Optimal patient outcomes using new systemic therapies for advanced basal cell carcinoma and malignant melanoma requires active involvement of the dermatologist in a multidisciplinary care team.
Advances in systemic therapy, including targeted approaches and immunotherapy options, are changing the landscape of management for patients with metastatic and advanced skin cancer. Although current use of the available agents falls predominantly under the purview of medical oncologists, dermatologists need to become educated about the new therapeutic modalities because a multidisciplinary team approach represents the best model for optimizing patient care, say experts in this area.
Familiarity with the new treatments for advanced skin cancer is essential for dermatologists to make appropriate referrals for their patients. However, the role of dermatologist does not stop there. Rather they provide valuable expertise going forward considering that some of the new therapies can cause treatment-limiting cutaneous side effects.
“In our experience, cross-specialty collaboration helps to optimize results with the new therapies for advanced and metastatic skin cancers. Therefore, I would encourage dermatologists in the community to begin establishing a relationship with physicians in nearby cancer centers or multispecialty programs that are managing the advanced cancer population,” said Clara Curiel, M.D., associate professor of dermatology, University of Arizona Medical Center, and director, of the Pigmented Lesion Clinic and Multidisciplinary Cutaneous Oncology Program, The University of Arizona Cancer Center, Tucson.
Dr. Curiel’s colleague, Lee D. Cranmer, M.D., Ph.D., associate professor of medicine, University of Arizona and director, Melanoma/Sarcoma program, The University of Arizona Cancer Center, noted that cutaneous toxicities can both limit patients from receiving maximally effective doses of the new therapies and also detract from any quality of life improvements that are achieved through a positive oncologic response.
“Therefore, dermatologists and medical oncologists need to work more closely together than ever before,” Dr. Cranmer says.
“While traditionally there has been a flow of skin cancer patients from the dermatologist towards the medical oncologists, with these new medications, there also has to be a reverse order of flow in order for patients to achieve maximum benefit.”
The development of new targeted systemic therapies for skin cancers is based on increasing understanding of the biology of these tumors. In January, 2012, dermatologists saw the approval of the first oral medication for the treatment of basal cell carcinoma (BCC) – vismodegib (Erivedge, Genentech), which is indicated for use in adults with metastatic BCC or with locally advanced BCC that has recurred after surgery or who are not candidates for surgery or radiation. Studies are now ongoing investigating vismodegib for treatment of patients with multiple, surgically resectable BCCs, a population of patients more likely to fall under the umbrella of dermatologist care. Meanwhile, however, dermatologists prescribing of vismodegib for its approved indication may begin to increase as they gain familiarity and comfort with its safety profile.
Dr. Cranmer notes that the safety profile of vismodegib makes it amenable to prescribing by dermatologists.
“From the standpoint of toxicity, I certainly believe vismodegib fits well into the dermatologist’s armamentarium. Although it can cause some significant side effects, by comparison, the overall toxicity of vismodegib is of similar magnitude to that of the systemic retinoids, drugs that dermatologists are accustomed to prescribe and manage,” he explains.
Dr. Curiel observed that dermatologists are still most likely to refer patients who are candidates for vismodegib to a medical oncologist.
“However, the situation may vary from community to community depending on the available resources for referral, and from individual to individual according to the willingness of the dermatologist to take the lead in prescribing and managing patients on vismodegib” Dr. Curiel says.
Targeted therapies for malignant melanoma include two BRAF inhibitors [vemurafenib (Zelboraf, Roche), dabrafenib (Tafinlar, GlaxoSmithKline)], and a mitogen-activated protein kinase enzymes (MEK) inhibitor [trametinib (Mekinist, GlaxoSmithKline)]. Dr. Cranmner notes that the introduction of these agents for patients with unresectable advanced disease and recurrent melanoma harboring a BRAF mutation has been a real breakthrough for medical oncology. However, while these medications can lead to dramatic responses, none is able to provide a cure.
“The responses that are being achieved are of a degree that I would not have imagined possible just five years ago. These patients can literally be pulled back from the brink of death,” Dr. Cranmer says.
“However, these medications eventually lose their efficacy. Therefore, it is not ‘mission accomplished,’ and we need to continue our search to find new and better tools.”
Dr. Cranmer also highlighted the available immunotherapy options for melanoma, ipilimumab (Yervoy, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck).
“Approval of these checkpoint inhibitors for melanoma therapy is a major breakthrough. These drugs exploit the immune system to yield durable remissions of melanoma, in some cases lasting years. Their novel toxicities, including prominent autoimmune skin toxicities, mean that dermatologists will be close collaborators in managing patients being treated with these agents,” he said.
Currently, there are no targeted therapies for cutaneous SCC available or on the near horizon. Various epidermal growth factor receptor (EGFR) inhibitors are approved for the treatment of other types of SCCs, but there is only a limited dataset pertaining to their use for cutaneous tumors.
“EGFR inhibitors clearly have some activity for cutaneous SCC, but currently, there are only underpowered trials investigating their use for treating the dermatologic SCC. It seems that researchers are still looking for some link to disease pathogenesis in order to establish a better target that will allow us to do have greater efficacy in treating SCC,” Dr. Cramner says.
He adds that because metastatic SCC is so uncommon, there has been little motivation for industry to allocate research resources to that condition. However, the situation may change if a candidate drug with a reasonably favorable side effect profile is found.
“If a targeted agent with a reasonable side effect profile is identified, it could be evaluated in a population of patients with less advanced disease. Then the opportunity for reaching into a larger patient population could incentivize development of additional drugs for SCCs of the skin ,” Dr. Curiel says.
Treatment-limiting cutaneous adverse events associated with the new skin cancer systemic therapies occur predominantly with the BRAF inhibitors. Development of SCC, primarily of the keratoacanthoma type, is one of the most common side effects, occurring in about 60 percent of patients. Photosensitivity to ultraviolet A light and rash are also common, both reported to occur at rates ranging from 30 percent to 50 percent. Other cutaneous disorders that occur at a relatively high incidence include alopecia and keratosis pilaris. Less frequently, but importantly, patients treated with the BRAF inhibitors may also develop an increased number of nevi, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Grover’s disease.
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Dr. Curiel notes that drug eruptions are common with the use of immunological therapies (ipilimumab and pembrolizumab). According to the prescribing information, these events occur at a rate of up to 50 percent to 60 percent. However, they are more of a bother than a serious concern, she and Dr. Cranmer agree.
“When counseling patients being treated with these agents about cutaneous toxicities, I describe the drug reactions as being annoying in most cases, rather than dangerous. While severe reactions are possible, they are rare, and the benefits of these agents in melanoma therapy vastly outweigh their risks,” Dr. Cranmer says.
Disclosures: Dr. Cranmer’s institution receives research funding from Genentech/Roche, Glaxo SmithKline, Merck, and Bristol Meyers Squibb. He has also served as a compensated speaker for Genentech/Roche and Bristol Meyers Squibb.
Dr. Curiel is a consultant for Medical Directions LTD, and is a founder and stock holder for DermSpectra LLC.