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Treatment of Basal Cell Carcinoma in the Elderly: What Nondermatologists Need to Know

      Abstract

      As the population ages and incidence of basal cell carcinoma continues to increase, we will be faced more frequently with difficult treatment decisions for basal cell carcinoma in the elderly. Different treatment options, including surgical excision, electrodessication and curettage, cryosurgery, imiquimod, photodynamic therapy, 5-fluorouracil, radiation therapy, vismodegib, combination therapy, and observation, may be considered on the basis of tumor characteristics. Given the wide range of therapeutic options, treatments can be tailored to achieve patients' goals of care within their anticipated life expectancy.

      Keywords

      Clinical Significance
      • As the population ages and incidence of basal cell carcinoma continues to increase, we will be faced more frequently with difficult treatment decisions for basal cell carcinoma in the elderly.
      • Different treatment options may be considered on the basis of tumor characteristics.
      • Given the wide range of treatment options for basal cell carcinoma, treatments can be tailored to achieve patients' goals of care within their anticipated life expectancy.
      In the United States, basal cell carcinoma accounts for approximately 25% of all diagnosed cancers, with more than 2.8 million new cases diagnosed each year, and is the most common malignancy in Caucasians.
      • Crowson A.N.
      Basal cell carcinoma: biology, morphology and clinical implications.
      • Goldsmith L.A.
      • Fitzpatrick T.B.
      Fitzpatrick's Dermatology in General Medicine.
      • Rogers H.W.
      • Coldiron B.M.
      Analysis of skin cancer treatment and costs in the United States Medicare population, 1996-2008.
      • Baxter J.M.
      • Patel A.N.
      • Varma S.
      Facial basal cell carcinoma.
      • Mohan S.V.
      • Chang A.L.
      Advanced basal cell carcinoma: epidemiology and therapeutic innovations.
      Although the US Preventive Services Task Force does not recommend routine screening for skin cancer and recently stated that the current evidence is insufficient to assess the balance of benefits and harms of visual skin cancer screening,
      because these malignancies often occur in sun-exposed areas, they often will be detected by patients, their families or friends, or examining physicians.
      In part because of a decline in fertility and a 20-year increase in average life span during the latter half of the 20th century, the median age of the world's population is increasing.
      Centers for Disease Control and Prevention
      Trends in aging–United States and worldwide.
      • Mathers C.D.
      • Stevens G.A.
      • Boerma T.
      • White R.A.
      • Tobias M.I.
      Causes of international increases in older age life expectancy.
      Given the recent increase in diagnosis of basal cell carcinoma without a change in death rate, some authors suggest that basal cell carcinoma is being overdiagnosed in the elderly and have proposed that practitioners differentiate the treatment of symptomatic vs screening-detected basal cell carcinomas in the elderly.
      • Linos E.
      • Schroeder S.A.
      • Chren M.M.
      Potential overdiagnosis of basal cell carcinoma in older patients with limited life expectancy.
      As the population ages and incidence of basal cell carcinoma continues to increase, we will be faced more frequently with difficult patient questions and treatment decisions: What is the appropriate treatment for basal cell carcinoma in the elderly? Should the basal cell carcinoma of a patient with a limited life expectancy be treated in the same way as that of a younger patient? Can nonagenarians safely undergo surgical excision or Mohs micrographic surgery? These questions and others are increasingly being addressed in the dermatologic and internal medicine literature, and nondermatologists should be able to discuss options with patients in clinical practice (Table).
      TableAdvantages and Disadvantages of Basal Cell Carcinoma Treatment Options
      ModalityAdvantagesDisadvantages
      Mohs micrographic surgeryComplete margin analysis

      Well tolerated by elderly

      Gold standard treatment
      Cost

      Longer procedure (stages)
      Conventional surgical excisionWell tolerated by elderlyCost

      Lack of complete margin analysis
      Electrodessication and curettageShorter procedure

      Does not require return visit

      Patients can avoid surgery
      Lack of histologic confirmation of malignancy removal

