Cutaneous Oncology Part 2

Neil Swanson, MD & Marc Brown, MD

 

Mohs Surgery: Thoughts and Guidelines – Neil Swanson, MD

Dr Swanson begins by stating that Mohs surgery is NOT indicated for all BCC/SCC and this is an important concept for dermatologists. In 2012, a group of experts developed guidelines for the appropriate use of Mohs micrographic surgery published in the JAAD and Derm Surgery.  It is important for physicians to familiarize themselves with the guidelines.

High Risk Squamous Cell Carcinoma – Marc Brown, MD

Squamous cell carcinoma (SCC) is the second most common type of cancer and more than 250,000 new cases are reported every year. The incidence of SCC increases dramatically with age and in older patients (80+), there are more skin cancer deaths from SCC than melanoma.

It is important that dermatologists understand the risk factors for SCC development; these include sun exposure, ionizing radiation, HPV infection, immunosuppression, genetic syndrome, chronic inflammation, burns and non-healing ulcers, chemical exposures, older men with fair skin and UV light. In addition, healthcare providers should recognize the risk factors for SCC recurrence and metastasis. This involves assessing the size, depth, histology and clinical features of the tumor as well as the overall immune status of the patient.  CLL patients also represent at “at risk” group for metastisis.

The NCCN has recently published guidelines for the treatment of high risk SCC and dermatologists can refer to these guidelines for optimal patient care.

Pigmented Lesions

This session began with a series of interactive case challenges and discussions on the optimal management congenital melanocytic nevi. Our panelists included Drs Hensin Tsao, Ashfaq Marghoob, Keith Flaherty, Whitney High, Ilona Frieden and Ken Tanabe.

Understanding the medical and surgical management of nevi and melanoma is extremely important for the practicing dermatologist.  Nevi are benign tumors composed of nevo-melanocytes and can arrive during fetal development (congenital nevi) or after birth (acquired nevi). The presence of many acquired nevi and the presence of dysplastic nevi, independent of each other, are two of the strongest risk factors for melanoma.

Some of the key takeaway points from the case study presentations are noted below:

  • The transformation of small congenital nevi to melanoma is rare and the vast majority of that risk is after puberty
  • Melanomas tend to arise at the periphery of congenital nevi
  • Family history is associated with an increased risk for melanoma, but not necessarily within the small nevus
  • There is a period of time when most dermatologists would not prefer to perform surgery on children with CMN (18-months to three years)
  • Multiple satellite lesions are associated with an increased risk for neuro-cutaneous melanocytosis (NCM) which is associated with a higher risk for melanoma in the central nervous system.  The number of satellite lesions is more important than their location.
  • Experts now acknowledge that the risk of developing melanoma is dependent on more than just size alone
  • There is little published data for immunotherapy in pediatric populations with melanoma; however, immunotherapy is tolerated children with advanced disease; risk of autoimmune toxicities is there; treatment selection similar to that of young adults
Detection and Management of Melanoma

The goal for the optimal management of nevi is to find early melanoma while avoiding the removal benign nevi. This can be accomplished through periodic screening, dermoscopy, and the use of total body photography and/or digital dermatoscopic monitoring.  If a lesion is found, the best method for biopsy is excisional biopsy.   A broad deep shave biopsy that removes the entire lesion is acceptable.  A punch biopsy may lead to sampling error if used to obtain tissue from larger lesions.  ,

The panel presented several clinical pearls with regards to melanoma:

  • Recognition of melanoma is based on a variety of factors
  • Change in size and change in color are the most significant factors in detection of melanoma
  • Primary prevention of melanoma is UV protection; secondary prevention includes removal of precursor lesions and early melanomas (surveillance)
  • Sentinal lymph node biopsies are of prognostic value only and have not yet been shown to increase survival.
  • Dermatopathology (biopsy, analysis, and report) plays an important role in the management of melanoma
  • Relapse-free survival consistently improved with high-dose interferon
  • Thin 1B melanomas can be aggressive and SLNBx should be considered on a case-by-case basis
  • Knowing if a patient has BRAF mutation (found in 50% of melanomas) can affect therapeutic choice ie selection of a BRAF inhibitor and overall survival rate
  • Ipilimumab has demonstrated improved survival in patients with metastatic melanoma however it can result in life threatening colitis.

