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ombination Treatment Modalitiesn Cutaneous T-Cell Lymphoma (CTCL)oan Guitart

A wide variety of cutaneous T-cell lymphoma therapies are now used in clinical practice.Treatment options include phototherapy, radiation, topical therapy, systemic mono-chemo-therapy, combination chemotherapy, and combined modalities. Many patients fail or de-velop resistance to monotherapy, resulting in a need for combined treatment modalities toimprove therapeutic results in terms of quality of life and duration of response. Recently,bexarotene, a selective antagonist of the retinoid X receptor, has been approved in thetreatment of patients with cutaneous T-cell lymphoma. Bexarotene offers new opportunitiesfor combination treatment strategies because of its novel and unique mechanism of action.In this article we review the rationale and examine key published evidence on combiningthese new treatment modalities.Semin Oncol 33(suppl 3):S17-S20 © 2006 Elsevier Inc. All rights reserved.

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ationale forombination Therapy

heoretically, the administration of combination therapyin patients with cutaneous T-cell lymphoma (CTCL) of-

ers a number of clinical benefits. Therapies that have distinctechanisms of action can act synergistically, and high effi-

acy rates comparable to those observed with monotherapyan be achieved using lower doses. Modified doses in com-ination treatment may reduce side effects and thus result in

mproved quality of life.Choosing the right combination therapy is crucial. Although

ome combinations can improve outcomes via their synergy,thers may evoke detrimental toxic effects. For example, theombination of psoralen ultraviolet A (PUVA) therapy and top-cal nitrogen mustard should be avoided because there may be aignificant increase in the incidence of skin cancer.

opical Monotherapyhere are many topical monotherapies suitable for treatingarly stage CTCL. These include: emollients, steroids, meth-

epartment of Dermatology, Feinberg School of Medicine, NorthwesternUniversity, Chicago, IL.

his supplement was supported by an unrestricted educational grant fromZeneus Pharma Ltd.

r Guitart is a member of the speakers bureau for Ligand Pharmaceutical.ddress correspondence and reprint requests to Joan Guitart, MD, Depart-

ment of Dermatology, Feinberg School of Medicine, Northwestern Uni-versity, NMH/Galter Room 19�150, 675 North St Clair, Chicago, IL

60611. E-mail: jguitart@northwestern.edu

093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.oi:10.1053/j.seminoncol.2005.12.018

hlorethamine, BCNU, bexarotene gel, tazarotene gel, andmiquimod.

The effectiveness of topical corticosteroids in the manage-ent of mycosis fungoides (MF) was investigated in a study

y Zackheim et al.1 The trial involved 79 patients with patch-r plaque-stage MF (51 stageT1 [less than 10% of skin in-olved]; 28 stage T2 [10% or more of skin involved]). Pa-ients were treated with topical class I to III corticosteroids.

edian follow-up period was 9 months.Thirty-two stage T1 patients (63%) and seven stage T2

atients (25%) achieved complete remission. Partial remis-ion rates were 31% in the T1 group and 57% in the T2roup. Total response rates (RRs) were 94% and 82%, re-pectively.1

The researchers concluded that topical corticosteroids, es-ecially class I compounds, were an effective treatment foratch-stage MF.1 They can also be used in combination withther topical or systemic treatments.In addition to their therapeutic effect, topical steroids may

elp relieve pruritus of the skin lesions. In a trial of over 200atients, researchers from Stanford recently showed that top-

cal mechlorethamine produces a RR of 83% and a CR (com-lete response) rate of 50%.2 A group from France recentlyhowed that the combination of twice-weekly application ofechlorethamine combined with betamethasone 10 minutes

fter resulted in CR in 58% of the patients. The decreasedrequency of application made this schedule user-friendlynd limited the irritation effects of the topical chemother-py.3

Skin atrophy is the most serious side effect of potent top-

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cal corticosteroids. Although the incidence of secondarykin cancer was low in the study reported above, other stud-es have emphasized that topical chemotherapy may have aynergistic effect with photocarcinogenesis.2

Topical retinoids have a modest effect on CTCL, often withdurable response. Irritation is a major side effect, but skin

trophy rates are low.An open-label, pilot study has shown that topical admin-

stration of the retinoid A receptor (RAR)-specific agent, taz-rotene gel, evokes a RR of 56%, and 84% of the patientsxperienced mild to moderate local skin irritation.4 However,hese results are not conclusive because many patients alsoeceived medium-potency topical steroids which could haveontributed to disease remission.

