Basal Cell Carcinoma of the Skin Treatment
Treatment for Basal Cell Carcinoma of the Skin
Treatment for Recurrent Basal Cell Carcinoma of the Skin
Treatment for Metastatic Basal Cell Carcinoma (or Advanced Disease Untreatable by Local Modalities)
Current Clinical Trials
There is a wide range of treatment approaches, including excision, radiation therapy, cryosurgery, electrodesiccation and curettage, photodynamic or laser-beam light exposure, and topical therapies. Mohs micrographic surgery is a form of tumor excision that involves progressive radial sectioning and real-time examination of the resection margins until adequate uninvolved margins have been achieved, avoiding wider margins than needed. Each of these methods is useful in specific clinical situations. Depending on case selection, these methods have recurrence-free rates ranging from 85% to 95%.
A systematic review of 27 randomized controlled trials comparing various treatments for BCC has been published. Eighteen of the studies were published in full, and nine were published in abstract form only. Only 19 of the 27 trials were analyzed by intention-to-treat criteria. Because the case fatality rate of BCC is so low, the primary endpoint of most trials is complete response and/or recurrence rate after treatment. Most of the identified studies had short follow-up times (only one study had a follow-up as long as 4 years) and were not of high quality. Short follow-up periods will lead to overestimates of tumor control. A literature review of recurrence rates in case series with long-term follow-up after treatment of BCCs indicated that only 50% of recurrences occurred within the first 2 years, 66% after 3 years, and 18% after 5 years. A rule of thumb was that the 10-year recurrence rates were about double the 2-year recurrence rates.Treatment for Basal Cell Carcinoma of the Skin
Treatment options include the following:
- Excision with margin evaluation.
- Mohs micrographic surgery.
- Radiation therapy.
- Curettage and electrodesiccation.
- Photodynamic therapy.
- Topical fluorouracil (5-FU).
- Imiquimod topical therapy.
- Carbon dioxide laser.
Excision with margin evaluation
This traditional surgical treatment usually relies on surgical margins ranging from 3 mm to 10 mm, depending on the diameter of the tumor. Re-excision may be required if the surgical margin is found to be inadequate on permanent sectioning. For example, in one trial, 35 of 199 (18%) primary BCCs were incompletely excised by the initial surgery and underwent a re-excision. In addition, many laboratories examine only a small fraction of the total tumor margin pathologically. Therefore, the declaration of tumor-free margins can be subject to sampling error.
Excision has been compared in randomized trials to radiation therapy, Mohs micrographic surgery, photodynamic therapy (PDT), and cryosurgery:
- In a single-center trial, 360 patients with facial BCCs less than 4 cm in diameter were randomly assigned to excision or to radiation therapy (55% interstitial brachytherapy, 33% contact radiation therapy, and 12% conventional external-beam radiation therapy [EBRT]). Excisional margins, assessed during surgery by frozen section during the procedure in 91% of cases, had to be at least 2 mm, with re-excision if necessary. Thirteen patients were not treated and were dropped from the analysis.
At 4 years (mean follow-up of 41 months), the actuarial failure rates (confirmed persistent or recurrent tumor) were 0.7% and 7.5% in the surgery and radiation therapy arms, respectively (P = .003). The cosmetic results were also rated as better after surgery by both patients and dermatologists, and also by three independent judges. At 4 years, 87% of surgery patients rated cosmesis as good versus 69% of radiation therapy patients.[Level of evidence: 1iiDii]
- In a two-center, intent-to-treat analysis, 374 patients with 408 primary facial BCCs were randomly assigned to receive either surgical excision or Mohs micrographic surgery with at least a 3-mm margin around the visible tumor until there were no positive margins in either case.
After 30 months of follow-up, the recurrence rate was 5 out of 171 tumors (3%) in the excision group and 3 out of 160 (2%) in the Mohs micrographic surgery group (absolute difference = 1%; 95% confidence interval [CI], -2.5%–+3.7%; P = .724). There was no difference in complication rates, and overall cosmetic outcomes were similar. Total operative costs were nearly twice as high in the Mohs group (405.79 Euros vs. 216.86 Euros (P < .001).[Level of evidence 1iiDii]
- In a multicenter, randomized trial, 101 adults with previously untreated nodular skin BCCs, excluding lesions of the midface, orbital areas, and ears, were treated with either excision (at least 5-mm margins) or PDT using topical methyl aminolevulinate cream (160 mg/g) followed by red-light exposure (wavelength 570–670 nm, 75 J/cm2) twice, 7 days apart. A per-protocol–per-lesion analysis was performed on the 97 patients who had an excision or at least one cycle of PDT.
