Combination therapies evolve to address countless dermatologic conditions

This story was updated October 15, 2013 to correct a misstatement on the FDA indications for which vismodegib is approved.

Dermatologists are using an evolving collection of combination therapies designed to address different aspects of disease, monotherapy limitations and failures, as well as enhance treatment.

Combination therapies are pivotal when treating skin cancer patients using the field cancerization approach, according to Alexandra Zhang, M.D., associate staff in the department of dermatology, Cleveland Clinic, Cleveland.

Dr. Zhang, a Mohs surgeon, says field therapy involves addressing not only skin cancers, but also surrounding actinic keratoses.

“Field cancerization sometimes makes surgical therapy difficult because if the tumor is ill-defined and sits in a field of precancerous and cancerous background, it is difficult for us to get clear margins. And it is difficult for us to treat the cancer completely. Therefore, combination therapies in that situation provide help,” Dr. Zhang says.

Skin cancer options

While surgical modalities remain the mainstay treatment for primary nonmelanoma skin cancer and melanoma, other options often help to clear the field of cancerization. Such options include electrodesiccation and curettage, cryotherapy, chemical peels and laser treatments, photodynamic therapy and topical modalities, according to Dr. Zhang.

“Topical modalities are more frequently used today,” she says.

Among the topical options: immunomodulators, such as imiquimod; chemotherapy agents, including 5 fluorouracil (5-FU); diclofenac (a nonsteroidal anti-inflammatory), topical retinoids and, a plant extract approved by the Food and Drug Administration in January 2012, ingenol mebutate.

Imiquimod, which is FDA-approved to treat actinic keratosis, has also been shown in studies to be an effective adjunct to surgery in the treatment of melanoma in situ, according to Dr. Zhang.

“There also are case reports indicating topical imiquimod in the treatment of melanoma in situ and melanoma cutaneous metastases. So that is potentially another important component … in combination with surgery for the treatment of melanoma in situ or possibly as part of the treatment regimen for metastatic melanoma in conjunction with BRAF inhibitors or targeted immunotherapy. Further studies need to be done to confirm this as a viable treatment modality,” she says.

Emerging modalities

Emerging nonsurgical modalities to treat precancerous and cancerous skin lesions include chemical peels and laser ablation, using a CO₂ laser or photodynamic therapy, she says.

Dr. Zhang also uses systemic medications in conjunction with surgery in the treatment of high-risk squamous cell carcinoma. These include oral retinoids and, on the horizon, oral capecitabine.

“Articles published have been using low dose capecitabine in the fashion of oral retinoids, for chemoprevention,” Dr. Zhang says. “Of course, the new revolution in the treatment of basal cell carcinoma is the new biologic medication, vismodegib. Although it is currently being investigated in clinical trials for the treatment of nevoid basal cell syndrome, it does not currently have FDA approval for this indication.”

While researchers have yet to publish studies on combination therapies using biologics, combinations in this realm are probably in the future, Dr. Zhang says.

In essence, if a dermatologic surgeon sees a skin cancer lesion is ill-defined, sitting in a field of a precancerous or actinic damaged background, Dr. Zhang says it’s often a good approach to first give the patient a course of topical therapy or other combination therapy to treat the field prior to surgery. 

“Photodynamic therapy is the emerging nonsurgical modality. We’ve been using it more often because it can treat a large field of actinic damage,” she says. “Photodynamic therapy has also been effective in reducing the incidence of new skin cancers.”

Combo therapies standard for acne

Using combinations of therapies is standard practice in acne treatment, according to Whitney Bowe, M.D., assistant clinical professor of dermatology, SUNY Downstate Medical Center, New York.

“There are multiple factors that lead to acne lesions and multiple contributors to acne pathogenesis. So, if you can attack acne from multiple perspectives and attack it at different points in that cascade that leads to acne, you’re more successful with therapy,” Dr. Bowe says.

There are important advantages to using combination acne treatments. Using retinoids, for example, in combination with other treatments speeds acne’s response to the retinoids, she says.

