Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis

Abstract

Background Prior to the era of immunomodulating or immunosuppressive (IS) treatments Multiple Sclerosis (MS) was linked to reduced rates of cancer.

Method A descriptive study of MS patients with a documented oncological event was performed. From 1 January 1995 to 30 June 2006, we collected and studied the profile of 7418 MS patients gathered from nine French MS centers. We evaluated the incidence of cancer in a Cancer Risk In MS Cohort.

Results Thirty one patients (1.75%) with confirmed MS had a history of cancer: mean age at MS diagnosis of 37.9 years and a mean age at cancer diagnosis of 46.4 years. The most frequent cancers were breast (34.5%), gynecological (12.5%), skin (10.2%), acute leukemia and lymphoma (5.9%), digestive (8.8%), kidney and bladder (5.1%), lung (3.4%) and central nervous system (3%). Calculated standardized incidence rates were 0.29 (0.17—0.45) for men and 0.53 (0.42—0.66) for women. The incidence of cancer in this MS population was lower than that expected for the general population. Matched to age, gender and histology, cancers in MS were associated with a young age and exposure to IS treatments. When considering all patients, treated patients had a 3-fold higher risk of developing cancer, if they had a history of IS (P = 0.0035). For treated patients, the cancer sites were more likely the breast, the urinary tract, the digestive system and the skin.

Conclusion Our data suggest that MS patients do not have an increased risk of cancer. Rather for several types of cancer a significantly reduced risk was observed, except for breast cancer in women treated with IS. The relative increased risk of breast cancer in MS women under IS treatment warrants further attention. Multiple Sclerosis 2008; 14: 399—405. http://msj.sagepub.com

Keywords

azathioprine cancer cyclophosphamide disease-modifying therapies glatiramer acetate interferon beta mitoxantrone multiple sclerosis

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References

Confavreux C. , Vukusic S. Natural history of multiple sclerosis: a unifying concept . Brain 2006; 129: 606-16.

Achiron A. , Barak Y. , Gail M. , Mandel M. , Pee D. , Ayyagari R. et al. Cancer incidence in multiple sclerosis patients and effects of immunomodulatory treatments . Breast Cancer Res and Treat 2005; 89: 265-70.

Allen I. , Millar J. , Hutchinson M. General diseases in 120 necropsy-proven cases of multiple sclerosis . Neuropath Applied Neurobiol 1978; 4: 279-84.

Fleming S. , Blake R. Patterns of comorbidity in elderly patients with mutiple sclerosis . J Clin Epidemiol 1994; 47: 1127-32.

Moller H. , Kneller RW , Boice JD , Olsen JH Cancer incidence following hospitalization for multiple sclerosis in Denmark . Acta Neurol Scand 1991; 84: 214-20.

Nielsen NM , Rostgaard K. , Rasmussen S. , Koch-Henriksein N. , Storm HH , Melbye M. et al. Cancer risk among patients with multiple sclerosis: a population-based register study . Int J Cancer 2006; 118: 979-84.

Palo J. , Duchesne J. , Wilkstrom J. Malignant diseases among patients with multiple sclerosis . J Neurol 1977; 216: 217-22.

Sadovnick A. , Eisen K. , Ebers G. , Paty D. Cause of death in patients attending multiple sclerosis clinics . Neurology 1991; 41: 1193-6.

Taylor L. , Hugues RA , Mc Pherson K. The risk of cancer from azathioprine as a treatment for multiple sclerosis . Eur J Neurol 2004; 11: 141 .

10.

Hjalgrim H. , Rasmussen S. , Rostgaard et al. Familial clustering of Hodgkin lymphoma and multiple sclerosis . J Natl Canc Inst 2004; 96: 780-4.

11.

Kurtzke JF , Hamtoft H. Multiple sclerosis and Hodgkin's disease in Denmark . Acta Neurol Scand 1976; 53: 358-75.

12.

Vineis P. , Crosignani P. , Vignano C. et al. Lymphomas and multiple sclerosis in multicenter case-control study . Epidemiology 2001; 12: 134-5.

13.

Midgard R. , Glattre E. , Gronning M. et al. Multiple sclerosis and cancer in Norway. A retrospective cohort study . Acta Neurol Scand 1996; 93: 411-5.