At 3 months, the complete response (CR) rate in the surgery group was 51 out of 52 lesions (98%) versus 48 out of 53 lesions (91%) in the PDT group (P = .25). CR rates assessed at 12 months were 96% versus 83% (P = .15).[Level of evidence: 1iiDiv] The investigators interpreted the results as noninferiority of PDT, but the study may have been underpowered. Both the investigators and the patients, however, rated the cosmetic results as either excellent or good in a higher proportion of PDT treatments at each time point of follow-up. At 12 months, patient ratings of excellent or good were 98% versus 84% (P = .03) and investigator ratings were 79% versus 38% (P = .001).
- In a randomized, single-center trial, 96 primary BCCs (patient number unclear) less than 2 cm in diameter involving the head and neck area were randomly assigned to excision with a 3-mm safe margin versus cryosurgery (i.e., curettage plus two freeze-thaw cycles by liquid nitrogen spray gun).
At 1 year, there were no recurrences in the excision group versus three in the cryosurgery group (P = NS), but this is a very short follow-up time. Patients and five independent professionals who were blinded to the treatment arm rated the cosmetic outcomes. Their overall assessments favored excision.[Level of evidence 1iiDiv]
Mohs micrographic surgery
Mohs micrographic surgery is a specialized technique used with the intent to achieve the narrowest margins necessary to avoid tumor recurrence, while maximally preserving cosmesis. It is best suited to management of tumors in cosmetically sensitive areas or for tumors that have recurred after initial excision (e.g., eyelid periorbital area, nasolabial fold, nose-cheek angle, posterior cheek sulcus, pinna, ear canal, forehead, scalp, fingers, and genitalia).[9,10] It is also often used to treat tumors with poorly defined clinical borders.
Mohs micrographic surgery requires special training. The tumor is microscopically delineated, with serial radial resection, until it is completely removed as assessed with real-time frozen sections. Noncontrolled case series suggested that the disease control rates were superior to other treatment methods for BCC.[9,11,12] However, as noted in the section on excision, the disease control rate was not clearly better when directly compared to surgical excision of facial BCCs in a randomized trial of primary BCCs.
Radiation therapy is particularly useful in the management of patients with primary lesions that would otherwise require difficult or extensive surgery (e.g., nose or ears). Radiation therapy eliminates the need for skin grafting when surgery would result in an extensive defect. Cosmetic results are generally good, with a small amount of hypopigmentation or telangiectasia in the treatment port. Radiation therapy can also be used for lesions that recur after a primary surgical approach. Radiation therapy is avoided in patients with conditions that predispose them to radiation-induced cancers, such as xeroderma pigmentosum or basal cell nevus syndrome.
In a single-center, randomized trial, radiation was superior to cryotherapy in local control at 2 years in 93 patients with primary BCCs. Patients were randomly assigned to receive either EBRT (130 kV x-rays, dosimetry depending upon lesion size) or cryotherapy (two freeze-thaw cycles with liquid nitrogen by spray gun). Patients with lesions on the nose or ear were excluded, since the investigators felt that electron beam therapy is the treatment of choice in these locations. By 1 year, the recurrence rates in the radiation and cryotherapy arms were 4% and 39%, respectively, in a per-protocol analysis. The investigators did not perform a statistical analysis, but the authors of a systematic literature review calculated a relative risk of 0.11 in favor of radiation (95% CI, 0.03–0.43).[Level of evidence 1iiDiv]
Curettage and electrodesiccation
This procedure is also sometimes called electrosurgery. It is a widely employed method for removing primary BCCs, especially superficial lesions of the neck, trunk, and extremities that are considered to be at low risk for recurrence. A sharp curette is used to scrape away the tumor down to its base, followed by electrodesiccation of the lesion base. Although it is a quick method for destroying the tumor, the adequacy of treatment cannot be assessed immediately since the surgeon cannot visually detect the depth of microscopic tumor invasion.
