- Email: [email protected]
Hemophilia and cancer: A new challenge for hemophilia centers
Cancer Treatment Reviews 35 (2009) 374–377
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
COMPLICATIONS OF TREATMENT
Hemophilia and cancer: A new challenge for hemophilia centers Massimo Franchini a,*, Giuseppe Lippi b, Martina Montagnana b, Giovanni Targher c, Marco Zaffanello d, Gian Luca Salvagno b, Gianna Franca Rivolta e, Caterina Di Perna e, Annarita Tagliaferri e a
Immunohematology and Transfusion Center – Department of Pathology and Laboratory Medicine, University Hospital of Parma, Via Gramsci, 14, Parma, Italy Section of Clinical Chemistry, Department of Biomedical and Morphological Sciences, University of Verona, Verona, Italy c Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona, Verona, Italy d Department of Mother–Child and Biology-Genetics, University of Verona, Verona, Italy e Regional Reference Centre for Inherited Bleeding Disorders, University Hospital, Parma, Italy b
a r t i c l e
i n f o
Article history: Received 12 November 2008 Received in revised form 7 January 2009 Accepted 8 January 2009
s u m m a r y The improved life expectancy of hemophilia patients due to the advances in hemophilia care and factor replacement therapy has permitted to hemophiliacs to reach an older age. As a consequence, age-related diseases, such as cardiovascular disorders and cancer, have been increasingly recognized in such patients. In particular, the management of cancer in people with inherited hemorrhagic disorders represents a new challenge for physicians working in hemophilia centers. The few published literature data document that there is a close relationship between hemophilia and neoplasia. Indeed, the congenital bleeding tendency may influence the cancer in different ways, by interfering with its clinical presentation, diagnosis and treatment. These aspects, along with the epidemiology of cancer in hemophiliacs will be discussed in this review. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Since the early 1970s there have been dramatic improvements in the availability and quality of treatment for persons with hemophilia.1 As a result of this progress, barring the consequences of the human immunodeficiency virus (HIV) and hepatitis c virus (HCV) epidemics in the 1980s, the life span of hemophiliacs has progressively become similar to that of males in the general population, at least in more developed countries.2,3 Accordingly, a considerable number of hemophiliacs now reach old age: in Italy, for instance, nearly 8% of persons with severe hemophilia A or B are 65 years old or older.4 However, with age, persons with hemophilia develop medical and surgical diseases (e.g., cardiovascular diseases, prostatic hypertrophy, cancers, renal disease) not previously seen in this group.5 Although, there is very little information in literature, mostly as anecdotal case reports, on these associated conditions, they represent a new challenge for physicians operating in hemophilia centers. In this review, we analyze the current knowledge on the cancers developing in patients with hemophilia, focusing on the epidemiology and management of these co-morbidities. Epidemiology of cancers in hemophiliacs The largest study on the epidemiology of cancer in patients with inherited bleeding disorders is that published in 1979 by Forman.6 * Corresponding author. Tel.: +39 0458348196. E-mail address: [email protected] (M. Franchini). 0305-7372/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2009.01.001
In a survey among physicians of patients with a bleeding diathesis, the author collected 61 cases of cancer in an estimated population of 10,500 patients. In the hemophilia group the primary site of cancer was similar to an age and sex matched population. In addition there was no evidence of a change in the onset of metastatic disease in these individuals, as compared with similar individual with cancer but without coagulopathy. An indirect estimation of the incidence of neoplasia in the hemophilia population comes from the analysis of the studies from different countries on the mortality rates, life expectancy and causes of death in people with hemophilia. Obviously, most papers focused on patients with HIV and/or HCV infections. For instance, Darby and colleagues, on behalf the United Kingdom Hemophilia Centre Doctors’ Organization, carried out a cohort study of mortality from liver cancer and liver disease in 4865 hemophilic men and boys in the UK treated between 1969 and 1985 with blood products contaminated with hepatitis C.7 A total of 5 deaths attributed to primary liver cancer were reported, with a mortality rate 5.6 higher than in the general population. The 25-year cumulative risk of death from liver cancer was 0.37%, significantly higher than that expected (0.03%) from national mortality rates. The same group found that 72 of the 89 cases (81%) of lymphoma recorded in the UK hemophilia population during the 22 year period 1978–1999 occurred in HIV-positive patients, with a high proportion of highgrade non-Hodgkin lymphoma (NHL), extranodal presentation (i.e., gastrointestinal tract) and cerebral lymphoma.8 Interestingly, the incidence of NHL in the HIV-positive cohort was significantly increased during the period 1985–1996, with a ratio of observedto-expected cases of 83.92. This ratio reduced to 42.15 during
M. Franchini et al. / Cancer Treatment Reviews 35 (2009) 374–377
375
Table 1 Summary of the main literature data on the cancer-related deaths in hemophilic patients. First authorReference
Hemophilic population
Period of the study
Main results
Darby7
1969–1993
Wilde
4865 Hemophiliacs exposed to HCV-infected blood products 89 Hemophiliacs with lymphoma
Plug9
967 Hemophiliacs
1992–2001
2450 Hemophiliacs
1980–1995
413 Hemophiliacs 2950 Hemophiliacs 919 Hemophiliacs 6018 HIV-negative hemophiliacs
1980–1994 1993–1995 1986–1992 1977–1998
The authors observed an increased 25-year cumulative risk of death from primary liver cancer in hemophilic patients than in the general population (0.37% vs. 0.03%) The great majority of the cases of lymphoma (72/89, 81%) occurred in HIV-positive hemophilic patients The overall SMR for malignancies in hemophilic patients was 1.5 and the SMR for liver cancer was 17.2 The SMR for all cancers was 1.1 in the whole population. SMR for lymphoma and liver cancer were markedly increased in HIV-positive population (78 and 70, respectively) The majority of cancer-related deaths (NHL and HCC) occurred in HIV- and HCV-infected patients The SMR for non-HIV- or liver-related cancers in hemophilic patients was 2.2 No excess mortality from cancer was observed during the study period (SMR 1.0) The SMR for cancers not related to HCV or HIV infection in hemophilic patients was 2.2
8
Walker10 12
Ludlam Soucie13 Triemstra14 Darby15
1978–1999
Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; SMR, standardized mortality ratio; NHL, non–Hodgkin’s lymphoma; HCC, hepatocellular carcinoma.
