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Journal of Clinical Oncology, Vol 26, No 9 (March 20), 2008: pp. 1532-1536 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4197 Randomization Reveals Unexpected Acute Leukemias in Southwest Oncology Group Prostate Cancer Trial
From the University of Colorado Health Science Center, Denver, CO; Southwest Oncology Group Statistical Center, Seattle, WA; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; University of Chicago, Chicago, IL; Cleveland Clinic Foundation, Cleveland, OH Corresponding author: Thomas W. Flaig, M.D., Department of Medicine, University of Colorado Health Science Center, Mail Stop 8117, P.O. Box 6511, Aurora, CO 80045-0511; e-mail: Thomas.Flaig{at}UCHSC.edu
Purpose Southwest Oncology Group (SWOG) study 9921 is a randomized, phase III, intergroup study to define the role of adjuvant chemotherapy in patients with high-risk prostate cancer. Patients and Methods We allocated 983 patients with prostate cancer with high-risk features to receive 2 years of androgen-deprivation therapy (ADT) with or without six cycles of mitoxantrone (12 mg/m2) after prostatectomy. Results In January 2007, SWOG 9921 was closed to further accrual after three cases of acute myelogenous leukemia (AML) were reported of a total of 487 patients in the mitoxantrone treatment arm. The key cytogenetic features of these cases included inv(16) in the first case, t(15;17) in the second, and del(5) in the third case. Time from the start of mitoxantrone to the detection of AML was 13, 48, and 72 months, respectively. Before SWOG 9921, there were no cases of mitoxantrone-induced AML reported in patients treated for prostate cancer. Conclusion The emergence of this possible pattern of secondary malignancy emphasizes the importance of randomized controlled trials in defining safety and efficacy of new approaches for patients in the adjuvant setting.
Adjuvant chemotherapy is widely used in the treatment of breast, colon, and lung cancers, with a proven survival advantage in each of these settings.1-3 In contrast, the efficacy of postoperative (adjuvant) chemotherapy in high-risk prostate cancer is unknown, though there are convincing data supporting immediate adjuvant androgen ablation therapy in selected high-risk postoperative patients.4 Mitoxantrone has a long history of use in hormone-refractory prostate cancer. In several studies of patients with advanced prostate cancer, mitoxantrone and glucocorticoids have provided palliation and have shown improved response rates with a prolongation in the time to progression when compared with glucocorticoids alone.5-7 A small study from investigators at the Hammersmith Hospital in London examined the use of adjuvant mitoxantrone in patients with prostate cancer.8 Ninety-six patients with locally advanced or metastatic disease were randomly assigned to androgen-deprivation therapy (ADT) with or without four cycles of mitoxantrone. Although there was no survival advantage observed for these patients as a group, a subgroup analysis of the 38 nonmetastatic patients revealed an improvement in the median survival with mitoxantrone treatment (80 v 36 months, P = .044). These studies provided us with a compelling rationale for carrying out a prospective, randomized trial of mitoxantrone in high-risk patients with prostate cancer following radical retropubic prostatectomy.
SWOG 9921 is a prospective, phase III, randomized, intergroup trial examining the efficacy of adjuvant mitoxantrone chemotherapy in addition to ADT in high-risk patients with prostate cancer. The Eastern Cooperative Group (ECOG) and the North Central Cancer Treatment Group (NCCTG) participated through the Cancer Trials Support Unit (CTSU), and the Cancer and Leukemia Group B (CALGB) also participated directly with SWOG. The primary end point was to compare the overall survival in the two treatment groups. This study was approved by the institutional review boards at each treating center, in accordance with all national and international standards. Written informed consent was obtained from each patient before their participation. Patient random assignment was stratified by Gleason sum score, planned future radiation therapy, and pathologic stage of disease.
