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Imiquimod Cream: The Genie Is Out Of the Bottle for Skin Cancer

Updated: Jul 26, 2021

Abstract: A paradigm shift in how we treat skin cancer is occurring. The ability of topical imiquimod (Aldara, TM 3M Pharmaceuticals) to cure many skin malignancies without surgical excision will have a major impact on our dermatologic practices.



​Imiquimod was first introduced in 1997 for the treatment of genital warts. This topical cream, as most dermatologists now know, is a potent immune response modifier when applied to problematic skin lesions, especially malignant ones. In essence, imiquimod stimulates innate and acquired immunity through the skin. The circulating plasmacytoid dendritic cell (monocyte) and the langherans cell are critical in this response. Besides activating toll-like receptor 7, inflammatory cytokines such as interferon, interleukin and tumor necrosis factors are released and usually resolve the problem. Imiquimod may act as a vaccine like BCG, which are known now as neoadjuvants. The specific details on the complex mechanisms are referenced (1-6). Reference six was a pleasure to read and will give the practicing dermatologist an understandable basic science course on some of these ideas. At any rate the packets or “sachets” of imiquimod sat in their carrier trays in my drawers for several years and I rarely used them even for the occasional genital wart patients I saw. In 2003 and subsequently I became more aware of the use of imiquimod in the treatment of skin cancers, melanoma and other diseases (7-16, 40-42). Photos from reference 15, which are enclosed, really changed my life.


​ About this time a 59-year-old woman came into my office for a second opinion on the treatment of a 0.6 cm basal cell cancer of the left tip of the nose. She had been scheduled for MOHS (microscopically oriented horizontal sectioning) surgery and wanted to know her options. I discussed with her about being my first “guinea pig” with the use of imiquimod. She agreed and I did a shave biopsy, which confirmed basal cell cancer. She was to leave for her summer vacation but agreed to apply the cream daily to the site for three weeks, and then she saw me in the fall when she returned. At the fall visit, she said she had decided to apply the cream to the entire nose as she saw other scaly areas. Her nose was so inflamed during that three-week period that some days she stayed home, but it calmed down over the next two weeks. Upon examination the entire nose looked “great” for lack of a medical term. The biopsy area was slightly red. Four months later I talked her into a 2mm punch biopsy of the site, which I sutured (gel foam is suggested by Mark Naylor, M.D.). Pathology revealed scar and now 16 years later the nose essentially shows no defect and I don't believe any other method would have produced such a result. I don't know who is happier, she or I.


​ Next, a 47-year-old HIV positive patient presented to my office with a 5-year history of an enlarging basal cell cancer of the left forehead. I had initially treated this apparent superficial basal cell cancer with cryotherapy and 5% 5-fluorouracil cream in 1998 but he was lost to follow up because of the complications of AIDS. By the time he reappeared in 2003, the basal cell cancer had ulcerated down to the subcutaneous fat and measured over 1.5 cm in diameter. I suggested local cryotherapy of the area then daily topical imiquimod. After 2 weeks, treatment was decreased to twice weekly because of a marked inflammatory response. By week six the tumor was clinically gone and the scar barely perceptible. This case I had to publish as any new method to avoid scalpel surgery in such patients must be reported. (Ref 17)


​ I have found that cryotherapy to the malignant lesions (before and during) hastens the process. Cryosurgery destroys malignant cells plus induces cryoimmunotherapy which is also a form of neoadjuvant therapy. Cryosurgery cannot be over appreciated and its benefits are presented in Zacarian’s book (Ref 18). However, I believe that imiquimod is the critical element. Some patients develop localized skin reactions, which can be problematic. As for many inflammatory skin eruptions I treat with wet compresses and invariably I end up “diluting the dilemma”. We all have our tricks in getting therapies to work, but as always, some patients just are not candidates for topical imiquimod therapy. These patients will do fine with well-accepted conventional therapy. How to use imiquimod in treating skin cancer is well presented by Mark Naylor, M.D. (Ref 19, 20). The average non-melanoma skin cancer will often only require several packets of imiquimod as I can get a few applications out of each sachet. Length of treatment is 6 to 12 weeks usually.