      Not appropriate for lesions with extension into deep dermis
      CryosurgeryPatients can avoid surgeryHigher recurrence rates than surgery

      Lack of histologic confirmation of malignancy removal

      Recurrent carcinoma could become extensive (can be obscured by fibrous scar tissue)

      Hypertrophic scarring

      Postinflammatory pigment changes
      ImiquimodPatient self-administration

      Excellent cosmetic results
      Local skin reactions

      Lack of histologic confirmation of malignancy removal

      Cost
      Photodynamic therapyExcellent cosmetic outcomeHigher recurrence rates than with surgery

      Lack of histologic confirmation of malignancy removal
      5-FUPatient self-administrationHigher recurrence rates than with surgery
      Radiation therapyGood option in patients who are not surgical candidatesCost

      Higher recurrence rates than with surgery

      Scars tend to worsen with time
      VismodegibApproved for metastatic BCC and locally advanced BCC that has recurred following surgery; option in patients who are not surgical or radiation therapy candidatesCan require 15-30 visits

      Side effects are considerable

      Cost
      ObservationPatients can avoid surgery

      Cost
      No standard as to length of time for which it is appropriate to monitor patients clinically

      More dangerous neoplasm may be missed (such as Merkel cell carcinoma or amelanotic melanoma)
      BCC = basal cell carcinoma; 5-FU = 5-fluorouracil.
      In a study of treatment patterns for nonmelanoma skin cancer including basal and squamous cell carcinomas among patients with limited life expectancy, defined as age of 85 years or older or a Charlson Comorbidity Index of 3 or higher, 70.1% underwent surgery, of whom 33.9% underwent Mohs surgery and 36.2% underwent simple surgical excision, 25.2% were treated with destruction (a broad category that included cryotherapy, electrodessication and curettage, laser, and irradiation), and 3.3% received no treatment. There was no significant difference noted in rates of the various treatment types, including surgery, according to patient life expectancy. This study also reported complications in approximately 20% of patients with limited life expectancy, compared with 15% in other patients.
      • Linos E.
      • Parvataneni R.
      • Stuart S.E.
      • Boscardin W.J.
      • Landefeld C.S.
      • Chren M.M.
      Treatment of nonfatal conditions at the end of life: nonmelanoma skin cancer.

      Treatment Options

      Different treatment options may be considered on the basis of tumor characteristics. “High-risk” basal cell carcinomas have been defined as those of long duration, larger than 2 cm in diameter, with anatomic location in the mid-face or ear, with aggressive histologic subtype (infiltrative, sclerosing, morpheaform, or micronodular), with recurrence despite previous treatment, that are neglected, or occurring in patients with a history of radiation exposure.
      • Randle H.W.
      Basal cell carcinoma. Identification and treatment of the high-risk patient.
      • Wiznia L.E.
      • Shanley K.M.
      • Federman D.G.
      Advanced, neglected basal cell carcinoma.
      Conversely, low-risk basal cell carcinomas are those on the trunk or limbs, less than 1 cm in size, and in patients without a history of radiation exposure and who are not organ transplant recipients. The incidence of metastatic basal cell carcinoma is low, reported between 0.0028% and 0.5%,
      • Saadoun D.
      • Resche Rigon M.
      • Pol S.
      • et al.
      PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis.
      with more than 80% of these originating from head and neck primary basal cell carcinomas.
      • von Domarus H.
      • Stevens P.J.
      Metastatic basal cell carcinoma. Report of five cases and review of 170 cases in the literature.
      Histologic subtypes that are more aggressive, such as the aforementioned infiltrative, sclerosing, morpheaform, and micronodular, are at increased risk of subclinical tumor extension and metastasis.
      • Lewin J.M.
      • Carrucci J.A.
      Management of aggressive basal cell carcinoma.
      Therefore, Mohs surgery, with its complete margin analysis, is typically preferred over standard excision followed by “bread loaf” processing of sections in these aggressive subtypes.
      • Salasche S.J.
      • Amonette R.A.
      Morpheaform basal-cell epitheliomas. A study of subclinical extensions in a series of 51 cases.

