Optimal follow-up for melanoma

Abstract

The increasing prevalence of melanoma is causing a growing number of patients to be in follow-up after treatment and places a large burden on scarce healthcare resources. This article aims to establish the optimal follow-up for melanoma patients by giving an overview of recommendations for initial treatment and staging of the disease, as well as the content and frequency of follow-up as stated in several national guidelines for treatment of melanoma. The evidence for these recommendations, if available, will be discussed. Furthermore, the article focuses on the role of sentinel lymph node biopsy, PET and biomarkers in follow-up and staging. The article concludes with the authors’ opinion on optimal follow-up for melanoma and on what changes in follow-up strategies are to be expected if new therapies become available in the next 5 years.

Keywords::

• biomarkers
• FDG-PET
• follow-up
• guidelines
• melanoma
• S-100B
• sentinel lymph node biopsy
• staging

The overall prevalence of melanoma is increasing, as a result of the rising worldwide incidence of melanoma and the stabilizing mortality rates [1,2]. For example, the prevalence of melanoma in the Netherlands has doubled in recent years [201]. This has resulted in a growing number of melanoma patients needing follow-up and consequently more doctors are required to deliver this service. Several healthcare authorities have developed guidelines for the management of melanoma patients, to help and advise doctors to deliver optimal care and provide patients with the best possible outcome.

Guidelines for the treatment of primary melanoma considering excision margins are well defined and widely accepted [3]. There is evidence that nonadherence to these guidelines can be harmful for the patient [4,5]. Primary staging by a sentinel lymph node biopsy (SLNB) is widely performed, although recommendations to perform this technique as a standard procedure are not uniform [6]. How to proceed after primary treatment and staging is considerably less well defined.

The general purpose of follow-up is diverse: early detection of local-regional or distant-recurrent disease, detection of second primary melanomas, patient reassurance and accumulation of data for research [7]. Several authors have investigated and discussed the topic of follow-up for melanoma patients [8–10]. To date, no international consensus has been reached regarding the optimal follow-up schedule, nor the extent of investigations. Patients with lymph node metastases without distant metastases can benefit from a lymph node dissection [11,12] and those in whom distant metastases are found may benefit from other individualized treatments, including surgery, immunotherapy, chemotherapy and recently developed targeted therapy [13,202].

The question is what the optimal follow-up is for melanoma patients, in a world in which the costs of health care are constantly in conflict with the development and implementation of new, sophisticated and, above all, expensive diagnostic tools to detect these recurrences. In an attempt to answer this question, the current article presents an overview of 19 national and regional guidelines for the management of melanoma from countries with the highest reported incidence of the disease. In this overview, the focus will be on the aspects of primary treatment and staging and the contents and frequency of follow-up reported in the guidelines. We argue that SLNB has an important role in determining the follow-up strategy, although the value of SLNB is still subject to debate.

The role of using the widely debated modalities positron emission tomography (PET) scanning and serum biomarker measurement, for example, S-100B, in these two phases of management will be discussed in separate sections. This article will conclude with the authors’ view of optimal follow-up for melanoma today and the expected changes and developments in the next 5 years.

Primary treatment & staging of melanoma patients

Patients with melanoma are staged according to the American Joint Committee on Cancer (AJCC) Tumor–Node–Metastasis (TNM)-staging manual. In 2009 the seventh version was published. A summary is given in Tables 1 & 2[11]. This updated manual has an evidence-based approach and reflects the increased understanding of the disease [14].

Guidelines for treatment & staging of primary localized melanoma

As mentioned in the introduction, no international consensus has been reached regarding the follow-up of melanoma patients. This is in sharp contrast to primary treatment and staging for melanoma. To underline this and because follow-up cannot be discussed without describing staging, an overview of the recommendations formulated in 19 national and regional guidelines for the management of melanoma patients concerning primary treatment and initial staging of patients presenting with localized melanoma is given in Table 3[15–20,203–215].

Recommendations are uniform on the subject of excision margins. The treatment of a suspect nevus or skin lesion is a diagnostic excision with a 2–3 mm margin of normal skin. The therapeutic, surgical excision margins are defined as 0.5 cm for in situ melanoma, 1 cm for T1–2 melanoma and 2 cm for T3–4 melanoma. In the majority of guidelines, excision margins of more than 2 cm are advised in case of unfavorable melanoma characteristics, but only if patient morbidity can be avoided. A recent review showed that therapeutic excision wounds on all locations of the body can either be closed primarily or with the use of plastic surgical reconstruction, making split-skin grafting infrequently necessary [21,22].

None of the published guidelines still recommend elective lymph node dissection as part of the standard of care, recognizing the evidence that no survival benefit is reached with this procedure [23]. The practice of SLNB followed by completion lymph node dissection in case of a tumor-positive sentinel node has virtually replaced this procedure. As shown in Table 3, in all countries SLNB is performed as a staging procedure in patients with melanomas over 1 mm Breslow thickness or under 1 mm in case of prognostic unfavorable tumor characteristics. In ten out of 19 guidelines, SLNB is a standard and routine staging procedure that all patients meeting criteria should undergo.

Only six guidelines recommend adding ultrasonography of the draining lymph node basins and/or the abdomen, chest x-ray and blood serum testing to the initial staging. A few radiologists are in favor of staging regional lymph node basins in stage I–II melanoma with high-resolution ultrasonography [24–26]. However, the general opinion is that targeted high-resolution ultrasonography is not an effective substitute for SLNB in patients with primary melanoma [27–30]. Several authors investigated the use of chest x-rays in staging and concluded that its use is questionable, because of low detection rates, high false-positive percentages and subsequent high patient anxiety [31–33]. The value of PET imaging and measurement of serum biomarkers in staging of patients with apparently localized disease will be discussed in the later sections devoted to these subjects.

Follow-up for melanoma

International consensus on the follow-up of melanoma patients does not exist and high-frequency follow-up after treatment for melanoma is still standard practice in many countries around the world [8]. National guidelines are predominantly based on historical precedent [9] and for this reason a wide variety of follow-up strategies are used. This will be discussed in the following paragraphs.

The main purpose of follow-up is early detection of recurrent disease and second primary melanomas that could be treated successfully by surgery or other treatment modalities [7]. However, it is still difficult to predict the behavior of melanoma in the individual patient and overall treatment results of metastatic or recurrent disease are disappointing.

