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Locally Advanced Basal Cell Carcinoma: Option “H”

by Debra Shelby, PhD, DNP, DCNP, FNP-BC, FACDNP, FAANP

Basal cell carcinoma (BCC) is the most common form of cancer with over 4 million cases are diagnosed annually.[1]  The two most common subtype is nodular BCC accounting for more than 60% of tumors and superficial BCC accounting for up to 15%, Infiltrating comprises 5% and morpheaform BCC accounts for 3% of all BCCs. [2] In up to 10% of cases, BCC can progress into locally advanced BCC (laBCC) and metastasis can occur in less than 1%.[3]

Current treatments for BCC 2  (not in order of preference):

  1. Mohs Surgery/excision/saucerization
  2. Biologic response modifiers: Interferon-?
  3. Cryotherapy
  4. PDT phototherapy
  5. EDC
  6. 5FU (Topical chemotherapy)
  7. Imiquimod
  8. Hedgehog Inhibitors
  9. Radiation Therapy
  10. Trichloroacetic acid (TCA)
  11. Laser

Before making the decision on what the best treatment options are for your patient, the clinician must consider factors which affect the best patient outcome. This includes the type of BCC, site, risk, and the age, comorbidities, financial and support system of the patient.

When treating patients with skin cancer, you may encounter other challenges. This is especially true when dealing with the geriatric population. With over 17 years of treating the elderly in my dermatology practice, the most difficult cases were encountered in extended living facilities. Limitations with treatment can occur with major comorbidities, dementia, disabilities, patients confined to the bed, and power of attorney issues. Financial concerns and lack of family support play a major role in deciding the best treatment options. Many patients have locally advanced BCC that cannot to be treated with the more conventional methods clinicians tend to prescribe.  These limitations leave the health care provider feeling frustrated after exhausting all options available for the patient and family. Fortunately, a new treatment option is available with the use of hedgehog pathway inhibitors, “option H”. Patients with locally advanced BCC who are not candidates for surgery and radiation can be evaluated for this medication.

Hedgehog (Hh) Pathway Inhibitors

Hedgehog signaling pathway controls proliferation, differentiation and cell fate. It is involved in the normal embryonic development. Hh pathway inhibitors target tumors with Hh mutations, like BCC, resulting in decreased tumor proliferation, increased apoptosis, and tumor regression.2 There are two current hedgehog inhibitors: Vismodegib (Genentech) and Sonidegib (Sun Pharmaceuticals). These medications are FDA approved for locally advanced BCC.

Hh Pathway Inhibitors*

Vismodegib                (Genentech) Sonidegib        (Sun Pharmaceuticals)
150mg hard capsule QD 200mg capsule QD
Erivedge was studied in one main study involving 104 patients with either metastatic or locally advanced basal cell carcinoma. The patients were given Erivedge until their disease got worse or they could no longer tolerate treatment or withdrew from the study. Erivedge was not compared

with another treatment. The main measure of effectiveness was the response to treatment, based on reduction by at least 30% in tumour size or disappearance of all signs of cancer (the objective response rate). Around 33% (11 out of 33) of patients with metastatic disease and 48% (30 out of 63) of patients with locally advanced disease responded to treatment.4 Study Trial used BCC-RECIST criteria.

Odomzo was studied in one main study involving 230 patients with basal cell carcinoma which was either locally advanced or metastatic (spread to other parts of the body). Patients were started on two different doses of Odomzo: 200 or 800 mg once a day. The main measure of effectiveness was the response to treatment, based on a reduction in tumor size and improvement in other signs of cancer; treatment was considered sufficiently effective if the response rate was at least 30%.Of those with locally advanced basal cell carcinoma, around 56% (37 of 66 patients) on the 200-mg dose and 45% (58 of 128 patients) started on the 800-mg dose responded to treatment. Response rates were less than 20% in patients with metastatic cancer started on either 200 or 800 mg Odomzo and the company withdrew its application for use in metastatic basal cell carcinoma. 5 Study trial used stringent mRECIST criteria.6

*Please review package inserts for complete study.

                                                        

  • co.UK .https://imedi.co.uk/erivedge. Updated October 20, 2016. Accessed November 12, 2017
  • co.UK. https://imedi.co.uk/odomzo. Update August 20, 2015. Accessed November 12, 2017
  • Lear JT, Migden MR, Lewis KD, et al. Long term efficacy and safety of sonidegib in patients with locally advanced and metastatsic basal cel carcinoma: 30-month analysis of randomized phase 2 BOLT study. J Eur Acad Dermatol Venereal. 2017.