      Surgical Excision

      Surgical treatment options for basal cell carcinomas include conventional surgical excision and Mohs micrographic surgery. Mohs surgery is considered the gold standard of therapy for a variety of nonmelanoma skin cancers in large part because of its complete margin analysis that can delineate subclinical tumor spread.
      • Lee K.C.
      • Higgins H.W.
      • Lajevardi N.
      • Cruz A.P.
      • Dufresne Jr., R.G.
      Characteristics of squamous cell carcinoma in situ of the ear treated using mohs micrographic surgery.
      The appropriate use criteria for Mohs surgery, which were developed in 2012 by the American Academy of Dermatology in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery, did not specifically address age in their recommendations of appropriateness of Mohs surgery for specific tumor types and anatomic locations.
      • Connolly A.H.
      • Baker D.R.
      • Coldiron B.M.
      • et al.
      AAD/ACMS/ASDSA/ASMS 2012 Appropriate Use Criteria for Mohs Micrographic Surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery.
      These criteria ascertained that Mohs surgery was appropriate for the majority of basal cell carcinomas, although it was designated inappropriate in certain forms and subtypes of patients (eg, for low-risk subtypes including recurrent superficial and primary nodular basal cell carcinoma when located on the trunk and extremities, excluding pretibial surface, hands, feet, nail units, and ankles).
      Mohs surgery has been reported to take 3 times as long as conventional excision, with mean procedure length of the former reported as 3 hours vs 1 hour for the latter.
      • Essers B.A.
      • Dirksen C.D.
      • Nieman F.H.
      • et al.
      Cost-effectiveness of Mohs micrographic surgery vs surgical excision for basal cell carcinoma of the face.
      This increase in procedure length has been suggested to be more problematic for frail patients,
      • Linos E.
      • Parvataneni R.
      • Stuart S.E.
      • Boscardin W.J.
      • Landefeld C.S.
      • Chren M.M.
      Treatment of nonfatal conditions at the end of life: nonmelanoma skin cancer.
      although Mohs surgery has been shown to be a safe procedure in the elderly. A retrospective study of 115 nonagenarians (average age of 92.4 years) who underwent Mohs surgery for skin cancer (including nonmelanoma skin cancer and melanoma) reported just 1 postsurgical complication and concluded that Mohs surgery is a safe and effective therapy for this population.
      • MacFarlane D.F.
      • Pustelny B.L.
      • Goldberg L.H.
      An assessment of the suitability of Mohs micrographic surgery in patients aged 90 years and older.
      A different study in nonagenarians having undergone Mohs for nonmelanoma skin cancer reported a median survival of 36.9 months, with no complications.
      • Delaney A.
      • Shimizu I.
      • Goldberg L.H.
      • MacFarlane D.F.
      Life expectancy after Mohs micrographic surgery in patients aged 90 years and older.
      This study also found that tumor type, size, location, number of stages, and defect size did not affect survival. Specifically, there was no survival difference between patients who underwent 1 to 2 stages and those who had ≥3. The only significant risk factor the study identified was gender, with women experiencing a survival advantage over men (P <.02), as is consistent with average life expectancy and earlier studies.
      • Charles A.J.
      • Otley C.C.
      • Pond G.R.
      Prognostic factors for life expectancy in nonagenarians with nonmelanoma skin cancer: implications for selecting surgical candidates.
      The role of comorbid conditions on survival after Mohs micrographic surgery also has been studied. A retrospective study of 99 nonagenarians who underwent Mohs micrographic surgery for nonmelanoma skin cancer found that patients without comorbidities (as quantified by the Charlson index) had a significantly longer survival than those with multiple comorbidities (≥3). The same study also found that women survived longer than men at both 1 and 5 years follow-up.
      • Charles A.J.
      • Otley C.C.
      • Pond G.R.
      Prognostic factors for life expectancy in nonagenarians with nonmelanoma skin cancer: implications for selecting surgical candidates.
      These findings suggest a role for considering comorbid conditions when evaluating life expectancy and treatment approach in basal cell carcinomas.

