University of Groningen. Primary and metastatic melanoma Francken, Anne Brecht

University of Groningen

Primary and metastatic melanoma

Francken, Anne Brecht

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date:

2007

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Francken, A. B. (2007). Primary and metastatic melanoma: aspects of follow-up and staging. [s.n.].

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Part I

Lancet Oncol 2005:6;608-621

1

C

h

a

p

t

e

r

Follow-up strategies in patients

with localised primary cutaneous

melanoma

Anne Brecht Francken

Esther Bastiaannet

Harald J. Hoekstra

SUMMARY

Follow-up services for patients with localised cutaneous melanoma are widely

discussed but there is no international consensus. Our aim was to discuss frequency

and duration of follow-up, type of health professional involved, optimum intensity

of routine investigation, and patients’ satisfaction with follow-up. Searches of

the published work were directed at publications between January, 1985, and

February, 2004 on recurrences, subsequent primary melanoma, routine tests,

and patients’ satisfaction. In a selection of 72 articles, 2142 (6.6%) recurrences

were reported, 62% of which were detected by the patients themselves. 2.6% of

patients developed a subsequent primary melanoma. Most investigators do not

support high-intensity routine up investigations. Of the various

follow-up investigations requested by physicians, only medical history and physical

examination seem to be cost effective. Lymph-node sonography seems to be a

promising method for detection, although survival benefit remains to be proven.

Patients were found to be anxious about follow-up visits, although other research

showed that provision of information to patients was much appreciated. Published

work on the follow-up of patients with cutaneous melanoma has mainly been

retrospective and descriptive. Recommendations can be given with only a low

grade of evidence. For meaningful guidelines to be developed, prospective,

high-quality methodological research is needed.

INTRODUCTION

Provision of routine

follow-up services for patients after

treatment

for

cutaneous

melanoma is standard practice

in most countries. The main

purpose of follow-up services

is early detection of recurrent

disease (figure 1) and subsequent

primary tumours, which could be

treated successfully by surgery

or other modalities.

Secondary

aims include offering education,

reassurance,

and

treatment

surveillance. The latter is important for medical audit and research purposes.

Follow-up services for patients with cutaneous melanoma are associated with

several difficulties and controversies. First, the prevalence of cutaneous melanoma

has risen over the past decades.

This increase is thought to be an effect of the

overall rising proportion of patients with melanoma of American Joint Committee

on Cancer stage 0, IA–B, and IIA who have a good outlook. As well as the increasing

prevalence of thin melanoma, these patients will probably need follow-up

surveillance for a longer time because of their longer survival. These effects have

resulted in doubling of the patient population who need follow-up surveillance.

Second, most patients detect recurrence themselves. Therefore, the value of

high-frequency follow-up surveillance has been questioned.

However, patients with

a history of melanoma are not necessarily in the best position to detect a second

primary melanoma.

Also, for disseminated disease, no convincing treatment

exists and therefore a cure cannot be guaranteed when a patient is diagnosed

with recurrent melanoma.

Third, the focus on cost-effectiveness in health care

has resulted in questioning of regular follow-up services.

During the past few

decades, many recommendations and proposals for follow-up services have been

issued, but consensus was not achieved. Recommendations mostly give guidance

on the intensity (including tests), the frequency, and the length of follow-up.

Almost all recommendations were made on the basis of retrospective assessment

of historical cohorts. The only prospective study, by Garbe and colleagues,

had

several shortcomings in the selection of patients. The investigators included all

patients who presented to their clinic, including those who already had metastatic

disease. Inclusion of such patients might have caused length-time bias and leadtime

bias in their results.