the period 1997–1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART). In the prospective cohort study conducted by Plug and colleagues on the mortality and causes of death in the Dutch hemophilia population during the decade 1992–2001, deaths from malignant neoplasm accounted for 22% of total deaths with a standardized mortality ratio (SMR, the ratio of the observed-to-expected mortality) of 1.5.9 This study also showed a highly increased risk of death of hepatocellular carcinoma (5 cases reported with a SMR of 17.2). Walker and Julian, on behalf the Association of Hemophilia Clinic Directors of Canada analyzed the causes of death in Canadians with hemophilia during the years 1980–1995.10 Although, deaths from liver cancer or lymphoma were markedly increased among individuals seropositive for HIV compared to those who were seronegative, deaths due to all cancers were not increased in the whole population (SMR 1.1). These findings were in keeping with those previously reported by Rabkin and colleagues, who observed 12 cases of NHL and 2 cases of HD in 1065 HIV-positive hemophilic patients and 2 cases of HD in 636 HIV-negative patients during a 12-year follow-up period.11 Similarly, in the study conducted by Ludlam and colleagues in Scotland during the period 1980–1994, most of he cancer-related deaths (i.e., NHL and hepatocellular carcinoma) occurred in patients with HIV or HCV infection.12 Interestingly, Soucie and colleagues, in a survey on the causes of deaths conducted in six US states among 2950 hemophiliacs during the period 1993–1995, found that 6% (14/236) of deaths were attributable to non-HIV- or liver-related cancers with a standardized mortality ratio of 2.2.13 By contrast, Triemstra and colleagues found no excess mortality from cancer in a cohort of Dutch hemophiliacs followed from 1986 to 1992 (SMR 1.0).14 More recently, Darby and colleagues, on behalf the UK Hemophilia Centre Doctors’ Organization, analyzed mortality rates and causes of death in 6018 HIV-uninfected people with hemophilia during the period 1977– 1998.15 Mortality from liver cancer and Hodgkin’s disease were substantially increased compared with mortality in the general population with a SMR of 13.51 and 4.95, respectively. For other cancers there was no evidence of increased mortality (SMR 0.90). In summary, the literature data seem to indicate that while liver cancer and lymphoma are most prevalent in hemophiliacs infected with HCV or HIV, respectively, there is no evidence of an increased incidence of other neoplasm in patients with hemophilia compared to general population (see Table 1). Management of cancers in hemophiliacs: analysis of the literature data The published literature data document that hemophilia may influence not only the treatment but also the clinical presentation
and the diagnostic evaluation of the associated neoplasia. However, only a few case reports have described so far the management of cancer in hemophilic patients. Anyway, the hemophilia-associated increased bleeding risk should be taken in account when a chemotherapy or radiotherapy program or a diagnostic invasive procedure is performed in such patients. Lambert and colleagues reported a case of a patient with mild hemophilia B and a colon cancer with liver metastases diagnosed in 2004.16 The patient underwent partial colectomy under continuous infusion of recombinant factor IX followed by conventional therapy (FOLFOX) consisting of 5-fluoruracil, folinic acid and oxaliplatin every 2 weeks. In spite of this treatment, his disease progressed over the next year. Two new lines of chemotherapy were then administered: FOLFIRI, consisting of irinotecan, 5-fluoruracil and folinic acid followed by irinotecan and cetuximab. As repeated imaging revealed new hepatic metastases, the decision to add to FOLFIRI treatment with the humanized monoclonal anti-angiogenic antibody bevacizumab (an agent targeting the vascular endothelial growth factor [VEGF]) was made. The agent (12 doses were administered) was well tolerated without bleeding complications. After a stable period of 8 months, the disease progression was documented and the patient died in June 2007. This case report is particularly important because documents, for the first time, the use in a hemophilia patient with a mild defect of a chemotherapeutic agent with effects on the vascular endothelium without aggravation of bleeding diathesis. Dawson and colleagues in 2007 reported the first description of an autologous stem cell transplantation in a patient with severe hemophilia A and an HIV-related plasmablastic lymphoma of the oral cavity without bleeding complications.17 Other studies have focused on the management of hepatocellular carcinoma in hemophiliacs, which is an important cause of death in hemophiliacs with chronic hepatitis C.18 This peculiar category of patients is at particularly increased risk of bleeding because of low factor VIII/IX levels owing to the