) is as high as the risk associated with exposure to 1.2 to 6 g/m² of epipodophyllotoxins. Anthracyclines are more widely used than epipodophyllotoxins in pediatric oncology: in our study, 53% of controls had been treated with anthracyclines (35% with 170 mg/m²), whereas 36% had received epipodophyllotoxins (26% with 1.2 g/m²).

We found no excess risk associated with alkylating agents, despite their recognized leukemogenicity.^{26,29,37–42} This result was independent of the method used to express total exposure to the different alkylating agents; that is, the weighted sum (see Methods and Table 2), the sum of milligrams per meters squared, the sum of millimoles per meters squared, or the sum of scores defined by Tucker.²⁶ This could partly be explained by the close association between exposure to alkylating agents and exposure to DNA topoisomerase II inhibitors in our population: all but one of the patients who received more than 6 g/m² of epipodophyllotoxins (high-risk group) also received alkylating agents. Therefore, our study does not have the power to separate the effects of exposure to epipodophyllotoxins and those of exposure to alkylating agents; this does not mean that there is no leukemogenic effect of alkylators. Another possible explanation may be related to little use of the most leukemogenic alkylating agents such as melphalan (10% of controls) and mechlorethamine (5% of controls).

Among the numerous characteristics of the primary tumor associated with the subsequent risk of leukemia in univariate analysis, only histologic type was independent of the drugs received. Secondary malignancies are a frequent complication of Hodgkin’s disease^{38,39,43–45} and are often attributed to heavy treatment, such as extended radiotherapy and high doses of alkylating agents. We have observed seven patients with leukemia occurring after first-line treatment combining 20 Gy to a limited field and either low doses of alkylating agents (five patients) or chemotherapy without alkylating agents (two patients). The emergence of osteosarcoma as an independent risk factor was unexpected because this association has only been described in isolated case reports.^46–52 Individual susceptibility might predispose patients to Hodgkin’s disease or osteosarcoma and to a second malignancy after chemotherapy.

In this case-control study, the risk of secondary leukemia after treatment of a primary solid malignancy depended both on the type of the first cancer and on exposure to DNA topoisomerase II inhibitors. The risk increased with the cumulative dose of epipodophyllotoxins, with an unacceptably high risk in patients who received more than 6 g/m². Patients who had received 1.2 to 6 g/m² of epipodophyllotoxins or more than 170 mg/m² of anthracyclines had a seven-fold higher risk of leukemia than patients who received lower doses of these drugs. Thus, the efficacy of continuous or semicontinuous etoposide administration as palliative treatment is offset by its strong leukemogenicity when the total dose exceeds 6 g/m². Such high cumulative doses can be reached when standard-dose etoposide is given continuously or semicontinuously for 6 months, which is standard practice.

	APPENDIX

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
We are indebted to Claire Alapetite, Anne Auvrignon, Paula Ballerini, Roland Berger, Marie-Hélène Bourg, Olivier Delattre, François Doz, Hélène Esperou, Christophe Hennequin, Guy Leverger, Christine Perot, Marie-France Portnoi, Erica Quintina, Marie-Dominique Tabone, Jacqueline Van den Akker (Paris); Sophie Ansoborlo, Philippe Bernard, Binh Bui N’guyen, Anne Notz-Carrere, Pierre Richaud (Bordeaux); Hervé Avet-Loiseau, Jean-Claude Cuilliere, Françoise Mechinaud-Lacroix, Dominique Menegalli-Boggelli, Axel de Kersaint-Gilly, Caroline Thomas (Nantes); Annie Babin-Boilletot, Philippe Quetin (Strasbourg); Laurence Baranger, Erick Gamelin, Xavier Rialland (Angers); Marie-Christine Baranzelli, Jean-Hugues Dalle, Nathalie Deligny, Anne-Sophie Desfachelles, Maurice Madelain, Françoise Mazingue, Jean-Luc Lai, Laurence Vanlemens (Lille); Eric Barthelme (Metz); Elisabeth Bernard, Jean-Louis Bernard, Anne-Marie Capodano, Carole Coze, Jean Gabert, Gérard Michel, Xavier Muracciole, Thierry Pignon (Marseille); Yves Bertrand, Christian Carrie, Anne-Marie Manel, Marie-Pierre Pages, Sabine Soulie, Isabelle Tigaud, Jean-Pierre Gérard (Lyon); Marie-Françoise Bertheas, François Freycon, Claire Berger, Jean-Louis Stephan (Saint Etienne); Marie-Christine Bone, Gérard Couillault, Francine Mugneret (Dijon); Pierre Bordigoni, Sylvette Hoffstetter, Françoise Piron, Jean-Francoise Leseve, Marie-José Gregorie (Vandoeuvre Les Nancy); Jean-François Bosset, Marie-Agnès Collonge-Rame, Emmanuel Plouvier (Besançon); Patrick Boutard (Caen); Laurence Brugières, Jacqueline Clavel, Stéphanie Clisant, Gisèle Da Silva, Marie-Gabrielle Dondon, Ariane Dunant, Marie-Catherine Gensse, Jean-Louis Habrand, Olivier Hartmann, Odile Oberlin (Villejuif); Jean-Paul Bureau, Jean Chiesa (Nîmes); Philippe Colin, Martine Munzer, Tan Dat N’guyen, Pierre Pauchet (Reims); Sophie Crenn Nondier, Yvon Graic, Jean-Pierre Vannier (Rouen); Nicole Dastugue, Rosine Guimbaud, Andrée Pons, Françoise Rigal-Huguet, Alain Robert, Hervé Rubie (Toulouse); Charles Dauriac, Christine Edan, Virginie Gandemer, Isabelle Tron, Francesa Le Mee, Elisabeth Le Prise-Fleury (Rennes); Anne De Truchis (Le Chesnay); Anne Deville, Jean-Léon Lagrange (Nice); Claude Dionet, Piotr Gembara, Caroline Schoepffer (Clermont-Ferrand); Patrick Dube, Brigitte Pautard (Amiens); Christian Francois (Lens); Zineb Gaci (Poitiers); Fabien Garcia (La Rochelle); Paul Gesta (Niort); Hélène Kolodie, Dominique Plantaz, (Grenoble); Lionel de Lumley, Bernard Roullet (Limoges); Geneviève Margueritte, Sylvie Taviaux (Montpellier); Claude Roche (Arras); and Brigitte Vigne (Montmorency).

	ACKNOWLEDGMENTS

 
We are indebted to David Young and Brenda Mallon for reviewing the manuscript and to numerous Société Française d’Oncologie Pédiatrique participants listed in the appendix.

	NOTES

 
Supported by La Ligue Nationale Contre le Cancer and l’Association pour la Recherche sur le Cancer, France.

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Submitted April 16, 2002; accepted November 19, 2002.

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