      Electrodessication and Curettage

      Dermatologists frequently use electrodessication with curettage to treat basal cell carcinomas, and cure rates as high as 97% to 98.8% have been reported.
      • Spiller W.F.
      • Spiller R.F.
      Treatment of basal cell epithelioma by curettage and electrodesiccation.
      • Rodriguez-Vigil T.
      • Vázquez-López F.
      • Perez-Oliva N.
      Recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation.
      This treatment is not considered appropriate for lesions with extension into the deep dermis. Lesional and perilesional skin are anesthetized, with curettage and electrodessication following in 2 to 3 cycles. The highest cure rates have been reported with a 2- to 8-mm peripheral margin from the initial curettage. One study reported an inverse relationship between cure rate and lesion size: The cure rate for lesions smaller than 1.0 cm was reported at 98.8% vs 84% for lesions larger than 2.0 cm.
      • Spiller W.F.
      • Spiller R.F.
      Treatment of basal cell epithelioma by curettage and electrodesiccation.

      Cryosurgery

      Cryosurgery is used frequently to treat actinic keratoses but also has been used to treat nonmelanoma skin cancer in patients who want to avoid surgery. At least 3 freeze-thaw cycles with liquid nitrogen (−196°C, freezing duration of 40-60 seconds) with tissue temperature of −50°C are required to destroy basal cell carcinoma. A margin of skin that clinically appears normal also must be destroyed to fully eradicate subclinical extension.
      • Ceilley R.I.
      • Del Rosso J.Q.
      Current modalities and new advances in the treatment of basal cell carcinoma.
      Five-year basal cell carcinoma recurrence rates after cryosurgery have been reported to range from 4% to 17%.
      • Thissen M.R.
      • Neumann M.H.
      • Schouten L.J.
      A systematic review of treatment modalities for primary basal cell carcinomas.
      Complications from cryosurgery include hypertrophic scarring and postinflammatory pigment changes. Other concerns include the lack of histologic confirmation of malignancy removal, and recurrent carcinoma can become extensive because it can be obscured by fibrous scar tissue.
      • Bolognia J.
      • Jorizzo J.L.
      • Schaffer J.V.
      Dermatology.

      Imiquimod

      Imiquimod signals to the innate arm of the immune system through toll-like receptor 7, promoting T-helper 1-type immunity, and is approved by the Food and Drug Administration for the treatment of superficial basal cell carcinomas located on the trunk, neck, or extremities (excluding anogenital skin and hands or feet) with a maximum diameter of 2 cm. The cream is applied 5 days/week for 6 weeks at bedtime, with the patient leaving the cream on overnight and washing it off in the morning. Advantages over surgery include patient self-administration and excellent cosmetic results.
      • Peris K.
      • Campione E.
      • Micantonio T.
      • Marulli G.C.
      • Fargnoli M.C.
      • Chimenti S.
      Imiquimod treatment of superficial and nodular basal cell carcinoma: 12-week open-label trial.
      Local skin reactions have been reported as adverse events.

      Photodynamic Therapy

      Photodynamic therapy requires topical application of a photosensitizer and illumination with a specific wavelength of visible light. The long-term cure rates with photodynamic therapy for superficial basal cell carcinoma are 75%.
      • Szeimies R.M.
      • Ibbotson S.
      • Murrell D.F.
      • et al.
      A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small superficial basal cell carcinoma (8-20 mm), with a 12-month follow-up.
      Other studies have shown a higher recurrence rate (30.7%) with photodynamic therapy than with surgery (2.3%) at 5-year follow-up.
      • Roozeboom M.H.
      • Aardoom M.A.
      • Nelemans P.J.
      • et al.
      Fractionated 5-aminolevulinic acid photodynamic therapy after partial debulking versus surgical excision for nodular basal cell carcinoma: a randomized controlled trial with at least 5-year follow-up.
      A Cochrane review noted that the cosmetic outcome with photodynamic therapy was better than that with surgery.
      • Bath-Hextall F.
      • Leonardi-Bee J.
      • Somchand N.
      • Webster A.
      • Delitt J.
      • Perkins W.
      Interventions for preventing non-melanoma skin cancers in high-risk groups.

