Mycosis Fungoides: Management With Topical ...

Mycosis Fungoides: Management With Topical Nitrogen Mustard By Richard T. Hoppe, Elizabeth A. Abel, David G. Deneau, and Norman M. Price The technique of treatment, response rate, freedom from relapse, survival, and complications of therapy in 123 patients treated with topical nitrogen mustard (HN2) for cutaneous mycosis fungoides (MF) at Stanford University Medical Center are reviewed. Patients were treated with HN2 in an aqueous or ointment base with equal efficacy. Response rates depended on the extent of skin involvement. In limited plaque (TI) disease, complete and overall response rates were 51% and 88%, respectively, while in generalized plaque (T2) disease they were 26% and 69%. No patients with tumorous involvement (T3) achieved complete skin clearance and all 13 of these patients developed progression of disease. Only two of nine patients with erythroderma (T4) achieved a complete response (CR), and both later relapsed. After achieving a CR, 40% of patients with TI disease and 60%

with T2 disease later relapsed; however, subsequent therapies, including repeat courses of topical HN2, often were successful in achieving later skin clearance. Overall, 42% of T1 patients and 31% of T2 patients were without evidence of MF at last followup. When death occurred, it was usually unrelated to MF in the Tl group. However, half of the deaths of patients with T2 disease were attributable to MF. Among the 22 patients with T3 or T4 disease, 80% of deaths were attributable to MF. The most common complication observed was a cutaneous hypersensitivity reaction, which occurred much more commonly with the aqueous than the ointment preparation. Fourteen patients (11%) developed subsequent cutaneous malignancies. J Clin Oncol 5:1796-1803. © 1987 by American Society of Clinical Oncology.

"M YCOSIS FUNGOIDES (MF) is a cutane-

skin electron beam therapy (EBT), photochemotherapy with psorelens and UVA (PUVA), and topical nitrogen mustard (HN2). In this report, we review the experience at Stanford University using topical HN2 in the management of patients with MF.

ous lymphoma with a lengthy natural history. In the limited plaque (TI) phase of skin involvement and in the absence of extracutaneous disease, it is difficult to demonstrate an effect of the disease on survival. Nevertheless, in some patients, the disease progresses with the development of cutaneous tumors or extracutaneous involvement, both of which are associated with significant morbidity and mortality. In addition, many patients, even with T or generalized plaque (T2) disease, may be symptomatic from severe pruritus or the unacceptable associated cosmetic deformity. For these reasons, topical therapies are used in the management of even very early phases of MF. The commonly effective topical treatments include partial or total From the Departments of TherapeuticRadiology andDermatology, and the Mycosis Fungoides Clinic, Stanford University Medical Center, CA. Submitted February 16, 1987; accepted June 15, 1987. Supported in part by "The Friendsof Radiology" and Grant No. CA34233 from the National CancerInstitute, National Institutes of Health. Address reprint requests to RichardT. Hoppe, MD, Department of Therapeutic Radiology, Stanford University Medical Center, Stanford, CA 94305. © 1987 by American Society of Clinical Oncology. 0732-183X/87/0511-0013$3.00/0

1796

PATIENTS AND METHODS From 1969 to 1985, topical HN2 was used in the treatment of 123 patients with MF in the Mycosis Fungoides Clinic at Stanford University Medical Center. Excluded from this number were four patients with documented extracutaneous disease (lymph node involvement, stage IVA) as well as six patients who failed to complete at least 1 month of treatment. Also excluded were patients who were receiving other significant concurrent therapy, with the exception of orthovoltage irradiation, which was occasionally administered to local regions for patients with tumorous involvement (T3). The biopsy material of all patients was reviewed at the time of initial diagnosis in the Dermatopathology Laboratory of the Department of Dermatology. Only patients whose biopsies were interpreted as "diagnostic of MF"' or "consistent with MF' were included. Our histologic criteria for the diagnosis of MF are summarized in Table 1. Patients whose diagnosis was only "suggestive of MF," frequently in the clinical setting of parapsoriasis en plaque, were excluded. The clinical staging of patients included a thorough physical examination, with a mapping of all cutaneous lesions and careful palpation of all the major lymph node areas. The only routine radiographic examination obtained was a chest x-ray. Complete blood counts including differential and screening serum chemistries were obtained in most instances. Peripheral smears were

Journalof Clinical Oncology, Vol 5, No 11 (November), 1987: pp 1796-1803

Information downloaded from jco.ascopubs.org and provided by at MIT Libraries on July 10, 2011 from 18.181.4.93 Copyright © 1987 American Society of Clinical Oncology. All rights reserved.