High-risk patients were defined as having at least one of the following: (1) a pathologic Gleason sum score of
All patients were treated with 2 years of combined ADT consisting of bicalutamide 50 mg by mouth daily and goserelin acetate 10.8 mg subcutaneously every 12 weeks. Participants were randomly assigned (1:1) to the addition of mitoxantrone 12 mg/m2 every 21 days for six cycles with prednisone 5 mg twice daily for six cycles. Adjuvant radiotherapy was allowed at the discretion of the treating physician and by patient preference. Patient accrual started in February 2000, enrolling 983 patients, with 487 in the mitoxantrone plus ADT arm, and 496 in the ADT-alone arm. Accrual to SWOG 9921 was closed, and mitoxantrone administration was suspended based on the recommendation of the data safety monitoring board in January 2007, after a request for review by the trial investigators consequent to the identification of three cases of acute myelogenous leukemia (AML) in the mitoxantrone arm. This decision was not based solely on a direct statistical comparison between the arms, but also on the observation of these three cases in the context of an unexpectedly low overall death rate for this patient population. The primary end point of the study was overall survival. The study assumptions of 1,360 patients (680 in each arm) accrued throughout 9.5 years, an additional 4 years of follow-up, and a median survival of 10 years on the standard ADT arm, give 0.93 power to detect a 30% increase in the median survival following the addition of mitoxantrone to standard ADT, using a one-sided log-rank test with .05 significance.
Case 1 A 64-year-old patient presented with a prostate-specific antigen (PSA) level of 8.7 ng/mL and proceeded to surgery after prostate cancer was identified on biopsy. The radical prostatectomy specimen revealed a Gleason sum score of 4 + 5 = 9, involvement of two obturator lymph nodes, seminal vesicle invasion, and extracapsular extension. Mitoxantrone was initiated about 3 months after his surgery, and he received a total of six cycles of mitoxantrone, without dose reduction or significant complication. Thirteen months after starting mitoxantrone, the patient presented with fever, abdominal pain, a decreased oxygen saturation of 83% on room air, and a WBC of 17.4 x 109/L. Bone marrow aspiration was performed, with cytogenetic analysis confirming AML with a 16(p13q22) inversion. The patient was treated with broad spectrum antibiotic coverage, and induction "7 + 3" (doxorubicin and cytarabine) chemotherapy was started on hospital day 3. Despite intensive supportive efforts, the patient died on hospital day 8, with the postmortem examination demonstrating multiorgan failure complicated by opportunistic infection. No evidence of prostate cancer was demonstrated at autopsy. This individual case was previously reported and is believed to be the first reported case of mitoxantrone-associated AML in a patient with prostate cancer9 (Table 2).
Case 2 In a 58-year-old patient with prostate cancer treated with a radical prostatectomy, pathologic examination revealed a Gleason sum score of 4 + 3 = 7 adenocarcinoma of the prostate, focal positive surgical margin, and extraprostatic extension (T3a), with the sampled lymph nodes negative for prostate cancer involvement. His preoperative PSA was 14.1 ng/mL. Six cycles of mitoxantrone (12 mg/m2) were given without any severe adverse events. ADT was continued for 2 years according to the protocol. Forty-eight months after starting mitoxantrone, the patient presented with leukocytosis and severe disseminated intravascular coagulation. Bone marrow examination was consistent with acute promyelocytic leukemia 47, XY, +8, t(15;17)(q22q11.2). As of this writing, he is under active treatment for his leukemia. The last PSA measurement was 0.1 ng/mL.
Case 3 The baseline laboratory evaluation revealed a WBC of 5.2 x 109, platelet count of 173 x 109, and an absolute neutrophil count of 3.2 x 109 with no noted abnormalities in any of the automated CBC indices. He received mitoxantrone (12 mg/m2) for three cycles, with concurrent ADT that continued for 2 years. His mitoxantrone treatment was discontinued after three cycles secondary to repeated hematologic toxicity including an absolute neutrophil count of less than 500, platelet count of 68 x 109, and neutropenic fever. Seventy-two months after starting mitoxantrone, the patient was noted to have low blood counts including a WBC of 1.5 x 109, hemoglobin of 9.4 g/dL, and platelets of 107 x 109. He proceeded to a bone marrow biopsy with the cytogenetic analysis demonstrating AML with an abnormal mosaic male karyotype: 46,XY[55%]/45,XY,-3,del(5)(q13q35),add(9)(p24),t(13,15)(q34;q21)[40%]/46,idem,+del(5)(q13q35)[5%]. He was treated with standard induction chemotherapy using daunorubicin and cytarabine. This was complicated by hypoxia with bilateral chest infiltrates, requiring a brief intensive care admission and bilevel positive airway pressure respiratory support. At the time of this submission, he continues to receive active treatment for AML. His prostate cancer is in clinical remission with a PSA of less than 0.1 ng/mL.
