Report

Risk of cancer with cyciosporine in psoriasisFelix Arellano, MD

From Zeneca Pharmaceuticals, Wiimington

CorrespondenceFeiix Areilano, MD, Zeneca Pharmaceuticals, 1800 Concorde Pike,

Wiimington, DE 19806

Assessing the risk of cancer in patients receiving cyclospor-ine for psoriasis is a cotnplex task that involves severalparameters. The risk associated with the disease itself tnustbe considered alotig with the risk associated with previoustreattnent.

Studies reported in the literature have examined therelationship between cancer and psoriasis. Olsen et al.followed 6910 Danish patients with psoriasis for an averageof 5.1 years. Tbey reported a total iticreased risk of 1.35for all types of cancer and a clear 2.5-fold increase in therelative risk of skiti cancers in particular.'

Sterti et al. focused on a cohort of patients treated withPUVA, controlling for age, sex, and geographical location.-They found a clear, dose-related risk for the developtnentof both squatnous cell and basal cell carcinotnas: therelative risk of squatnous cell carcitiotna was as bigb as22.3 for tnediutn dose therapy and 56.8 for high-dosetreattnent. Frotn an epidetniologic perspective, these relativerisks are itntnetise - the associatioti betweeti tobacco atidlutig cancer, for exatnple, is =13.

A sitnilar study frotn Swedeti supported tbese fitiditigs.'The relative risk of cancer was 1.5 in 4799 patientstreated witb PUVA, with the relative risks for skin cancer,respiratory systetn caticers, atid caticer of the pancreasbeing 6.2, 2.6, and 2.0, respectively.

While other studies reported in the literature cotnparedthe risk of caticer iti patietits with psoriasis with that ofthe general populatioti, the objective of this investigationwas to identify the risk of cyclosporitie relative to thatassociated with psoriasis itself and with other treattnentsfor the disease.

Methodology

Patient populationThis study, an intent-to-treat atialysis, surveyed reportsfrotn tbe cyclosporine clinical trials provided by investig-

ators at periodic intervals. The population included anypatietit who received cyclosporine for any period of titne.The current study included 1223 patients frotn 11 countrieswho were followed for periods of up to 60 tnotiths.

Risk assessmentRelative risk reflects the observed risk divided by thatwhicb would be expected in a given population. Values> t itidicate a positive risk; a relative risk of at least 2confirtns ati associatioti.

The risk assesstnent in this study included three steps.First, the incidence of cancer in the general populationwas compared with that of tnalignaticies in patients witbpsoriasis. Tbe control group consisted of patients withhypertetision, reflecting the assumption that these indi-viduals would have tbe satne risk of developing cancer asthe getieral population. Data for the control group wereprovided by Medicaid data on patients in Michigan andFlorida, so that the influence of sun exposure on rates ofskin cancer would differ. Tbe relative risk of tnalignanciesin patients with psoriasis tnultiplied by that in the hyperten-sioti cotitrol group provided the expected incidence rate oftnaligtiancies iti patients with psoriasis.

The next step was to determine the expected nutnberof tnalignancies in patients with psoriasis treated withcyclosporine in clinical trials. That figure was calculatedby tnultiplying the nutnber of patients iti the clinical trialsby tbe expected incidence rate of tnalignancies in patientswitb psoriasis as determined above.

Finally, the relative risk was calculated by dividing tbisexpected nutnber of tnalignancies by tbe number tbat wasactually observed in patients in tbe clinical trials.

Results

incidence of cancerTable 1 shows the nutnber of cancers foutid in patientstreated with cyclosporine, regardless of how long therapy 15

© 1997 Biackweli Science Ltd International Journal of Dermatology 1997, 36 (Suppl. 1), 1 5 - 1 /

16 Report Risk of cancer Arellano

Table 1 Nutnber of reported cases of caticer atnong patientsin cyclosporine clinical trials {N = 1223)

Table 4 Relative risk of caticer in patients with psoriasistreated with cyclosporine vs. control population

Location

SkinIVIeianomaLungEsophagusLymphomaALLMyeloma

Trans, cellStomachOtherTOTAL

Numb

13222111114

28

Table 2 Relative risk of cancer (95% confidence interval) inpatictits with psoriasis vs. control population

AM cancers Skin cancer only Lymphoma only

Michigan 0.9(0.8,0.9) 1.4(1.2,1.8) 1(0.8,1.2)Florida 1.3(1.1,1.5) 2.5(1.9,3.3)

Table 3 Relative risk (95% cotifidence interval) of cancer bytreatment modality in patients with psoriasis vs. controipopulation

Psoriasis PUVA immunosuppression

Michigan 0.9 (0.8, 0.9) 2.8 (0.8, 9.8) 3.3 (2.2, 5.2)Florida 1.3(1.1,1.5) No data available 4.2(1.7,10.5)

was adtninistered or how lotig after discontitiuation thecancer was diagnosed. The tnost frequent type of caticerwas skin cancer. Patients with neoplasms were older thanthe cohort group (tnean age 54 vs. 43 years) and hadpsoriasis for a mean of 20 years. Treattnent duration rangedfrotn 12 days to 3 years (tnean 9 tnonths).