​ We all realize that many skin cancers can be fragile. One in four non-melanoma skin malignancies will go away with just a biopsy (Ref 19). This must not be avoided but encouraged! When a tumor is injured or insulted, the body (skin) recognizes there is a problem and hastens to resolve it (immunologically) which it often does. If you excise the tumor, you bypass this valuable response. The adage, “when in doubt, cut it out”, may be counterproductive especially in malignancies like melanomas or ones that want to metastasize. This concept was well written in an editorial by Arjun V. Balar M.D. and is as follows, “This era of immunotherapy brings even more reason to pursue neoadjuvant treatment. The immune microenvironment of a primary tumor contains immune cell populations that attempt to control the tumor; thus, it is optimal to administer a systemic immunotherapy agent, designed to proliferate and expand the tumor resident immune populations, before surgery rather than after, when those precious immune cells were resected along with the tumor. That’s the immunobiology equivalent of throwing the baby out with the bathwater (Ref 21).


​ At a presentation by professor Mark Brown M.D. at the fall clinical dermatology conference held in Las Vegas 2004, he presented the four situations in which he wouldn't use imiquimod: size, aggressive histology, location and recurrence. Interestingly, I often find that these particular malignancies are the ones I prefer to use for imiquimod. I am even more intrigued in the use of topical imiquimod with diclofenac, tretinoin and hydrocortisone valerate in difficult squamous cell cancers (Ref 22). Imiquimod does not work on all the skin cancers I have treated; some will require radiation or MOHS surgery. This latter modality can be miraculous and who can argue against its use in difficult malignancies such as dermatofibroma sarcoma protuberans, sweat gland malignancies, recurrent skincancers, etc (Ref 22). There are just too many situations in which MOHS surgery can be avoided and the case reports continue to accumulate (Ref 23-27). The MOHS surgeon should save their expertise for when it is needed. They can even repair some of the post imiquimod defects, which could verify tumor eradication. Some of the MOHS repairs I have seen are so well done I challenge any plastic surgeon to do better. For example, see attached photos of excellent forehead flaps for repairs of defects. However, these approaches should be used if other less invasive methods don’t work.


​ The costs of imiquimod in the early 2000s were addressed (Ref 16). I will give an example. Around 2005, one of my patients had nine separate basal cell cancers of his face, trunk, and arms. He was a 79-year-old renal patient on chronic dialysis. He went through multiple cryotherapies and 48 packets of imiquimod. He did have erosions and open wounds but all the skin cancers resolved. He had Medicare and Medical insurance so his imiquimod was free to him. The local prescription costs would have been anywhere from $600 to $1000 dollars. Medicare payments to me were $789.86 so the total costs were approximately $1,500.00 in treating all these skin cancers. MOHS reimbursement for Medicare would have been around $1,500 per every basal cell cancer. Multiply this by nine (not that anyone would MOHS every lesion) and one would receive $13,500 dollars. In fact, MOHS reimbursement is now the number one expense from Medicare in 2005 and continues to this day. This was stated by Bruce Quinn, M.D. at the California Society of Dermatology and Dermatologic Surgery September meeting in Santa Barbara, 2005. However, again not subjecting this patient to multiple excisions cannot be overlooked.


​ Now that imiquimod has become generic, the price is very affordable. Again, imiquimod is not the cure all but it has changed my practice dramatically. I do less excisions and I no longer use my local hospital pathology departments to do frozen sections. I still refer difficult or resistant skin malignancies for MOHS and I guarantee that surgeon will earn their money. Imiquimod may require more time and hand holding, but not having to create possible disfiguring or noticeable excision scars is so gratifying that I am really enjoying dermatology again. This concept was published recently in “Cutis” (Ref 28).


​ Other exciting advances in non-surgical approaches to skin cancers (Ref 29, 30, 31) make me glad we didn't change the name of the American Academy of Dermatology to American Academy of Dermatology and Dermatologic Surgery. It wasn't too long ago that venereology was dropped from our moniker so keeping our name as is appears to be the reasonable course. Of course, surgery will always be required in our discipline but I think it is becoming more cosmetic than ever before. I have a particular interest in the use of imiquimod for the treatment of dangerous malignancies such as melanoma (Ref 8, 9,10,11, 12, 13, 44) and merkel cell cancer. This latter case was prompted by my success in clearing multiple merkel cell cancerous nodules on the forehead in a 79-year-old white male with imiquimod. The details are published in a letter to the editor in "Cutis" (Ref 32).