14.

Anderson M. , Hughes B. , Jefferson M. et al. Gliomatous transformation and demyelinating disease . Brain 1980; 103: 603-22.

15.

Confavreux C. Establishement and use of multiple sclerosis registers. EDMUS . Ann Neurol 1994; 36: 136-39.

16.

Poser CM , Paty DW , Scheinberg L. , Mac Donald WI , Davis FA , Ebers GC , Johnson KP , Sibley WA , Silberberg DH , Tourtelotte WW New diagnostic criteria for multiple sclerosis: guidelines for research proposal . Ann Neurol 1983; 13: 227-31.

17.

Mc Donald WI , Compston A. , Edan G. , Goodkin D. , Hartung HP , Lublin FD , Mc Farland HF , Paty DW , Polman CH , Reingold SC , Sanberg-Wolheim M. , Sibley W. , Thompson A. , Van Der Noort S. , Weinsheiker BY , Wolinsky JS Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis . Ann Neurol 2001; 50: 121-7.

18.

Taeger D. , Sun Y. , Keil U. , Straif K. A stand-alone windows application for computing exact person-years, standardized mortality ratios and confidence intervals in epidemiological studies . Epidemiology 2000; 11: 607-8.

19.

Feuillet L. , Boudinet H. , Casseron W. , Uzenot D. , Pelletier J. , Ali Chérif A. Association neurofibromatose de type I et sclérose en plaques . Rev Neurol ( Paris ) 2004; 160: 447-51.

20.

Khan OA , Bauserman SC , Rothman MI , Aldrich EF , Panitch HS Concurrence of multiple sclerosis and brain tumor: clinical correlation . Neurology 1997; 48: 1330-3.

21.

Shuangsshoti S. , Hjardermaal GTM , Ahmad Y. et al. Concurrence of multiple sclerosis and intracranial glioma. Report of a case and review of the literature . Clin Neuropathol 2003; 22: 304-8.

22.

Goldacre MJ , Seagroatt V. , Yeates D. et al. Skin cancer in people with multiple sclerosis: a record linkage study . J Epidemiol Community Health 2004; 58: 142-4.

23.

Deftereos S. , Farmakis D. , Papadogianni A. et al. Waldenstrom's macroglobulinemia developing in a patient with multiple sclerosis: coincidence or association ? Mult Scler 2004; 10: 598-600.

24.

Edan G. , Miller D. , Clanet M. et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomized multicentre study of active disease using MRI and clinical Criteria . J Neurol Neurosurg Psychiatry 1997; 62: 112-8.

25.

Ellison GW , Myers LW , Mickey MR , Graves MC , Tourtelotte WW , Syndulko K. et al. A placebo-controlled, randomized, double-masked, variable dosage, clinical trial of azathioprine with or without methylprednisolone in MS . Neurology 1989; 39(8): 1018-26.

26.

Goodkin DE , Rudick RA , Vanderbrug-Medendorp S. , Daughtry MM , Schwetz KM , Fisher J. , Vandyke C. Low dose oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis . Ann Neurol 1995; 37: 30-40.

27.

Yudkin PL , Ellison GW , Ghezzi A. et al. Overview of azathioprine treatment in multiple sclerosis . Lancet 1991; 338: 1051-5.

28.

Zephir H. , Deseze J. , Duhamel A. , Debouverie M. , Hautecoeur P. , Lebrun C. et al. Treatment of progressive forms of MS by cyclophosphamide: a cohort study of 490 patients . J Neurol Sci 2004; 218: 73-7.

29.

Hommes OR , Weiner HL Results of an international questionnaire on immunosuppressive treatment of MS . Mult Scler 2002; 8: 139-41.

30.

Amato MP , Pracucci G. , Ponziani G. , Siracusa G. , Fratiglioni L. , Amaducci L. Long term safety of azathioprine therapy in MS . Neurology 1993; 43: 831-3.

31.

Goodkin DE , Daughtry MM , Vanderburg-Medenddorp S. Incidence of malignancy following cyclophosphamide or azathrioprine treatment for MS . Ann Neurol 1992; 32: 257 .

32.