Furthermore, several patient-related features, such as the

definition of a patient-detected recurrence and a survival benefit of recurrences

detected by physician or patient, were not discussed. In most studies,

patient-related features—eg, reassurance of patients— are hardly mentioned and this issue

has barely been investigated for patients with melanoma, and even less in relation

to follow-up surveillance. The aim of this structured review of the published work

was to identify and integrate evidence on the effectiveness of follow-up strategies

for patients treated successfully for their primary localised melanoma. Searches

of the published work were done to find out the optimum frequency and length of

follow-up services, the type of health professional who should provide follow-up

care, the optimum intensity of routine follow-up investigation, and what is known

about reassurance for patients and their satisfaction with follow-up services.

METHODS

Search strategy and selection criteria

A comprehensive computer-aided search of the databases of the medical literature

(Pubmed, Medline, Embase) was conducted (Table 1). In-depth searches of MESH

Table 1. Search strategies

Subtopic Search terms all terms applied as Mesh and free text

Specified exclusion criteria

1. Recurrence development and detection

Melanoma and recurrence Evaluation of tests Single type of recurrence

2. Second primary melanoma development and detection

Melanoma and neoplasm and/or second primary

Second primary malignancy

3. Routine investigations

Melanoma and (ultrasound and/or computed tomography imaging and/ or chest X-ray and/or blood tests)

Staging at primary diagnosis Diagnostic validity of a specific technique (e.g. effect of sentinel node biopsy on recurrence development)

4. Patient reassurance and satisfaction

Melanoma and (QoL and/or patient satisfaction and/or anxiety)

Drug intervention Metastatic melanoma Screening related

General exclusion criteria

Applied to all subtopics

Not applicable Case study design Not directly related to FU Expert opinions Literature review Influence of interventions Ocular melanoma

FU = follow-up QoL = quality of life

headings and free term searches were focused on follow-up surveillance in relation

with four subtopics: 1: development and detection of recurrences; 2: development

and detection of second primary melanoma; 3: routine follow-up investigations; 4:

patient reassurance, preferences and education. Reference searches of identified

articles were carried out subsequently.

All studies reporting in English from January 1985 to February 2004 describing

empirical data of melanoma patients in relation to the aforementioned focuses

were selected. Excluded were: case study reports; health care professionals’

views or experiences; medical procedures or specific technology advancements,

literature reviews and consensus, conference reports and guidelines.

The selection criteria were applied to all abstracts identified by electronic search

strategies (ABF). If the identified article had no abstract, the full article was

obtained. Full articles of all abstracts meeting the review criteria were obtained

from library services.

RESULTS

Seventy-two articles were included in the final review selected from 2206 articles

initially identified by the different searches (Figure 2).

Follow-up surveillance and recurrences

Articles studied in this review regarding melanoma recurrence development are

presented in Table 2. All but one study

had a retrospective study design; one

study

included a patient questionnaire. In these articles several aspects of

follow-up surveillance were evaluated: 1: recurrence rates, 2: recurrence detection, 3:

follow-up schedules. This approach will also be used here.

Recurrence rates

Recurrence rates have been presented several times. The development of

recurrences in these studies is estimated for T-stadium, according to the previous

AJCC Staging System, or the pre-2001 AJCC Staging System.

Recurrences present locally, in transit, regionally or distant. The distribution of

recurrences in patient samples where all melanoma thicknesses were discussed

(mainly AJCC Stage I and II) is presented in Table 3. Overall patients present

initially with 20-28% local or in transit recurrences, 26-60% regional recurrences

and 15-50% distant metastases. Ultimately, 3-5% of patients of the total melanoma

population developed a local or in transit recurrence, 5-13% metastases in the

regional nodes and 3-10% distant metastases.