 

 

 

Important Safety Concerns and Side Effects

  1. When prescribing Hh inhibitors, it is important to remember that they play an important role in embryonic development. Therefore, when prescribing to child-bearing females, they must use effective contraception due to the risk of severe birth defects. Contraception must continue for at least 20 months after last dose. Males have a risk of exposure through semen and must use condoms with a pregnant partner or female partner who has reproductive potential for at least 8 months after last dose.
  2. Breastfeeding: Females must not breastfeed for at least 20 months after last dose.
  3. Semen/Blood Donation: Patients are not to donate blood or blood products for at least 20 months after last dose. Medication is found in semen so no semen donation for 3 months after last dose.
  4. Musculoskeletal Adverse Reactions: Musculoskeletal adverse reactions can occur with HHIs. The patient may have serum creatine kinase (CK) elevations and should be closely monitored for CK elevation in the presence of musculoskeletal reactions.
  5. Drug Interactions: Avoid concomitant administration with CYP3A inhibitors. If moderate CYP3A inhibitors must be used, administer for less than 14 days and monitor closely for adverse reactions. Avoid strong to moderate CYP3A inducers.
  6. Geriatric use: There was a higher incidence of serious adverse events in the geriatric population versus younger patient.
  7. Premature Fusion of the Epiphyses in pediatric patients

Most Common Side Effects: The most common side effects include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus.

Please review full prescribing information to review complete discussions on risks associated with HHI medications. 6 [4]

Workup

Guidelines for CK monitoring came with the development of musculoskeletal side effects and elevated CK levels. While the FDA study did not require CK monitoring for Vismodegib, it makes sense and is highly suggested to order baseline CK and monitor with both Hh pathway inhibitors. If elevation occurs with musculoskeletal adverse reactions, weekly CK levels should be ordered until resolved. Baseline pregnancy test must be ordered for any patient with reproductive capability. It is up to each individual clinician to determine additional baseline and monitoring laboratory testing they want to order. 6 7

Dosage

Typical dosage is 150-200mg QD. Clinicians who use this medication have used pulsed-dosing to reduce the occurrence of side effects and have been successful in achieving longer duration of treatment compared to QD dosing. 7

Case study

A 67 year old female in an extended living facility with multiple occurrences of nodule BCC and local advanced BCC. Patient and family refusing surgery, radiation therapy, topical medications, and cryotherapy. Hh inhibitors discussed with patient and family as an option to treat multiple sites. Consent was given in hope that not only these lesions would be treated, but also any subclinical BCC that had not yet presented itself clinically. Patient had a history of >15 nodule and laBCC neoplasms.

Left shoulder: Nine weeks post treatment. Patient received pulsed dosing 5 weeks of medication, one week off, four weeks on. Patient experienced mild nausea at 5 weeks. Drug stopped for one week and nausea resolved. Medication was restarted for an additional 4 weeks without any other adverse events. For my clinical practice, protocols include interrupted therapy consisting of 4 weeks of medication, one week off, then restarting medication for another 4 weeks. This regimen has worked well with avoiding and/or managing adverse events in the geriatric patient.

Patient, Family, and Facility Education

Treatment goals vary for each patient, especially for the geriatric patient and family who view success with tumor reduction and not complete resolution. Life expectancy and quality of life issues are raised with large, ulcerating tumors that are colonized with bacteria. Having an open discussion with the patient and family regarding potential side effects and management of adverse events are critical for the success of the treatment.

Many extended living facilities find the care of these ulcerating lesions difficult and often frustrating to manage. Wound care is costly and the patient is often isolated from the general population because of unsightly wounds and foul odors. Psychosocial affects include depression, anxiety and poor body image.

The approach to the care of this patient is a team effort. Education of new treatment modalities are crucial for having cooperation with everyone involved. Educating other providers on the medication should be at the beginning stages. The caretaker or nurse will need to be educated on adverse side effects and correct administration of the medication reviewed. These oral medications should be given one hour prior a meal or two hours after a meal. Compliance relies on education of these medications and mechanism of action.[5]

Conclusion

The dermatology specialist must be aware and of all treatment modalities for skin cancer. It is our duty as a health care provider to disclose all treatments available to the patient during informed consent. Our role is to educate on the risks and benefits of these treatments and help the patient and family decide what is best for their situation. While it is common for a provider to have a bias on preferred methods, sometimes the only option for patients are treatments outside of what they normally prescribe.

Hedgehog inhibitors are a viable, important option for patients with laBCC. Patient selection and education is paramount to successful outcomes. Equally important, is the provider’s understanding of the mechanism of action, management of adverse events, appropriate dosing and monitoring of patient. Prescribing these medications and seeing the impact on the patient’s physical and psychosocial wellbeing will help the clinician gain confidence in prescribing this valuable medication.

 

 

Disclosure: Author is a Sun Pharma independently contracted speaker on Odomzo. Please review medication packet inserts for study outcomes and additional information on these medications.

 

[1] Skin Cancer Foundation. http://www.skincancer.org/skincancerinformation/skincancerfacts. Updated February 2, 2017. Accessed November 12, 2017.

[2] Bolognia, J.,Jorizzo,J., Rapini, R, (2003). Dermatology. Elsevier: Mosby. page 1671, 1687

[3] Mohan, SV., Chang, ALS. Advanced basal cell carcinoma: epidemiology and therapeutic innovations. Curr Derm Rep. 2014, 3(1):40-45.

[4] Dreno, B. et al (2017).Two intermittent vismodegib dosing regimens in patients with multiple basal cell carcinomas (MIKIE): a randomized, regimen-controlled, double blind, phase 2 trial. Lancet Oncol. 2017 Mar, 18(3):404-412. Doi:10.10161/S14702045(17)30072-4.

[5] Odomzo (sonidegib) {Prescribing information].Cranbury, NJ:Sun Pharmaceutical Industries, Inc, 2017.

 

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