Leukemic Risk
Secondary or treatment-associated leukemia has been recognized in two major classes of chemotherapy drugs—alkylating agents and topoisomerase II inhibitors.10 Secondary leukemias after alkylating agents (eg, cyclophosphamide, melphalan) have traditionally been characterized by a preceding myelodysplastic syndrome (MDS), a latency period of 4 to 7 years, and characteristic cytogenetic abnormalities including deletions of chromosomes 5 and 7.11 Topoisomerase II inhibitors, such as mitoxantrone, have more recently been linked to treatment-related leukemia. In contrast to the leukemia observed with alkylating agents, these leukemias are observed earlier after treatment (at approximately 2 years) and oftentimes associated with balanced chromosomal aberrations.10 Many of these leukemias have translocations involving the 11q23 band,12 though inv(16) and t(15;17) abnormalities are also seen.13-16 The reported prevalence of mitoxantrone-associated leukemia in different disease settings is variable. In breast cancer, the risk of developing AML after mitoxantrone has been reported as 0.7% to 0.9%.17,18 The number of patients who developed AML in the mitoxantrone arm of SWOG 9921 (3/487 or 0.6%) is similar to the prevalence seen in patients with breast cancer treated with mitoxantrone.17,18 However, with the short follow-up duration for some of the SWOG 9921 participants and the observed latency of up to 6 years for the development of AML, additional cases of AML are possible, and a longer follow-up is needed to confirm this similarity. Mitoxantrone-associated AML is also seen in patients with multiple sclerosis. In a recent review of the multiple sclerosis literature, a total of 10 cases of treatment-related AML from mitoxantrone are reported.19 By combining the results of several series, the published incidence of treatment-related AML in this population is 0.21%.16 One recent publication challenges the traditional characterization of mitoxantrone-associated leukemias. Le Deley and colleagues report a case-control study of 182 patients with breast cancer who developed AML or MDS along with 534 matched controls.20 Using multivariate analysis, the relative risk (RR) of AML/MDS after mitoxantrone was 15.6 (95% CI, 7.10 to 34.2), which was notably higher than recorded with anthracyclines alone (RR, 2.73; 95% CI, 1.65 to 4.54). The use of alkylating agents was not related to an increased risk for the development of AML/MDS in multivariate analysis. Most surprisingly, mitoxantrone was associated with the development of both AML and MDS when considered separately, challenging the long-held belief that topoisomerase II inhibitors are not significantly associated with the development of MDS and related leukemias. Reports of treatment-related leukemia in patients with prostate cancer are uncommon and have been limited to case reports. Cases have been reported after ADT,21 strontium-89,22 oral etoposide,23 and recently, an additional case of AML after mitoxantrone for the treatment of prostate cancer.24 This paucity of mitoxantrone-induced leukemia in patients with prostate cancer is notable, despite mitoxantrone's frequent use in this setting, with no specific reports of AML described in the trials establishing mitoxantrone in the treatment of advanced prostate cancer.5-7 Based on Surveillance, Epidemiology and End Results data, the annual incidence rate of AML in men aged 60 to 64 years is 8.4 per 100,000,25 and thus the incidence reported in this trial represents an approximate 30-fold increase compared with the anticipated community risk in this general age group of men. The cytogenetic features and clinical history allow us to assess the likelihood that these three cases are associated with mitoxantrone. The first and second cases are probably related to mitoxantrone. Both the inv(16)(p13q22) abnormalities14,15,17 and t(15;17) abnormalities16,17,26,27 have been reported with mitoxantrone. The latency periods of 13 