Figure 2. Flow chart of study selection process

Table 3. Distribution of first recurrences in studies that discussed melanoma of all tumor

thicknesses

Author Total recurrences

Data available

Local In transit Nodal Distant

n (%) n n (%)**, (%)*** n (%)**, (%)*** n (%)**, (%)*** n (%)**, (%)*** Kelly19 _{295 (22) 177 35 (NR), (20)* 75 (NR), (42) 67(NR), (38)} Fusi24 _{302 (28) 250 42 (NR), (17) 20 (NR), (8) 130 (NR), (52) 58 (NR), (23)} Baughan8 _{65 (20) 16 (5), (25)* 39 (12), (60) 10 (3), (15)} Basseres25 _{115 (22) 12 (2), (10) 7 (1), (6) 66 (13), (57) 21 (4), (18)} Mooney23 _{174 (17) 170 12 (NR), (7) 84 (NR), (49)^ 74 (NR), (44)} Dicker17 _{293 (19) 156 26 (NR), (17) 9 (NR), (6) 88 (NR), (56) 34 (NR), (22)} Poo-Hwu22 _{78 (21) 19 (5), (24)* 20(5), (26) 39 (10), (50)} Hofmann12 _{100 (16) 28 (4), (28)* 39 (6), (39) 32 (5), (32)}

See Table 2 for more details * Local and in transit recurrences ** percentage of total population

*** percentage of total population that recurred NR=not reported

The occurrence of late recurrences, all with a minimum disease-free interval

of ten years varied from 1-25%.

The recurrence rate of thin melanomas

(Breslow thickness all <1.51mm) were frequently studied and varied from 3-24%.

8,16,18,20,21,34-37

Recurrence detection

Several authors have found that the patient detects most recurrences. However,

the detection of the recurrences was reported in different ways. Some authors

retrieved their information from the medical records.

Regan et al sent out

questionnaires to all their patients who had had a recurrence. In this questionnaire

patients were asked who detected the first recurrence.

Others used indirect

methods, e.g. recurrences resulting in patient-initiated consultation of the physician

or surgeon earlier than the scheduled follow-up visit or all symptomatic lesions were

considered to be patient-detected.

All but one of these studies described

a follow-up schedule which patients were supposed to follow. The minimum

frequency was twice a year in the first three years in all studies (Table 4).

To date, only one study on the follow-up surveillance of melanoma patients was

performed prospectively.

In this study the person detecting the recurrence was

recorded at the follow-up visit, although this was not clearly described. Only 17%

of the 233 recurrences, in 112 patients, were found to be detected by the patient.

Table 4. Literature overview of detection of first recurrences, patient or doctor.

Author Total Patient detected recurrences/total recurrences

Follow-up schedule supposed to be followed by patients (visits/yr) Method of assessment year n n/n (%) 1 2 3 4 5 >5 Regan38 _{- 54/78 (69) 4 2 2 2 1 1 Questionnaire}

Kersey51 _{393 28/64 (44) 4 4 4 2 2 nsv Medical records}

Baughan8 _{331 41/65 (63) 3 3 2 2 1 1 Symptomatic /}

non-symptomatic Bassères25 _{528 38/115 (33) 2* 2* 2* 2* 2* 2* Medical records}

Weiss11 _{261 99/145 (68) 6 3 2 2 2 1 Attendance before}

scheduled visit Shumate7 _{1475 176/195 (90) 4 4 2 2 2 1 Symptomatic /}

non-symptomatic Mooney23 _{1004 89/154 (58) no follow-up schedule reported Symptomatic /}

non-symptomatic Poo-Hwu22 _{373 34/78 (44) 2-4 2-4 2-4 1-2 1-2 1 Medical records}

Hofmann12 _{630 77/127 (61) 4 4 4 4 4 2 Medical records}

Total 636/1021 (62) ns=no scheduled visits

However, in this study first recurrence as well as subsequent recurrences were

considered. Therefore, comparison to previous studies is not valid. The study of

Garbe et al was not presented here because no details on first recurrence detection

for the individual patient were reported.

A few studies analysed survival for the person who detected the first recurrence:

no statistical difference was found between detection by patient or doctor.

Two other articles described the survival difference between symptomatic and

non-symptomatic lesions at the time of detection but results were contradictial,

Poo-hwu et al did found a survival benefit of patients with a-symptomatic lesions,

in contrast, Mooney et al did not.

