Clinical
Volume 48, Issue 6, June 2019

Cutaneous melanoma: Latest developments

Anthony J Dixon    Howard K Steinman    Alexander Nirenberg    Stuart Anderson    John B Dixon   
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Background
Several new medications have shown improved survival rates in high-risk patients with melanoma.
Objective
The aim of this article is to discuss the new medications and outline their roles, the expected benefit from each and the risk of adverse events. We explain the place of sentinel lymph node biopsy (SLNB) and ultrasonography with fine needle aspiration (US-FNA) in assessing and treating patients with melanoma.
Discussion
Ipilimumab has limited efficacy and a very concerning complication profile. More than 50% of patients taking ipilimumab have severe or life-threatening adverse events. BRAF inhibitors have greater efficacy and fewer adverse events than ipilimumab. Combining BRAF inhibitors with mitogen-activated protein kinase inhibitors enhances their effect and improves the overall adverse event profile. BRAF inhibitors are only effective when the melanoma has a BRAF gene mutation, something that occurs in only 50% of cases. Programmed cell death protein 1 medications are also more effective and have a much more acceptable adverse event profile than ipilimumab. Both SLNB and US-FNA can detect early node involvement in patients with melanoma, although US-FNA is a safer procedure.
ArticleImage

In this review, new treatment regimens found to improve melanoma survival in randomised controlled trials (RCT) are presented. Long-term data from RCTs of sentinel lymph node biopsy (SLNB) and subsequent completion lymphadenectomy, and the role of ultrasonography (US) with fine needle aspiration (US-FNA) using Berlin criteria for primary melanoma >1 mm Breslow thickness, are reviewed. Debates regarding the use of certain newer medications and the requirement of patients to undergo SLNB to participate in clinical trials is discussed.


Ipilimumab

Ipilimumab is a monoclonal antibody that activates the immune system.1 It is delivered intravenously. Robert et al evaluated patients with metastatic melanoma treated with ipilimumab and dacarbazine versus dacarbazine alone.1 Although dacarbazine has been used for 30 years, its efficacy in managing melanoma is poor.2 However, it was considered the best agent available for comparison with newer pharmaceuticals. Of the patients taking ipilimumab and dacarbazine, 20.8% were alive at three years versus 12.2% of the patients taking dacarbazine alone. Ipilimumab was subsequently found to slow progress in patients with brain metastases.3 Complications from therapy are concerning, with more than 50% of patients having either a grade 3 or 4 adverse event (Table 1). Immune-related colitis, in addition to liver function impairment, are among the concerning sequelae recognised. Other reported complications are diarrhoea, dehydration, fatigue, confusion and skin rashes.1,3 More recent trials of ipilimumab were conducted in combination with programmed cell death protein 1 (PD-1) medications.
 

Table 1. Common terminology criteria for medication adverse events. The risk of adverse events with each of the common drug protocols is identified as a percentage.
Grade Meaning IPI* BRAF + MEK PD-1* PD-1 + IPI*
Grade 1: Mild Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated
Grade 2:
Moderate
Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living
Grade 3:
Severe
Medically significant but not immediately life threatening; hospitalisation or hospital prolongation indicated; disabling; limiting self-care activities of daily living 46%16, 56%1 8%12, 15%29 14%16, 15%15 45%19, 55%17,
59%18
Grade 4:
Life threat
Life-threatening consequences; urgent intervention indicated Nil12
Grade 5:
Death
Death related to adverse events of therapy Nil1, 0.4%16 Nil8 Nil19
*The published studies of IPI, PD-1 and PD1 + IPI group grade 3 and 4 adverse events together, shown here in a combined grade 3/4 box.
IPI, ipililumab; MEK, mitogen-activated protein kinase kinase; PD-1, programmed cell death protein 1; –, not identified


BRAF inhibitors including vemurafenib and dabrafenib

BRAF inhibitors are one group of medications that first demonstrated a survival benefit for patients with melanoma. BRAF is a human gene that encodes the serine/threonine-protein kinase B-Raf (B-Raf) protein. The BRAF gene is integral to the Ras/mitogen-activated protein kinase (RAS/MAPK) signaling pathway, which controls several important cell functions.4,5 Inhibiting the BRAF pathway has been shown to prolong survival in patients with melanoma who have the V600E mutation. Some other variations of the BRAF mutation also respond to BRAF inhibitors.6 These BRAF mutations occur in approximately 50% of patients with melanoma.6