​ After hearing Mark Naylor M.D. discuss his results of imiquimod for melanoma at the Sacramento Valley Dermatologic Society in March of 2005 I was more stimulated. A recent review of cutaneous melanoma (Ref 32) didn't even mention imiquimod, incredibly. In a subsequent letter to the editor concerns about tumor angiogenesis from humoral antitumor immune response was raised (Ref 33). Although imiquimod was not studied, this could confirm the fears about tumor progression raised by the authors in using imiquimod to treat lentigo malignas (Ref 34). I agree that we must be vigilant in monitoring imiquimod but I propose a problem. What if one had an ulcerated level III (> .8 mm) or greater melanoma and had any of the unfavorable changes discussed in the reference enclosed (Ref 35). The traditional approach is to do a sentinel node biopsy and wide excision and pray. Even if the sentinel node was not involved, too many of these patients subsequently develop metastases and die, in my nearly fifty-year experience. Therefore, the well-known statement, “when in doubt, cut it out” has often failed. It may be preferable to partially biopsy a melanoma in order to use imiquimod as a neoadjuvant treatment (Ref 44). I would suggest applying imiquimod to the melanoma site like a vaccine until marked inflammation arises (say 3 to 6 weeks) then excise the area. In fact, this method usually lights up (treats?) the sentinel node, which could be addressed. Again, as I have discussed, if you perform aggressive surgery first then you never get the chance for the skin and immune system to attack the melanoma, and the possible melanoma stem cell. (Ref 40) This approach is not FDA approved but there is some support for this idea (Ref 29, 31, 36, 37, 40, 41, 42, 43, 44). Obviously this approach is off label, but until rat models and or clinical studies are done, melanoma deaths will continue. I can't help but feel that the eventual approach to melanomas will be non surgical, especially now that we have very effective systemic drugs to treat melanoma recurrences and metastases.


​ Dr. J Zitelli, a MOHS surgeon, had reservations about imiquimod and felt its benefits were over touted. He put it as “know the truth” (Ref 45). I now have over fifteen years of experience treating thousands of skin cancers with imiquimod and cryotherapy to answer his doubts. The following photos show typical examples of my results.


​ This above article now revised was submitted to the blue journal of the American Academy of Dermatology around 2003, but they asked me to resubmit it as a series of case reports. I had spent considerable time preparing the original manuscript but decided to wait until I had accumulated many more cases over the next 15 years. Again, see the many photos.


​If you are being scheduled for MOHS surgery and would like to know your options, I would be glad to share my experiences with your dermatologist.






References


1) Tomal, M. A., Birmachu, W., Case, M. T., Gerster, J. F., Gibson, S. J., Imbertson, L. ​M., … Wagner, T. L. (1997). Imiquimod: In vivo and in vital characteristics and ​toxicology. In Cutaneous Infection and Therapy (Vol. 32, pp. 405–415). Dekker.


2) Testerman, T. L., Gerster, J. F., Imbertson, L. M., Reiter, M. J., Miller, R. L., Gibson, ​S. J., … Tomai, M. A. (1995). Cytokine induction by the immunomodulators ​imiquimod and S-27609. Journal of Leukocyte Biology, 58(3), 365–372.


3) Kono, T., Kondo, S., Pastore, S., Shivji, G. M., Tomai, M. A., Mckenzie, R. C., & ​Sauder, D. N. (1994). Effects of a novel topical immunomodulator, imiquimod, ​on keratinocyte cytokine gene expression. Lymphokine and Cytokine ​Research, 13(2), 71–76.


4) Suzuki, H., Wang, B., Shivji, G. M., Toto, P., Tomai, M. A., Miller, R. L., & Sauder, ​D. N. (2000). Imiquimod, a topical immune response modifier, induces migration ​of Langerhans cells. Journal of Investigative Dermatology, 114(1), 135–141.


5) Hurwitz, D. J., Pincus, L., & Kupper, T. S. (2003). Imiquimod: a topically applied link ​between innate and acquired immunity. Archives of Dermatology, 139(10), 1347–​1350.


6) O'Neill, L. A. (2005). Immunity's early-warning system. Scientific American, 292(1), ​24–31.