Follow-up schedules and recurrences

In the last few decades, several attempts have been made to introduce a new

follow-up schedule that would find international consensus. Most proposed

follow-up schedules are based on the annual risk to develop a recurrence. Others

are based on the pattern of recurrences, the result of patient compliance or the

opinion of experts in the field (Table 5).

In this overview

a couple of aspects become evident: 1: all authors recommend more

follow-up visits for thicker tumours or higher AJCC Stage melanoma, and a reduction

of visits over time, 2: most authors ignored the influence of ulceration, which is

currently implemented in the AJCC Staging System 3: most authors recommend

a minimum of annual visits for ten years. Recommended in the studies is a range

of visits stratified per T-stadium: T1 1-4/year, T2 2-6/year, T3 2-12/year and T4 2-12/

year. It is important to realise that naturally, all recommended follow-up schedules

be either based on old T-classification or on pre-2001 AJCC Staging, because they

deal with patients from that time. Today we prefer to take notice of the influence

of ulceration next to tumour thickness and therefore use AJCC Stage instead of

Tumour classification. The recommended follow-up schedule of Poo-Hwu et al

could be used as an extract of all recommended follow-schedules.

Follow-up and subsequent primary detection

The literature that was studied in the scope of follow-up surveillance and subsequent

(second, third, et cetera) primary melanoma (SPM) is summarised in Table 6.

SPM rates

The SPM rate varies between 2-7%.

The risk of developing a SPM is

therefore similar to the risk of recurrence development in clinical AJCC Stage I

melanoma.

Detection of SPM

Although many authors have published on screening and the detection of primary

melanomas, not much is known about the detection of SPM. Brobeil et al found

93% of all SPMs detected by the physician and this finding was confirmed by Garbe

et al.

Several authors found the SPM to be thinner than the initial melanoma

and therefore the SPM does not decrease the overall prognosis.

Follow-up schedules and SPM

Most authors who assessed follow-up surveillance and the development of SPM

advocate long-term or even lifelong follow-up varying from 3-monthly visits to

annual check-ups.

However, findings of the time-interval between the initial

primary melanoma and the SPM are inconsistent. Goggins et al found that most

SPMs develop in the first few months up to two years after the initial melanoma

development.

Others found over 40% of the SPM diagnosed more than 7 years

after initial melanoma diagnosis or even a SPM diagnosed as long as 31 years after

the initial melanoma.

Follow-up surveillance and routine investigations

Several studies are performed to assess the use of routine investigations in

follow-up surveillance. Most studies investigating multiple diagnostic entities

were retrospectively performed and are summarised in Table 7.

Many authors conclude that history taking and physical examination have the

highest detection rate and are therefore most cost-effective for AJCC Stage I and

II melanoma patients.

On the other hand, Garbe et al recommended also

blood tests and like several other authors lymph node sonography as a routine

follow-up investigation.

Lymph node sonography

Several prospective studies have investigated the use of lymph node sonography in

the follow-up of melanoma.

This subject was recently reviewed and published

in the Lancet Oncology by Bafounta et al.

Reviewing the studies, concerning

lymph node sonography, ourselves we came to similar results and therefore no

details are repeated here. Lymph node sonography seems to be a promising

investigation in follow-up surveillance, although survival benefit remains to be

proven. Machet et al recently responded to the review of Bafounta et al in the

Lancet Oncology and stated that a randomised clinical trial is hardly feasible since

3000 patients would have to be included to prove a clinical survival benefit.

The health professional that should provide follow-up service and

physician-based variation in request of routine investigations

Ten of the 30 articles reviewed in this study on melanoma recurrence were published

by dermatologist primarily, also 10 studies were carried out by surgeons, plastic

surgeons performed 6 studies and the four remaining studies were performed by

oncologist/radiotherapists. One third of the total of 24 studies had been brought out

from a cancer unit or, even more specific, a skin cancer or melanoma unit.

