Case Report: Melanoma

Melanoma is responsible for approximately 1% of all skin cancers but is associated with the highest rate of deaths among patients with skin cancer.¹ Surgical resection remains the main treatment for early cutaneous melanoma; however, excised melanomas that have high-risk features and lymph node involvement are associated with an increased risk of recurrent disease. Until recently, adjuvant high-dose interferon has been the only approved medication for stage 3 melanoma. The use of ipilimumab (Yervoy), a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, has been shown to significantly decrease the rate of cancer recurrence and may offer an alternative to high-dose interferon.²

Melanoma is one of the most common and preventable cancers in the United States. This disease is notorious for being untreatable other than by complete cutaneous excision. According to the American Cancer Society, an estimated 76,380 new cases of invasive melanoma will be diagnosed in the United States in 2016.³ Excision is usually extremely effective but depends on early detection (at stage 1 or 2) prior to lymph node involvement.⁴

Stage 3 melanoma is diagnosed through a sentinel lymph node biopsy or through biopsy of other forms of lymphatic regional metastases.⁵ In stage 4, patients have known systemic metastases in distant sites.⁵ Until recently, the use of adjuvant immunotherapy with high-dose interferon-alfa has been the only approved therapy for stage 3 melanoma.¹ With the introduction of the new immunologic breakthrough pharmaceutical ipilimumab, patients with stage 3 or 4 melanoma may have a new treatment option that could put their disease in remission and allow them to live longer.

The Case

CP is an 80-year-old white man who presented to his dermatologist with an enlarging blister on his left forearm. He underwent a shave biopsy that showed nodular malignant melanoma with overlying ulceration, at least 4.1 mm in depth. The tumor was strongly positive for S100 (a calcium-binding protein that is a sensitive marker of melanocyte differentiation).⁶ The mitotic rate was up to 5 mitosis per high-power field, and the tumor was wild-type BRAF (a gene that provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell’s nucleus).⁷

CP was referred to an oncologist and a surgeon for excision of the melanoma and for a sentinel lymph node biopsy. Pathology showed a 1.5 × 1.2 × 0.8—cm tumor with a thickness of 8 mm and negative margins. The closest margin was 1.3 cm, and 1 of 6 lymph nodes examined was positive for micrometastatic disease. Positron emission tomography showed no metabolically active tumors or metastatic disease. However, the sentinel lymph node biopsy result was positive for metastatic disease. Therefore, the patient underwent lymph node dissection. The pathologist reported 2 positive lymph nodes of the 12 examined. The metastasis measured 0.4 cm.

CP’s final pathologic staging was stage 3B (T4a, N2, M0). He began treatment with ipilimumab on June 6, 2016, and received 4 treatments at 3-week intervals. He will continue to receive immunotherapy treatment once every 12 weeks beginning on week 24. CP tolerated the treatment well with minor adverse effects (AEs), such as itching, for which lotion was applied to keep the skin moist after treatments. Currently, CP is in remission and will continue to be screened on follow-up visits with his oncologist.

Discussion

To help prevent disease recurrence, interferon-alfa has long been the standard for adjuvant treatment following disease resection in patients with melanoma.⁸ Although the use of interferon-alfa may help postpone melanoma recurrence, it has not been proved to increase patient survival rates. For interferon-alfa to be effective, high doses must be administered over the course of 1 year, which may lead to intolerable AEs, which commonly include fever, chills, aches, depression, exhaustion, and certain effects on the heart and the liver.⁸ The severity of these AEs varies among patients; however, many patients find this treatment to be intolerable and, therefore, stop treatment.

In contrast, ipilimumab is a human cytotoxic T-lymphocyte antigen 4 blocking antibody indicated for treating unresectable or metastatic melanoma and as adjuvant treatment for cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm after complete resection.⁹ In 2015, the FDA approved the use of ipilimumab as adjuvant treatment for patients with stage 3 melanoma.¹⁰ Ipilimumab is dosed as 3 mg/kg IV every 3 weeks for a maximum of 4 doses. Common AEs of ipilimumab include fatigue, rash, and diarrhea. Ipilimumab carries a black box warning for immune-mediated adverse reactions that could be severe or fatal.⁹ Although the AEs of ipilimumab may be severe, they are generally more well tolerated than those of interferon-alfa. Ipilimumab has shown promise by using the patient’s immune system to treat melanoma when the patient is not a candidate for surgery. The drug may also prevent melanoma recurrence after lymph node resection.

The Table briefly compares these 2 agents.

Conclusion

In the case of CP, the oncologist made an appropriate decision to use ipilimumab to treat stage 3B melanoma. By choosing ipilimumab as adjuvant therapy, the patient received 4 doses, resulting in minimal AEs.

Melanoma is an unrelenting disease with a poor prognosis. The pharmacologic treatment options have been limited in the past, but immunotherapy offers a glimmer of hope. Surgery is often unsuccessful and disfiguring and, with the addition of high-dose interferon-alfa, may decrease patients’ quality of life.

With the new and early use of immunotherapy, such as ipilimumab, the medical community is learning how to harness the patient’s immune system to improve clinical outcomes. In the case presented here, the patient’s initial outcome has been positive, with minimal AEs. The black box warnings and AEs of currently marketed agents suggest that continued research and development is needed. We are grateful to participate in these exciting, new drug innovations.

Jerry Barbee, Jr, PharmD, BCPS, CPh, is a clinical pharmacist at HCA West Florida Hospital. Hania Joudeh, BSPharm, is a clinical pharmacist at HCA West Florida Hospital. Glenn Schulman, PharmD, MS, BCPS, BCACP, CGP, is a clinical pharmacist at HCA West Florida Hospital. Jessica Hay is a 2017 PharmD candidate at the University of South Florida.

References

• American Cancer Society. Key statistics for melanoma skin cancer. cancer.org website. cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. Accessed September 16, 2016.
• American Cancer Society. Immunotherapy for melanoma skin cancer. cancer.org website. cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-treating-immunotherapy. Accessed September 16, 2016.
• American Cancer Society. Cancer Facts & Figures 2016. cancer.org website. cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/index. Accessed September 16, 2016.
• Geller A, Swetter S. Screening and early detection of melanoma. UpToDate.com website. uptodate.com/contents/screening-and-early-detection-of-melanoma?source=search_result&search=melanoma&selectedTitle=1~150. Accessed September 16, 2016.
• American Joint Committee on Cancer. Melanoma of the skin. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:325-344.
• Blessing K, Sanders DS, Grant JJ. Comparison of immunohistochemical staining of the novel antibody melan-A with S100 protein and HMB-45 in malignant melanoma and melanoma variants. Histopathology. 1998;32(2):139-146.
• US National Library of Medicine. BRAF gene. Genetics Home Reference website. ghr.nlm.nih.gov/gene/BRAF. September 13, 2016. Accessed September 16, 2016.
• Sosman JA. Adjuvant immunotherapy for melanoma. UpToDate.com website. uptodate.com/contents/adjuvant-immunotherapy-for-melanoma?source=search_result&search=melanoma&selectedTitle=27~150. Accessed September 16, 2016.
• Yervoy [package insert]. Princeton, NJ: Bristol-Meyers Squibb; 2015.
• FDA. FDA approves Yervoy to reduce the risk of melanoma returning after surgery [news release]. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469944.htm. Published October 28, 2015. Accessed September 16, 2016.