hemophilia and low platelet counts and prolonged prothrombin times owing to the cirrhosis. Toyoda and colleagues analyzed the safety and complications of interventional radiology for hepatocellular carcinoma in 8 patients with hemophilia and cirrhosis.19 No bleeding for the site of vascular puncture was observed, indicating that the infusion of 40–60 UI/kg of factor VIII/IX concentrate prior to the treatment was sufficient for this procedure. Unexpectedly, gastrointestinal bleeding occurred in 3 patients 3–6 days after treatment. Thus the author concluded advising careful attention to this complication when performing interventional radiology in patients with hemophilia. Shen and colleagues described a successful partial hepatectomy in a patient with hemophilia and hepatocellular carcinoma.20 No postoperative bleeding complications were recorded, thanks to the administration of factor VIII concentrate during and
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M. Franchini et al. / Cancer Treatment Reviews 35 (2009) 374–377
immediately after surgery. Finally, Gordon and colleagues reviewed the published literature data on orthotopic liver transplantation in patients with hemophilia.21 Four of the 26 transplants reported were performed in patients with hepatocellular carcinoma without bleeding complications. As regards the impact of hemophilia on the clinical presentation of cancer, in rare cancer cases, unusual bleeding may lead to the diagnosis of previously undiagnosed mild/moderate hemophilia. On the other hand, a bleeding episode in a hemophilia patient may reveal an underlying oncologic disorder. Indeed, Larrain described a case of a HIV-negative hemophilia B patient in whom a diagnosis of chronic myeloid leukemia (CML) was made after an upper digestive tract bleeding. The patient was treated with busulfan with a survival more than twice the average survival of CML patients treated with the same agent.22 Another case of co-existence of leukemia and hemophilia was reported by Kawakami and colleagues.23 Zulfikar reported two boys with hemophilia and leukemia treated with conventional chemotherapy.24 While the first patient, with acute lymphoblastic leukemia, was in complete remission 15 months after chemotherapy, the second patients, with acute myelomonocytic leukemia, after an initial response relapsed and died at the seventh month of the treatment for disease progression. Based on the experience derived from the management of these two cases, the author outlined the importance of performing an adequate and regular factor concentrate usage in order to minimize the risk of hemorrhage related to the inherited bleeding disorder and to associated chemotherapy. In addition, the report concluded that a possible diagnosis of leukemia should not be overlooked in a patient with hemophilia and severe hemorrhagic problems. The recent description of two cases of leukemia following radioactive synovectomy with phosphorus 32sulfur colloid (P32)25 raised some concerns as regards the safety of this procedure and led the Centers for Disease Control and Prevention to investigate the incidence of leukemia in US patients with hemophilia. An increased incidence rate of leukemia was found in hemophilic patients, regardless the age and HIV-status, compared to the general male population.26 Sakurai and colleagues described another interesting case.27 Indeed, the authors presented the case of a mild hemophilia A patient who developed a soft tissue tumor mimicking subcutaneous hematoma. This rare possibility should be considered in the differential diagnosis of a skin mass in a hemophilia patient. Similarly, Allen and colleagues reviewed the literature and collected 6 case of primary malignancies (5 sarcomas and 1 NHL of bone), misdiagnosed as pseudotumors in hemophilic patients.28 Conclusions The management of cancer in hemophilia patients represents a new challenge for physicians of hemophilia centers. Indeed, the underlying inherited hemorrhagic diathesis may increase the potential risk of bleeding associated with some invasive diagnostic procedures, which should be performed only under an adequate replacement therapy and in close collaboration with hemophilia specialists. For example, a diagnostic biopsy requires the infusion of factor concentrates in order to reach and maintain the levels of deficient clotting factor above 50% for at least 3–4 days. For surgical procedures, higher clotting factor levels for longer period (i.e., above 80% for the first three days, then above 50% for 7–15 days after surgery) are needed.29 On the other hand, the chemotherapy-induced blood cell or mucosal toxicity or hemostatic disturbances may hinder the completion or require a dose reduction of anti-cancer treatments. Furthermore, patients with inherited bleeding disorders are nearly always excluded from trials evaluating new anti-cancer agents because of the uncertainty regarding