Although several studies have been performed to increase evidence, these studies are mainly focused on stage I and II patients [8]. It would be sensible to base the patient’s follow-up regimen on the risk of relapse [34]. Follow-up regimens for patients with nodal metastases, either micro- or macro-metastases, have barely been discussed and studied. Consequently, present recommendations for stage III patients are even less evidence-based. Several studies have addressed the use of routine investigations in follow-up surveillance [10,32,35–41]. Taking medical history and physical examination seem to be the only cost-effective measures for patients with AJCC stage I and II melanoma [32,35–37]. Other authors have recommended serum biomarkers as a routine follow-up investigation [10].

SLNB & follow-up

According to the recently published seventh AJCC staging system for melanoma, nodal staging plays a more important role compared with the sixth AJCC staging system [11,42]. In particular, the nodal tumor burden has become more specifically described, which is now feasible with histological and immunohistochemical measures [43]. Pathologic staging of lymph nodes is accurately available, since SLNB is widely performed. Approximately 20–28% of patients with clinically negative nodes, previously staged as stage I or II, are now classified as stage III patients. During the last decade immunohistochemical staining was further developed and is now becoming widely available [44,45]. This technique makes detection of micrometastases and even submicrometastases feasible. The specific sentinel node tumor burden has been found to be another major prognostic factor [46,47].

So, what are the consequences of performing the SLNB procedure for the follow-up of melanoma patients? Most important is that patients staged with a SLNB procedure have a great surplus of information for patient-tailoring follow-up management. If the sentinel node is tumor positive, completion lymphadenectomy is generally advised and patients will be followed more frequently thereafter. The major gain in follow-up, however, is reached in patients with a tumor-negative sentinel node. These patients can confidently be classified on the basis of their primary melanoma characteristics alone and some could even be discharged from follow-up. The current Dutch guideline for management of melanoma patients recommends this as standard of care for patients with thin melanomas (Breslow thickness <1 mm) [210]. The recurrence risk for this group is extremely low and for this group particularly there is a lack of evidence for follow-up [11].

This would have major implications for health care and financial costs. The more accurately melanoma patients can be staged, the more tailored follow-up can be offered. For example, SLNB could upstage a clinically stage IB patient to a pathologically stage IIIB with a significantly higher risk of recurrent disease, justifying more extensive follow-up. On the other hand, a pathologically stage IIIA patient with nodal involvement limited to isolated tumor cells, could have a prognosis similar to a stage I patient, justifying less extensive follow-up. The price we have to pay for this is the minor SLNB morbidity, such as slight lymphedema, wound infection and post-operative bleeding, which is found in 10% of patients [48–51].

Follow-up of melanoma patients could gain quality and be more cost-effective, once international consensus is reached on this tailored follow-up. Also, inclusion in major trials will only be possible by performing solid staging. As a consequence, patients can only be eligible for most new therapies, if a SLNB procedure is performed.

In conclusion, the SLNB procedure is an extremely valuable, delicate staging procedure of which the theoretical implications and practical use are still under further development and refinement and, amongst others, is currently being studied in the second Multicenter Selective Lymphadenectomy Trial (MSLT-2) [216]. Because of its important prognostic value, it has major implications on the follow-up of melanoma patients. Maybe not all patients should undergo SLNB procedure, specifically excluding those with melanomas thinner than 1 mm Breslow thickness, because nodal involvement rates are very low. However, some argue that even in this group the procedure will add significant prognostic value [52]. Faries et al. recently advised to use three clinical variables to select high-risk patients in this low-risk subgroup: male sex, younger age and increased Breslow thickness [53]. Therefore, patients should, in general, be informed about the availability of the procedure. The outcome could in fact have major implications not only for additional surgical treatment, but also for the need of adjusting the follow-up regime, for participation in clinical trials and eligibility for adjuvant therapies. This could have a dramatic impact on patients’ psychological cancer experience and therefore might have an impact on quality of life.

Follow-up visits

In Table 4, an overview of the follow-up recommendations is given per national or regional guideline originating from the countries with the highest reported incidences of melanoma. After presumably curative treatment for stage I–III melanoma, a follow-up regimen is proposed. All published guidelines give recommendations regarding the actions the doctor should take during this follow-up visit, although some of these are more clearly stated in the literature than others. As in all patient contact, first a medical history should be taken, focusing on symptoms that can indicate recurrent disease, for example, new skin or scar lesions, palpable tumors in lymph node basins or unexplained systemic complaints, such as fatigue, shortness of breath, headache and gastrointestinal symptoms.

There is uniformity amongst the guidelines for treatment concerning physical examination during follow-up: the scar and its surrounding skin should be checked for local recurrence, the skin of the so-called ‘in-transit pathway’ between the location of the primary melanoma and the draining lymph node basin(s) for lesions and these nodal basins for nodal recurrences.

The majority of guideline authors recommend a complete skin examination at each visit or at least once a year, because of the increased risk for second primary melanoma in patients who experienced melanoma. In only seven guidelines have the authors clearly stated the need for educating the patient on self-examination of their skin and lymph node basins. In the past, the majority of recurrences were doctor-detected at follow-up visits [32,37,54]. However, newer studies show that more and more recurrences are patient-detected in between visits, and it is unclear what has caused this trend [55,56]. If more emphasis is put on self-examination, it may be possible to enlarge the number of early, patient-detected and potentially curable recurrences.

Frequency & duration of follow-up

So, with the content of visits being reasonably well-defined, what should the frequency and duration of follow-up be? Most experts formulating recommendations advise checking patients two- to four-times a year (Table 4). However, in many countries physicians are left a considerable amount of freedom in choosing the interval between visits.

In 11 guidelines, the fact that 80–90% of recurrences occur in the first 3 years after diagnosis is reflected in the reduction of the number of visits per year after the third year [34]. Another ten guidelines have recognized the higher risk of disease recurrence for higher staged patients and reflect this in the frequency of visits accordingly. Three national guidelines provide no follow-up schedule at all and advise a patient-tailored follow-up based on an individual risk assessment for recurrent disease.

Generally, follow-up visits will be scheduled up to the tenth year after diagnosis with yearly visits for the last 5 years. In some countries, guideline authors recommend life-long follow-up or a yearly full skin examination for life, although the number of recurrences occurring more than 10 years after diagnosis is extremely low [57].

Seven of the 19 guidelines were published more than 5 years ago and a considerable number of these and other guidelines are due for revision soon. The most recent available evidence should be incorporated in the revised recommendations concerning follow-up frequency and duration, additional testing and staging. However, it remains to be seen to what extent this will lead to a change in guidelines.