Vemurafenib

Vemurafenib has also been shown to benefit patients with melanoma.4 Delivery is oral, avoiding patient hospitalisation. Overall survival at six months was 84% with vemurafenib versus 64% with dacarbazine, which acted as the control agent.4 Slightly more than 50% of patients with melanoma who have the BRAF mutation have a positive response to vemurafenib.6 Patients with melanoma who have brain metastases can benefit from vemurafenib therapy.7

Dabrafenib

The second BRAF inhibitor studied extensively is dabrafenib. In a large RCT of patients with metastatic melanoma with the BRAF mutation, median progression-free survival with dabrafenib was 5.1 months versus 2.7 months with dacarbazine.5 Dabrafenib has an established role for patients with brain metastases.8

Adverse events associated with BRAF inhibitors include fatigue, alopecia, photosensitivity, nausea and diarrhoea. Arthralgia can be severe and lead patients to cease therapy.4,6 The adverse event profile is similar for both BRAF inhibitors. Moreover, approximately 25% of patients developed cutaneous squamous cell carcinomas (SCCs) following BRAF inhibitor management.4,5,7,8


MEK inhibitors in combination with BRAF inhibitors

Adding a mitogen-activated protein kinase kinase (MEK) inhibitor to BRAF inhibitor treatment produced an additive therapeutic effect while reducing the adverse event profile of BRAF inhibitors alone.9,10 MEK enzymes work in another step of the RAS/MAPK pathway.9

Trametinib

Trametinib is the MEK inhibitor predominantly studied. Delivery is oral, and patients with metastatic melanoma reported feeling better and lived longer when taking a combination approach.10 Twelve-month survival was 72% with combination dabrafenib/trametinib treatment versus vemurafenib alone (65%).9 Importantly, the development of new SCCs associated with BRAF inhibitors is almost eliminated with the combined approach.9 Incidence of alopecia is also lower in patients on the combined therapy, though gastrointestinal adverse events, pyrexia and peripheral oedema increase in incidence.11

It is now standard for patients with melanoma to receive combination therapy, rather than BRAF therapy alone, when BRAF therapy is indicated. Even patients previously treated with BRAF therapy may benefit when re-challenged with combination therapy.12 Combination therapy can be continued for many years with patients continuing to benefit.11

Nodal involvement

While early trials showed benefit in BRAF-positive patients with melanoma with distant metastases, recent trials have shown a role for MEK/BRAF therapy in patients who have nodal disease but no evidence of metastases elsewhere. Patients with stage III melanoma had a three-year survival rate of 86% in comparison to 77% for patients who received the placebo.13 Patients in this trial had their involved nodes completely resected prior to commencing medication.


PD-1 medications including pembrolizumab and nivolumab

PD-1 medications are perhaps the most encouraging new treatment for melanoma. PD-1 is a checkpoint protein on T-cells that inhibits their activity when PD-1 attaches to PD-L1 proteins on some normal and cancer cells.1 Cancer cells may have large amounts of PD-L1, which inhibits a beneficial immune response. PD-1 medications inhibit this reaction and boost the immune response.3

Pembrolizumab

Schachter et al conducted an RCT comparing intravenous (IV) pembrolizumab versus IV ipilimumab for patients with advanced melanoma.14 After two years, 55% of the patients taking pembrolizumab were alive versus 43% of patients taking ipilimumab. Pembrolizumab has also been found to be effective in patients with melanoma who have nodal involvement.15 Fifteen per cent of patients taking pembrolizumab developed Grades 3–4 adverse events (Table 1). Hypothyroidism (14% of patients) and other endocrine disorders are recognised possible adverse events. Immune-related adverse events included colitis.

