For many years patients with metastatic melanoma to sites beyond the draining regional lymph nodes have had a bad prognosis with low rates of long term survival. Therapies have included a range of systemic treatments including chemotherapy, immune therapies such as interferon and vaccines, as well as other conventionally developed and alternative “non-scientifically” developed treatments. High level evidence for clinically relevant efficacy of any of these interventions has been missing. Patients have been best managed within a multidisciplinary team environment with all appropriate clinicians and support staff attending. Depending on the distribution and kinetics of the disease evolution, choices have been made as to whether the patient was offered systemic therapy or control of disease with local therapies such as surgery or radiotherapy or in some situations just offered best supportive care. Clearly the choice of therapy or combinations and sequencing of interventions has been based on the distribution and biological aggressiveness of the disease. The favoured systemic therapy has been “Clinical Trial Agent”, because the standard systemic therapy for many years, Dacarbazine, was clearly inadequate in terms of efficacy. Despite these attempts to prolong the lives of patients with stage 4 metastatic melanoma the vast majority usually succumbed to their disease within 12–18 months depending on the site (refer to the American Joint Committee on Cancer [AJCC] staging categories).
From around 2010 onwards, advances in targeted and immune check point inhibitor systemic therapy have revolutionised the treatment of patients with stage 4 metastatic melanoma. These agents and their improvements in overall survival rates for patients are documented separately. As these changes have only occurred in recent times there is a dearth of studies with meaningful follow-up that indicate the preferred sequencing of multimodality interventions for patients with stage 4 metastatic melanoma. The practical reality is that patients are still best discussed within a multidisciplinary team that has access to all modalities, in a group that actively collects data to document outcomes and is that is actively engaged in clinical trials (see Multidisciplinary care section). As the goal posts have been moving so quickly with systemic therapy alone the ability to do studies on patients with combinations of effective systemic therapy and surgery and/or radiotherapy is limited but clearly will become more important when the rapid advances in systemic therapy plateau.
Systematic review evidence
For patients with distant metastases, when is surgical therapy indicated?
There are no randomised controlled trials that have accrued and reported on the sequencing of surgery with systemic therapy options.
The literature evaluated during this evidence-based review process reported on patients who did not have access to effective systemic therapy. Due to the nature of the presentation of these patients, nearly all reported series would have been open to selection bias, with those patients with lower volume metastatic disease and less aggressive biology being more likely to be suitable for surgery, and those with worse disease being managed with largely ineffective systemic therapy.
As reflected in the AJCC staging system, the site of the metastastic disease has a major impact on survival in patients managed with surgery or systemic therapies, especially prior to the availability of effective targeted and immunotherapy. Nevertheless some information can be gleaned regarding situations where the clinical presentation mandates immediate removal of the disease causing life-threatening complications. Examples include:
2. small bowel metastasis (or less commonly other GI sites) causing obstruction or major bleeding
3. bone metastasis causing fracture or impending fracture
4. spine causing actual or threatened spinal cord compression.
Other situations where the preference is still to use surgery as an initial therapy may include isolated or a small number of metastases in surgically accessible sites after a long disease-free interval, e.g. lung metastasis, liver metastasis, adrenal metastasis, brain metastasis, bowel metastasis, distant soft tissue metastasis and bone metastasis.
Recommendations and practice points
Situations where surgery should be considered for stage 4 disease include the following, but when possible all cases should be discussed in an experienced multidisciplinary team setting:
1. Isolated site of metastatic disease that are causing life threatening symptoms or likely to cause irreversible damage if not treated immediately, eg. brain, small bowel, spine/causing spinal cord compression.
2. Isolated or a few resectable sites of metastatic disease after a meaningful disease-free interval.
3. Isolated progression or resistance in the face of otherwise effective systemic therapy.
Multidisciplinary team discussion is required for all melanoma patients with isolated or a small number of metastases. Patients should be informed of the nature of the multidisciplinary discussion including the range of options discussed and why the final recommendation was reached.
The multidisciplinary discussion would seek to consider the balance between surgical morbidity and likelihood of immediate reversal of symptoms or achievement of disease free status compared to the side effects, outcome and long-term results that would be achieved with other treatment modalities.
In the case of isolated or a small number of metastases in a surgically accessible sites, particularly after a long disease-free interval, surgery may be the preferred initial therapy, e.g. isolated lung metastasis, isolated liver metastasis, isolated adrenal metastasis, isolated brain metastasis, isolated distant soft tissue metastasis, isolated bone metastasis with impending fracture.
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