A Cochrane Collaboration systematic review found no randomized trials comparing this treatment method with other approaches. In a large, single-center case series of 2,314 previously untreated BCCs managed at a major skin cancer unit, the 5-year recurrence rate of BCCs of the neck, trunk, and extremities was 3.3%. However, rates increased substantially for tumors larger than 6 mm in diameter at other anatomic sites.[Level of evidence 3iiiDii]
Cryosurgery may be considered for patients with small, clinically well-defined primary tumors. It is infrequently used for the management of BCC, but may be useful for patients with medical conditions that preclude other types of surgery.
Contraindications include abnormal cold tolerance, cryoglobulinemia, cryofibrinogenemia, Raynaud disease (in the case of lesions on hands and feet), and platelet deficiency disorders. Additional contraindications to cryosurgery include tumors of the scalp, ala nasi, nasolabial fold, tragus, postauricular sulcus, free eyelid margin, upper lip vermillion border, lower legs, and tumors near nerves. Caution should also be used before treating nodular ulcerative neoplasia more than 3 cm in diameter, carcinomas fixed to the underlying bone or cartilage, tumors situated on the lateral margins of the fingers and at the ulnar fossa of the elbow, or recurrent carcinomas following surgical excision.
Edema is common following treatment, especially around the periorbital region, temple, and forehead. Treated tumors usually exude necrotic material after which an eschar forms and persists for about 4 weeks. Permanent pigment loss at the treatment site is unavoidable, so the treatment is not well suited to dark-skinned patients. Atrophy and hypertrophic scarring have been reported as well as instances of motor and sensory neuropathy.
As noted in the section above on radiation therapy, a small 93-patient trial comparing cryosurgery to radiation therapy, with only 1 year of follow-up, showed a statistically significant higher recurrence rate with cryosurgery than radiation (39% vs. 4%).
In a small, single-center, randomized study, 88 patients were assigned to either cryosurgery in two freeze-thaw cycles or PDT using delta-aminolevulinic acid as the photosensitizing agent and 635 nm wavelength light with 60 J/cm2 energy delivered by Nd:YAG laser versus cryosurgery in two freeze-thaw cycles. Overall clinical efficacy was similar in evaluable lesions at 1 year (5/39 recurrences for cryosurgery vs. 2/44 recurrences for PDT), but more re-treatments were needed with PDT to achieve complete responses.[Level of evidence 1iiD] Cosmetic outcomes favored PDT (93% good or excellent after PDT vs. 54% after cryosurgery, P < .001). In another randomized study of 118 patients, reported in abstract form only, cryosurgery was compared with PDT with methyl aminolevulinic acid.[18,19] Tumor control rates at 3 years were similar (74%), but cosmetic outcomes were better in the PDT group. These cryosurgery-PDT comparisons were reported on a per-protocol basis rather than an intent-to-treat basis.[18,19][Level of evidence 1iiDiv]
Photodynamic therapy with photosensitizers is used in the management of a wide spectrum of superficial epithelial tumors. A topical photosensitizing agent such as 5-aminolevulinic acid or methyl aminolevulinate is applied to the tumor, followed by exposure to a specific wavelength of light (whether laser or broad band), depending upon the absorption characteristics of the photosensitizer. In the case of multiple BCCs, short-acting systemic (intravenous) photosensitizers such as verteporfin have been used investigationally. Upon light activation, the photosensitizer reacts with oxygen in the tissue to form singlet oxygen species, resulting in local cell destruction.
In case series, PDT has been associated with high initial CR rates. However, substantial regrowth rates of up to 50% have been reported with long-term follow-up. A randomized trial of PDT versus excision is summarized in the section on simple excision above. Two small trials, one reported in abstract form only, comparing PDT with cryosurgery are summarized in the cryosurgery section above, showing similar antitumor efficacy but better cosmesis with PDT.[17-19]
Topical fluorouracil (5-FU)
Topical 5-FU, as a 5% cream, may be useful in specific limited circumstances. It is a Food and Drug Administration (FDA)-approved treatment for superficial BCCs in patients for whom conventional methods are impractical, such as individuals with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established.[22,23][Level of evidence: 3iiiDiv] Given the superficial nature of its effects, nonvisible dermal involvement may persist, giving a false impression of treatment success. In addition, the brisk accompanying inflammatory reaction may cause substantial skin toxicity and discomfort in a large proportion of patients.
