I IIIIII I II I I II IIII I I IIII II II II II I

General discussion of articles by Moon McCormick, Peck et al, and Meyskens

and

D. S. Alberts, M.D.: Dr. Peck, I was curious to know if you have done any studies with retinoic acid-binding protein in conjunction with your basal cell cancer studies.

G. L. Peck, M.D.: We have just begun studies of the retinoic acid-binding protein and have no data to report at this time.

D. S. Alberts, M.D.: One comment to Dr. Moon. I think that there is reason to think that anyone of these mouse models represents what one patient would be in a clinical study looking at the activity of a single agent. That is not a criticism, but is just a comment relative to the fact that when one looks at the results of such stud- ies with various retinoic acids, one can draw a specific conclusion with respect to that tumor, but I think we should be careful about generalizing as to the efficacy of the retinoids just on the basis of two or three differ- ent models.

R. C. Moon, Ph.D.: I think you have to be careful about generalizing about any biologic system. How- ever, we find that even within a single animal model, there are various biologically different tumors within that particular individual animal so that some tumors respond differently to different things. Now I am gen- eralizing to a certain degree that some retinoids are effective against some types of epithelial systems, and I hasten to point out that we are using epithelial model systems and we are not dealing with the particular tumors found in the human population.

P. G. t lazen, M.D.: Dr. Peck, since the doses of isotretinoin you used were generally higher than those used in other disorders of keratinization, were abnor- malities in the serum lipids observed by you?

G. L. Peck, M.D.: Approximately half of the pa- tients did have elevations in serum triglycerides, com- parable in magnitude to what was seen at lower dosages used in treating disorders of keratinization. Other fac- tors, such as genetic predisposition, obesity, diabetes, and high alcohol intake, appear to be necessary for the very high elevations previously reported.

L. H. Miller, M.D.: What was the age of the pa- tients with the basal cell nevus syndrome?

G. L. Peck~ M.D.: The age range was approxi- mately 25 to 55.

L. lrI. Miller, M.D.: Have you treated any xeroderma pigmentosum patients?

G. L. Peek, M.D.: No, not yet. D. S. Alberts, M.D.: I was struck by Dr. Peck's

conclusion, which I think is real, that one needs to maintain retinoid treatment for long periods of time, perhaps forever, in patients with established cancers in order to have a continuing effect. I just would comment to Dr. Meyskens that it may be that you will want to revise your Southwest Oncology Group studies so that patients do have continuing treatment with retinoid. Do you care to comment on that?

F. L. Meyskens, J r . , M.D.: I am reluctant to do that because I think that it is hard to justify treatment with any drug in an adjuvant setting for a lifetime. If you knew that all 100% of those patients were going to relapse, that is fine. But with stage I disease, depending on the level and the thickness, you are going to have a relapse rate of somewhere between 30% and 50%. It is hard to justify continuous therapy for the other 50% of patients, The second comment is that lifetime treat- ments may not be necessary if you believe that it may be possible to eradicate the few remaining residual cells through immunologic modification with a retinoid.

G. Plewig, M.D.: I can confirm what Dr, Peck has just said. We have six patients with multiple basal cell carcinomas who are under the care of my colleague, Dr, Galosi. Two of these patients have the basal cell nevus syndrome. They are receiving 0.5 to 1 mg/kg / day. Many of the superficial basal cell carcinomas dis- appear, but the undifferentiated types of basal cell car- cinomas respond poorly, if at all. Patients with the Chernosky-Freeman type of actinic porokeratosis have not responded. We have under our care one young girl with xeroderma pigmentosum. The results are en- couraging. She developed eighteen tumors within a month of starting etretinate therapy. Since she has been on retinoids, she has not developed a single new tumor.

E. M. Farber , M.D.: Dr. Peck, I was impressed with the high-dosage therapy for 1 month. It apparently was not too rough as far as toxicity is concerned. Have you considered using 3-4 mg/kg/day for fulminating acne conglobata?

G, L. Peck, M.D.: I have used short-term high-dose

828 0190-9622/82/040828+ 03500.30/0 © 1982 Am Acad Dermatol

Volume 6 Number 4, Part 2 April, 1982

General discussion 829

treatment schedules. For instance, 2 mg/kg/day of iso- tretinoin for 2 weeks followed by 0.5 mg/kg/day for the remainder of a 16-week treatment period is effec- tive treatment for most patients with cystic ache. In my initial studies, I did use 3 mg/kg/day in some compar- atively resistant patients toward the end of their course of therapy. However, I have no experience using 3 or 4 mg/kg/day during the initial 2-week period of a high- low dosage schedule. It is possible that these higher initial doses could lead to either more rapid responses or more complete responses. For chronic therapy, I now prefer to treat at 2 mg/kg/day for longer periods of time until clearing is observed, rather than increase the dosage in patients with acne of the back, nape of the neck, buttocks, or other location that is somewhat more treatment-resistant.

L. A. Sehachner , M.D.: Dr. Peck, in your patients with multiple basal cell carcinomas who have been treated with isotretinoin, have decreases in high-density lipoprotein been associated with the elevation of tri- glycerides. This observed association has not been commented on during this meeting. Is this association real and is it still of concern?