Nivolumab

Weber et al compared nivolumab with ipilimumab in patients with stage III and IV melanoma.16 Recurrence-free survival at 12 months was 70.5% with pembrolizumab versus 60.8% with ipilimumab. The likelihood of adverse events of grade 3 or greater is similar for both PD-1 medications (Table 1).16–18

Combination therapy

Nivolumab can also be combined with ipilimumab. However, 59% of patients developed severe (grade 3) adverse events on combination therapy (Table 1).18 Three-year survival was statistically significantly improved, being 58% in the combination therapy group versus 52% on nivolumab alone. Combination therapy has a particular role for patients with brain metastases.17 Other studies also suggest a role for patients receiving both pembrolizumab and ipilimumab.19

Some question whether this improvement in survival from combined therapy is in the patient’s best interests considering the concerning adverse events profile. This matter requires considerable discussion with patients, taking into consideration individual patient preferences and needs.


Sentinel lymph node biopsy

SLNB became a common part of melanoma management because it could potentially save lives. The two most important long-term prospective randomised trials of SLNB are the multicenter selective lymphadenectomy trials, denoted MSLT1 and MSLT2.

The MSLT1 trial randomised patients with a primary melanoma >1.2 mm in thickness to SLNB and subsequent completion lymphadenectomy versus observation alone. MSLT1 showed that SLNB and subsequent completion lymphadenectomy does not improve 10-year melanoma-specific survival.20 The MSLT2 trial randomised patients who had a positive sentinel node into those having completion lymphadenectomy versus observation alone. Once again, no survival benefit was identified.21

SLNB is still offered because it can provide added prognostic information for patients with melanoma. However, even when the test is offered, it is important that those who are found positive do not then receive completion lymphadenectomy.


Ultrasonography and fine needle aspiration

SLNB is not required to detect early nodal involvement in patients with melanoma. Disease can be accurately detected with US-FNA using the Berlin diagnostic criteria. These are different from criteria used in conventional US methods for other tumours.22,23 The Berlin US morphology criteria grades peripheral perfusion, loss of central echoes and balloon shape. The prognostic accuracy of this approach compares favourably with SLNB. Patients can be spared SLNB and its potential complications, with the exception of small numbers of patients for whom US is suspicious but FNA is negative.23 Availability of this approach is limited in Australia, despite its considerable use in Europe. Given its confirmed role, imaging departments in Australia are further using this approach.


Controversy

Eggermont et al conducted an RCT of pembrolizumab that required patients with positive nodes to have completion lymphadenectomy regardless of the Breslow thickness of the primary tumour.15 The trial found a one-year recurrence-free survival rate of 75.4% in the pembrolizumab group versus 61% for controls. Recruitment commenced in 2015 prior to the MSLT2 publication that found no survival benefit from completion lymphadenectomy.21 Trial subjects were thus required to have surgery that had not been demonstrated to improve their survival, in order to possibly receive a medication that might.

We have previously expressed our ethical concern that patients with high-risk primary melanoma could be ‘den[ied] participation in clinical trials of potentially curative therapy’24 because they choose not to have a further surgical procedure that has no proven survival benefit as demonstrated in completed RCTs. Surely cancer patients should be encouraged to undertake only procedures and therapies that have a demonstrated potential therapeutic benefit.

Pathology assessment alone of excised melanomas provides an array of accurate mortality prognostic information. This includes Breslow thickness, ulceration, tumour site, vascular invasion, mitotic activity and age (Table 2).20,25 It is yet to be demonstrated and seems implausible that SLNB, requiring a separate surgical procedure, is necessary to identify patients for trials rather than an algorithm of all information obtained from the excision along with nodal US-FNA.
 

Table 2. Multivariate hazard ratios for death of patients with melanoma of intermediate thickness*
Prognostic indicator Hazard ratio 95% confidence limits
Breslow thickness per 1 mm increase20 1.59 1.21, 2.09
Sentinel node status – positive versus negative20 2.40 1.61, 3.56
Location on trunk – compared with arm or leg20 1.91 1.26, 2.88
Ulceration – present or absent20 1.79 1.24, 2.58
Mitotic activity25 1.04 1.012, 1.067
Age – per 1 year increase25 1.009 1.003, 1.016
*Clark level and sex are not independent predictors on multivariate analysis.
 

We are concerned that patients are encouraged or required to have SNLB to enter trials.24 If this is the key reason for the surgery, and not improved health outcomes, then health insurers, governments and patients should be alerted to the ethical, equity and financial issues arising from such clinical trial designs.