Several authors have queried physicians regarding their follow-up surveillance

practice to investigate the variance in request of routine examinations in relation to

different factors such as TNM classification of disease, geographic distribution and

the age of the physician.

Four out of five studies performed have reported

several topics regarding “physician variance” within the same physician sample. A

summary of articles discussed is given in Table 8. Provost et al did not find much

variability amongst physicians.

However, the second sample of physicians showed

a lack of consensus in the request of follow-up tests, which was marginally dependent

on age or TNM stage, but clearly dependent on geographic factors.

Routine chest X-ray in follow-up surveillance

Two studies were specifically performed on the use of chest X-rays as a routine

investigation. Mooney et al performed a cost-effectiveness analysis and Tsao et

al recently did a survey to determine survival benefit of chest X-ray screening as

a possible result of early detection (Table 7).

Although Mooney et al could

only conclude that screening should by no means continue after ten years on

financial basis, Tsao et al could not support chest X-ray screening. They found no

survival benefit of chest X-ray screening in an unselected population. Also others

who investigated detection of recurrences with multiple devices have doubted the

value of the routine chest X-ray.

Follow-up surveillance and patients’ well-being

Not many studies have been performed on patients’ well-being and hardly any

in the scope of follow-up surveillance. In Table 9 the studies evaluated for this

review are summarised. Baughan et al assessed the value of follow-up surveillance

experienced by patients by using a questionnaire.

They concluded that 86% of

the patients found follow-up surveillance worthwhile. Only 5% of the 133 patients

in their study found the follow-up visits a waste of time. On the other hand, more

than half of the patients in their study reported anxiety prior to the follow-up visit.

Also, Longman et al found that any interaction with a physician produced feelings of

anxiety.

On the contrary, Brandberg et al found that regular follow-up surveillance

it might even help to cope with a recurrence. In this study however, patients with

disseminated disease were included.

Extra information supplied was also found

to be important by Schofield et al in 63% of their patient’s sample. Three-quarters

of patients said they would like to have answers to “frequently asked questions”

and the same proportion of patients endorsed the option of talking to a counsellor.

74

In a following study Brandberg et al investigated the influence of a specific

information program and found that this was highly appreciated by patients.

Other studies on melanoma patients’ well-being focus on communication strategies

of information disclosure

and coping with the diagnosis of melanoma.

DISCUSSION

In this review it is shown that many studies regarding follow-up surveillance

in melanoma patients have been performed. Despite many attempts to reach

international consensus on this topic no evidence can be found for any form of

follow-up surveillance. However, most studies were retrospectively performed or

had poor methodology. Therefore, more high-quality prospective research is needed

to establish evidence-based guidelines for follow-up surveillance in melanoma.

The optimal frequency and length of follow-up services

According to the articles reviewed in this overview no true evidence is found for

follow-up surveillance in localised melanoma. Overall 62% of the patients detected

their first recurrence themselves. Moreover, no study has proven any disease-free

survival or overall survival benefit related to follow-up surveillance. Although one

study showed a survival benefit of doctor-detected (asymptomatic) recurrences.

However, almost all studies evaluated in this review had a retrospective study

design and often a poor methodological quality. Therefore, recommendations on

the basis of the existing literature can only be made with a low level of evidence.

Looking at the (retrospective) evaluation of annual risk of recurrence development

for AJCC Stage I and II patients, and the results of retrospective investigations

regarding the first recurrence detection, arguments for frequent follow-up

service are hard to justify. Therefore, for this population we recommend only

infrequent follow-up visits (1-2/year) according to risk of recurrence development

in combination with elaborated patient education for self-examination. However,

prospective (randomised) trials are needed to give a higher level of evidence for

follow-up surveillance. Currently, our centre is setting up such a trial in which

elaborated follow-up consultation will be compared with a reduced amount of

follow-up visits.

The frequency of late recurrences is inconsistent and varies widely (1-25%).