      5-Fluorouracil

      5-Fluorouracil is a topically applied pyrimidine analog cream that is an antimetabolite. One study reported 90% histologic clearance of superficial basal cell carcinomas after 3 weeks of treatment with 5-fluorouracil, although no follow-up was reported.
      • Gross K.
      • Kircik L.
      • Kricorian G.
      5% 5-Fluorouracil cream for the treatment of small superficial Basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction.
      A recent large study of high-risk patients found that a history of the use of fluorouracil predicted the development of morpheaform basal cell carcinoma but did not increase the overall risk of basal cell carcinoma.
      • Xiong M.Y.
      • Korgavkar K.
      • Digiovanna J.J.
      • Weinstock M.A.
      Group VATTCT
      Fluorouracil and other predictors of morpheaform basal cell carcinoma among high-risk patients: the Veterans Affairs Topical Tretinoin Chemoprevention Trial.

      Radiation Therapy

      Although there are few health conditions that preclude a patient from undergoing office-based surgery with local anesthetia,
      • Kauvar A.N.
      • Arpey C.J.
      • Hruza G.
      • Olbricht S.M.
      • Bennett R.
      Consensus for nonmelanoma skin cancer treatment, part II: squamous cell carcinoma, including a cost analysis of treatment methods.
      if surgery is contraindicated or refused, radiation therapy is a primary option for treating. Patients aged more than 60 years are considered preferred candidates because of concerns of potential long-term side effects. External beam radiation, superficial x-ray therapy, and brachytherapy all have been used to treat basal cell carcinoma. Radiation therapy has higher recurrence rates than surgery for basal cell carcinoma, with recurrence rates of 2% at 2 years and 4.2% at 5 years reported in a retrospective review of 712 basal cell carcinomas treated with 5 sessions of superficial x-ray therapy.
      • Cognetta A.B.
      • Howard B.M.
      • Heaton H.P.
      • Stoddard E.R.
      • Hong H.G.
      • Green W.H.
      Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients.
      A study of 347 patients with primary facial basal cell carcinomas randomly assigned to surgery or interstitial brachytherapy revealed 4-year recurrence rates of 0.7% for surgery and 7.5% in the brachytherapy group.
      • Avril M.F.
      • Auperin A.
      • Margulis A.
      • et al.
      Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study.
      Unlike in surgery, scars from radiation treatment tend to worsen with time. A course of radiation requires 15 to 30 visits and is expensive; in fact, the cost for radiation therapy has been reported as 267% to 316% more expensive than Mohs surgery.
      • Lear W.
      • Mittmann N.
      • Barnes E.
      • Breen D.
      • Murray C.
      Cost comparisons of managing complex facial basal cell carcinoma: Canadian study.

      Vismodegib

      Vismodegib, a selective inhibitor of hedgehog pathway activation, was first reported to have antitumor activity in basal cell carcinoma in 2009. Since then, vismodegib has been Food and Drug Administration approved for the treatment of metastatic basal cell carcinoma and locally advanced basal cell carcinoma that has recurred after surgery, or in patients who are not surgical or radiation therapy candidates. Side effects including weight loss, muscle cramps, and loss of taste can be considerable and lead many patients to discontinue the treatment. One study of patients with basal cell nevus syndrome reported that more than half of the patients discontinued vismodegib treatment because of side effects.
      • Tang J.Y.
      • Mackay-Wiggan J.M.
      • Aszterbaum M.
      • et al.
      Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.
      Cost is another issue; vismodegib costs approximately $8600 per month, with typical courses lasting 10 months.