When medication trials have demonstrated a benefit for the intervention,13,15,16 applicability may be erroneously restricted to patients having positive nodes detected by SLNB. This could cement a clinical role for a procedure without proven survival value, and will therefore have far-reaching ethical and resource allocation implications for future patients who may be able to benefit from new interventions. Patients who decline to have SLNB must not be denied access to medications that can treat their conditions.


Discussion

Several new medications that prolong survival in patients with high-risk melanoma are now available. Their role is established in patients with metastatic disease. Some medication regimens require IV administration. Other combinations are available orally, allowing greater flexibility for patients with melanoma who may prefer oral therapy to having to attend a chemotherapy centre for treatment.

Long-term benefit

The survival benefit of these medications offers added months and potentially years for patients with melanoma. In every RCT of these medications thus far, the Kaplan–Meier graphic analysis shows a continuing reduction in survival over time. Whether there is a five-year or 10-year survival benefit from these medications, including combinations, remains unknown. Long-term outcomes from these trials will become available in time.

Adverse events

For all medications studied, including combination therapies, the severe adverse events demonstrated are concerning, both in percentage and nature. Many patients choose to withdraw from therapies because of intolerance of adverse events. Some patients will choose not to commence these therapies after balancing the potential for extra survival against the risk of adverse events.

Second primary melanoma

Anecdotally, there are some patients with melanoma who develop a second cutaneous primary melanoma who are not offered surgery for the new melanoma because they are on one or more of the medications listed previously. To suggest that the medications can also treat a primary melanoma is not reasonable, not based on evidence and outside of current guidelines. Further, one cannot assume that a new primary melanoma will have the same mitoses and/or medication-responsive characteristics as the primary tumour. It is recommended that patients on medication who develop a new primary melanoma undergo wide local excision.

Sentinel node biopsy morbidity

SLNB is expensive and can affect ongoing quality of life. Complication rates of 10%26 can include anaphylaxis, persistent seroma,27 lymphedema,27 tattooing at primary site from dye,28 mobility impairment,28 recurrent infection,27 chronic site pain,28 joint pain and nerve damage.27 Given that the purpose of SLNB is to determine early nodal involvement, and that this can be achieved more safely through US-FNA, we would hope that use of SLNB would now be infrequent.


Conclusion

Recent years have seen significant advances in the management of metastatic melanoma, including in patients with nodal spread. SLNB provides prognostic information but has not been demonstrated to improve survival in an RCT. When a sentinel node is positive, removing the remaining nodes offers no survival benefit. US-FNA can provide comparable long-term prognostic advice to SLNB for patients with melanoma.

While the new medications can prolong life, they are not a cure. All the new medications demonstrate disease-specific survival that continues to fall with time. We still do not know the long-term (>10 years) outcomes of these medications.

We are concerned that pressure remains on patients to have SLNB surgery, known to be unnecessary, in order to qualify for medications that can be used to prolong their lives. General practitioners (GPs) are well placed as the gatekeepers to monitor their patients with melanoma; this includes acting as an advocate for patients.

The role of the GP in managing melanoma, in collaboration with melanoma units where appropriate, may involve ongoing skin surveillance, management of new primary tumours (both melanoma and non-melanoma skin cancer) and management of adverse events of the new medications. GP management also extends to palliative care and psychological support as the disease progresses.


Key points

  • Medications that prolong survival in patients with metastatic melanoma including nodal spread are available.
  • Long-term (>5 years) benefits of currently available medications for patients with melanoma is unknown.
  • Adverse events on available medications can be serious or life threatening.
  • Neither SLNB nor subsequent completion lymphadenectomy has been shown to have a melanoma survival benefit in an RCT.
  • US-FNA using Berlin criteria provide prognostic information that can be achieved comparably, more cheaply and with fewer adverse events than with SLNB.
  • Patients with melanoma who are taking melanoma medication require continuing melanoma care, including regular skin checks.
  • New suspicious skin lesions in established patients with melanoma require appropriate biopsy and surgical excision on their merits.
Competing interests: None.
Provenance and peer review: Commissioned, externally peer reviewed.
Funding: None.

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DermatologyMelanomaSkin cancer

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