Basal Cell Carcinoma Treatment & Management

According to the 2011 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Basal Cell and Squamous Cell Skin Cancers, the goal of treatment is elimination of the tumor with maximal preservation of function and physical appearance. As such, treatment decisions should be individualized according to the patient's particular risk factors and preferences.^[58] In nearly all cases, the recommended treatment modality for basal cell carcinoma (BCC) is surgery.^{[12, 13]} Treatments vary according to cancer size, depth, and location. Dermatologists may perform nearly all of the therapeutic options in an outpatient setting. Most therapies are well established and widely applied; nevertheless, researchers are studying some additional options (eg, photodynamic therapy with photosensitizers)^{[59, 60, 61]} ) and awaiting further reports.

Local therapy with chemotherapeutic and immune-modulating agents is useful in some cases of BCC. In particular, small and superficial BCC may respond to these compounds. Topical 5% imiquimod is approved by the US Food and Drug Administration (FDA) for the treatment of nonfacial superficial BCCs that are less than 2 cm in diameter. Lesions are generally treated once daily, 5 days per week, for a duration of 6-12 weeks. Likewise, topical fluorouracil is approved by the FDA for the treatment of superficial BCC, administered twice daily for 3-6 weeks.^[62] Although no formal restrictions on fluorouracil have been determined based on lesion size or location, it is most commonly used on smaller superficial BCC on the trunk and extremities. Both imiquimod and fluorouracil may be used topically for prophylaxis or maintenance in patients who are prone to having many BCCs

For tumors that are more difficult to treat (ie, infiltrative BCC, morpheaform [sclerosing] BCC, micronodular BCC, and recurrent BCC) or those in which sparing normal (noncancerous) tissue is paramount, Mohs micrographic surgery should be considered and discussed with the patient.

For metastatic BCC, the 2011 NCCN guideline recommends clinical trials of systemic chemotherapy, particularly platinum-based combination therapy, which has been observed to produce useful, even complete, responses in a few patients. Clinical trials of investigational biologic modifiers such as hedgehog pathway inhibitors are also recommended.^[58]

The goal of therapy for patients with BCC is removal of the tumor with the best possible cosmetic result. By far, surgical modalities are the most studied, most effective, and most used BCC treatments. The effectiveness of surgical modalities depends heavily on the surgeon's skills; considerable differences in cure rates have been observed among surgeons. Modalities used include electrodesiccation and curettage, excisional surgery, Mohs micrographically controlled surgery, and cryosurgery.^{[63, 64, 65]}

The 2011 NCCN guidelines recommend that low-risk patients younger than 60 years of age be treated with curettage and electrodessication in non–hair-bearing areas. If fat is reached, surgical excision should generally be performed. An alternative is excision with postoperative margin assessment. High-risk patients should undergo excision with postoperative margin assessment or a Mohs resection.^[58]

Some studies suggest that dermato-oncological surgery is associated with a high risk of infection.^[33] This risk is greater in patients with diabetes and in those having such surgery in the thigh or lower leg and foot.

See the Medscape Reference topic Surgical Treatment of Basal Cell Carcinoma for more complete information on this topic.

Several topical creams are used in the management of BCC that is nonrecurring and superficial. The NCCN 2011 guidelines state that low-risk patients with superficial BCC who cannot undergo surgery or radiation can be treated with topical therapies, although the cure rate may not be as high. Such treatments may also be used in patients with a high risk of multiple primary tumors.^[58]

Topical 5-fluorouracil 5%

Topical 5-fluorouracil 5% cream^[20] may be used to treat small, superficial BCCs in low-risk areas. It interferes with DNA synthesis by blocking methylation of deoxyuridylic acid and inhibiting thymidylate synthetase and, subsequently, cell proliferation.

In properly selected (eg, thin) tumors, cure rates of approximately 80% have been obtained. The cream is generally applied twice daily and must be used for at least 6 weeks for the treatment of superficial BCC.^[66]

Given that 5-fluorouracil can act on BCCs that are too small to be seen with the unaided eye, it may be used in patients with basal cell nevus syndrome or to preemptively treat subclinical tumors. Nevertheless, because not all tumors respond completely, careful patient monitoring is essential.