1797

TOPICAL MUSTARD FOR MYCOSIS FUNGOIDES Table 1. Histologic Criteria for MF 1. Multiple Pautrier microabscesses with atypical mononuclear cells* 2. Diffuse infiltration of many individual atypical mononuclear cells* into the epidermist 3. A few small introaepidermal clusters of a few atypical mononuclear cells* 4. A few individual intraepidermal atypical mononuclear cells* 5. Dense upper dermal bandlike infiltrate, which is intimate with the epidermis and includes atypical mononuclear cells* 6. Mild to moderate polymorphous upper dermal infiltrate that includes atypical mononuclear cells* and isfocally intimate with the epidermis 7. Extension of the infiltrate into the dermis Categories diagnostic of MF: 1; 2; 3 + 4 + 5; 3 + 4 + 6 + 7 Categories consistent with MF: 3 + 5; 3 + 6; 4 + 5; 4 + 6 + 7

"*The degree of mononuclear atypia is variable. "tEpidermalinvolvement by the mononuclear cell infiltrate is characteristically free of associated spongiosis. Adapted from the criteria of Alvin J. Cox, MD, Professor Emeritus of Dermatology and Pathology, Stanford University. examined for the presence of Sezary cells, but no special studies were performed to assist in the identification of abnormal cells in the peripheral blood. Patients with clinically suspicious lymphadenopathy (enlarged nodes considered to be possibly involved by MF) usually underwent lymph node biopsy. When lymphadenopathy was subdiaphragmatic in location, selected patients underwent bipedal lymphography. Patients were staged initially according to the criteria of the Stanford staging system' and were reclassified subsequently according to the TNM criteria suggested at a National Cancer Institute (NCI) workshop. 2 However, inasmuch as all patients with palpable nodes did not undergo lymph node biopsy, the later system was expanded slightly,

as noted in the text. Between 1968 and 1980, patients were treated with an aqueous solution of HN2. A 10 to 20 mg/dL solution was prepared and the patients promptly applied this to their entire cutaneous surface (not just the involved sites) once a day. 3 If a hypersensitivity reaction developed, patients were placed on a cutaneous desensitization program.' If disease was slow to regress, the frequency of application was increased to twice or three times per day or the concentration of the solution was increased > 20 mg/dL. Since 1980, most patients have been treated with an ointment5 based preparation of HN2 in aquaphor. This method of application has several advantages, including a decreased risk of sensitization, decreased cost, ease of application, and an emollient effect. The concentration of HN2 used in this vehicle was 10 to 20 mg/dL at the outset, with increasing strength of the preparation if disease was refractory to therapy. In the last I to 2 years, six patients have been started on therapy and treated primarily with HN2 in a polyethylene glycol (PEG) lotion because of its better cosmetic acceptability compared with the ointment preparation. In general, the intent of treatment has been to achieve a

complete response (CR) of disease in the skin. Treatment was continued for 1 to 2 years after complete skin clearing, after which it was terminated. For the purpose of these analyses, CR has been defined as a complete clinical regression of all cutaneous lesions. Biopsy documentation of CR was not obtained. Partial response (PR) has been defined as any response that is less than complete. Relapse has been scored whenever a patient has developed biopsy documented recurrence of disease or if further therapy for MF has been initiated without biopsy documentation of relapse. Survival and freedom from relapse were calculated from the date of initiation of HN2 therapy and analyzed according to the 6 actuarial technique of Kaplan and Meier. Differences between groups were assessed by the generalized Wilcoxon test of Ge7 han. All causes of death were included in the survival analyses, whether or not they were secondary to MF or complications related to the disease or treatment. Five patients (4%) were lost to follow-up and, for the purpose of analysis, were assumed to have died at the time of the last follow-up examination.