Similarly, a recent phase I/II trial has shown that the reti-oid X receptor (RXR)-specific agent, bexarotene gel, shows aR of 63% and 74% of the patients experienced mild tooderate local skin irritations.5 In this study, bexarotene was

sed as monotherapy (ie, without corticosteroids or otherherapeutic modalities).

se of Topical Agentsn Combination Therapysing a topical treatment as part of a combination therapy

egimen has a number of benefits. It may allow the achieve-ent of a complete remission, consolidate a CR, and/or pro-

ide relief of side effects while allowing continuous therapy.owever, combinations such as topical chemotherapy plusUVA should be avoided.The addition of a topical corticosteroid or bexarotene can

elp achieve a CR in phototherapy-treated patients who de-elop residual or sanctuary lesions in hard-to-reach areas, oratients who are simply recalcitrant to phototherapy. In pa-ients with CTCL, increased photosensitivity with topical ste-oids or rexinoids has not been reported.

ytotoxic Therapylus Immunostimulation

n general, MF is an indolent low-grade lymphoma with theotential to undergo large cell transformation, becomingore aggressive. In addition to the intrinsic evolution of the-cell clone, advanced disease is marked by a deterioration of

he immune system. If the infection is serious, the deleteriousonsequences of profound immunosuppression are often as-ociated with higher morbidity and mortality than the tumoresions themselves. These underlying pathogenetic mecha-isms determine that combination therapy composed of cy-otoxic therapy and immunostimulation have theoreticallinical advantages.

Suchin et al5 designed a retrospective cohort study to com-are differences in pretreatment, prognostic factors, RRs, andurvival in 47 patients with CTCL receiving either combina-ion or single-modality therapy.

All patients received photopheresis for six or more cycles.

hirty-one patients received treatment with a combination of a

hotopheresis and one or more systemic immunostimulatorygents for at least 3 months. These included interferon alphaIFN-�), interferon gamma (IFN-�), sargramostim, or sys-emic retinoids.6 Despite the fact that patients in the combi-ation group had a poorer prognosis based on age, Sezaryounts, and previous therapies, combination immunomodu-atory therapy was associated with a better outcome. The RRnd median survival were 84% and 74 months for the com-ination group versus 75% and 66 months for the mono-herapy group.

The authors concluded that although the group who re-eived combination therapy had worse prognostic factors ataseline, they had higher response and overall survival ratesompared with those receiving photopheresis monotherapy.6

UVA plus IFN-�UVA plus IFN-�2a is widely regarded as the first successfulytotoxic combination therapy.7 The effectiveness of thisombination has since been confirmed by a number of othernvestigators. For example, Chiarion-Sileni et al7 treated 63atients across all disease stages with systemic escalatingoses of IFN-�2a plus PUVA for 1 year, followed by indefi-ite PUVA maintenance in patients who experienced a CR.edian follow-up was 37 months.Of the 63 patients, 51 achieved a CR (74.6%) or partial

esponse (PR; 6%). Median response duration was 32onths. The 5-year overall survival rate was 91% and the

-year disease-free survival rate was 75%.7 The authors con-luded that this combination of IFN-�2a and phototherapy isn effective and safe therapy for patients with symptomaticF.8

Clinical experience shows that the PUVA plus IFN-�2aombination is well-tolerated and results in high RRs, evenhen the dose of interferon is reduced. The combination is

lso associated with a reduction in neutralizing antibodies.

etinoids plus PUVAimilar results are observed with a combination of PUVA andetinoids. A study of 69 patients with plaque-stage MF inves-igated the effects of PUVA alone with the combination of oraletinoids and PUVA (RePUVA). Although the RR of theePUVA group was equal to that of the PUVA cohort (73%nd 72%, respectively), in the RePUVA group, remissionsere obtained with fewer PUVA sessions and with a lowerVA dose.9 This encouraging study prompted researchers toxplore the potential benefits of combining rexinoids withhototherapy.

exinoids plus PUVAeveral studies have shown the benefits of a monotherapyith the RXR-specific agent bexarotene. Its efficacy byose and stage when used as an oral agent is summarized

n Table 1.10,11

Bexarotene may be associated with hypertriglyceridemia

nd hypothyroidism, requiring the addition of lipid-lowering

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Combination treatment modalities in CTCL S19

gents (LLAs) and occasionally thyroid hormone replace-ent. Talpur et al12 attempted to optimize the clinical RRs of

exarotene by controlling dose-limiting hypertriglyceride-ia and combining bexarotene with other agents.Seventy patients with CTCL were treated with oral bexaro-

ene as monotherapy or in combination with other activegents. Fifty-four patients receiving bexarotene monotherapychieved an overall RR of 48%. Forty-two patients (77%) alsoequired one or more LLA: atorvastatin (n � 29; RR, 43%),torvastatin plus fenofibrate (n � 10; RR, 90%), or gemfibro-il (n � 3; RR, 33%), although gemfibrozil was discontinuedecause it increased bexarotene and triglyceride levels. Pa-ients taking two LLAs had a significantly higher RR of 90%uring monotherapy than those taking one or no LLAs (P.0001).12