7) Christophers, E., & Rigel, D. (2003). The therapeutic potential of immune response ​modifiers in dermatology. British Journal of Dermatology, 149(66), 1–70.


8) Steinmann, A., Funk, J. O., Schuler, G., & Von Den Dreisch, P. (2000). Topical ​imiquimod treatment of a cutaneous melanoma metastasis. Journal of the ​American Academy of Dermatology, 43(3), 555–556.


9) Bong, A. B., Bonnekoh, B., Franke, I., Schon, M., Ulrich, J., & Gollnick, H. (2002). ​Imiquimod, a topical immune response modifier, in the treatment of cutaneous ​metastases of malignant melanoma. Dermatology, 205(2), 135–138.


10) Wolf, I. H., Smolle, J., Binder, B., Cerroni, L., Richtig, E., & Kerl, H. (2003). ​Topical imiquimod in the treatment of metastatic melanoma to skin. Archives of ​Dermatology, 139(3), 273–276.


11) Chapman, S. M., Spencer, S. K., & Brennick, J. B. (2003). Histologic resolution of ​melanoma in situ (lentigo maligna) with 5% imiquimod cream. Archives of ​Dermatology, 139(7), 943–944.


12) Epstein, E. (2003). Extensive lentigo maligna clearing with topical ​imiquimod. Archives of Dermatology, 139(7), 944–945.


13) Dahl, M. V. (2002). Imiquimod: case reports of early clinical experience in various ​conditions. Journal of the American Academy of Dermatology, 47(4), S205–S208.


14) Maibach, H. I., Rosen, T., Berman, B., & Johnson, R. A. (2002). Dermatologic ​dilemmas: the role of immune response modifiers in challenging cases. Skin and ​Allergy News, 4–17.


15) Robins, P. (2004). Imiquimod photographic case study compendium. Physicians' ​Continuing Education Corporation.


16) Eklind, J., Tartler, U., Maschke, J., Lidbrink, P., & Hengge, U. (2003). Imiquimod to ​treat different cancers of the epidermis. Dermatologic Surgery, 29(8), 890–896.


17) Scott, D. R. (2004). Eradication of basal cell cancer in an HIV positive patient with ​topical imiquimod. Journal of Drugs in Dermatology, 3(6), 602.


18) Zacarian, A. S. (1985). Cryosurgery for skin cancers in cutaneous disorders. St. Louis, MO: The C.V. Mosby Company.


19) Swetter, S. M., Boldrick, J. C., Pierre, P., Wong, P., & Egbert, B. M. (2003). Effects ​of biopsy-induced wound healing on residual basal cell and squamous cell ​carcinomas: rate of tumor regression in excisional specimens. Journal of ​Cutaneous Pathology, 30(2), 139–146.


20) Balar, A.V. (2019) Investigators explore neoadjuvant immunotherapy in hepatocellular carcinoma. TargetedTherapies in Oncology, 8(15), 11.


21) Naylor, M. (2004). Excision vs. IRM therapy for bcc: How to choose. Practical ​Dermatology, 53-54.


22) Naylor, M. (2005). Imiquimod and Superficial Skin Cancer. Journal of Drugs in ​Dermatology, 4(5), 598–606.


23) Nouri, K., & Rivas, M. P. (2004). A primer of Mohs micrographic surgery: ​uncommon indications. Skinmed, 3(5), 259–265.


24) Vender, R. B., & Goldberg, O. (2005). Innovative uses of imiquimod. Journal of ​Drugs in Dermatology, 4(1), 58–63.


25) Martin-Garcia, R. (2005). Imiquimod: an effective alternative for the treatment of ​invasive cutaneous squamous cell carcinoma. American Society for Dermatologic ​Surgery, 31(3), 371–374.


26) Nouri, K., O'Connell, C., & Rivas, M. P. (2003). Imiquimod for the treatment of ​Bowen's disease and invasive squamous cell carcinoma. Journal of Drugs in ​Dermatology, 2(6), 669–673.


27) Perris, K., Campione, E., Micantonio, T., Marulli, G. C., Fargnoli, M. C., & ​Chimenti, S. (2005). Imiquimod treatment of superficial and nodular basal cell ​carcinoma: 12-week open-label trial. American Society for Dermatologic ​Surgery, 31(3), 318–323.


