Psoralen Prophylaxis Against Skin Cancer: Report of Clinical Trial I

PSORALEN PROPHYLAXIS AGAINST SKIN CANCER: REPORT OF CLINICAL TRIAL 1* ELEANOR J. MACDONALD, A.B.t, A. CLARK GRIFFIN, Ph.D.f, CARL E. HOPKINS, Ph.D., M.P.H.t, LESLIE SMITH, M.D., HENRY GARRETT, M.D. AND GORDON L. BLACK, M.D., Interest in use of the psoralen compounds as a cal tolerance. It was not possible to specify hosv possible prophylactic against cancer of the skin this secondary protective effect might be operatfollowed several years of their empirical use in ing, since the mechanism was not known for the treatment of vitiligo. These early efforts to either the psoralen activity or the carcinogenesis. confirm impressions of clinical usefulness were Since the mice were albino it was assumed that disappointing and resulted in diversion of the at least the pigment factor could be ruled out as principal research efforts toward elucidation of having a protective effect; five, epidemiologic basic mechanisms of photodynamic response of surveys based on cancer registries brought out the skin, with the empirical investigations as- that skin cancers are more prevalent on exposed suming a position of lesser but still complement- areas of the head) neck and hands among light ary importance. skinned people in high, dry and sunny climates By 1956 a working hypothesis had evolved of than elsewhere (5). possible practical significance. The considerations

While psoralen was no longer believed to afford

leading to this hypothesis were described in a preliminary report of these trials (1): one, patients using psoralen for vitiligo reported protection against sunburn (2); two, controlled

any primary shielding in the sense of a simple

experiments showed primary effects of psoralen,

sunscreen or ultraviolet absorber, it was reasoned that at low dose levels it would, without causing trauma, increase physiological pigmentation and cornification of the epidermis sufficient to filter

whether administered orally or topically, to be out a significantly increased amount of ultrapotentiation of the skth in its erythema and pig- violet energy. A small daily dose of oral psoralen mentation responses to ultraviolet irradiation for an outdoor worker might build up in the skin (3); three, the apparent protective effect of psora-

a natural protective covering. It was hypothesized

secondary result of increased activity of the skin

point below the carcinoma triggering level could

in raising its normal defenses by thickening of the stratum corneum and, finally, other layers, which then became effective against subsequent ultraviolet irradiation; four, experiments with ultraviolet induced skin cancers in albino mice (4) were interpreted as showing that a high dose of psoralen had augmented skin responses to ultraviolet irradiation beyond physiologically

be attained by this approach. Low toxicity and good human tolerance of

len against sunburn could be explained as a that reduction of cumulative ultraviolet to a

orally administered psoralen in the form of methoxsalen in low doses had been demonstrated

(6). While the mechanism of action was not understood, it was reasoned that if cancer protection could possibly eventuate, some risk was acceptable. Accordingly, a clinical trial was set

tolerable levels, causing trauma and subsequently up. triggering malignant growth. On the other hand, METHOD AND MAIEEJAL5 a low dose had been sufficient to stimulate an increase in the normal protective responses of A community (El Paso, Texas) was located in the skin against the carcinogenic action of the which a functioning cancer registry, which insubsequent irradiation without exceeding physi- cluded dermatologists' offices as well as clinics, laboratories and hospitals, showed high incidence Received for publication December 26, 1962. of cancer of the skin of the face and hands, with * From The University of Texas MI). Anderson some 1,500 living cases on the register. It also Hospital and Tumor Institutet, Hooston, Texas, happened to be a high, dry, sunny locale inhabited the University of Southern California School of Medicinet, Los Angeles, California, and El Paso, by 2 contrasting dermatologic groups, one lightly Texas, Drogs and supplies: The Elder Drog and the other rather darkly pigmented. A small Company. Financial Sopport: The Welch Found- group of dermatologists who see a large proporation. tion of the skin affections of the locale agreed to

213

214

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Figure I

conduct a trial study under our direction. We supplied the drugs, special study forms, and a clerk to work in their offices interviewing the