Dr. Bowe, who has published and lectured extensively on acne, says the most critical combination therapy in acne continues to be the use of benzoyl peroxide with any oral or topical antibiotic. The combination approach is especially important given that bacterial and antibiotic resistance has become a major issue, she says.

“Nowadays, there are very high resistance rates. Erythromycin is barely effective anymore, and there is a lot of resistance to topical clindamycin, oral tetracycline and doxycycline,” Dr. Bowe says. “The least amount of resistance is with oral minocycline, but even with oral minocycline, there are increasing levels of resistance.”

For acne on the face, chest and back, dermatologists often use oral antibiotics and benzoyl peroxide, in addition to a retinoid. And for acne in adult females who are experiencing flares that seem to be hormonal in nature, it’s important to consider adding an oral contraceptive or an oral androgen antagonist (spironolactone) to the topical retinoid and benzoyl peroxide regimen.

One of the newer acne combination therapies is Epiduo (Galderma), a combination of benzoyl peroxide and adapalene.

“Adapalene is a retinoid molecule, whereas, benzoyl peroxide has an antibacterial mechanism of action, where it actually kills bacteria rather than slowing its growth (it’s bactericidal, not simply bacteriostatic),” Dr. Bowe says. “The fact that this company was able to stabilize this molecule, adapalene, alongside benzoyl peroxide is very promising. Dermatologists would use it as a combination treatment topically, for people who are struggling with mild to moderate acne, or they would use it in combination with an oral antibiotic for people struggling with moderate-to-severe acne.”

New approaches

What’s new? A more holistic approach to acne treatment, according to Dr. Bowe.

“Stress reduction and diet modifications are meant to be used in conjunction with the tried-and-true prescription therapies for acne, so they can potentially help us to wean our patients off the prescriptions faster and maintain clearance longer in between flares,” she says. “We have a lot of data now showing that what we eat and drink is impacting our skin.”

The two strongest recommendations when it comes to diet, according to the dermatologist, are to avoid high glycemic index foods and dairy. High glycemic index foods have high amounts of refined carbohydrates and include white bread, white pasta, cornflakes and chips. Dr. Bowe recommends replacing these and other high glycemic index foods with low glycemic foods, such as barley, multigrain bread, sweet potatoes, nuts, vegetables and lean protein.

“Dairy seems to impact acne as well,” Dr. Bowe says. “We should encourage our patients to avoid skim milk, in particular. Skim milk seems to be a trigger of acne.”

Another combination therapy, which is outside the prescribing box, is stress reduction.

“We have a lot of basic science studies showing that certain stress hormones, like corticotropin releasing hormones and substance P, are actually able to bind directly to oil glands and promote acne flairs,” Dr. Bowe says. “… meditation, yoga, deep breathing, talking to friends, any of those things can be beneficial for people who have acne.”

Combinations show promise for psoriasis

There’s no question, combination approaches are important in psoriasis, says Johann E. Gudjonsson, M.D., Ph.D., assistant professor of dermatology, University of Michigan, Ann Arbor.

“Using combination therapies is something we’ve been doing for a very long time, most commonly with different combinations of topical treatments and UV phototherapy,” he says.

“With the advent of whole new classes of therapeutics, including the biologics, it has opened up the possibility of combining different therapies, both old and new, for increased therapeutic effect,” he says. “When we combine treatments, we can often get by with a lower dose of either agent that we use. By using a lower dose (of agents) with no or minimal overlapping of side effects, you can often offer a pretty safe treatment for psoriasis.”

Severe cases only

When using systemic drugs, dermatologists treating psoriasis patients should reserve combination therapies for more severe cases, where monotherapy isn’t achieving full control, Dr. Gudjonsson says.

Among the combinations used commonly in patients with more severe disease: systemic medication, such as methotrexate, with light treatment, or methotrexate with biologics.

“We often ‘rescue’ them, so to speak. They might be beginning to fail biologic treatment, then we use the combination to kind of get the effect back,” Dr. Gudjonsson says. “The other reason we often use combination of systemic therapies - especially with methotrexate - is to prevent development of anti-drug antibodies that may, with time, neutralize the biologic that we have been using.”