Routine additional testing in follow-up

Five out of the six national guidelines recommending the routine use of ultrasonography in screening for nodal metastases, also routinely screen for pulmonary metastases with chest x-rays (Table 4). A meta-analysis by Bafounta et al., as well as another French study, showed that ultrasonography is more accurate in detecting lymph node metastasis than palpation; however, a benefit for the patient could not be established [58,59]. Schäfer-Hestenberg and colleagues concluded that frequent routine lymph node ultrasonography leads to earlier detection of nodal metastases and seems to prolong patient survival [60]. Regarding the role of chest x-ray in follow-up, no randomized trials have been conducted, yet several observational studies have shown that its yield is very limited and authors have doubted its routine use [56,61,62]. Four of the guidelines mentioned in Table 4 recommend routine use of PET(/computed tomography [CT])-scanning and two routine measurements of the serum biomarker S-100B in follow-up of melanoma patients; the following sections will discuss these subjects in more detail.

In summary, although there is no consensus with respect to routine additional testing and imaging during follow-up, it is recommended to perform additional testing and imaging only if suspicion of (distant) recurrent disease is raised.

Who should perform follow-up?

All the guidelines mentioned in Table 4 are written by a multidisciplinary committee containing dermatologists, (plastic) surgeons and medical oncologists. The table shows their recommendations regarding who should carry out the follow-up of melanoma patients. Eight guidelines do not specify which doctor should perform follow-up and ten recommend follow-up by a melanoma specialist, thereby reflecting the absence of evidence for the ‘best follow-up doctor’. Only one retrospective study advocates a central role for dermatologists in a multidisciplinary melanoma management team, because of improved survival compared with surgeon’s patients [63]. Unfortunately, follow-up surveillance was not discussed and patient characteristics in the dermatology group were more favorable, so the value of this study is limited.

In contrast to the guidelines recommending follow-up by specialists alone, the Danish guideline recommends a transfer of follow-up to the patients’ general practitioner (GP) after 5 years [207]. The Australian guideline gives melanoma patients the opportunity to choose a doctor themselves, possibly their GP [203]. Recently, randomized controlled trial evidence was published that supports these statements. The authors concluded that GP-led follow-up is feasible and does not result in adverse effects on patients’ health status or quality of life [64]. Another British study, however, concluded that GP-led follow-up for melanoma can be appropriate for only a small subgroup of patients. Moreover, 70% of GPs felt unhappy to take over melanoma follow-up [65].

Another development in the field of follow-up for melanoma patients is that in daily clinical practice nurse-specialists are gaining more responsibilities. To our knowledge no published literature is available on the role of these healthcare professionals in melanoma care specifically. The Scottish Intercollegiate Guidelines Network have reported that the majority of melanoma patients in their focus groups are in favor of having access to a nurse-specialist able to spend more time with them and to offer psychological support [212]. An abundant amount of literature on the role of nurse-specialists in cancer care was reviewed by Lewis et al. [66] and Corner [67]. The authors concluded that patients are satisfied with nurse-led follow-up and that it may lead to better patient care, but well-designed research is needed to prove equivalence to doctor-led follow-up in terms of survival, cost–effectiveness and patient well-being. So, who should carry out follow-up is not proven, although a health care professional, doctor or nurse-specialist with knowledge of the disease and dermatology seems most appropriate.

Economic aspects of melanoma follow-up

The economic burden of melanoma, described in reduced quality-adjusted life years and the actual costs of treatment and follow-up has been scarcely documented over the last two decades. A recent study reported that costs for melanoma-related hospital stays in France represented less than 1% of total annual hospital costs for cancer [68]. A fifth of the estimated €59 million spent on melanoma care was attributed to follow-up evaluations, which were recommended by the national guideline to be relatively minimal [15]. The exact contents of these evaluations were not mentioned by the authors, making it difficult to put the data into perspective. In 1998, Tsao et al. estimated that only 5.7% of total annual melanoma care costs (US$563 million) was spent on follow-up, consisting of three to six outpatient visits and two chest x-rays per year [69]. The fact that these estimates were made in centers with frequent adjuvant interferon treatment, good for an estimated 27% of total costs, has to be taken into account when interpreting these numbers.

As stated earlier in this article, taking a medical history and performing a physical examination seem to be the only cost-effective measures during follow-up for stage I–III patients [32,36,37], rendering the role of radiological measures controversial. However, a more recent German study suggested that a recurrence, risk-adapted follow-up strategy is appropriate and cost-effective, whilst approximately halving follow-up costs over a 5-year period [70]. For stage I patients this strategy holds physical examination alone, for stage II lymph node ultrasonography and blood tests are added and for stage III chest x-rays and abdominal ultrasonography. Hengge et al. found that a similar risk-adapted follow-up strategy can yield a saving of more than €100,000 per year for their cohort of 526 patients [71]. Compared with the current German guideline, the described risk-adapted strategies are less extensive, but compared with the majority of guidelines (Table 4) these strategies are far more extensive and costly. Unfortunately, cost–effectiveness studies concerning these more common strategies do not exist.

Psychosocial & quality-of-life aspects of follow-up

An important reason for follow-up of melanoma patients is the possibility of offering patient reassurance and psychosocial support [7]. However, not many studies have been performed on these psychosocial and quality-of-life aspects of follow-up. Over 90% of patients think follow-up is worthwhile and feel reassured by outpatient visits, but more than 50% experience a certain amount of anxiety before and during these visits [65,72,73]. If this anxiety proves to be excessive, a reduction in follow-up visits can be offered to selected patients, if they feel at ease with self-examination.

Patients benefit from psychoeducational interventions provided in a structured group, when facilitated by qualified personnel. Some older studies suggest that facilitated groups can help patients cope better at all stages of the disease, increase knowledge levels and reduce affective stress [74–76]. A recent systematic review of health-related quality of life in melanoma patients concluded that approximately a third of patients in different follow-up regimes suffer from continued significant levels of distress, which is comparable with other cancers [77]. These levels are highest around the time of diagnosis and in the early stages of follow-up. The levels decrease over time. Patients involved in more aggressive treatments report significantly poorer mental and physical functioning. A study evaluating health-related quality of life aspects in patients after isolated limb perfusion reported no reduction, however during follow-up chronic fear of recurrence should be addressed more [78].

The study by Strong et al. suggested that all kinds of cancer patients, including melanoma, suffering from major depression and anxiety during medical specialist treatment can benefit from a psychosocial intervention programme [79]. The Distress Thermometer and problem list [217], its Dutch version for the Netherlands [80], or the recently developed melanoma-specific Functional Assessment of Cancer Therapy (FACT-M) quality-of-life questionnaire [81] may assist doctors in more accurately identifying those patients who suffer from significant levels of distress and are in need of psychoeducational interventions or reassurance through more intensive follow-up.

