RESEARCH - IV cyclophosphamide raises cervical-cancer risk in lupus patients

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IV cyclophosphamide raises cervical-cancer risk in lupus patients

Rheumawire

Sep 3, 2004

Janis

Ann Arbor, MI - Whether patients with systemic lupus erythematosus (SLE)

are at greater risk for cancer than the general population is uncertain,

but women with lupus who are treated with intravenous cyclophosphamide

(IVCYC) are at increased risk for the premalignant and malignant lesions

classed together as cervical intraepithelial neoplasia (CIN), according

to researchers from the University of Michigan. Lead author Dr Vladimir

M Ognenovski and colleagues report in the September 2004 issue of the

Journal of Rheumatology that each additional 1 g of cumulative IVCYC

exposure increases 3-year risk of CIN by 13% [1].

" [O]ur observations of high incidence of CIN, as well as the strong

association between IVCYC and development of CIN in this population,

highlight the importance of careful screening of women with lupus,

particularly those receiving immunosuppressive therapy. By inference,

the risk for other human-papillomavirus (HPV)-related gynecologic

lesions may also be increased in this setting, " Ognenovski writes.

Ognenovski and colleagues studied the incidence of CIN in women with SLE

recruited consecutively from outpatient rheumatology clinics at the

University of Michigan. Women with baseline abnormalities on cervical

smears were excluded, as were those with no previous sexual exposure.

(CIN is strongly correlated with exposure to sexually transmitted HPV.)

Those treated with oral CYC were excluded because there were not enough

of them to analyze separately, and the investigators were concerned that

the higher cumulative CYC dose typically seen in such patients might

have biased the results. Patients treated with methotrexate were also

excluded.

The study enrolled 69 women, who had cervical smears taken at baseline

and at 3 and 7 years. Cytologic abnormalities (CIN 1-3) were confirmed

by cervical biopsies scored by pathologists in a blinded fashion.

The patients were stratified into 4 treatment groups: prednisone alone

(control group, n=23), azathioprine (AZA) plus prednisone (n=4), IVCYC

plus prednisone (n=8), or IVCYC with AZA and prednisone (n=26). The

incidence of CIN was evaluated over a 3-year period, with follow-up

after 7 years.

The incidence of CIN in these lupus patients was 9.8% over a 3-year

period, vs about 3.2% in previous general population studies. None of

the control group treated with prednisone alone or the patients treated

with AZA plus prednisone developed CIN at the 3-year follow-up.

" Patients who had received either CYC alone (plus prednisone) or CYC in

combination with AZA and prednisone had a significantly higher risk of

developing CIN compared with the control group of patients receiving

prednisone alone (incidence of 0.25, p=0.0132, and 0.15, p=0.0497,

respectively). The only high-grade lesions were found in the combination

group, " the researchers report.

A subset analysis of the IVCYC patients found that, after controlling

for age, each 1-g increase in CYC exposure correlated with a 13%

increase in CIN risk (p=0.04, risk ratio 1.13). Mean CYC exposure was

14.6+10.5 g.

Ognenovski notes that most of the cervical abnormalities were seen in

the initial 3-year period and had resolved by the 7-year follow-up. In

the general population, up to 74% of similar abnormalities are thought

to regress spontaneously. " The clinical implication in these patients is

somewhat uncertain, but an important point is that immunosuppression in

general increases susceptibility to HPV. "

At the 7-year long-term follow-up, data for 45 of the surviving 61

patients showed abnormal cervical smears in 3, 2 of whom also had

abnormal cervical smears at the 3-year assessment. One of these had

atypical squamous cells of unknown significance (ASCUS), and the other

had condylomata. One patient had CIN grade 3 at 3 years that resolved at

7 years but subsequently developed vulvar disease and underwent

vulvectomy.

However, the strong association with IVCYC dose in the lupus patients is

worrisome because both treatment-related factors and factors related to

the underlying SLE disease process are suspected of contributing to

increased cancer risk. " The potential role of IVCYC in the pathogenesis

of CIN could be explained through direct mutagenic actions of the drug

and its metabolites or indirectly through its effects as a potent

immunosuppressive, " they point out.

" The dose-response relationship we observed further implicates IVCYC in

the pathogenesis of CIN and underscores the necessity of limiting the

cumulative dose of CYC to reduce end-organ damage. Unfortunately, it is

not certain that the substitution of alternative immunosuppressive

agents, such as AZA, will reduce the risk of developing CIN, " they

conclude.

Source

Ognenovski VM, Marder W, Somers EC, et al. Increased incidence of

cervical intraepithelial neoplasia in women with systemic lupus

erythematosus treated with intravenous cyclophosphamide. J Rheumatol

2004; 31:1763-1767.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org