28) Waldman, R.A., Grant-Kels, J. M. (2019). Reflectance confocal microscopy to facilitate knifeless skin cancer management. Cutis, 104(4), 213.


29) Tran, H., Moreno, G., & Shumack, S. (2004). Imiquimod as a dermatologic ​therapy. Expert Opinion on Pharmacotherapy, 5(2), 427–438.


30) Kondapalli, L., Soltani, K., & Lacouture, M. E. (2005). The promise of molecular ​targeted therapies: Protein kinase inhibitors in the treatment of cutaneous ​malignancies. Journal of the American Academy of Dermatology, 53(2), 291–302.


31) McArthur, G. A., Demetri, G. D., Van Oosterom, A., Heinrich, M. C., Debiec-​Rychter, M., Corless, C., … Fletcher, J. (2005). Molecular and clinical analysis of ​locally advanced dermatofibrosarcoma protuberans treated with imatinib: ​Imatinib Target Exploration Consortium Study B2225. Journal of Clinical ​Oncology, 23(4), 866–873.


32) Li, V. W., Li, W. W., Talcott, K. E., & Zhai, A. W. (2005). Imiquimod as an ​antiangiogenic agent. Journal of Drugs and Dermatology, 4(6), 708–717.


33) Scott, D. R. (2006). Apparent response of cutaneous merkel cell tumor to topical ​Imiquimod. Cutis, 77, 109–110.


34) Tsao, H., Atkins, M. B., & Sober, A. J. (2004). Management of cutaneous ​melanoma. New England Journal of Medicine, 351(10), 998–1012.


35) Barbera-Guillem, E., Nyhus, J. K., Wolford, C. C., Friece, C. R., & Sampsel, J. W. ​(2002). Vascular endothelial growth factor secretion by tumor- infiltrating ​macrophages essentially supports tumor angiogenesis, and IgG immune ​complexes potentiate the process. Cancer Research, 62(23), 7042–7049.


36) Heymann, W. R. (2005). Non-cosmetic dermatology surgery. Journal of the ​American Academy of Dermatology, 52(6), 1069–1070.


37) Barnhill, R. L., Katzem, J., Spatz, A., Fine, J., & Berwick, M. (2005). The ​importance of mitotic rate as a prognostic factor for localized cutaneous ​melanoma. Journal of Cutaneous Pathology, 32(4), 268–273.


38) Schon M.P., Wienrich B.G., Drewniok C., Bong A.B., Eberle J., Geilen C.C., ​Gollnick H., Schon M. (2004).Death receptor-independent apoptosis in malignant ​melanoma induced by the small-molecule immune response modifier ​imiquimod. Journal of Investigative Dermatology, 122, 1266–1276.


39) Craft, N. (2005). Imiquimod may potentiate melanoma vaccine effect. Dermatology ​Times.


40) Pinnix, C. C., Hogan, M., & Herlyni, M. (2005). Melanoma stem cells, have we ​overlooked them? The Melanoma Letter, 23(3), 3–4.


41) Grady, B., & James, S. (2016). topical imiquimod clears invasive ​melanoma. Cutis, 98(5), E28–E30.


42) Ocampo-Garza J, Gioia Di Chiacchio N, Haneke E, le Voci F, Paschoal FM. (2017)​Subungual melanoma in situ treated with imiquimod 5% cream after ​conservative surgery recurrence. Journal of Drugs andDermatology, 16(3), ​268–70.


43) Kubicki, S. L., Park, K. E., Aung, P. P., & Duvic, M. M. (2019). Complete ​resolution of primary cutaneous anaplastic large cell lymphoma with topical ​Imiquimod. Journal of Drugs andDermatology, 18(5), 460–462.


44) Narayan, R., Nguyen, H., Bentow, J. J., Moy, L., Lee, D. K., Greger, S., … Craft, N. ​(2012). Immunomodulation by Imiquimod in Patients with High-Risk Primary ​Melanoma. Journal of Investigative Dermatology, 132(1), 163–169. doi: ​10.1038/jid.2011.247


45) Zitelli, J. A. (2005). Use of Imiquimod for treating skin cancer. Journal of American ​Academy of Dermatology, 52(1), 177.





#imiquimod #aldara

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