The use of 5-fluorouracil for other types of BCC is generally not recommended because it may not penetrate deeply enough into the dermis to eradicate all tumor cells. Irritation and crusting are common and expected; significant irritation and discomfort are not uncommon, but scars are unusual. The recurrence rate is very high.

Interferon

Interferon alfa-2b is a protein product manufactured using recombinant DNA technology. It has shown some success in treating small (< 1 cm), nodular, and superficial BCCs. In appropriate BCC tumors, cures rates of up to 80% have been obtained.

Several early studies have shown variable responses of BCC to intralesional interferon alfa. In a small study by Greenway et al, 1.5 million IU interferon alfa-2b injected intralesionally 3 times per week for 3 weeks resulted in the clearing of 3 cases of primary nonrecurrent BCC and 5 cases of primary superficial BCC.^[67]

Because larger studies are needed, most practitioners consider this an experimental therapeutic modality. Further data are needed before this treatment modality is recommended for routine ophthalmic practice.

Interferon has not become a mainstay in BCC treatment because of its cost, the inconvenience of multiple visits, the discomfort of administration, and its adverse effects, which include flulike symptoms. Acetaminophen has been administered to alleviate the flulike symptoms associated with this therapy.

Imiquimod

Imiquimod 5% cream (Aldara) is approved by the US Food and Drug Administration for the treatment of nonfacial superficial BCC.^{[68, 69]} Several studies have shown imiquimod to be curative in all patients with superficial BCC if used twice daily and in 73-82% of patients when used once a day for 6-12 weeks. Smaller studies have shown similar responses for nodular BCC. Studies for other histologic types of BCC are under way.^{[14, 15, 18, 17, 16, 19]}

Treatment is usually initiated at 3 times per week and is increased as tolerated to once daily, and even twice daily if tolerated, to maintain mild-to-moderate skin irritation.^{[70, 71]} Patients can titrate the frequency of application to maintain low-to-moderate skin irritation. A 12-week course of treatment is often used, which does not need be contiguous.^[63]

Tazarotene

The receptor-selective acetylenic retinoid tazarotene (Tazorac) can also be used to treat small low-risk BCCs. Tazarotene is thought to cause BCC regression by increasing apoptosis and by decreasing cell proliferation in the skin cancer cells. In one case series, about 70.8% of the BCCs had clinical and dermoscopic regression of more than 50%, and 30.5% healed without recurrence after 3 years; most unresponsive tumors showed keratotic differentiation. The study involved the application of tazarotene 0.1% gel for 24 weeks in 154 small, superficial, and nodular BCCs (109 patients). Changes were followed up by dermoscopy and histologic examination.^[72]

In a published article by Wilson, topically applied tazarotene gel was shown to decrease tumor size in 47% of cases, and in 53% of cases, the tumor was eliminated completely.^[73]

In addition to being an off-label indication, another drawback to topical tazarotene for the treatment of BCC is that it requires long-term therapy, for 5-8 months. The only reported adverse effect is dry/irritating skin that is relieved after discontinuation of tazarotene.

GDC-0449

An investigational agent, GDC-0449, which is administered orally, shows promise for more advanced BCC.

At the 2008 meeting of the American Association for Cancer Research, a preliminary report was presented on promising results in locally advanced, multifocal, and metastatic BCC with GDC-0449. This compound is a synthetic chemical designed to reproduce the properties of the naturally occurring compound cycloamine. GDC-0449 blocks the hedgehog pathway in cells. This pathway contains 2 genes, patched and smoothened, which lead to a known tumor promoting gene, Gli1. A change in any of these genes has been associated with the development of BCC.

The 2011 NCCN guideline recommends patients with metastatic BCC be enrolled in clinical trials of hedgehog pathway inhibitors.^[58] GDC-0449 is an example of this class of agent.