G. L. Peck, M.D.: At the last Society for Inves- tigative Dermatology meeting my colleague, Dr. Earl Gross, presented our study of twenty patients with acne of the trunk who were treated with a high-low dosage schedule in which the patients received 2 mg/kg/day for either 2 or 4 weeks and then 0.5 mg/kg/day. In these patients we measured lipoproteins, triglycerides, and cholesterol. At the 2 mg/kg/day dose we saw about a 10% decrease in HDL, which returned to pretreat- ment values after the dose was decreased to 0.5 mg/ kg/day. We saw comparable changes in the basal cell carcinoma patients,

L. A. Goldsmith , M.D.: Dr. Moon, I think that one of the very profound things in your talk was the effect of some of the retinoids on breast development; do we have to be concerned that patients going through pu- berty may have an irreversible or reversible change once the retinoid is stopped. I just wonder if anyone who has had patients who have gone through puberty while on one of the drugs has any relevant experiences.

R. C. Moon, Ph.D.: I think it is a reversible effect. At least in our organ culture system, we are seeing more reversibility, both morphologically and biochem- ically. We have not really looked at the reversibility in long-term in vivo studies. We have treated animals with a number of retinoids, particularly retinyl acetate and 4-hydroxyphenyl retinamide and then mated these animals, We do find development of the gland during pregnancy in animals which have been on the retinoid

for a long while. There also appears to be little effect upon fertility in the retinoid-treated animal, although there does seem to be a decrease in lactation, in that the amount of milk secreted by these animals is less, From just looking at the gland, we have not really quantitated the amount of proliferation in these animals; it looks as if there is development at least comparable to that of normal lactation and there is some milk secretion, but not very much.

L. H. Miller, M.D.: You said there is recovery after discontinuing the drug?

R. C. Moon, Ph.D.: At least in our organ culture system, yes.

N. J . Lowe, M.D.: is there any preferential site of improvement, as we have heard with certain other dis- eases, with isotretinoin and the skin tumors? Do they clear any better from any particular site of the body? Secondly, has anybody any information as to whether it is possible to use adjunctive topical therapy in the treti- noin and isotretinoin-treated patients with skin tumors. For example, could topical 5-FU be used as an adjunc- tive therapy?

G. L. Peek, M.D.: Although it makes sense to eventually use isotretinoin as part of a combination therapy program, our protocol does not allow us to use combination therapy. Furthermore, I am not aware of any studies involving combination therapy. I have not analyzed the data with regard to preferential therapeutic responses according to body site, but my impression is that tumors of the head, neck, and upper trunk do better than tumors elsewhere, such as the legs.

K. H. Halprin, M.D.: Dr. Meyskens, why don't you use long-term therapy since it seems to be clear that the antitumor effects of these compounds are reversible if therapy is stopped?

F. L. Meyskens, Jr . , M.D.: Because I think that long-term vitamin A, even at I00,000 U per day, will produce significant toxicity. We are starting to see this in the patients in the pilot study at 12 to 18 months; the type of toxicity that is occurring will probably be in- tolerable to the patients. I feel uncomfortable giving a drug that has toxicity to a group of patients in whom there is only going to be a 50% relapse rate. Further- more, [ do not think you will be able to give it forever, as there probably will be significant skin and liver tox- icity. I do not think any of my colleagues would be in favor of continuing the drug for longer than a year because there is a concept in oncology that it is the initial 6 to 12 months that are important in the eradica- tion of metastatic disease. If you can get rid of the tumor at that point, then you should not have to give vitamin A forever.

830 General discussion

Journal of the American Academy of

Dermatology

D. S. Alberts , M.D.: I am rarely at odds with my colleague from Arizona, but there are a lot of data now accumulating in the treatment of stage II breast cancer wherein patients who have positive estrogen receptors and who are treated with tamoxifen citrate, an anties- trogen, alone have continuing or improved disease-free survivals until tamoxifen is stopped, at which point there is a very dramatic falloff in disease-free survival. That is the parallel I would use to suggest that vitamin A treatment be continued for perhaps up to 5 years. A real consideration, however, is that it may be impossi- ble to continue the kinds of doses that we are talking about.

L. H. Miller, M.D.: And ultimately the com- promise might be adjunctive therapy which remains to be developed in the future.

D. West, M.S. : On the subject of chemoprevention, would anyone care to comment on the potential role of beta carotene as a chemopreventive? Has anyone been looking at this in the field?

L. C. I t a rbe r , M.D.: It is my understanding that there are two ongoing NIH studies concerning two tribes of albinos who are living in Africa today, in an attempt to decrease not only the number but also the magnitude of the squamous cell carcinomas. There should be a preliminary report coming out of that

group, hopefully within a year or two. Other than that study, I know of no evidence that one has altered the rate of tumor formation in humans with beta carotene.

R. K. Boutwell, Ph.D.: I can also respond to that question. Perhaps many of you are aware that Dr. Richard Peto, of Oxford, published a review in which he suggested theoretical mechanisms by beta carotene might act other than as a vitamin A precursor (Nature 290:201, 1981). Furthermore, we have reported that, in contrast to retinoids, skin applications of beta carotene did not inhibit the induction of ornithine decarboxylase by the tumor-promoting phorbol esters. In contrast, large doses of beta carotene in oil administered by stomach tube did inhibit the induction of the enzyme. These studies are unpublished.

G. L, Peek, M.D.: The basis for the NIH study was the work of Dr. Mathews-Roth (Clin Res 28:477, 1980). She found that beta carotene and two other carotenoids, phytoene and canthaxanthin, inhibited carcinogenesis of the skin. Beta carotene inhibited both the chemical carcinogen-induced and the ultraviolet light-induced carcinogenesis, whereas the other two carotenoids only inhibited ultraviolet light-induced carcinogenesis. The inhibition seemed to be of tumor initiation as opposed to tumor promotion.