However, measurements are biased because of the retrospective nature of the

analyses and might therefore be overestimated.

Moreover, one could wonder

if e.g. yearly follow-up visits after 10 years of surveillance will improve survival if a

patients recurs. Although it is clear that melanoma can relapse after a long disease

–free interval, most profit might be gained by thorough patient education because

this could be maintained lifelong.

Which type of health professional should provide follow-up care?

No research is performed on the type of health professional that should perform

follow-up care in melanoma patients. Currently, general surgeons, dermatologists,

plastic surgeons and general practitioners are involved in the service and this

varies amongst countries. This was confirmed from the literature reviewed here,

dermatologist and surgeons had a comparable input of data. In practice, also nurse

practitioners are gaining responsibilities in the field of melanoma care. Recently,

McKenna et al discussed the treatment of melanoma patients by several specialist

and they concluded that dermatologist should have a more prominent role in the

management of melanoma because their patients showed an improved survival

compared to plastic or general surgeon’s patients.

The authors hypothised that

the more frequent two-stage excision treatment of melanoma by dermatologists

in their study might have been the reason of the survival benefit. This study was

retrospectively performed and therefore its value is limited and results should

be supported by studies of prospective design. Unfortunately, they did not bring

follow-up surveillance into their analyses.

One could argue which discipline is best in treating and following up melanoma

patients. Naturally the follow-up of surgical treatment is the responsibility of the

ones that performed the surgery, regardless of the primary profession. Also, if

treatment of metastases is feasible, it will mostly have a surgical approach

(e.g. lymph node dissection) in most cases, however this does not mean that

the surgeon is the specialist of first choice to perform follow-up surveillance.

Considering the search for second primary melanoma, especially in those patients

with many moles or even dysplastic neavi syndrome, dermatological knowledge is

essential. Several questions regarding the population with a history of melanoma

and the development of SPM are not studied yet: 1: Which medical specialist

should search for SPM? 2: Is there a learning curve for patients in the detection

of primary melanoma? 3: Do patients with a history of melanoma more easily or

sooner seek medical advice? A multidisciplinary approach is probably the finest

solution, particularly in patients suffering the dysplastic neavi syndrome and high

risk of recurrence development. Such approaches have been successfully carried

out for years in several countries, e.g. Sydney Melanoma Unit in Australia.

What is the optimal intensity of routine follow-up investigation?

Several authors studied the role of routine investigations in the follow-up

surveillance of AJCC I and II melanoma patients. From the results of those studies

it becomes clear that most recurrences are detected by the patient or by history

taking and physical examination of the physician. Only this form of follow-up

surveillance seems therefore to be cost-effective.

There are no data to justify

screening with chest X-rays.

Ultrasonography of the regional lymph node field is the only routine investigation

that might gain importance, since several prospective diagnostic trials have been

conducted on the performance of sonography. On the other hand, no information

is yet available on the specific cost-effectiveness of this diagnostic device and

only two studies determined a survival benefit as a result of a presumably earlier

detection with lymph node sonography.

Recently, Bafounta et al published

a meta-analysis on ultrasonography or palpation of melanoma nodal invasion.

They concluded that in spite of the positive results of this technique, several issues

regarding the selection of patients for sonography and the true survival benefit are

still to be solved. Therefore, lymph node sonography cannot be recommended for

the individual patient yet.

In addition to routine investigations, there is currently no insight yet with respect to

the use of serum markers such as protein S-100β and melanoma-inhibitory activity

in the follow-up or treatment evaluation of melanoma patients.

To find true evidence on the use of diagnostic tests and investigations a prospective

randomised controlled trial should be performed, like the studies that have been

conducted in breast cancer research in the past.

Recently, a meta-analysis

was published on the detection of locoregional recurrences after invasive breast

cancer.

About 40% of the recurrences was detected at routine follow-up visits,

but the extent of the interference of tests could not be determined. The authors

highlighted the need for prospective comparative studies on cost-effective

strategies also in this field.