PET imaging in melanoma

PET allows an assessment of tumor physiology by determining the uptake of radiolabeled tracers. Fluorodeoxyglucose (FDG) is a radiolabeled glucose analogue that is taken up by cells through glucose transporters [82]. It is subsequently phosphorylated intracellularly by hexokinase and trapped in the cells. FDG distribution within the body is thus a measure of glucose metabolism, which is increased in malignant cells [83]. Melanomas are typically FDG-avid and together with the erratic pattern of spread, high-risk patients are good candidates to screen with FDG-PET(/CT) for distant metastases. Several studies have suggested that FDG-PET is more sensitive and specific for the detection of melanoma metastases than conventional diagnostic tests, such as chest x-rays and CT alone [84–86]. Even though whole-body PET does not provide the same anatomical detail as CT or MRI, suspected sites can easily be identified because of usually high target–background contrasts. Furthermore, semi-quantitative measurement of glucose metabolism by calculating standardized uptake values might have prognostic relevance to predict disease-specific survival [87]. Disadvantages of PET include its limited ability to detect brain metastases and lesions smaller than 5 mm, its limited availability and higher costs compared with CT [88–91].

PET in melanoma staging

No national guideline (Table 3) recommends PET imaging as an initial staging tool. This raises the question of the importance of this relatively new technique in staging any melanoma patient. In several studies, FDG-PET has shown limited sensitivity to detect microscopic lymph node metastases in this selected group of patients with stage I and II melanoma [27–29,92–94]. Mijnhout et al. documented in a systematic review and meta-analysis of the literature from the 1990s, a pooled sensitivity of 79% and a specificity of 86% for the detection of melanoma metastases (both lymph nodes and distant) [93]. Two studies assessed the accuracy of FDG-PET to detect distant metastases exclusively in stage III patients, where FDG-PET seems to have the most value. The largest study of 251 patients with palpable lymph node metastases found that 27.1% of the patients were upstaged to stage IV as a result of the FDG-PET scan [95]. The FDG-PET scan was significantly better for identifying bone and subcutaneous metastases than CT. Overall, FDG-PET depicted more metastases than CT, and in 13.5% of patients FDG-PET had an additional value in the management of these patients above spiral CT. Tyler et al. studied 95 patients with palpable lymph node and/or in-transit metastases [96]. FDG-PET changed the management of 15% of the patients, compared with 19.1% in the study of Bastiaannet et al.[95,96]. Both studies found a high sensitivity (87.3 and 86.1%) and positive predictive value (78.6 and 85.0%) for the detection of distant metastases in stage III patients, however direct comparison is difficult because of differences in study design.

FDG-PET/CT is the current standard staging method for clinically stage III patients, but this modality has no role in further staging patients presenting with localized (stage I and II) melanoma.

PET in melanoma follow-up

There is no universally accepted consensus advocating the routine use of FDG-PET in the follow-up of melanoma [54,97]. Its routine use is only recommended in four guidelines and only for patients in stage IIC and higher (Table 4).

A recent study assessed methods to detect recurrent disease in patients who underwent SLNB [62]. Of the 1062 patients, 198 had a recurrence, established by symptoms and self-detection in 109 patients (55%), physician detection in 89 (45%), nearly half of which was by a scheduled radiographic test (chest x-ray 16%, CT 29%, PET 1%). A Finnish study studied the impact of FDG-PET to detect clinically silent metastases in the follow-up of patients with high-risk melanoma [97]. FDG-PET was performed together with CT and physical examination in 30 asymptomatic patients (stage IIB–IIIC) and was able to detect six of the seven recurrences. Both studies showed no evidence for the routine use of FGD-PET in the follow-up of high-risk melanoma patients outside a clinical trial setting. Exposure of the patient to ionizing radiation with the broader use of PET/CT is not negligible, particularly in patients for whom the scan is performed for surveillance purposes [98].

In stage I–IIIA patients, FDG-PET has no additional value in routine follow-up. However, for patients with palpable, proven lymph node metastases with no suspicion of lung metastases on chest x-ray, FDG-PET/CT does have additional value versus CT alone in terms of treatment planning [95]. The routine use of FDG-PET/CT in follow-up of curatively treated stage IIIB–C patients does not seem reasonable. For stage IV melanoma patients FDG-PET may be of importance in determining the extent of disease if surgical treatment is considered.

There are several limitations and pitfalls with the use of FDG-PET in melanoma patients. Firstly, due to physiological uptake of FDG in the brain, cerebral metastases are difficult to detect. Secondly, this modality has a low ability to detect pulmonary metastases, which has been attributed to, for example, respiratory movement and scatter from other organs in basal lung fields. And, thirdly, false-positive hotspots occur due to hypermetabolism for other reasons [99]. So, verification of PET and CT findings remains necessary in patients to prevent potentially beneficial surgery for localized disease being withheld.

Biomarkers in melanoma

A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal and disease processes or pharmacological responses [100]. Generally speaking, there are two types of biomarkers: tissue or tumor biomarkers and serum biomarkers. The ideal biomarker in oncology has the following characteristics: it recognizes (recurrent) malignancy at an early stage, it is organ specific, it correlates with tumor activity and provides prognostic information. Unfortunately, such a biomarker does not exist for any malignancy.

Current prognostic biomarkers based on the AJCC staging system are Breslow tumor thickness, presence or absence of ulceration, number of mitoses in the tumor, extent of nodal involvement for primary melanoma, as well as lactate dehydrogenase (LDH) and site of metastases for distant metastatic disease [11]. However, continuing research into other biomarkers such as S-100B, melanoma inhibitory activity (MIA) and the standardized uptake value of FDG in PET imaging could be the key to a well-defined predictive classification in the treatment and follow-up of melanoma.

Tissue biomarkers in follow-up

In the follow-up of melanoma patients without evidence of nodal or distant metastases, the most significant predictors of outcome are Breslow thickness, ulceration and tumor mitotic rate [11]. Increasing Breslow thickness is highly correlated with 10-year melanoma-specific mortality and the estimated hazard for patients with ulceration is twofold higher. Other significant predictors of outcome are age (a significant reduction of survival with every increasing decade of life), site of primary melanoma (axial location has a poorer prognosis than extremities) and sex (males have a poorer prognosis than females) [42,101].