TABLE I Summary of results

patients, recording the data, dispensing the drugs, monitoring the follow-up, and generally assuming the innumerable small extra burdens imposed by a study. It cannot be overemphasized that the suc- Patients entered into study cess of a clinical trial depends on provision of Outdoor occupation effective staff work of this sort. Indoor occupation All patients who already had 2 or more skin cancers or keratoses on head, neck or hands and Dropped out of study were willing to enter the study were admitted. Number of 3 months Once admitted they were given a study number examinations and study interview which included inventory Number of reports of new with photographs, of all lesions present, and skin lesions (Counting patients color readings on the reflectance meter. They only once) were given a 3 months' supply of the medication Outdoor occupation and instructions for its use. At 3 months intervals Indoor occupation they returned for examination by the physician, follow-up interview and photographs, and refill Number of new lesions observed (Counting lesions of their drug supply. Control of the drug effect was obtained by use only once) of 2 different psoralen compounds, A and B, which, Increased sunburn observed if our hypothesis was even approximately correct, (at 3 months) (X2 = 10.4

Drug Drug Total

86 61 25 15

87 64 23 16

173 125

370

328

698

48 31

60

59

51

50

9

9

119 101 18

122

142

264

would produce distinctly different prophylactic p= 42 27 69 effects. The 2 "drugs" were allocated to the pa- Increased0.001) tanning observed tients individually and blindly according to a (at 12 months) (X2 = 39 prearranged drawing of random numbers. They 9 3 12 p=0.05) were supplied by the manufacturer in identical appearing bottles and capsules bearing oniy the general "psoralen" name and the name and number of the patient. Only after our analysis of the being given a new drug which might cause inresults had been completed and our conclusions creased tanning and possibly prevent sunburning drawn did we decode and relate effects to the spe- and skin cancers. They took 20 mg. daily at breakcific drugs. The patients were all told that theywere fast time, the uptake time being about 2 to 4 hours.

215

PSORALEN PROPHYLAXIS VERSUS SKIN CANCER

Criterion of effect was the number of new lesions

difference of as much as 25 percentage points, e.g.

occurring during each trial period (3 months). 50 per cent versus 25 per cent having new lesions, It was expected that about half of the patients between the 2 treatment groups. The sequential would produce new lesions in a given period, plan gave a 95 per cent chance of detecting an The statistical control unit for the trial moni- adverse effect and a 90 per cent chance of detecting tored the records sequentially so that the trial a prophylactic effect if such existed, and permitted could be stopped as soon as a statistically signifi-

us to stop the trial as soon as such an effect became

cant decision became possible. Patients on the evident. 2 contrast drugs were paired randomly and anaFor this part of the trial, the immediate effects lyzed sequentially following the Bross (7) plan part, we anticipated following about 500 patients for detection of a moderate difference. This plan for 2 years. To initiate studies of latent effects guaranteed a good chance of detecting a true we provided for 100 of the patients to be selected TABLE II Study patients classified by drug, age, sex, occupation and number of initial lesions Outdoor Occupations Age/Drug

6 or More Lesions ________

Less than 6 Lesions ____________ Total

6 or More

—

1

45

2 4

5 1

3 2

33

5

5

1

— ——

21

4

6 2

1

2

4 3

1

—

1

4

1

3 16

40—49

14

1

50—59

20

1

11

1

60—69

12

2

6

1

70—79

2

1

1

3 —

Total

1 1

— — —

80—89

Lesions

Male Female Total

Male Female Male Female

2 11 30

30—39

Less than 6

Lesions

Male Female Male Female 20—29

Total

Other Occupations

8

3 21 46

2 6 7

5 27 53

17

41

9

50

9

23

7

30

1

5

—

————

4

3

—

3

1

—

2 11

—

1

Total ......

80

4

36

5

125

13

14

12

9

48

141

32

173

Drug A... .

41 39

— 4

17 19

3 2

61

7 6

7 7

6 6

5

25

71

15

86

64

4

23

70

17

87

80

4

36

5

125

13

14

12

9

48

141

32

173

Drug

B... .