Relative riskThe relative risk of cancer atnotig patients with psoriasis,compared with that of the control populatioti, is shown inTable 2. The disease increases the risk of skin cancer to agreater degree in patients with greater sun expositre, doesnot increase the risk of lytnpbotna, and increases the riskof cancers in general only slightly. As shown iti Table 3,treattnent with PUVA significantly Increased the risk ofcancer. Itnmunosuppressive therapy with tnethotrexateincreased the risk approxitnately fourfold.

Location Relative risk (95% confidence interval)

All cancersSkin cancerSolid tumorsLymphoma

5.6 (3.9, 8)12.4 (7.3, 21.2)3.2 (1.8, 5.6)5.1 (1.2, 21.2)

Patients treated witb cyclosporine for psoriasis experi-enced a significant increase in the risk of cancer (Table 4).

Discussion and conclusion

Interpretation of relative risk assesstnent data is a cotnplic-ated process. For example, the vast tnajority of patietits inthe cyclosporine clinical trials had received prior treattnentfor psoriasis, tnaking it impossible to pinpoint the individualcontributions of previous treattnents or of cyclosporineitself to the risk of caticer. Furthertnore, causality is difficultto prove and subject to tnatiy different types of bias. Lesionsin patietits receiving tnethotrexate, for exatnple, may bemore readily detected by specialists highly aware of tberisk than those in patients receiving routine care forhypertension. Finally, up to 70% of patients receivingcyclosporine were treated intertnittently, creating tnethod-ological difficulties for risk assesstnetit.

The data in this analysis, however, do itidicate severaltrends. First, psoriasis itself does not sectn to iticrease therisk of caticer, with the exception of skin caticer; however,the risk of cancer, especially skin cancer, is clearly increasedby conventional treattnetits for psoriasis. Itntnunosuppres-sion, which in this database tneant treattnent with tnetho-trexate, was found to increase the risk of lytnphoma, skiticancer, atid solid caticers.

Treattnent witb cyclosporitie appears to increase therisk of caticer to approxitnately the satne range as otherimtnunosuppressants. That increase in relative risk trans-lates into an absolute increase of 1-2%.

Discussion

Dr Gottleib: It is tny guess that populations of Medicaidpatietits will include a higher proportion of patietits withdarker skin types. In that case, the PUVA data shown heretnay be artificially low cotnpared with published data,wbich have tended to involve fair skinned individuals.Dr Drake: When considered at a national level, theMedicaid population does not necessarily have more per-sons with pigmented skin thati tbe getieral populatioti.Since it includes as tnany white people as it does persons

Internalionai Journal of Dermatology 1997, 36 (Suppi. 1), 15-17 © 1997 Biackweii Science Ltd

Arellano Risk of cancer Report 17

with pignietited skin, we need to be careful aboutassutnptions.Dr Drake: We need to be very careful when we say thatpsoriasis itself causes skin cancer. Frotn the tnotnent theyfirst learn they have psoriasis, patietits tetid to spend titnein the sun. Therefore, tnost psoriasis patients have tnoreUV exposure in getieral, atid not necessarily frotn PUVA,than the population at large. It is essential to account forvariables before drawitig conclusions. Were tbe populationsstratified by UV exposure in any way?Dr Arellano: There were no additional tnetbods for stratify-ing the population, since the tiutnbers of patietits receivitigUVB were too stnall to achieve any tneaningful confidenceinterval. Data frotn patients receiving cyclosporine fortransplatits, where no additional UV exposure would beexpected, do sbow an increased risk of lytnphotna.

We are curretitly cotisidering a tnore cotnprehensivestudy that would allow us to overcotne the litnitations inthe data used here. It would involve a large population ofseveral tnillion patients with psoriasis, stratified by differenttreattnetit modalities, age, gender, atid otber factors thatmay bias results.Dr Attisloy: Remetnber that the aetiology of basal cellcarcinotna is not clear. In contrast to squatnous cells, wherecaticer can be induced by UVB exposure, sitnilar exposurein anitnals does not produce basal cell carcinotna. Othertnechanistns, including getietic predispositioti, tnay be atwork in tbese cells, and they ultitnately tnay be relevantto psoriasis.

Dr Drake: However, ==85 % of basal cell carcinoma appearsin sun-exposed areas. It would be a tnistake to discounttbe infiuetice of UVB exposure, whatever those othertnechatiistns tnay be.Dr Gottleib: Because of the nature of the data reportedhere, 1 atn concerned with what we tell our patients. In tnyopinion, we can only point out that the risk of cancerassociated witb cyclosporine is probably stnall, but thatwe sitnply do tiot know at this titne.Dr Ellis: I agree. Of —1400 patients in the Novartisdatabase who bave been treated with cyclosporine forvarying letigths of titne, fewer than t % developed cancerof any type. Half of those cancers were skin cancers. Thereis therefore no evidetice that this itntnunosuppressive drugis substantially different with respect to caticer than otheritnmunosuppressive agents we tnight use.

References

1 Olsen ]H, NdoUer H, Frentz G. Malignant tumors inpatients with psoriasis. / Am Acad Dermatol 1992; 27:716-722.

2 Stern RS, Laird M, Melski J, et al. Cutaneous squatnouscell carcinoma m patients treated with PUVA. Netv EngIJ Med 1984; 310: 1156-1161.

3 Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA andcancer: a large-scale epidetniological study. Lancet1991; 338: 91-93-

© 1997 Biackweii Science Ltd International Journal of Dermatology 1997, 36 (Suppl. 1), 15-17