GDC-0449 is given orally once a day. Its side effects include some loss of sense of taste and some loss of hair and weight. In the first clinical trial of GDC-0449, approximately 90% of the patients responded to treatment with tumor shrinkage or stabilization. Decreased amounts of GLI1 were found in the skin of patients after treatment.^{[74, 75]}

Basal cell carcinomas are usually radiosensitive, and radiation therapy (RT) can be used for advanced and extended lesions and in those patients for whom surgery is not suitable (eg, because of allergy to anesthetics, current anticoagulant therapy, a tendency to form keloids,^[76] or facial tumors). Postoperative radiation can also be a useful adjunct when patients have aggressive tumors that were treated surgically or when surgery has failed to clear the margins of the tumor.^[77]

In the past, RT was a common treatment modality because of its high cure rate (97% for primary tumors). It is now used sparingly, because it is time consuming and extremely expensive. With the advancement in surgical techniques and other treatment modalities, RT is a reasonable treatment choice for recurrent tumors. It may be reserved for primary lesions requiring difficult or extensive oculoplastic surgery. It also eliminates the need for skin grafting when surgery would result in an extensive defect.

RT is contraindicated in young patients because of the high risk of radiodermatitis and scars; in lesions on the trunk and extremities; and in delayed cancer recurrence (eg, especially in patients previously treated with radiation). RT requires multiple visits. Treatment results in radiation damage and, therefore, should be reserved for older patients. RT is less effective for nonfacial tumors.

RT also is contraindicated in patients with connective tissue diseases or genetic conditions predisposing to skin cancer (eg, xeroderma pigmentosum, epidermodysplasia verruciformis, and basal cell nevus syndrome.) This histologic type in conjunction with RT may induce more tumors in the treated area. Radiation adverse effects include dermatitis, keratinization of the conjunctiva, and chronic keratitis.

Cosmetic results are generally good to excellent, with a small amount of hypopigmentation or telangiectasia in the treatment port. This therapy can be less disfiguring than surgical excision. Nevertheless, long-term results after several years can be deforming. Another disadvantage of this technique is that surgical margins cannot be examined. Tumors recurring in previously radiated sites tend to be aggressive and difficult to treat and reconstruct. RT remains an important, feasible option in selected patients with BCC.

The 2011 NCCN guideline supports radiation therapy for patients whose condition is appropriate, with the reservation that in order to achieve its benefits (high cure rates and good comesis), it must be administered carefully and with attention to algorithm details by well-trained specialists. Training and proper support are particularly essential to the use of intensity modulated radiation therapy as primary treatment. Medical physicists must provide the necessary support and training in this new technology.^[58]

Photodynamic therapy (PDT) for basal cell carcinomas (BCCs) has been used for more than 20 years.^{[78, 79]} PDT is the process of using specific wavelengths of light to photoexcite porphyrins that have been applied to neoplastic and preneoplastic cells. This increased energy is rapidly absorbed by adjacent tissue oxygen, causing the formation of singlet oxygen radicals. These radicals rapidly react with adjacent tissue and destroy it. 5-Aminolevulinic acid (ALA-PDT) is the only US Food and Drug Administration approved photoreactive molecule for PDT in the United States, and it is only approved for actinic keratoses. It is photoactivated with blue light for 1000 seconds after 1 hour of incubation.

PDT is administered orally or parenterally, as well as applied topically, and localizes into tumor cells before activation by exposure to light (eg, laser). The efficacy is low, and this treatment is frequently palliative. PDT may cause local edema, erythema, blistering, and ulceration, but the final cosmetic effect is good.

PDT yielded only a 50% cure rate for superficial BCC, versus an 83% cure rate for nodular BCC, in a study by Calzavara-Pinton et al.^[80] At present, PDT has no distinct advantage over other well-established therapies for BCC of the eyelid. In a study by Puccioni et al, PDT using methyl aminolevulinate showed notable success and appears to be a viable option in the treatment of BCC of the eyelid in selected patients.^[81]

PDT as an adjunct is a reasonable choice in the following cases:

• Tumor recurrence with tissue atrophy and scar formation
• Elderly patients or patients with medical conditions preventing extensive oculoplastic reconstructive surgery
• Tumor with poorly defined borders based on clinical examination
• Tumor requiring difficult or extensive oculoplastic surgery

Although its use is off label, PDT has been used for treatment and prevention of BCCs, including those patients with immunosuppression and nevoid BCC syndrome. Shallow tumors, such as superficial BCCs, respond most consistently. Surgical excision has been shown to be significantly more effective than ALA-PDT in the treatment of nodular BCC.^[82]

The strongest support for PDT as a modality for BCCs comes with data on thin lesions treated with methylaminolevulinate (used outside the United States), but at least one long-term follow-up trial has also shown surgical excision to be superior.^[83]

Various protocols have been followed to achieve varying levels of success—increasing incubation time, increasing occlusion time, and using longer and/or deeper-penetrating wavelengths of light (eg, red light or pulse-dye laser). Many patients continue to prefer PDT because of its short healing time, excellent cosmesis, and relative affordability.