Total

TABLE III

New lesions by period, occupation and initial lesion status Total New Lesions

t er

Ut oor

Visit Drug A

A

3months

31 22

34 34

16

12

l5months

13 15

l8months

6

2lmonths 24 months

11

28 21 9 2 2

122

142

6 months

9months l2months

Total

8

6 or More Lesions

Less Than S Lesions

Drug Drug

Drug Drug A

Drug

Drug

3

11

11

3

14 9

14 9

Drug B

Drug Drug B

Total

Patients By Initial Lesion Status

Patients by Occupation

Drug Drug A

B

A

B

B

8

9

3

2

13 7 7

11

1

3

9 9

11

8

2

1

9

6

1

4

6

3

4

7

10

7

8

1

4

7

5

4

2

1

4

2

2

—

3

2

2

1

1

—

2

1

1

—

9 4 3 3

9 3

3

— —

2

51

50

9

9

44

43

16

16

60

59

9

— 2 —

8

2 5

—

3

1

—

2 1

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TABLE IV Summary of report of new lesions by visit and by drug Pts. in Study

Patients Examined

Total Number

New Lesions per

Patient

New Lesions

Nombee Reports of New Lesions

Visit

No. New Lesions

per Pt. with any New Lesions

Drug Drug Total Drug Drug Drug Deug Total Drug Drug Total Drug Drug Total Drug Drog Total B

Initial 3 months 6 months 9 months 12 months 15 months 18 months 21 months 24 months

86 87 173

75 69 144 64 70 63 133 58 61 52 113 45 55 46 101 42

44 42 86 34 31 30 61 26 20 17 37 17 12 13 25 10

Total

61

31

56 38 42 35

22

26 15 8

16 13 15 6 8 11

122

34 34 12 28 21 9 2 2

65 0.4 0.5 0.4 11 56 0.3 0.5 0.4 14 28 0.3 0.2 0.2 9 41 0.2 0.6 0.4 7 36 0.3 0.5 0.4 9 15 0.2 0.3 0.2 4 10 0.4 0.1 0.3 3 13 0.9 0.2 0.5 3

142 264

at entry into the study as long-termers who would stay in a continued study for 5 years or more. By

comparing rates of new lesions in their first,

second, third and up to twentieth 3 months period we hoped to get information on latent and cumu-

60

11

14

9 10

9 3

2 1

22 2.8 28 1.6 18 1.8 17 1.9 18 1.7 7 1.5

3.1 3.0

2.4 2.0 1.3 1.6

2.8 2.3 3.0 1.0

2.4

2.0 2.1

5 2.7 2.0 4 3.7 2.0 3.3

59 119

TABLE V Drop outs by reason Drug

Reason

Drug

Total

3 1

1 1 5 1

9 3 4 1 1 3 9 1

16 59 12

31 117 25

87

173

lative effects of the drugs.

The median induction time for the appearance 6 of new lesions in all the patients in the registry Nausea 2 with more than 1 lesion on the exposed areas of Nausea and other reasons. the head, neck and hands was 18 months. It was Uncooperative 1 therefore expected that 50 per cent of the patients Inconvenient would develop new lesions in 18 months regardless Diarrhea of drug. It turned out that 61 per cent of the pa- Ulcers 2 tients on drug A developed new lesions in 18 Other reasons 4 months and 63 per cent on drug B. Not Stated Patients were entered into the study from June 3, 1957, through January 22, 1959, and follow-np Total drop outs for continued until the Bross stopping rule (7) inreasons 15 dicated a decision had been reached. Using the criterion new lesions in outdoor workers at 12 Not followed full 24 months. 58 13 months point of treatment, the stop-trial decision In study 24 months was reached in January, 1959, with the 24th nontied pair of patients (figure 1) out of 42 pairs Total 86 treated 12 months. Five of the pairs had indoor

4

occupations and should not have been entered into

the study. Thirteen pairs were tied in number of salen daily by mouth; B: 0. mg. methoxsalen new lesions at 12 months. These 18 pairs thus daily by mouth (inert pill). Psoralen failed to contributed nothing to the stop-trial decision, but demonstrate a skin cancer prophylactic effect. are included in the analysis of results. DISCU55ION RESULTS

The stop rule led to the verdict of no important difference between drug A and B. The results

The significant increase in sunburn and tanning5 obtained on the psoralen treatment affords evidence of drug adherence and effective dose. The stopping rule was designed to make the trial sensitive to substantial drug differences, but not

are summarized in Table I. The conclusion with respect to prophylactic effect of the psoralen treatment is negative. The * Clinician-appraised, confirmed by reflectance 2 drugs had essentially equal effects. Decoding meter readings and color photographs taken on revealed that the drugs were: A: 20 mg methox- all patients.