The Role of HPV in Skin Cancer

Eggert Stockfleth, MD

In this presentation, Dr Stockfleth reviews the latest data and the role of the human papillomavirus (HPV) in skin cancer.

We know that HPV is very stable. The virus is host specific and has a very special DNA from the oncogenic type (E6 and E7). HPV is approximately 45-55 nm in size and its genome size is 8kb.

Currently, there are 200 different types of HPV.

HPV is one of the most frequently transmitted STDs.

HPV Prevention Strategies
  • Reduce duration of infectiousness through treatment
  • Decrease transmission efficiency with consistent condom use
  • Reduce/limit  number of sex partners
  • Quadrivalent HPV vaccine
    • Gardasil® : protects against HPV types 6, 11 (responsible for >90% EGWs) 16, 18 (responsible for 70% cervical cancer)
    • Administered as 3 injections over 6 month period (0,2,6 mo’s)
    • ACIP recommended: females 9-26 yrs of age


Human Immunity

Therapeutic Modalities for External Genital Warts (EGWs)

Various therapeutic modalities exist for the treatment of EGWs. These can be both patient-applied or provider-administered. Patient applied therapies include Imiquimod cream, Podofilox gel/solution, and Sinecatechins ointment. Provider-administered therapy includes Trichloracetic acid, Bichloroacetic acid, Cryotherapy, Podophyllin resin, laser therapy, excision/electrosurgery and interferon.

The Role of Cutaneous HPV in Skin Carcinogenesis

The association between HPV and non-melamona skin cell was first described in patients with epidermodysplasia verruciformis (EV). Cutaneous HPV types include HPV 5, 8, 9, 12, 14, 15, 17, 19-25, and many more. 30-60% of HPV patients develop multiple cutaneous squamous cell carcinomas (SCCs) on sun-exposed sites after 10-30 years. These SCCs harbor the ongenic types of HPV 5 and HPV 8 in more than 90% of cases.

Cutaneous HPV and SCC

SCC is prevalent on 80% of sun-exposed areas in cutaneous SCC and the main risk factor is UV radiation (UVA and UVB).  There are multiple risk factors during skin carcinogenesis. With a functional immune system, your body can repair DNA image or lead to programmed cell death, i.e, apoptosis.

The p53 gene is involved in almost 75% of all skin cancer. HPV positive cells can block p53; therefore, blocking apoptosis.

Criteria to Define a Causal Role in Disease by Infectious Agents (HPV and Skin Cancer (SCC))

Biology of HPV:

  • Presence of HPV in (pre)cancer cells
  • Expression of viral genes in (pre)cancer cells (E6, E7)
  • Transforming properties (in vitro and in vivo models)

Epidemiology:

  • Relative risk (RR) and Odds Ratio (OR)

HPV 23 was the most prevalent type of virus in immunocompetent and immunosuppressed OTR. The accumulation of the HPV23 E6 protein is caused by HIPK2.  HPV23 E6 interacts with HIPK2 upon UV-induced DNA-damage; therefore, inhibiting HIPK2.p53 complex formation which is the key event in the induction of UV-induced apoptosis.

Cutaneous HPV infected cells may overcome UV-induced apoptosis and be causal in the early onset of skin carcinogenesis.

Conclusions

Current data suggests that cutaneous HPV may play a role in the development of cutaneous SCC.  HPV induced anti-apoptotic effects in UV-damaged cells may lead to persistence and accumulation of further mutations.

Research is still ongoing regarding vaccination and treatment.

Cutaneous Oncology: Recent Drug Approvals Part 2

Keith Flaherty, MD & George Martin, MD

Vismodegib (ErivedgeTM) for the Treatment of Advanced Basal Cell Carcinoma (BCC)

Dr Keith Flaherty, an oncologist at MGH, spoke on ErivedgeTM for the treatment of advanced and metastatic BCC.   Historically,  the treatment of patients with advanced BCC with either metastatic or locally advanced disease employed standard chemotherapeutic regimens using agents such as cis-platinum. Reports of success were few and generally limited to individual case reports until the recent FDA approval of Erivedge® a hedgehog pathway inhibitor.