In patients with nodal metastases, the number of metastatic nodes and the presence of primary melanoma ulceration are all significant predictors for survival. In stage IV, disease-specific survival is significantly better for metastases located at nonvisceral sites (skin, subcutaneous and distant lymph node sites) compared with visceral sites [42,101].

Serum biomarkers in follow-up

Lactate dehydrogenase

Almost 60 years ago Hill et al. already reported on increased LDH serum parameters in melanoma patients [102]. In the 1970s, LDH was reported to be an indicator for liver metastases with a specificity of 95% and a sensitivity of 83% in AJCC stage II patients and, respectively, 87 and 57% in stage III patients [103]. Even stage I disease patients with elevated serum LDH seemed to have a significant decreased survival [104]. Weighing today’s evidence, LDH has high specificity for melanoma and the literature demonstrates that LDH is especially elevated in advanced disease, predominantly when disease has progressed to the liver [105].

Although LDH has a low sensitivity and seems therefore not to be an adequate parameter in staging and follow-up for the earlier stages of disease (AJCC stage I, II and III), it is an independent prognostic factor in disseminated disease [89,103,106,107]. Deichmann et al. even claimed LDH to be the only significant marker for disease progression when analyzing the marker in combination with S-100B and MIA in stage IV disease [108]. LDH is part of the AJCC staging manual for patients with distant metastases (stage IV M1c) [11].

S-100B

Currently, the best studied melanoma biomarker is S-100B. S-100 is a 21-kDa protein that was first isolated from the CNS in vertebrates. The name is derived from its 100% solvency in saturated ammonium sulphate with neutral pH. It has calcium-binding properties and as a dimer it consists of two isomers α and β. All possible combinations can occur (S-100αα, S-100αβ, S-100ββ) [109]. The S-100B protein is of neuroectodermal and mesodermal origin and is expressed in various parts of the body. S-100B is chiefly found in glial cells and Schwann cells [110].

Increased S-100B levels were first detected in melanoma patients in 1980 [111]. Later, S-100B was found to be a serological tumor marker for melanoma and seemed to be mostly increased in stage III and IV [109,112]. According to the literature to date, the proportions of patients with elevated S-100B concentrations are 0–9% in stage I/II, 5–98% in stage III and 40–100% in stage IV [113]. The highest S-100B concentrations were found in patients with liver and bone metastases [114,115]. It can, therefore, be concluded that S-100B concentrations are correlated with the clinical stage of the disease.

Several studies have recommended the use of S-100B as a tumor marker to monitor the course of the disease in stage III melanoma or to evaluate the effect of therapy in stage IV disease. Successful treatment with lymph node dissection, chemotherapy or immunotherapy was associated with decreased S-100B concentrations, whereas increased concentrations were an expression of disease progression [112,116,117]. Recently it was reported by several studies that S-100B can be used as a prognostic marker for disease-free survival and overall survival directly after therapeutic lymph node dissection in stage III melanoma [118–121]. Data from our center were not only in concordance with the above described findings, but also revealed that S-100B can be used as a prognostic marker for disease-free survival when determined before dissection. Multivariate analysis showed that preoperative elevated S-100B was an important predictor for a significantly worse survival [112].

S-100B could be used to perform a more refined individualized risk assessment before administering adjuvant treatment. Above all, it provides information to stage III melanoma patients who want to be optimally informed about their disease prognosis.

Despite the described prognostic values, this biomarker is not suitable for routine screening purposes in stage I–III melanoma patients; that is, early detection of recurrences in follow-up, as was suggested in Swiss and German guidelines [16,19]. The main reason is that the results of these measurements do not translate into an adequate therapeutic intervention nor survival benefit due to limited treatment options in advanced melanoma.

Melanoma-inhibiting activity

Melanoma-inhibiting activity was identified in 1990 as a soluble 11-kDa protein with growth-inhibiting activities secreted from malignant melanoma cells [122–124]. The first important manuscript from Bosserhof in 1997 reports on the protein-enhanced MIA serum concentrations in 13% of stage I, in 23% of stage II disease and in 100% of patients with stage III and IV disease [125].

Later the combination of S-100B, MIA and LDH in 373 melanoma patients was analyzed; MIA had a lower sensitivity compared with S-100B and lower specificity compared with both S-100B and LDH. It was, therefore, concluded that S-100B is a more reliable tumor marker than MIA or LDH in peripheral blood in patients with newly developed metastases [126].

In a prospective study published by Garnier et al., the serum biomarkers L-DOPA/tyrosine ratio, S-100B, MIA and LDH were evaluated in 170 patients in all stages of disease. S-100B and MIA were highly correlated especially in stage IV [127]. The combination of L-DOPA/tyrosine ratio with S-100B displayed the highest sensitivity/specificity (73/70%) to confirm stage III or stage IV (69/75%). The only marker increased during progression from stage I to higher stages (III) was the L-DOPA/tyrosine ratio. The other markers were all elevated in stage IV disease and responded when a patient progressed towards death. All markers were prognostic parameters for survival in deceased patients. However, S-100B and MIA were the most powerful predictors for survival time. In conclusion, there is no role for routine measurement of the serum biomarkers LDH, S-100B or MIA during follow-up in asymptomatic and nondisseminated patients.

Expert commentary

Studies of the primary treatment of melanoma have resulted in well-defined and internationally adhered to evidence for diagnostic and therapeutic excisions, and in our opinion no more research resources should be put into that subject. We recommend that patients presenting with stage I and II melanoma should be offered SLNB, which is now by far the best tool for optimally staging patients and thereby helping to assign them to a well-defined or patient-tailored follow-up schedule. These patients do not need to be staged with additional PET scanning or measurement of serum LDH and S-100B. On the other hand, for patients presenting with palpable lymph nodes (clinically stage III) these modalities seem to be useful in staging. PET/CT very accurately detects distant metastases and causes a considerable amount of patients to be upstaged, and an elevated level of serum S100-B in these patients is associated with worse prognosis.

Many investigators have touched on the subject of follow-up for melanoma, however this has not resulted in uniform follow-up recommendations for melanoma patients. We think the ideal follow-up schedule should be based on the risk for recurrence per stage, resulting in more intensive follow-up for higher staged patients. Francken et al. have developed such a follow-up schedule (see Table 5) based on retrospective data from the Sydney Melanoma Unit and this remains the most evidence-based schedule [34]. Ideally, the optimal follow-up regime should be based on randomized controlled trial evidence, as was recently argued by the same authors [128].