potential adverse effects of these agents on the hemostatic system. For instance, the patient described by Lambert and colleagues16 was excluded from trials evaluating bevacizumab and decided to support personally the costs of the treatment. However, in spite of these limitations, we think that the diagnosis of hemophilia should not preclude the access of these patients to adequate chemotherapy regimens. Further studies on large population of patients or reports similar to those previously described are needed to optimize the management of such patients. In this context, on behalf the Association of Italian Hemophilia Centers (AICE), we are conducting a study on cancers in hemophilic patients. The results of this survey will be available in the late 2010 and will help us to know the epidemiology and management of cancer in Italian hemophilic population. Finally, recent in vitro studies suggest that while congenital prothrombotic disorders facilitate metastasis, congenital susceptibility to bleeding may have a protective effect against metastatic capacity of murine cancer cells.30,31 Scope of the future clinical and laboratory research will be to confirm in vivo in hemophilic patients these very interesting preliminary experimental findings. Conflict of interest statement All authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. References 1. Mannucci PM, Tuddenham EG. The hemophilias–from royal genes to gene therapy. N Engl J Med 2001;344(23):1773–9. 2. Street A, Hill K, Sussex B. Haemophilia and ageing. Haemophilia 2006;12(Suppl. ):8–12. 3. Mejia-Carvajal C, Czapek EE, Valentino LA. Life expectancy in hemophilia outcome. J Thromb Haemost 2006;4(3):507–9. 4. Tagliaferri A, Franchini M, von Mackensen S. Health status and quality of life in elderly Italian patients with hemophilia. Haemophilia 2006;12(Suppl. 2):252. [abstract]. 5. Franchini M, Tagliaferri A, Mannucci PM. The management of hemophilia in elderly patients. Clin Interv Aging 2007;2(3):361–8. 6. Forman WB. Cancer in persons with inherited blood coagulation disorders. Cancer 1979;44(2):1059–61. 7. Darby SC, Ewart DW, Giangrande PL, et al. UK Haemophilia Centre Directors’ Organisation. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet 1997;350(9089):1425–31. 8. Wilde JT, Lee CA, Darby SC, et al. UK Haemophilia Centre Directors’ Organisation. The incidence of lymphoma in the UK haemophilia population between 1978 and 1999. AIDS 2002;16(3):1803–7. 9. Plug I, Van Der Bom JG, Peters M, et al. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost 2006;4(3):510–6. 10. Walker IR, Julian JA. Association of Hemophilia Clinic Directors of Canada. Causes of death in Canadians with haemophilia 1980–1995. Haemophilia 1998;4(5):714–20. 11. Rabkin CS, Hilgartner MW, Hedberg KW, et al. Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with hemophilia. JAMA 1992;267(8):1090–4. 12. Ludlam CA, Lee RJ, Prescott RJ, et al. Haemophilia care in central Scotland 1980– 94. I. Demographic characteristics, hospital admissions and causes of death. Haemophilia 2000;6(5):494–503. 13. Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia: relations with source of medical care. The hemophilia surveillance system project investigators. Blood 2000;96(2):437–42. 14. Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Int Med 1995;123(11):823–7. 15. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110(3):815–25. 16. Lambert C, Deneys V, Pothen D, Hermans C. Safety of bevacizumab in mild haemophilia B. Thromb Haemost 2008;99(5):963–4. 17. Dawson MA, Schwarer AP, McLean C, et al. AIDS-related plasmablastic lymphoma of the oral cavity associated with an IGH/MYC translocation– treatment with autologous stem-cell transplantation in a patient with severe haemophilia-A. Haematologica 2007;92(1):e11–2.
M. Franchini et al. / Cancer Treatment Reviews 35 (2009) 374–377 18. Tradati F, Coombo M, Mannucci PM, et al. The Study Group of the Association of Italian Hemophilia Centers. A prospective multicenter study of hepatocellular carcinoma in italian hemophiliacs with chronic hepatitis C. Blood 1998;91(4):1173–7. 19. Toyoda H, Fukuda Y, Yokozaki S, Hayashi K, Saito H, Takamatsu J. Safety and complications of interventional radiology for hepatocellular carcinoma in patients with haemophilia and cirrhosis. Br J Haematol 2001;112(4):1071–3. 20. Shen SC, Harada A, Kurokawa T, et al. Partial hepatectomy for hepatocellular carcinoma in a patient with hemophilia: a case report. Hepatogastroenterol 1994;41(3):283–6. 21. Gordon FH, Mistry PK, Sabin CA, Lee CA. Outcome of orthotopic liver transplantation in patients with haemophilia. Gut 1998;42(5):744–9. 22. Larrain C. Chronic myeloid leukemia in hemophilia B. Rev Med Chil 2002;130(8):897–900. 23. Kawakami K, Takezaki T, Nakazono S, et al. Acute childhood leukemia in a patient with hemophilia: first report in Japan. Acta Paediatr Jpn 1994;36(1):91–4. 24. Zulfikar B. Two patients with haemophilia and acute leukaemia. Haemophilia 2002;8(5):698–702.