RESULTS

One hundred twenty-three patients were identified who satisfied the criteria noted. There were 108 whites, seven blacks, six hispanics, and two oriental patients. The male to female ratio was 75 to 48 (1.6: 1), and the age range was 19.8 to 89.6

years (mean, 58.6; median, 58.8 years). The time from the onset of symptoms to initiation of therapy ranged from 2 to 769 months (mean, 143; median, 97 months). The time from diagnosis of MF until the initiation of treatment ranged from < 1 to 310 months (mean, 23.5; median, 6.5 months). A variety of prior treatments were used in these patients. The major previous type of therapy was total skin EBT, which was used in 50 patients. Since many patients did not undergo biopsy of palpable nodes, the TNM system has been expanded to incorporate this group. A subscript has been added to the NI category as follows: o, not biopsied; n, biopsy interpreted as normal; r, biopsy interpreted as reactive hyperplasia; d, biopsy interpreted as dermatopathic lymphadenitis. This expanded TNM system is outlined in Fig 1. The stage distribution of patients included in this analysis also is shown in Fig 1. One hundred one patients (82%) had either T1 or T2 phase of skin involvement at the time of initiation of treat-

ment with topical HN2. Forty-eight patients (39%) had palpable lymphadenopathy and 19 of them underwent lymph node biopsy. In thirteen instances, lymph node biopsies showed the characteristic changes of dermatopathic lymphadeni-


HOPPE ET AL

1798 T TI N-Stage

T2 Generalized

Limited

pDlaaue

N 0

Stage T3 Tumorous

T4 Erythroderma

plaque

IA

IB

IIIA

(38)

(30)

(2)

N lo N In N Ir N

Fig 1. IIA (33)

IIB (13)

IIIB (7)

ld

N 3

IVA

tis, while six other biopsies were either negative or showed reactive changes only. 8 Sixty-five patients (53%) were treated with the aqueous preparation of HN2, 52 (42%) with the aquaphor preparation, and six patients (5%) with the PEG lotion. A response was noted in 89 patients (72%). This included 39 patients (32%) with a CR and 50 (41%) with a PR. In the treatment of patients with plaque disease, the response rate for HN2 in the aqueous preparation was 76% and in the aquaphor base was 79%. The time to skin clearance ranged from 1.0 to 50.7 months (mean, 12.9; median, 7.9 months). The duration of maintenance therapy following skin clearance ranged from 0 to 56.5 months (mean, 13.3; median, 8.2 months). The range of total follow-up was 6 months to 16 years (median, 5.2 years). Relapse occurred in 22 of 39 patients (56%) who achieved a CR. In every instance, the initial relapse was limited to the skin. Subsequent therapy was generally either with a repeat course of topical HN2, EBT, or PUVA, When a second course of topical HN2 was employed (13 patients), the CR rate was 54%. Current patient status, categorized by initial Tstage, is summarized in Table 2. Overall, 37 patients (30%) were without evidence of MF at the time of last observation, although 19 of these

TNM staging system for

MF, modified slightly from that proposed at the NCI workshop in 1978.2 Patients with palpable adenopathy, whether unbiopsied or biopsied and failing to show MF, are all included in the NI category. Subscripts in the Ni category indicate biopsy results (see text). The numbers in parentheses indicate the number of patients in each stage for the 123 patients included in this analysis.

patients required subsequent treatment to achieve that status. No patient with tumorous involvement or erythroderma (T3 or T4) remains disease free after the initial course of topical HN2. Among patients with T3 disease, none achieved complete clearing of the skin and all subsequently developed progressive skin disease. In the T4 group, two of the nine patients cleared, but both later relapsed. Seven other erythroderrmic patients failed to clear, two of whom were unable to tolerate concentrations of topical HN2 > 2 mg/dL because of contact hypersensitivity. Table 2.

Current Status of 123 Patients T stage

Alive, NED, never relapsed Alive, NED, prior relapse Alive with active MF Dead, NED, never relapsed Dead, NED, prior relapse Dead, other causes, MF present Dead secondary to MF

T1 (43)

T2 (58)

12

3

5 20

12 15

1

1

2

2

2

4 1

11 14

T3 (13)

T4 (9)

Total 15

6

1 6

1 5

1 2

18 46

17 23

Abbreviation: NED, no evidence of disease.