Although melanoma can recur more than 10 years after diagnosis, this concerns a very small percentage of patients. We conclude that it is not necessary to keep patients in life-long follow-up. During follow-up, doctors are recommended to emphasize educating the patient in detecting recurrences and second primary melanoma, in order to promote early detection. Self-examination seems suitable for many patients, but could be improved for optimal benefit, for example, by using modern technology, such as the internet [129].

To date, there is no evidence for routine imaging studies, for example PET scanning, or routine measurement of any available serum biomarkers, such as S-100B and LDH, in optimal follow-up for melanoma. Recent studies have shown promising results for the routine use of ultrasonography in the early detection of nodal recurrence by dedicated, highly experienced radiologists. In our opinion this does not justify its use in all centers involved in melanoma care today.

Future research should be focused on content, frequency and impact on quality of life of patient-tailored follow-up, preferably in randomized controlled trials. It should also be considered where follow-up is done and by whom, how to effectively educate patients and how to incorporate newly available evidence.

Five-year view

In the current treatment of melanoma, the indications for excision margins and staging with SLNB are widely accepted and based on well-designed trials [3,49]. Only clinical stage III melanoma patients should be staged with whole-body FDG-PET, PET-CT or spiral-CT as well as using the serum biomarker S100-B [95,113]. Further regional treatment, curative or palliative, should be based on the extent of the disease. A randomized clinical trial showed that adjuvant radiotherapy improved regional control in melanoma patients at high risk of regional relapse after lymphadenectomy without affecting survival [218]. The loco-regional treatment of melanoma is well-defined, in contrast to treatment of in-transit disease. Various options are available: excision, cryo-ablation, laser ablation, radiotherapy, electrochemotherapy, isolated regional perfusion and isolated limb infusion [130]. These options have reached their technical limits, and both patients and physicians must cope with the fact that no major breakthrough should be expected in the local treatment of in-transit disease.

Melanoma patients with loco-regional disease are at risk of developing distant disease and various therapeutic agents have been studied. Adjuvant systemic chemotherapy or immunotherapy with various nonspecific immune-stimulatory agents in the treatment of high-risk melanoma is not indicated outside the context of a clinical trial [131]. Adjuvant immunotherapy with high-, intermediate- and low-dose IFN-α was extensively studied during the last decade. High-dose interferon therapy was approved and recommended in the USA and Canada as standard therapy for patients with nodal disease, but was not recommended in Europe. Interferon therapy has considerable treatment-related toxicity and, although it might increase disease-free survival, this is not translated into an overall survival benefit. As a result, this therapy was not recommended in Europe. A recent European Organisation for Research and Treatment of Cancer study with pegylated IFN-α2b showed a statistically significant prolongation of relapse-free survival for all patients and a significant benefit in distant metastasis-free survival for melanoma patients with nodal micrometastases [132]. The indication for pegylated IFN-α2b as adjuvant in the treatment of melanoma is currently being further explored.

Currently, two promising treatment concepts are being explored. First, the administration of cytotoxic T-lymphocyte antigen-4 monoclonal antibody (ipilimumab) is currently being studied in a Phase III trial in R0-resected high-risk stage III melanoma patients. Second, since the identification in 2002 of a mutation in the B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) gene in melanoma, research is focused on developing inhibitors of the mutated BRAF protein as a therapeutic target in disseminated melanoma [202]. Within 5 years it will be clear if one of these new therapies will change the outcome in disseminated melanoma. Other therapies, such as tumor vaccines and cellular therapies, are being explored in a few experimental studies, but no major breakthrough is currently expected to come from these modalities in the treatment of (disseminated) melanoma. As soon as an effective (adjuvant) therapy for loco-regional metastatic and disseminated melanoma is discovered, the whole discussion with respect to follow-up intensity and routine imaging will be altered [133].

For the near future, changes concerning content, frequency and location of follow-up are to be expected. History, physical examination and patient education on self-examination will remain the mainstay of follow-up contents. No significant changes are to be expected in the value of PET imaging in follow-up, but more evidence will be available concerning the cost–effectiveness and appropriateness of lymph node ultrasonography and the value of routine S-100B measurement. In 5 years the first results of the Melanoma Follow-up Study (MELFO) will be analyzed. This study, currently conducted in the Netherlands and the UK, randomizes stage IB–IIC patients between the follow-up schedule proposed by the national guideline [210] and an evidence-based schedule (Table 5) with a reduced follow-up frequency. With its primary end point being health-related quality of life, these results should clarify if reduced follow-up frequency has any effect on patient well-being.

As stressed by Christensen et al., the challenge for medicine is to create the right kind of focus in the health care delivery process [134]. This can be done by creating hospitals within hospitals; units that excel in delivering one type of care [134]. For melanoma this implicates a need for creating integrated multidisciplinary practice units within focused (oncology) clinics [135]. So in the coming years these dedicated multidisciplinary clinics are the next step in melanoma patient care. It is a crucial step towards higher treatment efficiency and efficacy; by increasing quality of care and reducing costs, higher Phase I, II and III trial participation and optimizing follow-up. The ultimate goal of melanoma clinics is to improve the survival of patients diagnosed with melanoma. Consequently, the University Medical Center Groningen has recently started a melanoma clinic in which dedicated nurse practitioners participate in the routine follow-up of melanoma patients and clinical trials to reduce the workload of specialists and improve patient satisfaction. Additionally, following the results of the trial by Murchie [64], part of melanoma care may possibly be transferred to GPs.

Individual patients prognostic models for stage I, II and III were recently developed, made available online and can be used for patient-tailoring initial management and subsequent follow-up [136,219]. Finally, melanoma is to be included in The Cancer Genome Atlas project [220] and this will, in the future, provide more insight into molecular-based profiling studies in melanoma patients, will individualize prognosis and will help select patients for targeted therapies.

Table 1. Tumor–Node–Metastasis staging categories for cutaneous melanoma (American Joint Committee on Cancer 2010).

Tumor	Breslow thickness	Ulceration status/mitoses
Tis	NA	NA
T1	≤1.0 mm	T1a: without ulceration and mitoses <1/mm^2 T1b: with ulceration or mitoses ≥1/mm^2
T2	1.01–2.0 mm	T2a: without ulceration T2b: with ulceration
T3	2.01–4.0 mm	T3a: without ulceration T3b: with ulceration
T4	>4.0 mm	T4a: without ulceration T4b: with ulceration
Node	Number of metastatic nodes	Nodal metastatic burden
N0	0	NA
N1	1	N1a: micrometastasis^† N1b: macrometastasis^‡
N2	2–3	N2a: micrometastasis^† N2b: macrometastasis^‡ N2c: in-transit metastases/satellites without metastatic nodes.
N3	4+ metastatic nodes, or matted nodes, or in-transit metastases/satellites with metastatic nodes
Metastasis	Site	Serum LDH
M0	No distant metastasis	NA
M1a	Distant skin, subcutaneous or nodal metastases	Normal
M1b	Lung metastasis	Normal
M1c	All other visceral metastasis	Normal
	Any distant metastasis	Elevated

^†Micrometastases are diagnosed after sentinel lymph node biopsy.

