survival and has produced consistent drug induced inhibition of cell growth in human melanoma, prostate, and breast cancer cell lines. This growth inhibitory effect occurred with treatment times as short as 1-h application. Animal model dose regimen studies showed that the most effective topical dose was 10 mg applied overnight for 8 h, repeated daily for three consecutive days. PEP005 has limited skin penetration into systemic circulation after topical application and results in dermal irritation. No systemic toxicity has been observed in single or repeated doses in nonclinical studies of topical PEP005. PEP005 is an activator of protein kinase C, and other members of this pharmacological class have been found to have tumor promoting potential. However, no definitive studies have been conducted to evaluate the carcinogenic potential of PEP005. Because PEP005 may be severely irritating to the eye, precautions such as wearing gloves during application of the product and discarding those gloves immediately afterwards or using a clean Q-tip for application of the medication are important during patient instruction of this medication. Accidental ocular exposure could cause severe irritation to anything with which it comes into contact.

In three previous clinical trials, the safety and efficacy of PEP005 were impressive. In the early phase I/ II trials, the final outcome of the treatment showed a complete clinical response rate of 66% for actinic keratoses, 57% for basal cell carcinomas (BCC), 50% for squamous cell carcinomas (SCC), and 81% for SCC in situ. In phase I trials, the most frequently observed adverse side effects were mild, local erythema (73%); scaling (27%); and scabbing (27%). In phase II trials, 71% of all lesions in the 0.05% PEP005 group were completely cleared compared to only 32% of lesions in the vehicle-controlled group.

On day 1 of the 3-day topical regimen, mild erythema was noted in all lesions and some of the surrounding skin. On day 4, after the three-dose regimen was completed, moderate erythema was noted of the entire area plus slight scabbing of each target lesion. On day 8, 5 days after the regimen was completed, the erythema persisted and adjacent areas begin to react. This may demonstrate local immunostimulation. On day 15, 12 days after the completion of the 3-day dose regimen, the erythema of the target area was subsiding, and the edges and area on the forehead showed persistent erythema. On day 29, the entire area was

healed, and the target lesions were invisible. Six months posttreatment, the target area remained clear, and the adjacent areas also appeared to be cleared.

A robust response to the study drug was seen in one patient. This may indicate that there may be a cohort of patients who have extremely strong reactions to the medication. This patient developed mild erythema on day 1. On day 4, the patient had extreme erythema with ulceration and crusting. On day 8, the erythema and crusting persisted but were beginning to resolve. On day 15, the erythema was mild and the crusting was completely resolved. On day 29, the patient was healed with residual hyperpigmentation. Six months posttreatment, the area was completely clear, and the patient was very happy with the cosmetic result. PEP005 is the latest of topical medications that cause local irritation and some type of immunostimulation that has been successful in treating actinic keratoses and superficial nonmelanoma skin cancers.

Summary: Photodynamic Therapy

•Photodynamic therapy (PDT) consists of a chemical reaction activated by light energy that is used to selectively destroy tissue. PDT has proven to be effective for the treatment of actinic keratosis, basal cell carcinoma, and Bowen’s disease. Intraoperative PDT after micrographic surgery is a new combination modality for patients with severe photo damage in order to prevent a neighboring secondary tumor.

37.5Photodynamic Therapy

In our practice, we utilize photodynamic therapy (PDT) as a preventative and therapeutic measure for actinic keratoses [19]. We recommend a technique called enhanced-cyclic PDT three times a year for patients who have multiple actinic keratoses as the technique has been shown to reduce the tumor burden of patients in our clinic. Our treatment regimen is as follows:

Step I – microdermabrasion utilizing a mechanical, crystal-free microdermabrasion of the treatment area including the target lesions, for example, the entire face or arms or chest.

Fig. 37.3 Pre-PDT microdermabrasion. This technique uses two passes of a medium coarse wand, one horizontal pass, and one vertical pass using a diamond-studded hand piece with medium grit (100 mm particle)

Fig. 37.4 ALA activation with IPL. Two passes of IPL using a 560 nm filter at 20 J/cm2. Program one, 21 = 2.4 ms, 22 = 4.0 ms, with a 20 ms interpulse delay

Step II – is a 3-h incubation time of aminolevulinic acid (ALA). The ALA is applied in the provided stick to the entire area. Larger areas require multiple ALA Levulan® sticks to be utilized. The treatment time begins after the last medication has been applied. After 3 h, the ALA is washed off only if a lesser effect is desired. If the patient agrees to a stronger treatment, the ALA remains on the skin during treatment and is washed off after treatment. The standard illumination time of 16 min and 40 s is used with the BLU-U per treatment area. For example, if the scalp is treated for 16 min and 40 s and the next treatment area is the face, the ears and scalp are covered during the second illumination time so as not to expose the patient to a double treatment. In this way the arms, neck, back, legs, and any desired area can be treated. This procedure is repeated three times a year for 1–2 years until the patient and doctor agree the tumor burden has been decreased.

