Immune Response Modulators in the Treatment of Skin Cancer

Malignant melanoma

Surgical excision using a 5 mm margin is the standard treatment for lentigo maligna (LM) (melanoma in situ) but currently there is evidence supporting other therapeutic modalities that can be applied in those cases where surgery is not possible.

IFN-α2b was the first immunotherapeutic agent approved for adjuvant treatment of stage IIB/III melanoma. It remains a mainstay of treatment and is the only adjuvant therapy for patients with melanomas thicker than 4 mm or with lymph node metastasis. In a retrospective study, the combination of IFN- α2b and surgery led to a 48% 2-year and 36% 5-year relapse-free survival (RFS) rate in 150 patients with high-risk melanoma (stage IIC, III). A randomized prospective trial did not find a significant difference between IFN-α2b-treated stage I–II melanomas and untreated controls. In patients with disease limited to the skin and lymph nodes, the combination of isotretinoin and IFN-α has been reported to be only partially effective. In addition, the combination of IFN-α and chemotherapeutic regimens have failed to demonstrate efficacy over chemotherapy alone. As monotherapy for metastatic melanoma, IFN has not been shown to be efficacious, which has precluded its approval for the treatment of stage IV melanoma.

Low-dose, adjuvant IFN-α used in stage II melanoma before sentinel node staging has been shown to prolong RFS before clinically detectable node metastases develop. High-dose IFN has been shown to have an impact on RFS but a minor effect on overall survival (OS). In stage III melanoma, long-term adjuvant therapy (5 years) with pegylated IFN-α2b had a significant and sustained effect on RFS. The efficacy was evident in sentinel-node-positive stage III patients compared with macroscopically involved stage III patients.

A high-dose IFN-α regimen incorporated an induction phase of maximally tolerated doses of IV therapy for the first 4 weeks. This is the only trial that showed prolongation of OS and RFS when compared to observation. Therefore, the induction phase may represent a critical component of this regimen, although this has not yet been tested prospectively.

In a prospective, randomized study, 364 patients with melanoma stage IIB–III received either IFN-α2b five times per week for 4 weeks or the same regimen followed by subcutaneous (SC) IFN-α2b for 48 weeks. At a median follow-up of 63 months, the median RFS was 24.1 months and 27.9 months, respectively (p = 0.9) with median OS of 64.4 months and 65.3 months, respectively (p = 0.49). Patients treated with the second regimen had more hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. An ongoing randomized trial comparing adjuvant IFN at a high dose for 1 month versus observation will provide more insight on the efficacy of this regimen in the adjuvant setting.

The identification of patients who are IFN-α sensitive is important in order to improve outcomes. Gogas et al. observed a correlation between the presence of auto-immune antibodies and improved outcomes after high-dose IFN-α treatment. Other randomized trials determined that the presence of autoantibodies was not an independent predictive or prognostic factor, but found IFN sensitivity to be higher in patients with ulcerated primary lesions.

A study assessing health-related quality of life (HRQOL) examined the effects of adjuvant pegylated IFN-α2b (PEG-IFN-α2b) on patients with stage III melanoma. At a median of 3.8 years of follow-up, RFS was reduced by 18% more in the PEG-IFN-α2b group compared with observation. Clinically, differences in social and role functioning scales and in appetite loss, fatigue, and dyspnea symptom scales were seen. The use of IFN-α2b leads to significant and sustained improvement in RFS but has negative effects on global HRQOL and selected symptoms. PEG-IFN allows patients to undergo prolonged weekly injections with the potential to improve the toxicity of IFN.

Eleven biopsy-proven cases of lentigo maligna (LM) were treated three times per week with perilesional and intralesional IFN-α2b. All lesions cleared after treatment, without scarring. Controlled trials are needed to further characterize the use of IFN-α2b for LM when surgery is not an option.