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TOPICAL MUSTARD FOR MYCOSIS FUNGOIDES Table 3.

Causes of Death in 44 Patients T stage

Definite MF ± infection Probable MF ± infection Secondary cancer Other (eg, cardiac, pulmonary) Unknown (lost to follow-up)

TI (6/43)

T2 (28/58)

T3 (7/13)

T4 (3/9)

Total

1

12 3 3 6 4

4 2

1 1

1

1

18 6 5 10 5

2 2 1

disease. Furthermore, 30% of patients (60% of CR) with limited plaque disease enjoy long-term disease-free survival after a single course of HN2, compared with only 10% of patients (40% of CR) with generalized plaque disease. Twenty-four patients with limited plaque disease and 26 patients with generalized plaque disease had been treated with total skin EBT before treatment with topical HN2. The CR rate, freedom from relapse, and survival (calculated from the date of initiation of topical HN2) of these patients was similar to those who had not received prior EBT (data not shown). The influence of lymphadenopathy was analyzed in detail for patients with T2 disease. The survival and freedom from relapse of the 28 patients (47%) who had palpable lymphadenopathy (Nlo, Nln, Nlr, or Nld) was worse than that of patients who had no palpable lymphadenopathy (5-year survival, 63% v 70%; 5-year freedom from relapse, 14% v 30%). However, the differences were not statistically significant (P = .99; P = .19). In the T1 group, only five of 43 patients (12%) had palpable adenopathy at the onset of treatment. The outcome of treatment in this small group was equivalent to that of patients with no palpable adenopathy.

The causes of death in 44 patients are noted in Table 3. Only six deaths have occurred among the 43 patients with T1 disease, and only one of these deaths was directly or indirectly attributable to MF. On the other hand, among 58 patients with T2 phase of skin involvement, 28 have died and half of these deaths were directly or indirectly attributable to MF. Figure 2 displays the survival and freedom from relapse for the entire patient population. The median survival was 12.0 years. The freedom from relapse curve starts at 32%, indicative of the CR rate. The median time to relapse of CRs was 3.6 years. There is no significant difference in either survival (P > .6) or freedom from relapse (P = .3) comparing treatment with the aquaphor v water-based regimen. The extent of skin involvement had a significant impact on response, freedom from relapse, and survival. Table 4 displays the response rate and Fig 3 displays the survival and freedom from relapse according to T-stage. Only patients with TI or T2 disease are included in the actuarial analyses, since there were too few patients with T3 or T4 disease to infer any conclusions. The median survival was twice as long and the CR rate twice as great among patients with T1 v T2

123 PATIENTS

100

-

SURVIVAL

-

FREEDOM FROM RELAPSE

80 PROBABILITY (percent)

60 40

Fig 2. Actuarial survival and freedom from relapse of 123 patients treated witharetopical All .au...es ur aJor incJuaJ-InHN2.

20 I

0 0

2

4

6

a

10

12

14

16

iAll causes the

TIME (years)

survival

or aealm analysis.

are

incluaea The

CR rate

is 329b.


,n

1800

HOPPE ET AL Table 4.

Response to HN2

No. of Patients T1 T2 Subtotal T3 T4 Total

Response PR (%) None (%)

CR (%)

43 58 101 13 9 123

22 (51) 15(26) 37 (37)

16(37) 25 (43) 41 (41) 5 (33) 4 (44) 50 (41)

2 (22) 39 (32)

5(12) 18(31) 23 (23) 8 (62) 3 (33) 34 (28)

Complications

As has been reported previously, the most common complication related to topical HN2 therapy is the development of allergic contact dermatitis.3 We have observed a delayed hyper-

sensitivity reaction in two thirds of patients treated initially with the aqueous preparation at a concentration of 10 to 20 mg/dL. However, the majority of these patients could be desensitized by reduction in the concentration of HN2 to 0.01 mg/dL and with gradual escalation over a period of months. 4 In contrast, the frequency of hypersensitivity reactions in patients treated with the ointment-based preparation of HN2 was