Compliance critical with at-home tx

The at-home regimens and close follow-up requirements of nonsurgical treatments for skin cancer demand that dermatologists reserve these treatments for appropriate patients, said an expert at the 72nd American Academy of Dermatology Annual Meeting (San Francisco, 2015).

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With surgical treatment for skin cancers, Anthony M. Rossi, M.D., said "Once you have negative margins, you know the tumor is out." He is an assistant attending physician in dermatologic, Mohs and laser surgery at Memorial Sloan-Kettering Cancer Center.

With nonsurgical treatments, "The key is picking the right patients beforehand. They must be compliant." Treatments that don't allow one to check margins microscopically require close long-term follow-up for catching recurrences, he explained, and some nonsurgical skin cancer treatments require at-home application as often as daily.

Among nonmelanoma skin cancers, he said, "Not every basal cell carcinoma (BCC) is created equal." He usually tries nonsurgical treatments on superficial and early nodular BCCs.

NEXT: Practical prescribing tips: Imiquimod

Practical prescribing tips: Imiquimod

Imiquimod is Food and Drug Administration-approved for superficial BCC; using it for early nodular BCCs is off-label. Dr. Rossi also prescribes it off-label for squamous cell carcinomas (SCCs).

In counseling patients, he outlines cure rates of all BCC treatments. These range from 97% to 98% for Mohs surgery (primary tumors at 5 years), to 61% for cryosurgery (at 2 years).

Studies involving imiquimod for early nodular BCC show 5-year cure rates between 82% and 73%.¹ However, he quotes patients a 5-year cure rate of roughly 70% for imiquimod overall. "That's basically for all comers, in a mixture of studies. In some studies it's higher. But I try not to overshoot because I don't want to give people false expectations."

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With imiquimod, Dr. Rossi favors a step-wise approach, starting every other day, then five days weekly, and finally daily, as tolerated. "I basically titrate it up" until patients experience a stable reaction, which includes a level of erythema and crusting they can accept. "If that happens at 5 days a week, then I keep them there. But if they're not getting a reaction, I step it up to 7 days a week." Even at that level, he said, some patients don't respond, so he switches them to other treatments or adds a topical retinoid. "However, even if they do get a reaction, that doesn't always mean it's working. They still have to follow-up" to make sure.

With imiquimod, "I always stress that it has to do with patient compliance and how people react. Some patients will use imiquimod diligently even if they get a lot of crusting and redness. Others will stop and not tolerate the effects."

Patients typically apply a 25 cm² dose. "I usually prescribe it for 8 to 12 weeks, based on the studies." For small treatment areas, "I usually wait until the skin heals, then rebiopsy, if I see anything clinically," to make sure the tumor is cleared.

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Dr. Rossi also uses imiquimod for adjuvant therapy of BCCs and SCCs incompletely cleared with Mohs surgery in cases where achieving complete clearance of superficial disease may not be possible, or there is a large actinic field effect. "Say I can clear the invasive part, but there's still a lot of superficial BCC all around it. I'll use imiquimod afterwards to try to clear up the superficial part if Mohs surgery may lead to a more excessive morbidity."

Very small studies of adjuvant therapy with imiquimod have yielded mixed results, he said. "The cases where I find imiquimod does not work are usually those with a more aggressive histological subtype such as infiltrative BCC."

For SCC in situ, Dr. Rossi uses 5-fluorouracil (off-label), titrating up to daily use, if tolerated, as with imiquimod. Patients typically require 2 4-week cycles, he said.

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Photodynamic therapy pearls

Before using PDT for BCC or SCC, Dr. Rossi typically prepares the skin with acetone or a fractional CO₂ laser at a superficial setting to attempt to remove the stratum corneum. "I'm trying to create better absorption of the aminolevulinic acid. I still do a traditional 3-hour incubation, with occlusion, because you want to get as much absorption as possible by the skin cancer."

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Giving the patient antihistamines (preferably nonsedating) pre-procedurally can help minimize post-treatment swelling, he added. "Then I use blue light for more superficial BCCs or SCCs."

For deeper nodular BCCs or slightly thicker SCCs, Dr. Rossi uses red light. Additional light sources that have been used for PDT in skin cancer include pulsed dye lasers and intense pulsed light.

In solid organ transplant recipients (SOTRs), studies have shown that cyclical PDT performed every couple months reduces precancers and skin cancers.² "Now I offer it as a treatment to clear actinic damage for my SOTR patients who are on immunosuppression."

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For keratoacanthomas (quickly erupting SCCs), "I use injectable methotrexate (typically 1cc total, injected in 4 quadrants at the lesion's base) to either shrink the keratoacanthoma to possibly make the Mohs surgery smaller, or to treat it definitively without doing Mohs afterwards. We know that some keratoacanthomas will respond completely to methotrexate, while others may not, so close follow-up is needed to assess for residual disease or a more aggressive SCC." Patients typically require 2 to 3 sessions total, spaced 2 to 3 weeks apart, he said.

NEXT: Radiation patient selection, oral tx considerations

Radiation patient selection

Radiation offers a higher cure rate for BCC than SCC.^3,4 Dr. Rossi typically reserves this treatment for patients with BCC or SCC who reject surgery or are not candidates for topical treatment or PDT. Patients for whom he typically does not use radiation include the following:

• Those under age 55 (radiation can increase the risk of future skin cancers, he explained).

• Patients with basal cell nevus syndrome or other conditions that predispose them to radiation-induced skin cancers.