Variations on our enhanced-cyclic PDT regimen for those patients who have a robust reaction to the 3-h incubation time include 1-h incubation time, no microdermabrasion in advance, or microdermabrasion with 1-h incubation time illuminated with two passes of the intense pulsed light (IPL), and additionally BlU-U illumination of 16 min and 40 s. Figure 37.3 shows the microdermabrasion technique which uses two passes of a medium coarse wand, one horizontal pass, and one vertical pass using a diamond-studded hand piece with

medium grit (100 mm particle). Figure 37.4 shows the IPL technique – two passes of IPL using a 560 nm filter at 20 J/cm2. Program one, 21=2.4 ms, 22=4.0 ms, with a 20 ms interpulse delay.

Intraoperative PDT is a new combination modality for the treatment of SCC and BCC. Mohs surgery followed by PDT, either topical or injectable ALA, has been used in my practice in regions that have lesions, in areas of severe photodamage where I suspect a new secondary lesion will occur within a short amount of time. This combination modality may lower the recurrence rate of the surgically treated SCC and BCC, may treat early SCC and BCC that are not clinically evident in the area, may reduce the incidence of new SCC or BCC developing from actinic keratoses, may improve the healing process; may improve photodamaged skin, and ultimately, may be more convenient to patients by reducing the need for follow-up.

Summary: Off-Label Intraoperative PDT with Topical and Intralesional Aminolevulinic Acid on SCC of the Penis

•Micrographic surgery in combination with intraoperative PDT for nonmelanoma skin cancers of the penis has reduced the rate of penectomy at our institution.

37.6Off-Label Intraoperative PDT with Topical and Intralesional Aminolevulinic Acid on SCC of the Penis

Squamous cell carcinoma in situ and stage T1 SCC of the glans penis have been indications for penectomy in the past. In our clinic, we collaborate with the Department of Urology to utilize Mohs surgery and intraoperative PDT plus cyclic PDT to treat patients with this disease in order to prevent penectomy. To date, this alternative has been extremely successful in a series of eight patients since 2005. Patients have ill-defined, macerated erythematous erosions on the glans and shaft of the penis. Surveillance biopsies are done of the outside margins for preoperative planning purposes. On the day of Mohs surgery, the most invasive lesions are removed using a bendable blade which allows for superficial planning of the skin. Our slides are reviewed by a dermatopathologist to evaluate for high-grade tumors and invasion into the dermal vasculature. The area is numbed with buffered 2% lidocaine with epinephrine 1:200,000 for surgery. Intralesional injection of ALA can be painful if the area is not anesthetized as the ALA does burn. Topical application of the ALA is done by using the Levulan Kerastick.

Topical PDT technique for penile SCC: The lesion itself plus the area surrounding the affected area is treated generously with ALA using the entire contents of the Kerastick. Overnight incubation is suggested for these cases. The patient returns to clinic in the morning and undergoes 16 min 40 s illumination with the BlU-U. The patient is instructed to rotate the area while under illumination in order to ensure thorough treatment of the area. Patients repeat overnight incubation PDT every 3 months and are instructed to use topical imiquimod three times a week for 16 weeks to any new or suspicious lesions. Side effects have included erythema and irritation for up to 1 week in the area. No infections have been seen and scarring from the Mohs surgery has been mild. No functional side effects have been reported including no strictures of the urethra and no phimosis has been reported.

Summary: Conclusion

•There are many adjunctive therapies available with Mohs micrographic surgery, including: immunomodulators, radiation, chemotherapeutic agents, and photodynamic therapy.

37.7Conclusion

In conclusion, there are multiple options for adjunctive therapy with Mohs micrographic surgery. Current evidence does not support neoadjuvant therapy with imiquimod before Mohs micrographic surgery. Outcome data for high-risk SCC treated with adjuvant radiotherapy are sparse and inconclusive. Radiotherapy may benefit some patients with high-risk SCC, particularly those with uncertain or positive surgical margins or with more advanced nerve involvement. Aggressive BCC may have a chemotherapeutic option in the future. In addition, topical gel PEP005 for actinic keratoses has the benefit of a 3 day only treatment ensuring good compliance in addition to good success rates.

Finally, cyclic PDT and intraoperative PDT for nonmelanoma skin cancers and actinic keratoses may prevent tumor incidence in areas of field cancerization and may prove to be preventive medicine. Lastly, PDT with Mohs mircrographic surgery for superficially invasive penile carcinoma may prove to be an alternative to penectomy in selected patients.