The “hedgehog pathway” (Hh pathway: Figures 1 & 2) and its role in the development of basal cell carcinomas (BCC) has been the subject of intense research over the last decade.  Aberrant activation of the Hh pathway (Figures 3 & 4) has been identified in both hereditary BCC syndrome ie Gorlin syndrome (Basal Cell Nevus Syndrome) as well as sporadic BCCs.  Gorlin syndrome patients carry a germ-line heterozygous mutation in the PTCH gene and are highly predisposed to developing multiple BCCs. Mutations in the PTCH gene (Figure 3), remove its ability to inhibit the Hh pathway through its inhibition of SMO (Smoothened protein).  Approximately 90% of sporadic BCCs have a PTCH gene mutation and an additional 10% of sporadic BCC have activating mutations in the SMO gene (Figure 4), which is downstream of PTCH, and this mutation leads to overstimulation of the Hh pathway.

Vismodegib (Erivedge®) is a hedgehog pathway inhibitor (figure 5), which binds to and inactivates SMO.  Its use is indicated for the treatment of adults with metastatic basal cell carcinoma (mBCC), or with locally advanced basal cell carcinoma (laBCC) that has recurred following surgery or who are not candidates for surgery or radiation.

Dr Flaherty presented data evaluating the safety and efficacy of Erivedge in mBCC and laBCC obtained from an international, single-arm, multi-center, open-label, 2-cohort phase II study involving 104 patients (Erivance BCC/SHH447g). Patients with laBCC either had histologically-confirmed BCC that was unresectable or were not appropriate candidates for surgery: >1 cm or 2 or more recurrences after surgery; curative resection unlikely; anticipated substantial morbidity and/or deformity after surgery.  mBCC patients had histologic confirmation of mBCC and radiographically measurable tumors. The patient demographics are listed in figure 6. Patients received vismodegib 150 mg/day orally until tumor progression or intolerable drug toxicity.

The objective response rates (ORR) were assessed by an independent review facility (IRF) and were 42.9% for laBCC and 30.3% for mBCC.  The median duration of response was 7.6 months and the median progression-free survival was 9.5 months for both cohorts.

The rate of severe toxicities (grade III + IV) for vismodegib is quite low. Mild to moderate toxicity (grades I + II toxicity) seen with vismodegib included fatigue, muscle spasms and dysgeusia (altered taste).

In summary, vismodegib is dramatically effective for BCC treatment in patients with advanced.  Approximately 80% of patients with advanced BCC have regression of disease with 30 – 60% of patients having objective responses.  Now FDA approved for patients with advanced BCC, it will be interesting to see how this drug will be used both therapeutically and in an adjuvant setting in combination with other surgical and non-surgical modalities.

 

 

Cutaneous Oncology: Recent Drug Approvals Part 1

Keith Flaherty, MD & George Martin, MD

The hot topics of discussion at Maui Derm 2012 were January’s FDA approval of two innovative products in the cutaneous oncology arena: (Picato®), ingenol mebutate 0.015% gel and 0.05% gel for the treatment of actinic keratoses (AKs) and Erivedge®  (vismodegib) for the treatment of advanced basal cell carcinoma.  At Maui Derm, Dr Martin discussed the data on Picato® and Dr. Keith Flaherty, an oncologist from MGH, discussed ErivedgeTM.

Ingenol Mebutate (Picato®): 0.015% and 0.05% gel

Ingenol Mebutate is derived from the sap of the plant Euphorbia peplus, a commonly found plant whose sap has been used in traditional medicine for the treatment of a wide variety of skin lesions ranging from warts to skin cancer. The active pharmacologic ingredient, ingenol mebutate (ingenol‐3‐angelate), has been formulated as a field therapy for the treatment of AKs.

Mechanism of Action

Extensive work has been done to determine the mechanism of action of ingenol mebutate.  In high concentrations it induces tumor cell necrosis. It also up-regulates keratinocyte and endothelial cell cytokine and chemokine production presumably via the protein kinase C (PKC) pathway.  In response to ingenol mebutate, IL-8 a neutrophil chemo-attractant is produced in significant quantities by rapidly proliferating keratinocytes and endothelial cells following exposure to ingenol mebutate.  Also upregulated in response to ingenol mebutate is the expression of adhesion molecules ICAM-1 and E-selectin by endothelial cells, which in turn promotes neutrophil migration into the treatment area. In mouse models ingenol mebutate was show to reduce mutated p53 patches of skin in UV irradiated mice compared to placebo.