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25. Dunn AL, Manco-Johnson M, Busch MT, Balark KL, Abshire TC. Leukemia and P32 radionuclide synovectomy for hemophilic arthropathy. J Thromb Haemost 2005;3(7):1541–2. 26. Dunn AL, Soucie JM. Incidence of leukemia in patients with hemophilia. J Thromb Haemost 2007;5(Suppl 2):OT-016. 27. Sakurai Y, Sugimoto H, Yoshida K, et al. Superficial fibromatosis mimicking subcutaneous hematoma: an unusual and difficult diagnosis in a patient with mild hemophilia A. Int J Hematol 2007;85(1):1–4. 28. Allen DJ, Goddard NJ, Mann HA, Rodriguez-Merchan EC. Primary malignancies mistaken for pseudotumours in haemophilic patients. Haemophilia 2007;13(4):383–6. 29. Santagostino E, Mannucci PM. Italian Association of Haemophilia Centers (AICE). Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy. Haemophilia 2000;6(1):1–10. 30. Langer F, Amirkhosravi A, Ingersoll SB, et al. Experimental metastasis and primary tumor growth in mice with hemophilia A. J Thromb Haemost 2006;4(5):1056–62. 31. Bruggemann LW, Versteeg HH, Niers TM, Reitsma PH, Spek CA. Experimental melanoma metastasis in lungs of mice with congenital coagulation disorders. J Cell Biol Med 2008 [Epub ahead of print].
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
COMPLICATIONS OF TREATMENT
Hemophilia and cancer: A new challenge for hemophilia centers Massimo Franchini a,*, Giuseppe Lippi b, Martina Montagnana b, Giovanni Targher c, Marco Zaffanello d, Gian Luca Salvagno b, Gianna Franca Rivolta e, Caterina Di Perna e, Annarita Tagliaferri e a
Immunohematology and Transfusion Center – Department of Pathology and Laboratory Medicine, University Hospital of Parma, Via Gramsci, 14, Parma, Italy Section of Clinical Chemistry, Department of Biomedical and Morphological Sciences, University of Verona, Verona, Italy c Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona, Verona, Italy d Department of Mother–Child and Biology-Genetics, University of Verona, Verona, Italy e Regional Reference Centre for Inherited Bleeding Disorders, University Hospital, Parma, Italy b
a r t i c l e
i n f o
Article history: Received 12 November 2008 Received in revised form 7 January 2009 Accepted 8 January 2009
s u m m a r y The improved life expectancy of hemophilia patients due to the advances in hemophilia care and factor replacement therapy has permitted to hemophiliacs to reach an older age. As a consequence, age-related diseases, such as cardiovascular disorders and cancer, have been increasingly recognized in such patients. In particular, the management of cancer in people with inherited hemorrhagic disorders represents a new challenge for physicians working in hemophilia centers. The few published literature data document that there is a close relationship between hemophilia and neoplasia. Indeed, the congenital bleeding tendency may influence the cancer in different ways, by interfering with its clinical presentation, diagnosis and treatment. These aspects, along with the epidemiology of cancer in hemophiliacs will be discussed in this review. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Since the early 1970s there have been dramatic improvements in the availability and quality of treatment for persons with hemophilia.1 As a result of this progress, barring the consequences of the human immunodeficiency virus (HIV) and hepatitis c virus (HCV) epidemics in the 1980s, the life span of hemophiliacs has progressively become similar to that of males in the general population, at least in more developed countries.2,3 Accordingly, a considerable number of hemophiliacs now reach old age: in Italy, for instance, nearly 8% of persons with severe hemophilia A or B are 65 years old or older.4 However, with age, persons with hemophilia develop medical and surgical diseases (e.g., cardiovascular diseases, prostatic hypertrophy, cancers, renal disease) not previously seen in this group.5 Although, there is very little information in literature, mostly as anecdotal case reports, on these associated conditions, they represent a new challenge for physicians operating in hemophilia centers. In this review, we analyze the current knowledge on the cancers developing in patients with hemophilia, focusing on the epidemiology and management of these co-morbidities. Epidemiology of cancers in hemophiliacs The largest study on the epidemiology of cancer in patients with inherited bleeding disorders is that published in 1979 by Forman.6 * Corresponding author. Tel.: +39 0458348196. E-mail address: [email protected] (M. Franchini). 0305-7372/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2009.01.001