PSORALEN PROPHYLAXIS VERSUS SKIN CANCER

217

small differences. The remarkably close equality of the new lesion experience in the 2 groups sug-

middle aged men, and 32 women, primarily in outdoor occupations, who had already had at gests that if there is any prophylactic effect of least 1 histologically verified skin cancer. the psoralen it must be extremely slight. 2. Methoxsalen was administered at the rate Some further details of interest to the clinician of 20 mg daily by mouth, taken in the morning. are shown in Tables II through V. Table II Patients were seen every 3 months for inventory shows the distribution of patients by age, sex, of new lesions. 3. Side effects were minimal. Dropouts were occupation, drug allocation, and number of initial lesions (lesions observed before entry equally frequent in methoxsalen and inert coninto study). Table III gives the record of inci- trol series. dence of new lesions, by successive periods of 4. Effective dose level and patient adherence treatment. Outdoor occupations included 72 were confirmed by observation of the expected percent of the patients, but 85 percent of the primary effect, increased sunburn, and later, reports of new lesions, lending support to the tanning, in the methoxsalen patients. Increased initial hypothesis of relationship between solar sunburn and tanning were the only significant exposure and skin cancer induction. The number differences obtained in the 2 series. 5. By the time 24 controlled pairs of patients of females is so small, and is concentrated so heavily in occupations not subject to solar ex- had been followed 1 year and the results analyzed posure, that the sex breakdown is not continued sequentially, the decision was reached that there was no difference between the methoxsalen pain subsequent tables. In Table IV incidence rates of new lesions per tients and their inert drug treated controls in the patient examined and per patient with any new incidence of new lesions. At this time 12 patients lesions are given. These rates appear to be es- had been treated for 2 full years on methoxsalen sentially constant through the 24 months of the and 13 on control. 6. It is concluded that methoxsalen in humanly trial and equal for the drug treatments. Finally, an analysis of the dropouts is given in tolerable tanning doses has no immediate effect Table V. Fifteen patients were dropped from on incidence of new lesions of skin cancer. drug A and 16 from drug B. Dropouts were dis- Whether larger doses or treatment over a longer tributed evenly between the 2 drugs, indicating period than 2 years might be effective cannot be the failures were due to factors other than the determined from this trial. drug. Current sequential monitoring emphasized REFERENCES the similarity of response of patients to drugs A 1. HoPKINs, CARL E.: Psoralen prophylaxis and B. By the time patients had been in the study against skin cancer: progress of field trials. 1 year it was apparent that no differences in J. Invest. Derm., 32: Part II 383, 1959. response were measurable by this form of study, 2. kEENER, A. B., I)ENT0N, C. R. AN!) FInPATRIcK, T. B.: Clinical and experimental and follow-up was discontinued on 117 patients studies with 8-metboxypsoralen in vitiligo. J. Invest. 1)erm., 20: 299, 1953. short of 24 months. Twenty-five of the entered T. B., HOPKINS, C. E., patients remained in the study for 24 months. 3. FITZPATRICK, BLIcKENSTAFF, M. S. AND SWIFT, S.: AugThe difficulty of carrying out a long term study mented pigmentation and other responses of normal human skin to solar radiaton followand maintaining physicians' and patients' ining oral administration of 8-methoxyterest when response to either of a pair of drugs psoralen. J. Invest. Derm., 25: 187, 1955. is so similar, is demonstrated in a study of this 4. O'Ns&L, M. A. AND GRIFFIN, A. C.: The effect of oxypsoralen upon ultraviolet carcinotype. Such a study does dissipate false enthugenesis in albino mice. Cancer Res., 17: 911, siasms based on clinical impressions that a drug 1957. 5. MACDONALD, ELEANOR J.: The epidemiology of

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