Cancer patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Cleveland Clinic oncologist Pauline Funchain, MD, how she would handle her own diagnosis of advanced melanoma.
Curious Dr. George: What would you do if you personally were discovered on a routine exam to have abnormal liver function tests that led to scans and the finding of several liver masses? Remembering back some 15 years, you had surgery to remove a 7-mm-diameter, 2-mm-thick melanoma from the skin of your lower leg, treated by wide excision with clear margins. No spread detected at that time. No tumor testing then, aside from light microscopy. How would you proceed?
Pauline Funchain, MD:
Starting line: First, I would take a deep breath. I would remind myself that stage IV melanoma of the skin has become a disease state that can have durable remissions well over 5 years, and that such remissions are not rare. I would be heartened knowing that results approaching cure are possible for some stage IV melanomas.
Next, I would contact my nearest academic medical center. I would carefully research teams known to have good bedside manners, clear communication, and melanoma expertise. The field of melanoma is rapidly changing for the better, and I would want a team that is not only well aware of these developments, but also would be able to clearly explain the multiple therapy options available to me in the context of a briskly moving field. Lastly, I would prefer a medical center where medical subspecialists were readily available and accustomed to timely multidisciplinary communication, as immune-mediated adverse events (irAEs) are commonly elicited during the course of systemic therapy for melanoma.
Workup: At this center, I would first undergo a biopsy of a liver mass. I would ensure BRAF mutation screening was performed by immunohistochemistry (IHC), the most rapid of available BRAF testing modalities. If enough tissue was available, I would send for next generation sequencing (NGS) of the tumor specimen, to prepare for possible second- or third-line therapies. If I had a family history of cancer, personal history of multiple cancers, or was relatively young, I would see a genetic counselor to discuss germline genetic testing. For staging I would get either a CT chest/abdomen/pelvis or PET CT. MRI brain is absolutely essential, as brain metastases are common, often asymptomatic, and may influence first-line therapy choices.
First-line therapy: With staging complete, I would inquire about first-line immunotherapy-based trials. While the best outcomes for stage IV disease, particularly involving liver and/or brain, have been seen with combination ipilimumab/nivolumab, I would welcome the opportunity to try something new in a rapidly evolving melanoma treatment landscape. I would be reassured knowing that all gold standard therapies would still be available to me should a first-line clinical trial fail. If I was not eligible or did not like available clinical trials, I would proceed to first-line treatment with ipilimumab/nivolumab. If I had a personal history of autoimmune disease, I would request a consultation with the appropriate medical subspecialty prior to starting immunotherapy. Other medical conditions might influence me to prefer single-agent immunotherapy, and it is these situations that highlight the importance of having a medical team who is able to have a careful discussion with me to understand my individual needs.
While on therapy I would undergo systemic imaging every three months to assess response to therapy. If my original staging did not demonstrate brain metastases, I would undergo MRI brain every 6 months in the stage IV setting. If I had fast-growing disease, was rapidly losing weight, had a very large burden of disease, or some combination of these factors, I may prefer to invoke the rapid response typically seen with targeted BRAF/MEK therapy. On targeted therapy, I would consider imaging every 2 months, given a higher likelihood of developing therapeutic resistance with the combination of factors that led me to start targeted therapy. I would follow my status closely with serial LDH levels, which correlate well with BRAF-mutant disease burden.
Closing thoughts: In the landmark trial of first-line combination immunotherapy for stage IV melanoma, median melanoma-specific survival has not yet been reached after 6.5 years of follow-up. In plain English, more than half of those who underwent combination immunotherapy have survived stage IV melanoma at the 6.5-year mark. Because not everyone experiences prolonged survival, I would be realistic about having a stage IV cancer diagnosis that might be fatal, yet remain optimistic given the pace of new drug development that immunotherapy and targeted therapy have precipitated in the last decade.
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