Small pilot studies have suggested that bexarotene is safend effective when combined with PUVA plus IFN-�2a (n �; RR, 50%), extracorporeal photopheresis (ECP; n � 8; RR,5%; 1 CR), ECP/IFN-�2a (n � 4; RR, 50%), ECP/IFN-�2a/UVA (n � 1; RR, 100%), and IFN-�2a/PUVA/topical nitro-en mustard (n � 1; RR, 100%).12 The authors concludedhat when bexarotene is combined with other active CTCLherapies higher RRs are achieved in patients with advancedisease, without serious side effects. They also stated that theoncomitant use of statins may increase RRs by permittingigher doses to be administered without interruption, and/ory modulating the immune response.12

Several small studies involving MF patients (patch/laque stage) have investigated the effects of a combina-ion of PUVA and low-dose bexarotene tablets. Singh etl13 treated eight patients with PUVA plus bexarotene 75g daily, and Heald et al14 treated 12 patients with PUVA

lus bexarotene 150 mg daily. The results were very en-ouraging, with a combined RR of 100% (60% CR and0% PR).The PUVA plus bexarotene combination may also be effec-

ive at lower doses. A case study involving a 47-year-oldoman with a 4-year history of MF has been reported bytern et al.15 Their patient developed debilitating side effectsrom an acitretin plus PUVA combination and was subse-uently switched to a low-dose oral bexarotene (75 mg onceaily) plus PUVA combination. The switch evoked a success-ul response, prompting the researchers to conclude that theegimen may be a useful method for treating MF.

Furthermore, McGinnis et al16 reported a sustained remis-ion in three out of four cases of Sezary syndrome treatedith bexarotene 150 mg combined with PUVA.

able 1 Response to Oral Bexarotene by Dose and Stage

Bexarotene Dose(mg/m2/day)

Early Stage(n � 58)

Late Stage(n � 94)

6.5 20% –300 54% 45%Over 300 67% 55%

eprinted with permission.10 © 2001 American Medical Association.All rights reserved.

A multicenter, dose-randomized study of low-dose bex- t

rotene combined with PUVA is near completion in thenited States. Initial results show that 38 of the 43 patientsompleted the study. Five patients were excluded from eval-ation because of poor compliance. The RR was 87% (33/8), with a CR of 53% (20/33) requiring a cumulative dose of73 J at the time of remission. PR was observed in 13 patients34%).

However, a flaw of this study is that some centers under-reated the patients. For example, five patients with stableisease (13%) received a suboptimal cumulative average dosef 49 J. Among the patients treated at our phototherapy cen-er, a CR was achieved with less cumulative Joules (133 J)han our previous institutional experience with PUVA mono-herapy in similar patient population (157 J).17

Skin biopsies were performed at the end of the study.istologic remission was 85%. Six patients with clinical par-

ial remission had a biopsy that was morphologically negativeor MF. The results with bexarotene 150 mg were similar to00 mg, with no significant advantage noted in the higher-ose group. Furthermore, the lower dose was generally betterolerated, with dose reduction being required for eight ofhose patients receiving 300 mg. Mild hyperlipidemias (Na-ional Cancer Institute grade 1 or 2) were frequently observed53%), but all cases were corrected using LLA adjustmentnd/or bexarotene dose reduction. Mild hypothyroidismased on laboratory values was noted on 35% of the patients.ost patients were asymptomatic and, in most cases, pro-

hylactic hormone supplementation was added. Serioushotoreactions were not reported, and overall the addition of

ow-dose bexarotene does not seem to render the patientsore sensitive to ultraviolet rays.Compared with patients with the same Fitzpatrick photo-

ype on PUVA monotherapy, the initial PUVA dose of com-ination therapy patients was lower. However, dose escala-ion can be carried out without problems in this patientopulation.These preliminary findings are encouraging to support the

urther exploration of this combination modality. Bexaroteneay also be useful in combination with narrow-band UVB,

lthough studies using this combination are still in the pre-iminary stages.

exarotene plus IFN-�2aexarotene plus IFN-�2a has been investigated by French etl.18 A 43-year-old man with persistent multifocal, skin-re-tricted, CD30-positive, large T-cell lymphoma was initiatedith systemic IFN-�2a and oral bexarotene in the hope of

ircumventing therapies such as methotrexate, radiotherapy,r multiple-agent chemotherapy. The treatment was associ-ted with rapid and marked regression of the patient’s cuta-eous lesions.McGinnis et al19 also reported clinical benefits using a

ow-dose combination of these two agents. Two patients withrythrodermic CTCL and one with follicular MF experiencedapid clearing of their skin disease while being treated with

his combination, prompting the authors to conclude that

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ow-dose bexarotene and low-dose IFN-� is well-toleratednd leads to rapid clinical improvements.