Also see the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee’s clinical guidelines summary, Guidelines for topical photodynamic therapy: update.^[79]

Although several clinical trials have shown some efficacy for available systemic retinoids in chemotherapy and chemoprevention, the long-term toxicity of these agents generally excludes them as treatment choices for most patients.^[84] Studies are exploring their value as cancer preventive agents in patients at high risk for developing multiple tumors.

Vismodegib

Vismodegib (Erivedge) is the first FDA-approved drug for advanced forms of basal cell carcinoma. It selectively inhibits Smoothened (SMO), a key transmembrane protein involved in hedgehog signal transduction of cancerous epithelial cells. In a phase I dose-ranging study by Von Hoff et al, 18 of 33 patients showed an objective response. Two of the 18 had complete response, and the remaining 16 showed a partial response.^[85] FDA-approval was based on a single, international, open-label trial (n=104). Of the 104 participants, 96 were evaluable. Of those with metastatic BCC (n=33), 30.3% had partial response, but none had complete response. With locally advanced BCC (n=63), 22% showed a partial response and 20% showed complete response.^[86]

The following is a list of treatments and their 5-year recurrence rates for primary BCCs:

• Surgical excision - 10.1%
• Radiation therapy - 8.7%
• Curettage and electrodesiccation - 7.7%
• Cryotherapy - 7.5%
• All non-Mohs modalities - 8.7%
• Mohs micrographic surgery - 1.0%

These rates are probably affected by the fact that most clinicians use cryotherapy, curettage, and desiccation mostly on smaller and better-demarcated lesions.

Avoid possible potentiating factors (eg, sun exposure, ionizing radiation, arsenic ingestion, tanning beds). The regular use of sun-protecting clothing (eg, wide-brimmed hat, long-sleeved shirts, sunglasses with ultraviolet [UV] protection) is recommended when outdoors. Instruct patients to avoid sun exposure particularly during the middle of the day (ie, 11:00 am to 3:00 pm), which is the most dangerous time. Also, the sun's rays are especially intense in sunny climates and at high altitudes, and UV radiation can also pass through clouds and water. Patients should be instructed to be careful on the beach and in the snow because sand, water, and snow reflect sunlight and increase the amount of received UV radiation.

Researchers are investigating chemoprevention with systemic administration of retinoids as cancer preventive agents in patients at high risk for developing basal cell carcinoma; the efficacy of these agents will take several years to evaluate, however.

The American Cancer Society recommends a dermatologic examination every 3 years for people aged 20-40 years and every year for people older than 40 years.

Ideally, treatment options for the patient with basal cell carcinoma should be evaluated jointly with a surgeon, dermatologist, and radiotherapist and based on histologic diagnosis.

Although early basal cell carcinoma can be treated adequately by means of local excision, advanced and recurrent tumors are best managed by a multidisciplinary approach involving head and neck surgical oncologists, Mohs micrographic surgeons, reconstructive plastic surgeons, pathologists, prosthetists, and radiation oncologists.

Mc Loone et al found that patients who are diagnosed with BCC have a 35% chance of developing another tumor within 3 years and a 50% chance of developing another (not recurrent) BCC within 5 years.^[40] The NCCN 2011 guidelines state that 30-50% of patients will develop another nonmelanoma skin cancer within 5 years. These patients are also at an increased risk of developing cutaneous melanoma.^[58] Therefore, regular skin screenings are recommended.^{[40, 58]}

Less than 1% of BCCs spread to another site in the body; nevertheless, after treatment, which is curative in more than 95% of cases, BCC may develop in new sites. Recommend appropriate prolonged or lifelong follow-up care.

Tumors occurring after radiotherapy tend to be more aggressive and infiltrative than other tumors. Metastasis is rare but has been reported with rates of 0.01-0.1%. Metastases most often originate from large, ulcerated tumors. Metastases usually occur in regional lymph nodes. Follow-up visits are scheduled 3 months after therapy and every 6 months to 1 year thereafter for the life of the patient.