Recognizing Unusual Tumors Part 2: Disruptive Technologies for Skin Cancer: Electronic Brachytherapy and Superficial Radiation

Hayes B. Gladstone

As noted in previous sections, a wide range of treatment modalities are available for patients with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC).  Surgical options include curettage with electrodessication, Mohs micrographic surgery, and surgical excision; and they provide high control rates and generally satisfactory cosmetic results. However, some patients are not suitable candidates for surgery and some cases of non-melanoma skin cancer (NMSC) may not be optimally treated with surgery due to the potential for disfigurement.

Radiation Therapy

Radiation therapy, including external beam and brachytherapy techniques, has been used as primary and post-surgical adjuvant therapy for NMSC and results from published studies have indicated local control ranging from 84-97% with good tolerability (Khan, 2014).

Electronic Brachytherapy

Electronic brachytherapy (EBT) is the administration of high dose rate brachytherapy without the use of a radioactive isotope and with minimal shielding requirements due to the low energies utilized with this system.  This novel approach has been demonstrated to be effective in a large series of 187 patients with 277 NMSC lesions.  At a mean follow-up of 13 months (range = 1-51 months) there were no recurrences. The most frequent acute effects were rash in 90 (44.1%), pruritus in 9 (4.4%) and hyperpigmentation in 4 (2.0%) of 204 lesions evaluated at 1 month after treatment. The most frequent late effects were hypopigmentation in 17 (10.1%) and alopecia in 4 (2.4%) of 168 lesions evaluated at 1 or more years after treatment. Cosmesis at 3 years was excellent for 25 (89.3%) and good for 3 (10.7%) of 28 evaluable lesions; and at 4 years, was excellent for all 6 (100%) evaluable lesions Bhatnagar, 2014).

How would EBT fit into your practice?

  • Personnel:
    • Radiation oncologist
    • Radiation therapist
    • Physicist
  • Treatment:
    • Patient comes into room; portable shield (lead walls not required); machine calibrated and dose parameters set
    • Patient treated
    • Visit takes about 15 minutes twice per week for 8-12 treatments
    • Currently, can be performed in office or at a center

Superficial Radiation: a Different Model

Superficial x-ray therapy (SXRT) has been used by dermatologists for many years and it differs from modern electron beam radiotherapy in that light is the energy source rather than a charged particle. The beam in SXRT is very focused with less collateral tissue damage than EBRT; and the treatment duration is 90 seconds. A retrospective analysis performed on 1715 histologically confirmed primary cutaneous BCC and SCC 2000 and 2010 indicated cumulative recurrence rates for all tumors at 2 and 5 years of 1.9% and 5.0%, respectively.  The recurrence rates for BCC at these evaluations were 2% and 4.2% respectively; and those for SCC were 1.8% and 5.8% (Cognetta, 2012). This approach to treatment for NMSC is appropriate for patients with larger tumors in very cosmetic sensitive areas, those receiving anticoagulants, frail/elderly patients who may not tolerate surgery, and those who refuse surgical intervention.

Dermatologists should be leaders in the use of radiation therapy for the treatment of NMSC.  How do we get there?

  • Develop a method where dermatologists can independently perform EBT and SXRT:
    • Dermatologists are skin cancer experts
    • Dermatologists have historically performed external beam radiotherapy for skin conditions
    • Some dermatologists are currently performing EBT
  • There is a Task Force of Conference of Radiation Control Program Directors:
    • Dermatology is represented
    • Develop guidelines and recommend training for dermatologists in either an independent or hybrid system

 

If we aren’t proactive in advances in skin cancer treatment, then other
specialties will and patients will look elsewhere

 

References

Bhatnagar A. Electronic brachytherapy for the treatment of nonmelanoma skin cancer: results up to 4 years. Int J Radiation Oncol. 2014;90:S756.

Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J Am Acad Dermatol. 2012;67:1235-1241.

Khan L, Breen D, Zhang L, et al. Predictors of recurrence after radiotherapy for non-melanoma skin cancer. Curr Oncol. 2014;21:e326-329.

 

Recognizing Unusual Tumors Part 1: Defining and Managing High-risk Basal Cell and Cutaneous Squamous Cell Carcinoma

Dr. Suneel Chilukuri and Dr. Neil A. Swanson

Basal Cell Carcinoma

Despite the fact that treatment for basal cell carcinoma (BCC) is curative in the vast majority of cases, some patients are at high risk of recurrence and, in a few patients, lesions can progress to a point where local therapy is not possible and the prognosis is quite poor (Puig, 2015).

Characteristics of High-risk Disease

Treatment decisions in patients with BCC are usually made on the basis of estimated risk for recurrence. Aggressive, infiltrating tumors are frequently ulcerated and have ill-defined margins; ulcerated BCC is usually larger than non-ulcerated tumors and may be locally destructive. Risk associated with tumor size varies with location and is defined as >6 mm for the mask area, >1 cm for the cheek, forehead, scalp, and neck, and >2 cm in other body areas. Histological subtype should also be considered in assessing risk for relapse. Morpheaform, sclerosing, infiltrating, desmoplastic, micronodular, basosquamous, keratotic, and metatypical subtypes are associated with higher risk vs superficial and the nodular forms of BCC. Perineural invasion is also associated with a higher risk of relapse; but vascular invasion does not appear influence long-term outcomes.  Importantly, more than 30% of BCCs have mixed pathology, combining less and more aggressive subtypes (e.g., nodular BCC with areas of infiltrating BCC) (Marzuka, 2015; Puig, 2015; Proceddu, 2015).

There is no agreement on the prognostic significance of other factors, such as a previous history of radiotherapy, in patients with BCC.

Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all non-melanoma skin cancer, and has the ability to metastasize to any organ in the body. It is estimated that cSCC is diagnosed at a rate of 15-35 per 100,000 people and this is expected to increase 2-4 % per year (Burton, 2016).

Risk and Staging cSCC

Although most sSCC are easily cured, there is a high-risk subset with an increased risk of metastasis and death (Karia, 2014). Factors believed to be associated with higher risk cSCC include location on the ear, lip, or genitalia; poorly differentiated, acantholytic desmoplastic, or adenoid squamous histology; perineural invasion; and clinical features that include rapid growth, pain, paresthesias, invasion to bone, and cranial nerve involvement.

Despite identification of individual factors associated with higher risk cSCC, there is no consensus definition of high-risk disease and there is limited published information on best approaches to treatment.  At present, these high-risk patients are typically managed with a multidisciplinary approach decided on a case-by-case based on tumor board discussions. Several clinical and histologic risk factors are associated with increased risk of recurrence, metastasis, and death in patients with cSCC, but high-risk cSCC has not been consistently defined, nor has associated prognosis been estimated (Karia, 2014).  There are multiple staging systems for SCC, including those from the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and a more recently developed system developed at the Brigham and Women’s Hospital (BWH) (Jambusaria-Pahlajani, 2013; Karia, 2014). A comparison of these systems indicated that current UICC and AJCC tumor (T) staging fail to identify high-risk sSCC because the majority of poor outcomes occur in low T stages and heterogeneous tumors with diverse risk profiles. Conversely, the BWH system has four statistically distinct stages and enhanced ability to appropriately upstage high-risk tumors from low to high stages (Karia, 2014).

What to do in defining risk in your patients with BCC or cSCC:

  • Consider clinical presentation and histology
  • Be aware of a new validated approach to staging patients with SCC.

Interventions in cSCC and BCC

Retinoids for Prevention Treatment of Skin Cancer

Systemic retinoids have been shown to be effective for the prevention of skin cancer (Tilley, 2015); and initiation of prophylaxis is indicated to prevent morbidity from multiple primary tumors and to decrease the risk of death from high-risk tumors.  Candidates for retinoid administration include patients with xeroderma pigmentosum, basal cell nevus syndrome, or severe sun damage; and patients who are immunosuppressed for solid organ transplantation or with chronic lymphocytic leukemia (Reilly, 2004).

Delivering retinoids for skin cancer prevention – practical considerations:

  • Start Low: 10 mg/day
  • Gradually increase the dose to 20-30 mg/day
  • Titrate the dose to prevent/manage side effects (chelitis, skin peeling, scalp alopecia, hyperotosis, hyperlipidemia)
  • Understand that this is potentially life-long treatment and educate your patient
  • Drug holidays may help to treat transient side effects
  • Try to decrease immunosuppression in conjunction with this treatment
  • Be aware of risk for elevations in triglycerides and hepatic transaminases

Smoothened Inhibitors in the Treatment of BCC and Risk for cSCC

The smoothened inhibitors, vismodegib and sonidegib, have been shown to be highly effective for the treatment of patients with advanced BCC (e.g., Sekulic, 2012; Migden, 2015); and many new agents from this class (e.g., saridegib, CUR61414, BMS-833923, LEQ506, PF-04449913, TAK-441) are in development for the treatment of BCC and other cancers. However, extensive use of vismodegib in patients with BCC has been associated with increased risk for the development of cSCC.  Case reports have described emergence of new-onset keratoacanthomas and cSCCs in patients with advanced BCCs during vismodegib therapy (Aasi, 2013; Orouji, 2014); and results from a recent case-control study carried out at the Stanford Medical Center which included 180 patients indicated that treatment of BCC with vismodegib was associated with a >6-fold increase in the risk for cSCC (Mohan, 2016).  The mechanism(s) underlying this phenomenon are not understood, but it has been suggested that smoothened inhibition may inadvertently activate the RAS/MAPK pathway, thereby promoting tumorigenesis (Zhao, 2015).

What to remember and what to do:

  • BCC with apparent resistance to vismodegib may actually be newly developed cSCC
  • Perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors
  • Patients with advanced BCCs who are considering vismodegib should be advised that this treatment seems to increase the risk for subsequent cSCC

References

Aasi S, Silkiss R, Tang JY, et al. New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol. 2013;149:242-243.

Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol. 2016 Jun 29. [Epub ahead of print].

Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149:402-410.

Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32:327-334.

Marzuka AG, Book SE. Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J Biol Med. 2015;88:167-179.

Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-728.

Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol. 2016;152:527-532.

Orouji A, Goerdt S, Utikal J, Leverkus M. Multiple highly and moderately differentiated squamous cell carcinomas of the skin during vismodegib treatment of inoperable basal cell carcinomas. Br J Dermatol. 2014;171:431-433.

Porceddu SV. Prognostic factors and the role of adjuvant radiation therapy in non-melanoma skin cancer of the head and neck. Am Soc Clin Oncol Educ Book. 2015:e513-518.

Puig S, Berrocal A. Management of high-risk and advanced basal cell carcinoma. Clin Transl Oncol. 2015;17:497-503.

Reilly P, DiGiovanna JJ. Retinoid chemoprevention in high-risk skin cancer patients. Dermatol Nurs. 2004;16:117-120, 123-126; quiz 127.

Sekulic A, Migden MR, Oro AE, et al Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171-2179.

Zhao X, Ponomaryov T, Ornell KJ, et al. RAS/MAPK activation drives resistance to Smo inhibition, metastasis, and tumor evolution in Shh pathway-dependent tumors. Cancer Res. 2015;75:3623-3635.