Imiquimod topical therapy
Imiquimod is an agonist for the toll-like receptor 7 and/or 8, inducing a helper T-cell cytokine cascade and interferon production. It purportedly acts as an immunomodulator. It is available as a 5% cream and is used in schedules ranging from twice weekly to twice daily over 5 to 15 weeks. Most of the experience is limited to case series of BCCs that are less than 2 cm2 in area and that are not in high-risk locations (i.e., within 1 cm of the hairline, eyes, nose, mouth, ear; or in the anogenital, hand, or foot regions). Follow-up times have also been generally short. Reported CR rates vary widely, from about 40% to 100%.[Level of evidence 3iiiDiv]
There have been a number of randomized trials of imiquimod.[24-29] However, the designs of all of them make interpretation of long-term efficacy impossible. Most were industry-sponsored dose-finding studies, with small numbers of patients on any given regimen; and patients were only followed for 6 to 12 weeks, with excision at that time to determine histologic response.[Level of evidence 1iDiv] Therefore, although imiquimod is an FDA-approved treatment for superficial BCCs, some investigators in the field do not recommend it for initial monotherapy for BCC; some reserve it for patients with small lesions in low-risk sites who cannot undergo treatment with more established therapies.
Carbon dioxide laser
This method is used very infrequently in the management of BCC because of the difficulty in controlling tumor margins. Few clinicians have extensive experience with the technique for BCC treatment. There are no randomized trials comparing it with other modalities.Treatment for Recurrent Basal Cell Carcinoma of the Skin
After treatment for BCC, patients should be followed clinically and examined regularly. Most recurrences occur within 5 years, but as noted above, about 18% of recurrences are diagnosed beyond that point. Patients who develop a primary BCC are also at increased risk of subsequent primary skin cancers because the susceptibility of their sun-damaged skin to additional cancers persists.[31-33] This effect is sometimes termed field carcinogenesis. Age at diagnosis of the first BCC (<65 years), red hair, and initial BCC on the upper extremities appear to be associated with higher risk of subsequent new BCCs.
Mohs micrographic surgery is commonly used for local recurrences of BCC. In a separate group within a randomized trial comparing excision to Mohs micrographic surgery for primary BCCs, 204 recurrent BCCs were randomly assigned to excision versus Mohs micrographic surgery. The recurrence rates were 8 out of 102 patients and 2 out of 102 patients, respectively, after a mean follow-up of 2.08 years (P = NS).[Level of evidence 1iiDii] There were more postoperative complications, including wound infections, graft necrosis, or bleeding in the excision group than the Mohs surgery group (19% vs. 8%, P = .021). As with primary tumors, the operative costs associated with Mohs surgery were higher than with excision (489.06 Euros vs. 323.49 Euros [P = .001]).Treatment for Metastatic Basal Cell Carcinoma (or Advanced Disease Untreatable by Local Modalities)
Metastatic and far-advanced BCC is rare, and reports of systemic therapy are limited to case reports and very small case series with tumor response as the endpoint.[Level of evidence 3iiiDiv] Cisplatin, alone or in combination with other drugs, is the most commonly reported systemic therapy and appears to be associated with the best tumor-response rates.[36,37] A variety of other agents have been reported but have low-associated response rates, including cyclophosphamide, vinblastine, 5-FU, methotrexate, and doxorubicin.
Since there is no standard therapy, clinical trials are appropriate if available. Because BCCs often exhibit constitutive activation of the Hedgehog/PTCH1-signaling pathway, Hedgehog pathway inhibitors are under investigation. An orally administered Hedgehog pathway inhibitor (GDC-0449) has produced objective responses in patients with advanced or metastatic sporadic BCC, and another topical inhibitor has produced objective responses in patients with nevoid basal cell carcinoma syndrome.[Level of evidence: 3iiiDiv]
Information about ongoing clinical trials is available from the NCI Web site.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with basal cell carcinoma of the skin. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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