Confavreux C. , Saddier P. , Grimaud J. , Moreau T. , Adeleine P. , Aimard G. Risk of cancer from azathioprine therapy in MS . Neurology 1996; 46: 1607-12.

33.

Bristish and Ditch Multiple Sclerosis Azathioprine Trial Group. Double-masked trial of azathioprine in multiple sclerosis . Lancet 1988; 2: 179-83.

34.

De Ridder D. , Van Poppel H. , Demonty L. , D'Hooghe B. , Gonsette R. , carton H. , Baert L. Bladder cancer in patients with MS treated with cyclophosphamide . J Urol 1998; 159: 1881-4.

35.

Lhermitte F. , Marteau R. , Roullet E. Not so benign long-term immunosuppression in MS ? Lancet 1984, i: 276-7.

36.

Portaccio E. , Zipoli V. , Siracusa G. , Piacentini S. , Sorbi S. , Amato MP Safety and tolerability of cyclophosphamide pulses in MS. A prospective study in a clinical cohort . Mult Scler 2003; 9: 446-50.

37.

Brassat D. , Recher C. , Waubant E. , Lepage E. , Rigal-Huguet F. , Laurent G. , Edan G. , Clanet M. Therapy-related acute myeloblastic leukemia after mitoxantrone treatment in a patient with MS . Neurology 2002; 59: 954-5.

38.

Delisse B. , De Seze J, MackowiakA , N'Kendjuo JB , Verier A. , Derepeer O. , Boisselier C. , Devos P. , Hautecoeur P. , Vermersch P. Therapy related acute myelodysplasic leukemia after mitoxantrone therapy in a patients with MS . Mult Scler 2004; 10: 92 .

39.

Edan G. , Brochet B. , Clanet M. , Clavelou P. , Confavreux C. , Debouverie M. , Heinzlef O. , Lebrun C. et al. Safety profile of mitoxantrone in a cohort of 802 MS patients . Neurology 2004; 62(7): P06-093.

40.

Nollet S. , Berger E. , Deconinck F. , Baldauf E. , Rumbach L. Leucémie aiguë chez deux patients atteints de sclérose en plaques et traités par mitoxantrone . Rev Neurol 2006 ; 162: 195-9.

41.

Tanasescu R. , Debouverie M. , Pittion S. , Ausiovrot R. , Vespignani H. Acute myeloid leukemia induced by mitoxantrone in a multiple sclerosis patient . J Neurol 2004; 251(6): 762-3.

42.

Vicari AM , Ciceri F. , Folli F. , Lanzi R. , Colombo B. , Comi G. et al. Acute promyelocytic leukemia following mitoxantrone as single agent for treatment of MS . Leukemia 1998; 12: 441-2.

43.

Norrish AE , Jackson RT , McRae CU Non steroidal antiinflammatory drugs and prostate cancer progression . Int J Cancer 1998; 77: 511-5.

44.

Rosenberg L. Aspirin and breast cancer: no surprise yet . J Natl Cancer Inst 1996; 88: 941-2.

45.

Sorensen HT , Friis S. , Norgard B. et al. Risk of cancer in a large cohort of nonaspirin NSAID users: a population-based study . Br J Cancer 2003; 88: 1687-92.

46.

Schreinemachers DM , Everson RB Aspirin use and lung, colon, and breast cancer incidence in a prospective study . Epidemiology 1994; 5: 138-46.

47.

Edwards LJ , Constantinescu CS A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic . Mult scler 2004; 10: 575-81.

48.

Freedman D. , Dosemeci M. , Alanja M. Mortality from multiple sclerosis and exposure to residential and occupational solar radiation . Occup Environ Med 2000; 57: 418-21.

49.

Koch-Henriksen N. The Danish MS registry. A 50-year follow-up . Mult Scler 1999; 5: 293-96.

50.

Bronnum-Hansen H. , Koch-Henriksen N. , Stenager E. Trends in survival and cause of death in Danish patients with MS . Brain 2004; 11: 1-7.

51.

Sumelahti ML , Pukkala E. , Hakama M. Cancer incidence in MS: a 35-year follow-up . Neuroepidemiology 2004; 23(5): 224-7.