Two Strengths/Two Dosing Regimens

Ingenol mebutate was approved for the treatment of AKs using two different concentrations employing different dosing regimens. Ingenol mebutate 0.015% gel applied daily for 3 consecutive days was approved for treatment of AKs of the face and scalp. Ingenol mebutate 0.05% gel applied daily for 2 consecutive days was approved for treatment of AKs on the trunk and extremities.

In two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials the efficacy and safety of ingenol mebutate 0.015% gel applied daily for 3 consecutive days to the face and scalp was evaluated as a field therapy (4-8 AKs in a 25 cm2 area).  Of the treated patients completing both studies, 37% and 47% of drug treated patients achieved 100% clearance compared to 2% and 5% for vehicle controls.  Partial clearance (≥ 75% lesions cleared) was achieved in 60% and 68% of drug treated patients compared to 7% and 8% for vehicle controls.  Median percent lesion reduction for drug treated side were (83.3%) and (86.6%) compared to (0%) and (0%) for vehicle controls.  These clearance rates are comparable or better than currently FDA approved AK field therapies used on the face and scalp. Hypopigmentation and hyperpigmentation were ≤ 1%.  No scarring was reported.  There was no systemic absorption of ingenol mebutate above the limit of quantification in blood samples of subjects evaluated.

The efficacy and safety of ingenol mebutate 0.05% gel applied daily for 2 consecutive days (4 – 8 AKs in a 25 cm2 area) to trunk and extremity lesions (arm, back of hand, chest, back, shoulder and leg) was evaluated in two multicenter, randomized, parallel-group, double-blind, vehicle controlled pivotal phase III trials. Of the treated patients completing both studies, 28% and 42% of drug treated patients achieved 100% clearance compared to 5% and 5% for vehicle controls.  Partial clearance ( ≥ 75% lesions cleared) was achieved in 44% and 55% of drug treated patients compared to 7% and 7% for vehicle controls.  Median lesion percent reduction for drug treated side were (69%) and (75%) compared to (0%) and (0%) for vehicle controls. Hypopigmentation and hyperpigmentation were ≤1 %. There was no systemic absorption of ingenol mebutate above the limit of quantification in the blood samples of subjects evaluated.

A 12-month follow-up study was performed evaluating patients who completely cleared their lesions during the phase III studies. No recurrent lesions were observed in 46.1% of patients treated on the face or scalp and in 44% of patients treated for trunk and extremity lesions.  The overall reduction in AKs from baseline to 12 months was 87.2% for face and scalp lesions and 86.8% for trunk and extremity lesions

Clinical Pearls

The take home points on both 0.015% and 0.05% gel is that they have comparable or better efficacy in clearing AKs in comparison to currently FDA approved field therapies, produce sustained clearance in 12 month follow-up studies, cause limited downtime (peak inflammation on day 4 for the face/scalp with resolution of scabbing by day 8; peak inflammation on the trunk and extremities by day 4 – 8 with resolution by day 15), achieve excellent patient compliance with the 3 and 2 day application regimens and induce minimal side-effects post therapy in terms of hypopigmentation, hyperpigmentation and scarring.

Video: Treatment Options for AKs

Evolving Landscape of Therapeutics for Actinic Keratoses (AKs)

George Martin, MD

George Martin, MD

Watch video of Dr. Martin’s full talk

At the podium during Maui Derm 2011, I discussed the evolving landscape of therapeutics for actinic keratoses (AKs).  In the US nearly 60% of “at risk” individuals over the age of 40 have at least 1 AK.  Therapy for AKs has resulted in over 5 million office visits with an estimated healthcare burden of over 1 billion dollars.

As healthcare initiatives examine and reward patient therapeutic “outcomes”, the clear lack of efficacy of cryosurgery as a “field therapy” for patients with numerous AKs will cause a shift in therapeutic algorithms toward field therapies.  However; field therapies, when performed according to the package insert, are associated with prolonged side effects that dramatically affect patient compliance.  As a result, small investigator initiated studies examining short course, combination and interval therapy in efforts to enhance patient compliance while maintaining efficacy are becoming more prevalent in the literature. Additionally new drugs such as the plant derived ingenol mebutate gel are ready to be brought to the marketplace and new formulations of existing drugs such as imiquimod 3.75%, which employs a more “user friendly” protocol compared to 16 weeks of twice daily 5% imiquimod, have been introduced.