• Those with BCCs on poorly healing areas, such as the legs or dorsal hand.

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Additionally, "If the tumor is very deep, radiation can cause a breakdown of the cartilage or bone. And with verrucous carcinoma (an SCCs subtype), we don't want to irradiate because there's a documented increase in metastases after radiation."⁵

Oral therapy considerations

Typically, Dr. Rossi reserves the oral Smoothened inhibitor vismodegib for advanced and metastatic BCCs, which are rare. Similarly, "For some advanced patients in whom radiation would be contraindicated, or if the tumor is so large that it would cause significant cosmetic deformity and postsurgical morbidity, vismodegib is now an option." However, he said, more research is needed to determine appropriate vismodegib uses beyond its labeled indication.

In one study, 30% of patients with metastatic BCC and 43% of patients with locally advanced BCC experienced at least 30% reductions in tumor size. Median duration of response was 7.6 months.⁶

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Currently, Dr. Rossi said, researchers are experimenting with drug "holidays" to reduce side effects – mainly hair loss, muscle cramps and taste changes. "Some people can live with those side effects; other people cannot." Some patients experience tumor regrowth after stopping the medication, he added, so follow-up is crucial here as well.

For basal cell tumors with squamous cell features (basal-squamous differentiation), Dr. Rossi said, "Vismodegib might not be so helpful. Although it may treat the basal-cell part, the squamous-cell part may still be growing." In cases where it's unclear whether a tumor is purely BCC or otherwise, he recommended extra biopsies to sample the tumor thoroughly.

NEXT: Melanoma tx recommendations

Melanoma tx recommendations

"For melanoma, pretreatment mapping and sampling are the keys. So I often do pretreatment mapping biopsies (along the periphery of the lesion) to try to gauge where the melanoma is. Melanomas can have not only subclinical extension horizontally, but they can also have occult invasion." In his research, Dr. Rossi also uses confocal microscopy, with or without biopsies, for suspected melanomas, BCCs and SCCs. "Confocal microscopy helps me to map out the lesion better, to hone in on where we're going to treat, and look for recurrences or invasion."

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For biopsy-confirmed melanoma in situ (MIS), Dr. Rossi offers imiquimod and, in rare cases, radiation. "With imiquimod, the treatment is longer than for BCC or SCC. I usually say at least 12 weeks. Some patients have gone up to 20 weeks. It really depends on how consistently patients use it and what results they're getting. We want to see that they're getting redness, crusting and some skin breakdown. But again, when this was studied, these treatment effects did not correlate with clinical success."⁷   

In one recent study of 347 patients, histologic clearance rate was 76.2% and the clinical clearance rate was 78.3%.  The incidence of clinical recurrence was 2.3% at a mean follow-up of 34.2 months.  After statistical analysis, treatment with greater than 60 total imiquimod applications was associated with an odds ratio of 8.4 for histological clearance.  Also, treatment with greater than 5 applications per week was associated with an odds ratio of 6.0 for histological clearance.⁸

For patients with invasive melanoma that has a wide MIS on its periphery, "Sometimes I will do surgery to debulk the invasive melanoma, if patients can't undergo the full surgery. Then I prescribe imiquimod for the surrounding area postsurgery, or for incomplete margins. These patients must be followed up regularly because we know melanoma may not recur within the first year. It may take longer. I use confocal microscopy, dermatoscopy and close clinical follow-up to monitor for any signs of recurrence or invasion."

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Finally, Dr. Rossi said he uses radiation as a noninvasive treatment for melanoma in patients who cannot undergo surgery or fail imiquimod. Because melanoma can have subclinical extension, "You must have a wider field. Some advocate at least a 1 cm margin around the whole lesion depending on anatomical location." Here too, strong follow-up is essential. In one study, "The mean time to recurrence was about 45 months."⁹

Disclosures: Dr. Rossi is an advisory board member for Novartis.

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References

1. Eigentler TK, Kamin A, Weide BM, et al. A phase III, randomized, open label study to evaluate the safety and efficacy of imiquimod 5% cream applied thrice weekly for 8 and 12 weeks in the treatment of low-risk nodular basal cell carcinoma. J Am Acad Dermatol. 2007;57(4):616-21.

2. Willey A, Mehta S, Lee PK. Reduction in the incidence of squamous cell carcinoma in solid organ transplant recipients treated with cyclic photodynamic therapy. Dermatol Surg. 2010;36(5):652-8.

3. Alam M, Nanda S, Mittal BB, Kim NA, Yoo S. The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review. J Am Acad Dermatol. 2011;65(2):377-88.

4. Lansbury L, Bath-Hextall F, Perkins W, Stanton W, Leonardi-Bee J. Interventions for non-metastatic squamous cell carcinoma of the skin: systematic review and pooled analysis of observational studies. BMJ. 2013;347:f6153.

5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Squamous Cell Skin Cancer. Version 1.2015.  www.nccn.org. Accessed August 1, 2015.

6. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-9.

7. Powell AM, Robson AM, Russell-Jones R, Barlow RJ. Imiquimod and lentigo maligna: a search for prognostic features in a clinicopathological study with long-term follow-up. Br J Dermatol. 2009;160(5):994-8.

8. Mora AN, Karia PS, Nguyen BM. A quantitative systematic review of the efficacy of imiquimod monotherapy for lentigo maligna and an analysis of factors that affect tumor clearance. J Am Acad Dermatol. doi: 10.1016/j.jaad.2015.05.022. [Published online ahead of print June 15, 2015]

9. Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol. 2002;146(6):1042-6.