^‡Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically.

LDH: Lactate dehydrogenase; NA: Not applicable.

Data from [11].

Table 2. Anatomic stage groupings for melanoma (American Joint Committee on Cancer 2010).

Clinical staging^†					Pathological staging^‡
O	Tis	N0	M0	O	Tis	N0	M0
IA	T1a	N0	M0	IA	T1a	N0	M0
IB	T1b	N0	M0	IB	T1b	N0	M0
	T2a	N0	M0		T2a	N0	M0
IIA	T2b	N0	M0	IIA	T2b	N0	M0
	T3a	N0	M0		T3a	N0	M0
IIB	T3b	N0	M0	IIB	T3b	N0	M0
	T4a	N0	M0		T4a	N0	M0
IIC	T4b	N0	M0	IIC	T4b	N0	M0
III	Any T	N1–3	M0	IIIA	T1–4a	N1a	M0
					T1–4a	N2a	M0
				IIIB	T1–4b	N1a	M0
					T1–4b	N2a	M0
					T1–4a	N1b	M0
					T1–4a	N2b	M0
					T1–4a/b	N2c	M0
				IIIC	T1–4b	N1b	M0
					T1–4b	N2b	M0
					Any T	N3	M0
IV	Any T	Any N	M1	IV	Any T	Any N	M1

^†Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.

^‡Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial (i.e., sentinel node biopsy) or complete lymphadenectomy. Pathologic stage 0 or stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.

Data from [11].

Table 3. Guidelines for primary treatment and staging primary stage I–II melanoma.

Country	Excision margins (cm)					Initial staging						Ref.
	Primary	Tis	T ≤2 mm	T >2 mm		SLNB^†			Imaging		Blood tests
						Tumor	Routine		US	CXR
Australia & New Zealand	0.2	0.5	1–2	2		>1 mm	-		-	-	-	[203]
Austria	0.3–1.0	0.5	1–2	3		>1 mm	+		+	+	LDH, CBC	[204]
Belgium	0.2	0.5	1^‡	2^‡		≥pT1b	-		+	+	-	[205]
Canada (British Columbia)	NR	0.5–1	1	2		1–4 mm	+		-	+ (T4)	-	[206]
Denmark	0.5	0.5	1–2	2–4		pT1b	+		-	-	-	[207]
France	NR	0.5	1–2	2–3		≥pT1b	-		-	-	-	[15]
Germany	NR	0.5	1	2		>1 mm	+		+	+	LDH, S100, CBC	[16]
Ireland	0.1–0.3	0	1–2	2		≥pT1b	+		+^§	+^§	LDH^§	[208]
Italy	1.0	0	0	1–2		>1 mm	-		-	-	-	[209]
Netherlands	0.2	0.5	1	2		>1 mm	-		-	-	-	[210]
Norway	0.2–0.5	0.5	1	2–3		Trial	-		-	-	-	[211]
Poland	0.1–0.2	0.5	1	2		≥1 mm	+		-	-	-	[17]
Scotland	0.2	0.2–0.5	1–2	2		≥pT1b	-		-	-	-	[212]
South Africa	0.2	0.5	1–2	2		NR	-		-	-	-	[18]
Spain	0.1–0.2	0.5	1–2	2–3		≥pT1b	+		+	+	LDH	[213]
Sweden	0.2	0.5	1–2	2		≥pT1b	+		-	-	-	[214]
Switzerland	NR	0.5	1	2		>1 mm	+		-	-	-	[19]
UK	0.2–0.5	0.2–0.5	1–2	2–3		Stage II	-		+^§	+^§	LDH, CBC^§	[20]
USA	0.1–0.3	0.5	1–2	2		≥pT1b	+		-	-	-	[215]

^†All guidelines recommend that completion lymph node dissection should follow positive SNLB or otherwise in clinical trial setting.

^‡T ≤1 mm and T >1 mm.

^§ Only for stage IIB and higher.

CBC: Complete blood cell count; CXR: Chest x-ray; LDH: Lactate dehydrogenase; NR: Not reported in guideline; SLNB: Sentinel lymph node biopsy; US: Ultrasound of draining lymph node basins with/without abdomen.

Table 4. Follow-up recommendations per guideline for follow-up in stage I–III primary melanoma.