I presented the work of Prof. Eggert Stockfleth of Charite Hospital in Berlin who has published compelling molecular data on the role of human papilloma virus (HPV) 21 as a co-carcinogen along with UV.  The role of HPV 21 is analogous to the role of certain oncogenic HPV sub-types in cervical cancer.  HPV 21 has been found in 95% of AKs and 100% of cutaneous SCCs in Prof. Stockfleth’s study. Tumour-inducing effects of HPV 21 have been attributed to its production the viral protein E6.  E6 interacts with pro-apoptotic Bak-protein and the p53 protein resulting in inhibition of apoptosis.   A vaccine directed against the HPV 21 is in early stages of development. Because of the increased risk of SCC development in organ transplant patients  (>20x the rate of SCC development compared to non-immunocompromised individuals) the efficacy of pre-operative immunization in preventing AKs and SCC in this high-risk group will be studied first.

Figure 1: Fluorokinetic Analysis

Figure 1: Fluorokinetic Analysis

ALA PDT has come a long way from its lengthy 14 – 18 hr. incubation times in efforts to become user friendly.  However, I presented data that the shorter 1-hour ALA incubation times may have sacrificed significant efficacy for convenience.  Based on fluorokinetic data on the accumulation of the photosensitizer protoporphyrin IX (PpIX) inside AKs following ALA application (Figure 1) and patient observation, we now regularly treat patients using a minimum of 3-hour ALA incubation period to allow more PpIX accumulation inside AKs.  In patients with “stubborn” AKs we pre-treat with 5-FU daily for 7 days on the face and 10 days on the scalp and extremities followed by PDT using 1 – 3 hour incubations.  Lastly, for the patient with extensive AKs on the face and scalp who I never seem to get close to clearing, pretreating with 3.75% imiquimod for 1 week followed by ALA PDT using a 3 hour incubation has produced remarkable sustained clearance not achieved in either ALA PDT alone or in combination with 5-FU.

Figure 2: Therapeutic "Downtime"

Figure 2: Therapeutic “Downtime”

I addressed the issue of pharmaco-economics involving our currently available field therapies.   Medicare insurance covers the cost of ALA PDT, which is a decision factor for cash strapped seniors unable to afford the several hundreds of dollars for topical field therapies.   In terms of downtime for working individuals, ALA PDT affords the least amount of downtime (generally 1 week) compared to other field therapies (Figure 2).

5-FU remains a cornerstone of  field therapy in most our practices.  I was noted that phase III data on 0.5% 5-FU showed that 1 week of daily use of 0.5% 5-FU cleared nearly 75% of individual AKs.    I think that it is time that we should re-examine the scorched earth policy of 4-week 5-FU therapy!

Figure 3: AK of the Lip

Figure 3: AK of the Lip

What’s been overlooked for actinic chelitis?   3% diclofenac gel applied twice daily for 3 months is particularly effective for this problem. It is very tolerated and results in excellent clearance data with over 80% of individual lesions clearing and patient satisfaction was rated as very high.  (Figure 3) For those patients not wishing at least 2 weeks of downtime following any of the current modalities ranging from PDT, CO2 laser resurfacing, 5-FU or imiquimod this is a tolerable option that allows people to continue socializing.  Recent data on 3% diclofenac has shown significant long-term clearance during the phase IV study involving 1-year follow-up evaluations.

The evolution of imiquimod therapy for the treatment of AKs has undergone an evolution since the introduction of 5% imiquimod applied twice weekly for 16 weeks.  While the efficacy of this regimen is significant, the tolerability and patient compliance is wanting.  In Europe the use of 5% imiquimod 3-times weekly 4 weeks followed by a 4-week rest period and repeated produces excellent clinical and histologic clearance long term (1 year) clearance but is once again associated with significant patient downtime.  Limiting therapy to only 4 weeks results in only <30% clearance compared to two cycles that result in approximately an 85% clearance.  The introduction of 3.75% imiquimod applied daily for 2 weeks-2 weeks off- 2 weeks on has resulted in better patient tolerance and impressive individual lesion clearance (>80%). Long-term complete clearance (1 year) data for those phase III study patients initially completely clearing was 40%. In light of the role of HPV 21 as a co-carcinogen responsible for the development of AKs and cutaneous SCCs, the use of imiquimod as an immune modulator used either alone or in combination would seem to have a therapeutic advantage.