In a survey among physicians of patients with a bleeding diathesis, the author collected 61 cases of cancer in an estimated population of 10,500 patients. In the hemophilia group the primary site of cancer was similar to an age and sex matched population. In addition there was no evidence of a change in the onset of metastatic disease in these individuals, as compared with similar individual with cancer but without coagulopathy. An indirect estimation of the incidence of neoplasia in the hemophilia population comes from the analysis of the studies from different countries on the mortality rates, life expectancy and causes of death in people with hemophilia. Obviously, most papers focused on patients with HIV and/or HCV infections. For instance, Darby and colleagues, on behalf the United Kingdom Hemophilia Centre Doctors’ Organization, carried out a cohort study of mortality from liver cancer and liver disease in 4865 hemophilic men and boys in the UK treated between 1969 and 1985 with blood products contaminated with hepatitis C.7 A total of 5 deaths attributed to primary liver cancer were reported, with a mortality rate 5.6 higher than in the general population. The 25-year cumulative risk of death from liver cancer was 0.37%, significantly higher than that expected (0.03%) from national mortality rates. The same group found that 72 of the 89 cases (81%) of lymphoma recorded in the UK hemophilia population during the 22 year period 1978–1999 occurred in HIV-positive patients, with a high proportion of highgrade non-Hodgkin lymphoma (NHL), extranodal presentation (i.e., gastrointestinal tract) and cerebral lymphoma.8 Interestingly, the incidence of NHL in the HIV-positive cohort was significantly increased during the period 1985–1996, with a ratio of observedto-expected cases of 83.92. This ratio reduced to 42.15 during
M. Franchini et al. / Cancer Treatment Reviews 35 (2009) 374–377
375
Table 1 Summary of the main literature data on the cancer-related deaths in hemophilic patients. First authorReference
Hemophilic population
Period of the study
Main results
Darby7
1969–1993
Wilde
4865 Hemophiliacs exposed to HCV-infected blood products 89 Hemophiliacs with lymphoma
Plug9
967 Hemophiliacs
1992–2001
2450 Hemophiliacs
1980–1995
413 Hemophiliacs 2950 Hemophiliacs 919 Hemophiliacs 6018 HIV-negative hemophiliacs
1980–1994 1993–1995 1986–1992 1977–1998
The authors observed an increased 25-year cumulative risk of death from primary liver cancer in hemophilic patients than in the general population (0.37% vs. 0.03%) The great majority of the cases of lymphoma (72/89, 81%) occurred in HIV-positive hemophilic patients The overall SMR for malignancies in hemophilic patients was 1.5 and the SMR for liver cancer was 17.2 The SMR for all cancers was 1.1 in the whole population. SMR for lymphoma and liver cancer were markedly increased in HIV-positive population (78 and 70, respectively) The majority of cancer-related deaths (NHL and HCC) occurred in HIV- and HCV-infected patients The SMR for non-HIV- or liver-related cancers in hemophilic patients was 2.2 No excess mortality from cancer was observed during the study period (SMR 1.0) The SMR for cancers not related to HCV or HIV infection in hemophilic patients was 2.2
8
Walker10 12
Ludlam Soucie13 Triemstra14 Darby15
1978–1999
Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus; SMR, standardized mortality ratio; NHL, non–Hodgkin’s lymphoma; HCC, hepatocellular carcinoma.
the period 1997–1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART). In the prospective cohort study conducted by Plug and colleagues on the mortality and causes of death in the Dutch hemophilia population during the decade 1992–2001, deaths from malignant neoplasm accounted for 22% of total deaths with a standardized mortality ratio (SMR, the ratio of the observed-to-expected mortality) of 1.5.9 This study also showed a highly increased risk of death of hepatocellular carcinoma (5 cases reported with a SMR of 17.2). Walker and Julian, on behalf the Association of Hemophilia Clinic Directors of Canada analyzed the causes of death in Canadians with hemophilia during the years 1980–1995.10 Although, deaths from liver cancer or lymphoma were markedly increased among individuals seropositive for HIV compared to those who were seronegative, deaths due to all cancers were not increased in the whole population (SMR 1.1). These findings were in keeping with those previously reported by Rabkin and colleagues, who observed 12 cases of NHL and 2 cases of HD in 1065 HIV-positive hemophilic patients and 2 cases of HD in 636 HIV-negative patients during a 12-year follow-up period.11 Similarly, in the study conducted by Ludlam and colleagues in Scotland during the period 1980–1994, most of he cancer-related deaths (i.e., NHL and hepatocellular carcinoma) occurred in patients with HIV or HCV infection.12 Interestingly, Soucie and colleagues, in a survey on the causes of deaths conducted in six US states among 2950 hemophiliacs during the period 1993–1995, found that 6% (14/236) of deaths were attributable to non-HIV- or liver-related cancers with a standardized mortality ratio of 2.2.13 By contrast, Triemstra and colleagues found no excess mortality from cancer in a cohort of Dutch hemophiliacs followed from 1986 to 1992 (SMR 1.0).14 More recently, Darby and colleagues, on behalf the UK Hemophilia Centre Doctors’ Organization, analyzed mortality rates and causes of death in 6018 HIV-uninfected people with hemophilia during the period 1977– 1998.15 Mortality from liver cancer and Hodgkin’s disease were substantially increased compared with mortality in the general population with a SMR of 13.51 and 4.95, respectively. For other cancers there was no evidence of increased mortality (SMR 0.90). In summary, the literature data seem to indicate that while liver cancer and lymphoma are most prevalent in hemophiliacs infected with HCV or HIV, respectively, there is no evidence of an increased incidence of other neoplasm in patients with hemophilia compared to general population (see Table 1). Management of cancers in hemophiliacs: analysis of the literature data The published literature data document that hemophilia may influence not only the treatment but also the clinical presentation