In recent years, dermatologists have been combining anti-tumor necrosis factor (anti-TNF) agents, such as adalimumab, infliximab, with methotrexate either at the start of treatment, or when patients begin to fail biologic monotherapies. Dr. Gudjonsson says the newest psoriasis combination treatment that he has been using has been Stelara (ustekinumab, Janssen Biotech) and methotrexate.

“Again, it comes down to having a patient who is not fully controlled on biologic monotherapy, and we’re trying to maintain the therapeutic response or preventing treatment failure by adding another agent that has minimal overlap in side effects,” he says.

While data on combining different biologic treatments for psoriasis is lacking, there is limited data indicating the efficacy of combining biologic treatments with older, traditional systemic medications such as methotrexate or acitretin, or UV phototherapy. 

Paying it forward

One of the most important combinations today in cosmetic dermatology, according to dermatologist Christopher B. Harmon, M.D., of Birmingham, Ala., is that of neurotoxins and fillers.

Dr. Harmon says dermatologists have long known neurotoxins are best for the upper third of the face and fillers for the lower third.

“We’ve also known there are lots of exceptions. There are great uses for neurotoxins around the mouth. But the neurotoxin combined with the filler often gives greater longevity to the filler,” he says.

Combining neurotoxins with laser resurfacing or medium-depth chemical peels also helps enhance those laser treatments or peels. According to Dr. Harmon, new combined ablative and nonablative fractionated devices offer a significant improvement in what dermatologists can do to rid patients of unwanted rhytids.

“When you combine (these devices) with a neurotoxin, then, it multiplies the long-term benefit of the resurfacing procedure,” he says.

The benefit of adding a neurotoxin to a medium-depth chemical peel is the skin peels and remodels when muscles are adynamic, preventing the muscle from reforming nearby lines. Essentially, the peel does its job to even the skin tone and texture, while the neurotoxin helps diminish rhytids.

“(Adding a neurotoxin) prolongs and maximizes the impact of the resurfacing treatment, whether it’s a chemical peel or light and laser,” he says. “Ideally you want to do it two or three weeks ahead of the resurfacing, so during the wound healing phase those muscles and that skin are inactive.”

Cosmetic approaches

Another trend in dermatology is ushering a cosmetic-medical dermatology combination approach for acne. Thinner fillers, such as Belotero Balance (Merz Aesthetics), are becoming increasingly popular because dermatologists can place these superficially in the papillary dermis and not worry about inflammatory papules occurring. These thinner fillers are ideal for filling in acne scars, according to Dr. Harmon.

“Often, patients who have acne scarring will still be undergoing some acne outbreaks, so the acne patient comes in for management of their active lesions and … to address lingering scars,” he says.

Macrene Alexiades-Armenakas, M.D., Ph.D., assistant clinical professor, Yale University School of Medicine, New Haven, Conn., says there are other combination approaches involving that can boost therapeutic efficacy from cosmetic procedures. One example: The combination of devices that treat rhytids and photodamage, such as intense pulsed light (IPL) or fractional CO₂, with devices that treat skin laxity, such as infrared or radiofrequency.

“Another example is combining devices with topical anti-aging actives. Currently, I am conducting an IRB trial combining topical application of 37 Extreme Actives, an anti-aging cream … with an ultrasound device, the Alma Impact (Alma Lasers), which has been shown to increase penetration of topically applied agents into the skin,” Dr. Armenakas says. “This is a new area of research that is sure to open up new vistas in our field.”

Disclosures: Dr. Gudjonsson has conducted clinical trials with Amgen. Dr. Bowe has served as a consultant for Johnson & Johnson consumer products, Proctor & Gamble, L’Oreal and Galderma. Dr. Alexiades-Armenakas has a research grant from Alma and is finishing a funded study with Syneron. Drs. Bowe, Harmon and Zhang report no relevant financial interests.