Finally, ingenol mebutate 0.015% gel when applied for 3 consecutive days during phase III studies, produced very nice and consistent clearance data (80% range) as a field therapy for the head area (face and scalp).  The 3-day topical therapy had excellent patient compliance, which is a major challenge for other field therapies.  Downtime following ingenol mebutate was on average 2 weeks.  It will be interesting to see how this drug will be used as a field therapy because of the inability to “titrate” its response following application.  Likely most of us will begin using it a “limited area” field therapy. However the future seems very bright for this latest pending addition to our therapeutic toolbox.

 

Melanoma

What’s your strategy in managing this lesion?

  1. In 1970 the overall melanoma survival rate was less than 60%. Today the overall survival rate is over 90%. Much of this improvement in melanoma survival can be attributed to earlier diagnosis.
  2. Diagnosis of melanoma at earlier stages of evolution is, in part, due to increased awareness and increased surveillance.
  3. The notion that the in vivo diagnosis of melanoma is solely dependent on its clinical primary morphology derides the true complexity involved in diagnosing this malignancy. Components of the clinical examination used in the evaluation of skin lesions include touch, patient-derived anamnestic data, analytical reasoning (e.g., ABCD), comparative recognition (e.g, change), and differential recognition (e.g., ugly duckling sign).  The human cognitive process integrates this clinical information, extracting the pertinent information and rendering a diagnosis.
  4. Utilizing total body photography, dermoscopy, and dermoscopic short-term mole monitoring has contributed to the detection of many clinically subtle melanomas (improved sensitivity) and has also increased our diagnostic specificity. This translates into an improved ability to detect melanoma while concomitantly decreasing the number of unnecessary biopsies being performed on benign lesions.  Pigmented lesion experts utilizing baseline photography and dermoscopy remove approximately 5 benign nevi for every MM found. In contrast, non-experts remove as many as 30 benign nevi for every MM found.
  5. Future technologies such as confocal microscopy, computer vision, telemedicine, etc. are likely to continue to enhance the sensitivity and specificity for diagnosing early melanomas.

Maui Derm 2010: Surgical Management of Melanoma   K. Tanabe MD

In the surgical management of melanoma it is critically important to obtain adequate surgical margins. Ken Tanabe, oncology surgeon at MGH, discussed surgical margins for melanoma and the role of sentinel node biopsy and lymphatic mapping.  Recommended margins: melanoma in situ – 0.5 cm;  < 1 mm thickness – 1 cm;  1 – 2 mm thickness – 1 – 2 cm;  > 2 mm thickness – 2 cm.  These recommendations have been developed from the results of prospective randomized trials.  These margins may be modified to accommodate for anatomic or functional considerations in cases of melanomas of the face and hands.

In patients who are potential candidates for lymphatic mapping and sentinel node biopsy what does one need to know?   Dr Tanabe stated that while both offer clear advantages in enhancing accuracy of staging and regional disease control, their value in improving likelihood of long term survival remains a subject of debate. Sentinel node biopsy should be discussed with all patients with invasive, clinically localized melanoma before definitive wide local excision. Sentinel node biopsy should be considered in the following groups of patients with clinically localized melanoma > 1 mm Breslow thickness; < 1 mm Breslow thickness with positive deep margin, or > 1 mitoses, or ulceration. Patients with metastatic melanoma identified in their sentinel nodes should undergo completion lymphadenectomy, since approximately 20% of these patients will have additional (non-sentinel) nodes with melanoma. What can we offer our patients with advanced disease?  According to Dr Tanabe, in patients with hematogenous metastases, immunotherapy with IL-2 produces rare, but durable complete responses.  Conventional chemotherapy (e.g. dacarbazine) has limited activity.  Based on early trial results there is much interest in agents that target specific molecular pathways, such as Braf mutant tumors.