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Dr. Frederic E. Mohs was always generous in welcoming interested dermatologists to his practice in Madison, WI, and teaching his technique [1]. Training was informal and consisted of shadowing Dr. Mohs in his office for a period of 3 days to several weeks. The emphasis of this training was to understand Dr. Mohs’ approach to the patient with large or recurrent skin cancer, use of fixative in vivo, method of excision of tissue, technique of orientation and mapping of the specimens, and histologic diagnosis and correlation between the histopathologically involved margins and the tumor remaining in the patient at the edges of the wound. He also taught the concepts of wound care and the advantages of repair by second intention healing; other reconstructive procedures were not generally addressed. Several of the people who spent time with Dr. Mohs, including Dr. Perry Robins of New York and Dr. Philip Bailin of the Cleveland Clinic, taught the technique to their visitors and to residents in dermatology programs. The first international interest in Mohs surgery was initiated by Dr Robins’ outreach through the International Society of Dermatologic Surgeons, and several individuals who learned the technique, including Dr. Gunter Burg of Germany and Dr. Antonio Picoto of Portugal, became important in Europe as trainers of a younger generation of Mohs surgeons, following the informal preceptorship model initiated by Dr. Mohs [2]. South American physicians studied in Spain with Dr. Francisco Camacho and Dr. Julian Sanchez Conejo Mir and took the technique back to their home countries.

In 1967, Dr. Mohs founded the American College of Chemosurgery (now called the American College of Mohs Surgery) to bring together those interested in the technique in order to foster mutual education and promote advances in science and practice. In a book published in 1970, Dr. Mohs wrote, “Facilities and personnel for the practice of chemosurgery eventually should be available in every large center of population. Presently, there are over fifty physicians who have been trained to use the method, but many sections of the country are still without this useful addition to our armamentarium against cutaneous cancer” [3]. The interest in performing the procedure at that time however was limited because of the difficulties for both patient and physician in the use of the in vivo chemofixation technique. Fortunately, in the 1970s, the procedure was modified to use fresh frozen tissue instead of in vivo fixed tissue for the histologic analysis of the tumor present in the margins of the wound. This major

advance allowed the procedure to become mainstream since it was now practical and easy for both patients and physicians. It soon became apparent that extending the procedure to more patients would require more trained physicians.

In the late 1970s and early 1980s, the American College of Mohs Surgery (ACMS) with great foresight decided to foster the development of the technique and promote the highest quality of education, practice, and patient care by establishing criteria for formal fellowships and maintaining a process for certifying fellowships that met these criteria. The goal was to move the fellowships from the preceptor model to training programs with academic rigor. The Board created the Site Inspection and Slide Review Board LLC (SISRB) and charged it with setting standards, approving, and maintaining oversights for fellowships offered by ACMS members. The first approved fellowships began in the USA in the early 1980s. The first international fellowships were approved in 1996 with Dr. Alistair Carruthers in Canada and Dr. Robert Paver in Australia. Graduates of these programs could in turn become members of the ACMS and establish fellowships if so desired. The annual meeting of the ACMS changed to accept abstracts by fellows for oral or poster presentation, and the Tromovitch award became a highly coveted prize for the first ranked presentation. As programs evolved, more emphasis was placed on reconstruction so that graduating fellows were accomplished in not only the Mohs technique but also sophisticated repair techniques.

By 2007, there were 77 approved fellowships scattered about the United States and in Australia, Canada, Israel, and New Zealand. ACMS developed a core curriculum [4], policies for appropriate training [5], and a computer-based ranking process for approved fellowship positions in order to facilitate application and matching of applicant and program [6]. Table 38.1 defines the requirements of the ACMS for an approved program. Table 38.2 lists the requirements and responsibilities of the program director. SISRB annually reviews surgical logs and academic contributions of programs, directors, and fellows as well as written evaluations of the fellow’s proficiency and the fellow’s assessment of the educational value of the program. Site inspection and slide review of all programs are performed on a rotating basis as indicated by the approval process. Programs may be approved for 1–5 years.

Table 38.2 Requirements and responsibilities of the program director

Because quality assurance is a matter of importance to the public, the Accreditation Council for Graduate Medical Education (ACGME) was established as a private, nonprofit organization responsible for the evaluation and accreditation of postgraduate medical education in the USA, overseeing residency and subspecialty programs. In 1998, the Residency Review Committee (RRC) for Dermatology asked the ACGME to accredit dermatology surgery fellowships. After much discussion, with comments from

the public and from other medical and surgical specialties, the ACGME-approved program requirements in procedural dermatology in 2003 [7]. ACGME program requirements [8] are similar to the requirements already defined by the ACMS with some notable differences. The approved programs are approved by site, not director, although the director’s qualifications remain intact. The fellow must be at least a PGY5, graduate of an ACGME-accredited dermatology residency program. Institutional oversight as required of other residency programs (e.g., a graduate medical office, grievance procedures, institutional evaluation) must be arranged. The curriculum for these fellowships is widened to include aesthetic procedures as well as those for the management of skin cancer. Of most concern to the ACMS is that the site inspector is an educator, not a Mohs surgeon, and cannot judge if the Mohs surgery is appropriately performed or the slides are of good quality and read accurately. Regardless, in 2007, the ACMS Board and the membership voted to move toward transitioning the approval and oversight of programs to the ACGME. Since July 2009, no new programs have been approved, and no existing programs have been renewed by the ACMS so that by 2014, ACMS will no longer have oversight for any programs in the USA. The ACMS however is committed to facilitating quality patient care and fellow education within programs and maintains the