and 48 months are both within the range reported from one large series28 and approximate the expected latency of 2 years. The third case does not fit the customary pattern of mitoxantrone-associated leukemia, with its long latency (6 years) and del(5) abnormality, a common feature of MDS. However, with the recent report linking mitoxantrone to the development of MDS, this case is regarded as potentially related to mitoxantrone.20 The efficacy of adjuvant chemotherapy in high-risk prostate cancer remains an important question. With the role of adjuvant chemotherapy established in other common tumor types, its use in prostate cancer is rational but remains unproven. Although short of its accrual goal of 1,360, a reasonable opportunity to identify a difference in the treatment arms remains with 983 patients enrolled in SWOG 9921, though meaningful conclusions are not likely for many years. Other trials of adjuvant therapy in prostate cancer are underway or planned, though the results are not expected soon. In conclusion, the role of adjuvant mitoxantrone was investigated in SWOG trial 9921. All patients will continue to be observed, and active patients in both arms will be treated with ADT for a total of 2 years as planned. The risk for mitoxantrone-associated AML seems similar to the risk in patients receiving adjuvant breast cancer treatment. The final acceptance or rejection of adjuvant mitoxantrone in high-risk postprostatectomy patients will ultimately depend on the overall survival and time to progression data which will mature during the years to come. These observations serve as an important reminder of the role of randomized clinical trials in the introduction of novel therapies for patients with cancer who have a long expected survival, and specifically, for the design of studies of adjuvant therapy.
The author(s) indicated no potential conflicts of interest.
Conception and design: Thomas W. Flaig, Cathy M. Tangen, Maha H.A. Hussain, Walter M. Stadler, Derek Raghavan, E. David Crawford, L. Michael Glodé Provision of study materials or patients: Thomas W. Flaig, Cathy M. Tangen, Maha H.A. Hussain, Walter M. Stadler, L. Michael Glodé Collection and assembly of data: Thomas W. Flaig, Cathy M. Tangen, Maha H.A. Hussain, Walter M. Stadler Data analysis and interpretation: Thomas W. Flaig, Cathy M. Tangen, Maha H.A. Hussain, Walter M. Stadler, Derek Raghavan, E. David Crawford, L. Michael Glodé Manuscript writing: Thomas W. Flaig, Cathy M. Tangen, Maha H.A. Hussain, Walter M. Stadler, Derek Raghavan Final approval of manuscript: Thomas W. Flaig, Cathy M. Tangen, Maha H.A. Hussain, Walter M. Stadler, Derek Raghavan, E. David Crawford, L. Michael Glodé
Supported in part by the following Public Health Service Cooperative Agreement Grant Nos. awarded by the National Cancer Institute, Department of Human Health and Services: CA38926, CA32102, CA42777, CA27057, CA41287, CA04919. The manuscript contains original results and analysis not previously presented. One case was previously reported, but not in the context of the additional cases and the subsequent closure of the trial.9 Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 2. O'Connell MJ, Mailliard JA, Kahn MJ, et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15:246-250, 1997 3. Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol 7:719-727, 2006[CrossRef][Medline] 4. Messing EM, Manola J, Yao J, et al: Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7:472-479, 2006[CrossRef][Medline] 5. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: Results of the cancer and leukemia group B 9182 study. J Clin Oncol 17:2506-2513, 1999 6. Berry W, Dakhil S, Modiano M, et al: Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol 168:2439-2443, 2002[CrossRef][Medline] 7. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756-1764, 1996 8. Wang J, Halford S, Rigg A, et al: Adjuvant mitozantrone chemotherapy in advanced prostate cancer. BJU Int 86:675-680, 2000[CrossRef][Medline] 9. Bowles DW, Flaig TW: Mitoxantrone-associated acute myelogenous leukemia in a patient with high-risk adenocarcinoma of the prostate: A case report and brief review. Cancer Invest 24:517-520, 2006[CrossRef][Medline] 10. Pedersen-Bjergaard J, Rowley JD: The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood 83:2780-2786, 1994 11. Pedersen-Bjergaard J, Specht L, Larsen SO, et al: Risk of therapy-related leukaemia and preleukaemia after Hodgkin's disease: Relation to age, cumulative dose of alkylating agents, and time from chemotherapy. Lancet 2:83-88, 1987[Medline] 12. Pui CH, Behm FG, Raimondi SC, et al: Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 321:136-142, 1989[Abstract] 13. Andersen MK, Larson RA, Mauritzson N, et al: Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: Report from an international workshop. Genes Chromosomes Cancer 33:395-400, 2002[CrossRef][Medline] 14. Dissing M, Le Beau MM, Pedersen-Bjergaard J: Inversion of chromosome 16 and uncommon rearrangements of the CBFB and MYH11 genes in therapy-related acute myeloid leukemia: Rare events related to DNA-topoisomerase II inhibitors? J Clin Oncol 16:1890-1896, 1998[Abstract] 15. Pedersen-Bjergaard J, Andersen MK, Johansson B: Balanced chromosome aberrations in leukemias following chemotherapy with DNA-topoisomerase II inhibitors. J Clin Oncol 16:1897-1898, 1998[Medline] 16. Voltz R, Starck M, Zingler V, et al: Mitoxantrone therapy in multiple sclerosis and acute leukaemia: A case report out of 644 treated patients. Mult Scler 10:472-474, 2004 17. Linassier C, Barin C, Calais G, et al: Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy. Ann Oncol 11:1289-1294, 2000 18. Kroger N, Damon L, Zander AR, et al: Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients. Bone Marrow Transplant 32:1153-1157, 2003[CrossRef][Medline] 19. Fox EJ: Management of worsening multiple sclerosis with mitoxantrone: A review. Clin Ther 28:461-474, 2006[CrossRef][Medline] 20. Le Deley MC, Suzan F, Cutuli B, et al: Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: Risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol 25:292-300, 2007 21. Matsuura H, Sakurai M, Arima K: [Two cases of prostate cancer associated with acute myeloid leukemia presenting as thrombocytopenia during endocrine therapy]. Hinyokika Kiyo 49:87-90, 2003[Medline] 22. Kossman SE, Weiss MA: Acute myelogenous leukemia after exposure to strontium-89 for the treatment of adenocarcinoma of the prostate. Cancer 88:620-624, 2000[CrossRef][Medline] 23. Katato K, Flaherty L, Varterasian M: Secondary acute myelogenous leukemia following treatment with oral etoposide. Am J Hematol 53:54-55, 1996[CrossRef][Medline] 24. Martinez V, Mir O, Domont J, et al: Mitoxantrone-related acute myeloblastic leukaemia in a patient with metastatic hormone-refractory prostate cancer. Anticancer Drugs 18:233-235, 2007[CrossRef][Medline] 25. SEER Cancer Statistics Review 1975-2003. Myeloid leukemia: SEER incidence rates, age-adjusted and age-specific rates, by race and sex. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/sect_13_leukemia.pdf 26. Mistry AR, Felix CA, Whitmarsh RJ, et al: DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 352:1529-1538, 2005 27. Beaumont M, Sanz M, Carli PM, et al: Therapy-related acute promyelocytic leukemia. J Clin Oncol 21:2123-2137, 2003 28. Rowley JD, Olney HJ: International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy-related myelodysplastic syndromes and acute leukemia: Overview report. Genes Chromosomes Cancer 33:331-345, 2002[CrossRef][Medline] Submitted July 20, 2007; accepted October 30, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
8; (2) pathologic T3b disease, pT4 disease, or N1 disease; (3) pathologic Gleason sum score of 7 with a positive surgical margin; or (4) preoperative PSA higher than 15 ng/mL, a biopsy Gleason sum score of 
0.2 ng/mL) before random assignment. Patient characteristics are summarized in 