onclusionombination treatment modalities in CTCL offer flexibilitynd new treatment options. Synergism may lead to higherfficacy than monotherapy regimens and dose optimizationay result in lower rates of adverse events and thus improve-ent of quality of life. To date, most of the literature on

ombination therapy is composed of case reports and smallonrandomized studies, with few large clinical studies avail-ble. There is a need to further explore these exciting combi-ation modalities that will allow evidence-based decisions inTCL therapy.

eferences1. Zackheim HS, Kashani-Sabet M, Amin S: Topical corticosteroids for

mycosis fungoides. Experience in 79 patients. Arch Dermatol 34:949-954, 1998

2. Kim YH, Martinez G, Varghese A, et al: Topical nitrogen mustard in themanagement of mycosis fungoides: Update of the Stanford experience.Arch Dermatol 139:165-173, 2003

3. de Quatrebarbes J, Esteve E, Bagot M, et al: Treatment of early stagemycosis fungoides with twice-weekly applications of mechlorethamineand topical corticosteroids. Arch Dermatol 141:1117-1120, 2005

4. Apisarnthanarax N, Talpur R, Ward S, et al: Tazarotene 0.1% gel forrefractory mycosis fungoides lesions: an open-label pilot study. J AmAcad Dermatol 50:600-607, 2004

5. Breneman D, Duvic M, Kuzel T, et al: Phase 1 and 2 trial of bexarotenegel for skin-directed treatment of patients with cutaneous T-cell lym-phoma. Arch Dermatol 138:325-332, 2002

6. Suchin KR, Cucchiara AJ, Gottleib SL, et al: Treatment of cutaneousT-cell lymphoma with combined immunomodulatory therapy: A 14-year experience at a single institution. Arch Dermatol 138:1054-1060,2002

7. Kuzel TM, Roenigk HH Jr, Samuelson E, et al: Effectiveness of inter-feron alfa-2a combined with phototherapy for mycosis fungoides and

the Sezary syndrome. J Clin Oncol 13:257-263, 1995

8. Chiarion-Sileni V, Bononi A, Fornasa CV, et al: Phase II trial of inter-feron-alpha-2a plus psolaren with ultraviolet light A in patients withcutaneous T-cell lymphoma. Cancer 95:569-575, 2002

9. Thomsen K, Hammar H, Molin L, et al: Retinoids plus PUVA (RePUVA)and PUVA in mycosis fungoides, plaque stage. A report from the Scan-dinavian Mycosis Fungoides Group. Acta Derm Venereol 69:536-538,1989

0. Duvic M, Martin AG, Kim Y, et al: Phase 2 and 3 clinical trial of oralbexarotene (Targretin capsules) for the treatment of refractory or per-sistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 137:581-593, 2001

1. Duvic M, Hymes K, Heald P, et al: Bexarotene is effective and safe fortreatment of refractory advanced-stage cutaneous T-cell lymphoma:Multinational phase II-III trial results. J Clin Oncol 19:2456-2471,2001

2. Talpur R, Ward S, Apisarnthanarax N, et al: Optimizing bexarotenetherapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 47:672-684, 2002

3. Singh F, Lebwohl MG: Cutaneous T-cell lymphoma treatment usingbexarotene and PUVA: A case series. J Am Acad Dermatol 51:570-573,2004

4. Heald P, Mehlmauer M, Martin AG, et al: Topical bexarotene therapyfor patients with refractory or persistent early-stage cutaneous T-celllymphoma: Results of the phase III clinical trial. J Am Acad Dermatol49:801-815, 2003

5. Stern DK, Lebwohl M: Treatment of mycosis fungoides with oral bex-arotene combined with PUVA. J Drugs Dermatol 1:134-136, 2002

6. McGinnis KS, Shapiro M, Vittorio CC, et al: Psoralen plus long-waveUV-A (PUVA) and bexarotene therapy: An effective and synergisticcombined adjunct to therapy for patients with advanced cutaneousT-cell lymphoma. Arch Dermatol 139:771-775, 2003

7. Hermann KK, Roenigk HH Jr, Hurria A, et al: Treatment of mycosisfungoides with photochemotherapy (PUVA): Long-term follow-up.J Am Acad Dermatol 33:234-242, 1995

8. French LE, Shapiro M, Junkins-Hopkins JM, et al: Regression of mul-tifocal, skin-restricted, CD30-positive large T-cell lymphoma with in-terferon alfa and bexarotene therapy. J Am Acad Dermatol 45:914-918,2001

9. McGinnis KS, Junkins-Hopkins JM, Crawford G, et al: Low-dose oralbexarotene in combination with low-dose interferon alfa in the treat-ment of cutaneous T-cell lymphoma: Clinical synergism and possible

immunologic mechanisms. J Am Acad Dermatol 50:375-379, 2004