      Combination Therapy

      More than 1 therapeutic modality can be used to treat a given patient's basal cell carcinoma. Both topical 5% imiquimod and 5-fluorouracil cream have been used to pretreat basal cell carcinoma sites before Mohs surgery, decreasing the overall wound size.
      • Ceilley R.I.
      • Del Rosso J.Q.
      Current modalities and new advances in the treatment of basal cell carcinoma.
      Curettage after 6 weeks of topical 5% imiquimod cream was reported to have excellent cosmetic results.
      • Bolognia J.
      • Jorizzo J.L.
      • Schaffer J.V.
      Dermatology.

      Observation

      Observation has been proposed as a treatment option in the elderly, although there is no accepted standard as to a length of time for which it is appropriate to monitor patients clinically. Recently, some authors have proposed active surveillance of patients with life expectancy of less than 1 year, suggesting to photograph and measure the concerning lesion and follow up with the patient in 3 months.
      • Linos E.
      • Berger T.
      • Chren M.M.
      Point: care of potential low-risk basal cell carcinomas (BCCs) at the end of life: the key role of the dermatologist.
      Basal cell carcinomas are considered slow-growing tumors, but we cannot predict just how slowly a basal cell carcinoma grows. Furthermore, if a lesion clinically suggestive of a basal cell carcinoma is not biopsied and is instead observed, there is concern that a more dangerous neoplasm such as Merkel cell carcinoma or amelanotic melanoma could be missed.

      Cost

      In a study of costs related to treatment, electrodessication/curettage was the cheapest modality, with radiation therapy being the most expensive. In this study, treatment of a basal cell carcinoma on the cheek with imiquimod ($959) was less expensive than Mohs surgery ($1263).
      • Rogers H.W.
      • Coldiron B.M.
      Analysis of skin cancer treatment and costs in the United States Medicare population, 1996-2008.
      Office-based excision has been reported as costing $1006, although with increased lesion size, excision can become more expensive than imiquimod. Mohs surgery costs approximately 25% more than excision with immediate repair, although with increasing lesion size, the cost of the 2 procedures becomes closer.
      • Rogers H.W.
      • Coldiron B.M.
      A relative value unit-based cost comparison of treatment modalities for nonmelanoma skin cancer: effect of the loss of the Mohs multiple surgery reduction exemption.
      Radiation therapy for a basal cell carcinoma on the cheek was reported as costing between $2591 and $3460.
      • Rogers H.W.
      • Coldiron B.M.
      A relative value unit-based cost comparison of treatment modalities for nonmelanoma skin cancer: effect of the loss of the Mohs multiple surgery reduction exemption.

      New Treatment Algorithms

      The aforementioned treatments depend on a biopsy that identifies the basal cell carcinoma. A new study compared this traditional management scheme with a “detect-and-treat”scheme that eliminated the biopsy before initiating treatment. By eliminating the biopsy and instead undergoing either shave removals with histologic confirmation of diagnosis and margin clearance (in small lesions on the trunk and extremities) or direct referral to Mohs surgery for histologic confirmation of diagnosis followed by Mohs excision (for patients with lesions in Mohs-indicated areas as assessed by the aforementioned Appropriate Use Criteria), patients can avoid several office visits and waiting for appointments and histopathologic results before treatment is initiated. The authors found that their new scheme led to an average cost savings of 15% per treated lesion, and they conclude that this reduction in cost is possible without compromising care.
      • Wu X.
      • Elkin E.B.
      • Jason Chen C.S.
      • Marghoob A.
      Traditional versus streamlined management of basal cell carcinoma (BCC): a cost analysis.

      Conclusions

      Nondermatologists may be the initial clinicians to encounter an elderly patient with basal cell carcinoma. A discussion among the physician, patient, and family members can include the expected biological behavior of the tumor on the basis of the anatomic location and the pathologic findings of the biopsy, treatment options and anticipated results, cost and duration of care, and time to achieve the final result.
      • Lee E.H.
      • Brewer J.D.
      • MacFarlane D.F.
      Optimizing informed decision making for basal cell carcinoma in patients 85 years or older.
      Given the wide range of therapeutic options for basal cell carcinoma, treatments can be tailored to achieve patients' goals of care within their anticipated life expectancy.

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