and the diagnostic evaluation of the associated neoplasia. However, only a few case reports have described so far the management of cancer in hemophilic patients. Anyway, the hemophilia-associated increased bleeding risk should be taken in account when a chemotherapy or radiotherapy program or a diagnostic invasive procedure is performed in such patients. Lambert and colleagues reported a case of a patient with mild hemophilia B and a colon cancer with liver metastases diagnosed in 2004.16 The patient underwent partial colectomy under continuous infusion of recombinant factor IX followed by conventional therapy (FOLFOX) consisting of 5-fluoruracil, folinic acid and oxaliplatin every 2 weeks. In spite of this treatment, his disease progressed over the next year. Two new lines of chemotherapy were then administered: FOLFIRI, consisting of irinotecan, 5-fluoruracil and folinic acid followed by irinotecan and cetuximab. As repeated imaging revealed new hepatic metastases, the decision to add to FOLFIRI treatment with the humanized monoclonal anti-angiogenic antibody bevacizumab (an agent targeting the vascular endothelial growth factor [VEGF]) was made. The agent (12 doses were administered) was well tolerated without bleeding complications. After a stable period of 8 months, the disease progression was documented and the patient died in June 2007. This case report is particularly important because documents, for the first time, the use in a hemophilia patient with a mild defect of a chemotherapeutic agent with effects on the vascular endothelium without aggravation of bleeding diathesis. Dawson and colleagues in 2007 reported the first description of an autologous stem cell transplantation in a patient with severe hemophilia A and an HIV-related plasmablastic lymphoma of the oral cavity without bleeding complications.17 Other studies have focused on the management of hepatocellular carcinoma in hemophiliacs, which is an important cause of death in hemophiliacs with chronic hepatitis C.18 This peculiar category of patients is at particularly increased risk of bleeding because of low factor VIII/IX levels owing to the hemophilia and low platelet counts and prolonged prothrombin times owing to the cirrhosis. Toyoda and colleagues analyzed the safety and complications of interventional radiology for hepatocellular carcinoma in 8 patients with hemophilia and cirrhosis.19 No bleeding for the site of vascular puncture was observed, indicating that the infusion of 40–60 UI/kg of factor VIII/IX concentrate prior to the treatment was sufficient for this procedure. Unexpectedly, gastrointestinal bleeding occurred in 3 patients 3–6 days after treatment. Thus the author concluded advising careful attention to this complication when performing interventional radiology in patients with hemophilia. Shen and colleagues described a successful partial hepatectomy in a patient with hemophilia and hepatocellular carcinoma.20 No postoperative bleeding complications were recorded, thanks to the administration of factor VIII concentrate during and
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immediately after surgery. Finally, Gordon and colleagues reviewed the published literature data on orthotopic liver transplantation in patients with hemophilia.21 Four of the 26 transplants reported were performed in patients with hepatocellular carcinoma without bleeding complications. As regards the impact of hemophilia on the clinical presentation of cancer, in rare cancer cases, unusual bleeding may lead to the diagnosis of previously undiagnosed mild/moderate hemophilia. On the other hand, a bleeding episode in a hemophilia patient may reveal an underlying oncologic disorder. Indeed, Larrain described a case of a HIV-negative hemophilia B patient in whom a diagnosis of chronic myeloid leukemia (CML) was made after an upper digestive tract bleeding. The patient was treated with busulfan with a survival more than twice the average survival of CML patients treated with the same agent.22 Another case of co-existence of leukemia and hemophilia was reported by Kawakami and colleagues.23 Zulfikar reported two boys with hemophilia and leukemia treated with conventional chemotherapy.24 While the first patient, with acute lymphoblastic leukemia, was in complete remission 15 months after chemotherapy, the second patients, with acute myelomonocytic leukemia, after an initial response relapsed and died at the seventh month of the treatment for disease progression. Based on the experience derived from the management of these two cases, the author outlined the importance of performing an adequate and regular factor concentrate usage in order to minimize the risk of hemorrhage related to the inherited bleeding disorder and to associated chemotherapy. In addition, the report concluded that a possible diagnosis of leukemia should not be overlooked in a patient with hemophilia and severe hemorrhagic problems. The recent description of two cases of leukemia following radioactive synovectomy with phosphorus 32sulfur colloid (P32)25 raised some concerns as regards the safety of this procedure and led the Centers for Disease Control and Prevention to investigate the incidence of leukemia in US patients with hemophilia. An increased incidence rate of leukemia was found in hemophilic patients, regardless the age and HIV-status, compared to the general male population.26 Sakurai and colleagues described