Basal cell carcinoma

Although surgical modalities such as full-thickness excision and cryosurgery have high cure rates (95% and 94–99%, respectively), and acceptable associated morbidity, IFN represents an effective (70–100% cure rate) non-surgical approach to the treatment of basal cell carcinoma (BCC). Buechner reported complete remission (CR) in four patients with nodular BCC (nBCC) treated with IFN-α at a low dose (1.5 million IU) three times weekly for 4 weeks. A multicenter, randomized controlled trial (RCT) evaluating 172 patients with biopsy-proven BCCs reported that the optimal intralesional dose of IFN-α2b was 1.5 million IU, administered three times weekly for 3 weeks ( Fig. 44.2 ). This IFN regimen resulted in an 86% clinical and histological CR rate compared with a 29% rate in the placebo group (P<0.0001). Similar doses when used for aggressive (recurrent or morpheaform) BCC resulted in CR in only 27% of patients.

In a recent study, 20 histologically proven BCC lesions were treated with intralesional IFN-α2a three times weekly for 3 weeks (1.5 × 10 ⁶ IU for lesions <2 cm in diameter and 3.0 × 10 ⁶ IU for lesions ≥2 cm). Eight weeks after the last injection, it was found that 55% of the lesions had clinical and histological CR, 30% had partial remission (PR), and 10% showed no response. Patients with a CR were followed up for 7 years, during which there was only one recurrence, at the fifth year. Another study, by Tucker et al., using IFN-α2b to treat BCC, confirmed the long-term effectiveness of this treatment. Clinical cures were noted in 95/98 BCCs (51 nodular and 44 superficial), with a mean follow-up period of 10.5 years. The results showed 98% response rates at years 5 and 10, and a 96% response rate at year 15. Although these studies show that intralesional and perilesional injections of IFN-α2b are effective in clearing BCCs with low long-term recurrence rates, it is not used as a standard treatment, due to its cost, safety profile, and the inconvenience of multiple injections.

Squamous cell carcinoma

Squamous cell carcinoma (SCC) of the skin constitutes 10–25% of NMSCs. The standard treatment is surgical excision or Mohs surgery; however, multiple studies have demonstrated the efficacy of intralesional IFN in the treatment of SCCs. Intralesional IFN-α2b, at a dose of 1.5 million IU, three times weekly for 3 weeks, was used in the treatment of 34 biopsy-proven SCCs, localized to sun-exposed areas. At the end of the study, 33/34 lesions revealed a histological CR. Another study evaluated the efficacy and cosmetic results of intralesional recombinant IFN-α2b in 27 invasive and 7 in-situ SCCs (sizes ranging from 0.5 to 2.0 cm) at a dose of 1.5 million IU, three times weekly for 3 weeks. Over 97% of the SCCs showed clinical and histological CR at 18 weeks, with a 96.2% CR rate in the 27 invasive lesions. The investigators and patients independently judged 93.9% of the cases to have a ‘very good’ or ‘excellent’ cosmetic result. In transplant-associated metastatic SCC, combination therapy with retinoids and IFN-α was used, with a 7% CR rate and a 36% PR rate. IFN-α2b represents an important alternative treatment option for low-risk cases of SCC where surgery is not an option.

Keratoacanthoma

Keratoacanthomas are fast-growing, solitary, cutaneous neoplasms of unknown etiology that usually regress spontaneously. It is unclear whether or not they represent low-grade SCCs. Grob reported total resolution within 4–7 weeks with excellent cosmesis in five of six large kerato- acanthomas (>2 cm in diameter) after receiving 9–20 injections with intralesional IFN-α2b. Two other studies evaluated weekly doses of intralesional and perilesional IFN-α2b in a total of 11 large, rapidly growing keratoacanthomas. In a period of 7–15 weeks all lesions resolved completely, with satisfactory cosmetic results. IFN-α is an option to treat large keratoacanthomas that cannot be surgically removed. Avoidance of scarring following surgery is one benefit of interferon, but the number of injections and patient visits may discourage its use as an alternative treatment.