Country	Year	Follow-up schedule (number of visits per year after diagnosis)							Routine additional testing (type and number per year)				General contents of follow-up visits						Follow-up by which doctor?	Ref.
		AJCC or T-class	1	2	3	4	5	6–10	US LN	CXR	PET/CT	S-100	History	Scar exam	ITM exam	LRLN	Compl. skin	Self-exam
Australia & New Zealand	2008	I	2	2	2	2	2	1	-	-	-	-	+	+	+	+	-	+	Doctor preferred by patient	[203]
		II	3–4	3–4	3–4	3–4	3–4	1	-	-	-	-
		III	3–4	3–4	3–4	3–4	3–4	1	-	-	-	-
Austria	2010	Tis	1	1	1	1	1	1	-	-	-	-	+	+	+	+	-	-	Surgeon in specialized center	[204]
		T1	2	2	2	2	2	2	1	-	-	-
		T2–3a	2–4	2–4	2–4	2–4	2–4	2–4	2	1–2	1–2	-
		T3b–4b	4	4	4	4	4	4	2	1–2	1–2	-
		III	4–12	4–12	4–12	4–12	4–12	4–12	4	4	4	-
Belgium	2007	I	4	4	2	2	2	1	-	-	-	-	+	+	+	+	+	-	Dermatologist	[205]
		II	4	4	2	2	2	1	-	-	-	-
		III	4	4	2	2	2	1	-	-	-	-
Canada (British Columbia)	2009	I	2	2	1	1	1	1^†	-	-	-	-	+	+	+	+	+	-	Not specified	[206]
		II	2–4	2–4	2	2	1	1^†	-	-	-	-
		III	2–4	2–4	2	2	1	1^†	-	-	-	-
Denmark	2003	Ia Ib	1 4	1 4	1 2	1 2	1 2	1 1	-	-	-	-	+	+	+	+	+	-	Year 1–5: DMG member Year 5–10: GP	[207]
		II	4	4	2	2	2	1	-	-	-	-
		III	4	4	2	2	2	1	-	-	-	-
France	2005	I	2	2	2	2	2	1^†	-	-	-	-	+	+	+	+	+	+	Not specified	[15]
		IIA–IIB	4	4	4	4	4	1^†	2–4	-	-	-
		IIC–III	4	4	4	4	4	1^†	2–4	-	-	-
Germany	2007	I (≤1 mm)	2	2	2	2	2	1–2	-	-	-	-	+	+	+	+	+	-	Dermatologist	[16]
		I–IIB	4	4	4	4	4	1–2	2	-	-	2–4
		IIC–III	4	4	4	4	4	2	2–4	2	-	2–4
Ireland	2006	I (≤1 mm)	2	2	-	-	-	-	-	-	-	-	+	+	+	+	+	+	Pigmented skin lesion specialist	[208]
		I–II	2	2	2	2	2	-	-	-	-	-
		III	2	2	2	2	2	1^†	-	-	-	-
Italy (Veneto)^‡	2009	O	1	1	1	1	1	1	-	-	-	-	+	+	+	+	+	-	Surgeon or dermatologist
		I	2	2	2	1	1	1	-	-	-	-
		IIAB–IIIA	3	3	2	2	1	1	1–3	1–2	-	-
		IIC–IIIB	3	3	3	1	1	1	1–3	1	1
		IIIC	3	3	3	2	2	1	2–3	2	0–3	2–3
Netherlands	2005	I^¶	4	3	2	2	2	-	-	-	-	-	+	+	+	+	-	-	Not specified	[210]
		II	4	3	2	2	2	1	-	-	-	-
		III	4	3	2	2	2	1	-	-	-	-
Norway	2007	Tis	1	-	-	-	-	-	-	-	-	-	+	+	+	+	+	-	Surgeon or dermatologist	[211]
		<1 mm	4	4	4	-	-	-	-	-	-	-
		≥1 mm	4	4	4	2	2	-	-	-	-	-
Poland	2009	All stages	3–4	3–4	2	2	2	1	-	-	-	-	+	+	+	+	+	-	Specialist in oncology center	[17]
Scotland	2007	All stages	Frequency and duration individually based on tumor and patient characteristics						-	-	-	-	+	+	+	+	+	+	Appropriate local specialist	[212]
South Africa	2004	All stages	Frequency and duration individually based on tumor characteristics						-	-	-	-	+	+	+	+	+	-	Not specified	[18]
Spain	2006	O	1	1	1	1	1	1^†	-	-	-	-	+	+	+	+	+	-	Dermatologist	[213]
		IA	2	2	2	1	1	1^†	1	1	-	-
		IB–IIA	2–4	2–4	2–4	1–2	1–2	1^†	2	2	-	-
		IIB/C–III	2–4	2–4	2–4	1–3	1–3	1^†	-	-	1–2	-
Sweden	2007	All stages	No follow-up schedule provided by national guideline^§						-	-	-	-	+	+	+	+	+	+	Not specified	[214]
Switzerland	2005	<1 mm	2	2	2	2	2	1^†	-	-	-	-	+	+	+	+	+	-	Not specified	[19]
		IB–IIB	4	4	4	2	2	1^†	1	1	-	-
		IIC–III	4	4	4	2	2	1–2^†	1	-	1	-
UK	2002	<1 mm	4	4	4	-	-	-	-	-	-	-	+	+	+	+	+	-	Not specified	[20]
		≥1 mm	4	4	4	2	2	-	-	-	-	-
USA	2009	O	1	1	1	1	1	1^¶	-	-	-	-	+	+	+	-	-	+	Not specified	[215]
		IA–IIA	1–4	1–4	1–4	1–4	1–4	1^¶	-	-	-	-
		IIB–IV	2–4	2–4	1–4	1–4	1–4	1^¶	-	-	-	-

^†Lifelong follow-up.

^‡Personal communication from Dr CR Rossi, University of Padova, Italy.

^§No follow-up for Breslow <1 mm and melanoma in situ.

^¶At least annual skin exam for life.

AJCC: American Joint Committee on Cancer; Compl. skin: Complete skin examination; CT: Computed tomography; CXR: Chest x-ray; DMG: Danish Melanoma Group; GP: General practitioner; ITM Exam: Examination of in-transit metastasis pathway; LRLN: Palpation of loco-regional lymph nodes; PET/CT: Positron emission tomography with/without CT scanning; USLN: Ultrasonography of draining lymph node basin(s).

Table 5. Proposed optimal follow-up schedule^† and experimental schedule (MELFO study).

AJCC stage	Number of visits per year after diagnosis
	1	2	3	4	5	6–10
IA	1
IB	1	1	1	1	1
IIA	2	2	1	1	1	1
IIB	3	3	2	1	1	1
IIC	3	3	2	1	1	1
III	4	3	2	2	2	1
IV	Individually tailored to patient’s needs

^†Data taken from [34].

AJCC: American Joint Committee on Cancer.

Key issues

• • According to multiple published guidelines for the management of melanoma, there is broad consensus regarding excision margins, the use of sentinel lymph node biopsy and additional testing in staging.

• • Sentinel lymph node status is an important factor in determining the optimal follow-up regimen for melanoma patients.

• • No evidence-based optimal follow-up schedule for melanoma patients exists, although most guidelines for management advise a more vigorous follow-up strategy for patients in more advanced stages.

• • There is no place for routine measurement of serum biomarkers, such as lactate dehydrogenase, S-100B or melanoma-inhibiting activity, nor for routine imaging studies, such as PET/computed tomography, in staging and follow-up for melanoma.

• • Future investigations should be focused on determining patient-tailored follow-up regimens.

• • Melanoma patients in follow-up seem to report a reduction in health-related quality of life comparable to other malignancies.

• • In the near future the opening of specialized multidisciplinary melanoma clinics will be the next step in improving all aspects of melanoma patient care.

• • Content and frequency of follow-up for melanoma patients are likely to change dramatically following the discovery of a more effective systemic treatment for disseminated disease.

Acknowledgements

The authors thank Dr CR Rossi, Instituto Oncologico Veneto, IRCCS, Padova, Italy and Dr P Rutkowski, Department of Soft Tissue/Bone Sarcoma and Melanoma, M Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland for sharing their guidelines for management of melanoma.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.