another interesting case.27 Indeed, the authors presented the case of a mild hemophilia A patient who developed a soft tissue tumor mimicking subcutaneous hematoma. This rare possibility should be considered in the differential diagnosis of a skin mass in a hemophilia patient. Similarly, Allen and colleagues reviewed the literature and collected 6 case of primary malignancies (5 sarcomas and 1 NHL of bone), misdiagnosed as pseudotumors in hemophilic patients.28 Conclusions The management of cancer in hemophilia patients represents a new challenge for physicians of hemophilia centers. Indeed, the underlying inherited hemorrhagic diathesis may increase the potential risk of bleeding associated with some invasive diagnostic procedures, which should be performed only under an adequate replacement therapy and in close collaboration with hemophilia specialists. For example, a diagnostic biopsy requires the infusion of factor concentrates in order to reach and maintain the levels of deficient clotting factor above 50% for at least 3–4 days. For surgical procedures, higher clotting factor levels for longer period (i.e., above 80% for the first three days, then above 50% for 7–15 days after surgery) are needed.29 On the other hand, the chemotherapy-induced blood cell or mucosal toxicity or hemostatic disturbances may hinder the completion or require a dose reduction of anti-cancer treatments. Furthermore, patients with inherited bleeding disorders are nearly always excluded from trials evaluating new anti-cancer agents because of the uncertainty regarding
potential adverse effects of these agents on the hemostatic system. For instance, the patient described by Lambert and colleagues16 was excluded from trials evaluating bevacizumab and decided to support personally the costs of the treatment. However, in spite of these limitations, we think that the diagnosis of hemophilia should not preclude the access of these patients to adequate chemotherapy regimens. Further studies on large population of patients or reports similar to those previously described are needed to optimize the management of such patients. In this context, on behalf the Association of Italian Hemophilia Centers (AICE), we are conducting a study on cancers in hemophilic patients. The results of this survey will be available in the late 2010 and will help us to know the epidemiology and management of cancer in Italian hemophilic population. Finally, recent in vitro studies suggest that while congenital prothrombotic disorders facilitate metastasis, congenital susceptibility to bleeding may have a protective effect against metastatic capacity of murine cancer cells.30,31 Scope of the future clinical and laboratory research will be to confirm in vivo in hemophilic patients these very interesting preliminary experimental findings. Conflict of interest statement All authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. References 1. Mannucci PM, Tuddenham EG. The hemophilias–from royal genes to gene therapy. N Engl J Med 2001;344(23):1773–9. 2. Street A, Hill K, Sussex B. Haemophilia and ageing. Haemophilia 2006;12(Suppl. ):8–12. 3. Mejia-Carvajal C, Czapek EE, Valentino LA. Life expectancy in hemophilia outcome. J Thromb Haemost 2006;4(3):507–9. 4. Tagliaferri A, Franchini M, von Mackensen S. Health status and quality of life in elderly Italian patients with hemophilia. Haemophilia 2006;12(Suppl. 2):252. [abstract]. 5. Franchini M, Tagliaferri A, Mannucci PM. The management of hemophilia in elderly patients. Clin Interv Aging 2007;2(3):361–8. 6. Forman WB. Cancer in persons with inherited blood coagulation disorders. Cancer 1979;44(2):1059–61. 7. Darby SC, Ewart DW, Giangrande PL, et al. UK Haemophilia Centre Directors’ Organisation. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet 1997;350(9089):1425–31. 8. Wilde JT, Lee CA, Darby SC, et al. UK Haemophilia Centre Directors’ Organisation. The incidence of lymphoma in the UK haemophilia population between 1978 and 1999. AIDS 2002;16(3):1803–7. 9. Plug I, Van Der Bom JG, Peters M, et al. Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost 2006;4(3):510–6. 10. Walker IR, Julian JA. Association of Hemophilia Clinic Directors of Canada. Causes of death in Canadians with haemophilia 1980–1995. Haemophilia 1998;4(5):714–20. 11. Rabkin CS, Hilgartner MW, Hedberg KW, et al. Incidence of lymphomas and other cancers in HIV-infected and HIV-uninfected patients with hemophilia. JAMA 1992;267(8):1090–4. 12. Ludlam CA, Lee RJ, Prescott RJ, et al. Haemophilia care in central Scotland 1980– 94. I. Demographic characteristics, hospital admissions and causes of death. Haemophilia 2000;6(5):494–503. 13. Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia: relations with source of medical care. The hemophilia surveillance system project investigators. Blood 2000;96(2):437–42. 14. Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Int Med 1995;123(11):823–7. 15. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007;110(3):815–25. 16. Lambert C, Deneys V, Pothen D, Hermans C. Safety of bevacizumab in mild haemophilia B. Thromb Haemost 2008;99(5):963–4. 17. Dawson MA, Schwarer AP, McLean C, et al. AIDS-related plasmablastic lymphoma of the oral cavity associated with an IGH/MYC translocation– treatment with autologous stem-cell transplantation in a patient with severe haemophilia-A. Haematologica 2007;92(1):e11–2.
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