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Stage IV


A patient in this stage has melanoma with distant metastasis to skin, soft tissue (e.g., muscle), organs (e.g., lung, liver or brain). The tumor (T) status and the lymph node (N) status are not as important. Only the metastasis (M) status (i.e., melanoma spread to distant part of the body) matters. The M status is further classified into the following 4 groups: M1a: spread to skin or soft tissue including muscle. M1b: spread to lung. M1c: spread to non-brain visceral sites, such as the liver. M1d: spread to the brain. Elevation of LDH (lactate dehydrogenase), a biological blood marker, is also used to subcategorize within each of the 4 groups.

Survivor Outcome:

According to the 2018 AJCC data, the 5-year survival rate was about 22%. The survival data for stage IV can be disheartening. 

It is important to remember that treatment options for advanced stages of melanoma are improving continuously. The above quoted survival rates are from 2018. Since then, improved therapy protocols and newer drugs have already increased the overall survival rates for patients with advanced disease.
There is already good clinical evidence showing an improvement of survival rate for patients with these late staged diseases in this interim 5-year period, when compared to the historical data. Data from leading academic centers have shown that the survival rate for advanced stages of melanoma has increased to 45%.
Finally, remember, modern science and clinical research are advancing at a breathtaking pace. New treatment regimens to combat melanoma have been developing rapidly. It is almost certain that the overall survival rate will continue to improve.

Adopted from NCCN Guideline 2022

For patients with metastatic melanoma, there are four types of therapies including immunotherapy, targeted therapy, chemotherapy, and radiation used for advanced stages of melanomas. In general, immunotherapy and targeted therapy are used as the first and second lines of treatment, respectively. Chemotherapy is used very infrequently. Lastly, there are many clinical trials offered for patients in this stage. 

I. Immunotherapy is a medical breakthrough that prevents the immune cells from turning themselves off prematurely, thereby maintaining an active, always-on mode to attack the cancer cells.

4 classes of immunotherapy drugs:
1. Anti-PD1 Inhibitor: 
- Pembrolimzumab (Keytruda)
- Nivolumab (Opdivo)

2. Anti-CTLA-4
- Ipilimumab (Yervoy)

. Anti-PD-L1 Inhibitor: 
- Atezolizumab (Tecentriq)

4. Lag-3 Inhibitor
-Opdualag (combination of Relatlimab + Nivolumab)

II. Targeted Therapy
This class of drugs target and destroy melanoma cells with specific BRAF v600 mutations. There are two classes of drugs, namely the BRAF inhibitors and MEK inhibitors. In actual clinical practice, a combination of these two drugs are often given together to achieve a higher efficacy rate and fewer side effects. 

BRAF | MEK inhibitors approved by the FDA:

1) Dabrafenib/trametinib

2) Vemurafenib/cobimetinib

3) Encorafenib/binimetinib

III. Radiation
Radiation has been used as a palliative purpose to treat distant metastasis of melanoma. In this clinical setting, the goal is not to achieve a complete cure or prevent the disease from recurring, rather the goal is to reduce pain and discomfort. Radiation has been used to treat bone, brain, and deeper tissue metastasis.

IV. Clinical Trials. 
Immunotherapy and targeted therapy are real game changers in our fight to treat patients with advanced stages of melanoma, but not every patient responds to these treatments. If the disease progresses and does not respond to treatment, one option to consider is looking for novel treatments in various clinical trials offered around the country. For more detailed information on clinical trial options, please watch my interview with Dr. Richard Carvajal and Dr. April Salama who are medical oncologists.




Dr. Paul Chapman discussing his approach to manage patients with stage IV disease



Dr. Paul Chapman discusses the challenges in knowing when to stop treatment. Also defines Progression Free Survival, Overall Survival, Complete response, metabolic Complete response, and Pathologic Complete Response



Dr. Paul Chapman discusses immune mediated side effects. How to treat and manage those side effects



Dr. Paul Chapman discusses BRAF mutation



Dr. Paul Chapman discusses BRAF targeted therapy



Dr. Richard Carvajal discusses the consultation process for patients with stage IV disease



Dr. Richard Carvajal discusses immunotherapy for patients with stage IV disease



Dr. Richard Carvajal discusses the importance of monitoring his patients for the immune-mediated side effects



Dr. Richard Carvajal discusses clinical trial



Dr. April Salama discusses her philosophy in consulting her patients



Dr. April Salama discusses her process to decide the type of treatments for patients with stage IV disease



Dr. April Salama discusses her decision making process to use immunotherapy, such as single vs. dual agents therapy



Dr. April Salama discusses the importance of monitoring immune mediated side effects associated with immunotherapy



Dr. April Salama discusses what to do when immunotherapy does not work



Dr. April Salama discusses some of the misconceptions about clinical trials

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