Actinic keratoses

A study evaluating intralesional IFN-α2b, 0.5 million IU three times weekly for 2–3 weeks, in the treatment of actinic keratoses (AKs) found a 93% CR following IFN-α2b injection, while no clearance was seen in the placebo group. Edwards et al. examined the effects of topical IFN-α2b gel on AKs. Twenty-four subjects each treated three AKs with either topical IFN gel, 30 million IU/g, or placebo four times a day for 4 weeks. Although the results were not statistically significant, more lesions showed clinical improvement when treated with IFN. The clinical usefulness of this treatment modality for AKs is quite limited because of the need for injections and multiple physician visits, which are not required by other treatments currently available.

Cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL), including mycosis fungoides (MF) and Sézary syndrome, is a malignant proliferation of T cells with initial presentation in the skin. Most of the data on the use of IFN-α in CTCL has come from studies using recombinant IFN-α2a.

Bunn et al. described an overall response rate of 55% and a CR rate of 17% among 207 patients with MF and Sézary syndrome treated with IFN-α2a. As a monotherapy, recombinant IFN-α2a is less toxic when used at low doses, and shows greater activity in patients with early-stage disease. Based on their review, the authors concluded that 3 million units administered SC three times per week is the optimal treatment for CTCL, with no apparent therapeutic differences between IFN-α2a and 2b.

The effectiveness of IFN-α has been found to be stage-dependent, with higher CR rates seen in stage I patients (50–62%) than in stage IV patients (8–16%). Intralesional injection of MF lesions with IFN-α2b, at a dose of 1 million IU three times per week for 4 weeks, produced clinical and histological improvement, with 10/12 plaques obtaining CR.

The effect of combining psoralen ultraviolet A (PUVA) with subcutaneous injections of IFN-α2a was evaluated in 63 CTCL patients (stage IA [n=6], IB [n=37], IIA [n=3], IIB [n=3], III [n=12], and IVA [n=2]). IFN-α2a was administered at a dose of 9–12 million IU three times per week, given simultaneously with PUVA up to the minimal erythema dose. The initial treatments were administered three times a week until complete skin clearance, then once a week for 4 weeks, followed by treatments once every 2–4 weeks for an indefinite period of time. Seventy-five percent (47/63) obtained a CR, 6/63 obtained a PR, 2/63 were non-responders and 5/63 had progressive disease. The median time to remission was 7 months; the median duration of response was 32 months, with a range of 6–57 months. CRs were obtained in all stages of disease. The combination of PUVA and IFN-α was assessed in a study involving 113 patients with all stages of MF or Sézary syndrome. A CR rate of 57% in early disease stages and 33.3% in later stages was found. The combination of IFN-α and PUVA is superior to either agent alone. The combination of IFN-α and retinoic acid receptor (RAR) retinoids used in all stages of CTCL has shown an overall response rate of 60% with a CR of 11%, similar to the rates achieved with either modality when used alone.

Kaposi sarcoma

The use of IFN-α2a and IFN-α2b in the treatment of Kaposi sarcoma (KS) in patients with acquired immune deficiency syndrome (KS/AIDS) is approved by the U.S. Food and Drug Administration (FDA), but infrequently used. IFN has antiviral and antiangiogenic effects, both of which are important for the survival of KS tumors.

The overall response rates with IFN-α2a and IFN-α2b were equivalent or superior to those achieved with conventional cytotoxic chemotherapy. The recommended subcutaneous doses of IFN-α2a and IFN-α2b are 36 and 30 million IU, respectively, three times per week. The average response rate of KS to high-dose IFN-α therapy has been approximately 30%. In many cases, tumor recurrence occurs within 6 months in complete responders and the response to a second treatment is not reliable. These facts led to the current recommendation of maintenance therapy as long as adverse events (AEs) are tolerated.

Due to the decrease in the incidence of KS since the introduction of highly active antiretroviral therapy (HAART), it has been difficult to recruit patients for the evaluation of therapies including IFN. In addition, multiple AEs associated with IFN and the need for multiple injections has precluded its widespread use. Further research in order to better understand the mechanisms of action of IFN on KS and to determine optimal dosage is necessary.