What is known about patient reassurance and satisfaction with

follow-up services?

There is not much information of the effect of follow-up surveillance on patients.

Only few studies have investigated the psychological effect of follow-up. The

overall result was that regular check-ups have a positive impact on the majority

of patients, and most of them are satisfied by additional information delivery.

8,75,83

However, the aims and methodology of these studies were inconsistent

and therefore give only premature indications on how follow-up is experienced by

patients.

In breast cancer research a few more investigations have been performed on

this topic and those indicate that patients’ well-being is hardly influenced by the

intensity or profession who provides follow-up visits.

In melanoma research

the information on this topic is clearly lacking.

Follow-up practice, guidelines and evidence

Follow-up services for melanoma patients are common practice in melanoma

care all over the world. In many countries the format of this service is based on

common sense or historical practice. However, in other countries guidelines have

been brought out and have been renewed in the last decennia. Some guidelines

are formulated as a national consensus, others are used in a local context.

Amongst others, follow-up guidelines are developed in the United Kingdom,

Germany, Scotland, the Netherlands, the United States of America, Switzerland,

and Australia.

A writing group in Australia and the Netherlands are currently

independently developing their new guidelines. Most of these guidelines are based

on the same literature as discussed in this article. Nevertheless the content of

guidelines has a wide variance. Most guidelines do not recommend any follow-up

for patients with melanoma in situ

, but some do not even recommend

follow-up for patients with a primary melanoma with a tumour thickness <1mm.

Few

guidelines recommend only follow-up for three-five years after primary melanoma

diagnosis

, but others recommend ten-year follow-up for thicker melanoma

,

or even lifelong for melanoma from AJCC Stage IB.

In the Scottish guideline

it is recommended to let patient’s emotional and psychological status play a

role in frequency and duration of follow-up. Most guidelines do not recommend

any routine investigation, but only when specific symptoms are present

,

however some do recommend routine or optional chest X-rays, ultrasonography

and blood tests for patients with thicker melanoma.

The wide variance in guidelines of different entities illustrates in the first place that

historical policy, cultural expectance and personal views still play an important

role in guidelines and practice of follow-up care in melanoma patient. Second,

it illustrates that the evidence, which can be found in the existing literature, is

marginal and therefore subject to personal interpretation. In this review we tried to

give an objective overview of the existing literature and we hope it will contribute

to more research, open discussion and consistent guidelines for the follow-up of

melanoma patients in the future.

Conclusions

Literature on follow-up surveillance in cutaneous melanoma patients is mainly

retrospective and of descriptive nature. With a low level of evidence we can draw

a few conclusions: follow-up does not seem to contribute to disease-free interval

or overall survival, as doctor-detected lesions do not have a better prognosis than

those detected by the patient. We do not know to what level patients are able to

detect early state subsequent melanoma, but it seems that education could play

an important role. The request of routine investigations is not useful, although

lymph node sonography might contribute to earlier detection of metastases. It

seems that patients do appreciate follow-up and additional information provided.

However, they do experience anxiety in relation to the control visit.

Since almost all findings are based on retrospective literature, which is liable

to known bias and shortcomings, the level of evidence for recommendations is

low. However, a few recommendations can be given: There is no true evidence in

the existing literature that supports the value of frequent follow-up surveillance.

Therefore, follow-up should be reduced to a minimum frequency, depending on the

individual patient. The aim of follow-up should be patient education, reassurance

and SPM detection, rather than recurrence detection although this should be

verified in future research. Lymph node ultrasonography seems to contribute

to early detection of lymph node metastases and prolonged survival. Further

research is needed to determine subgroups of patients to which this investigation

is most useful. It seems that an individual patient profile should determine what

is the best surveillance for the particular patient. In order to develop meaningful

applicable guidelines, prospective, randomised and high quality methodological

research should be performed. A clinical randomised trial is currently developed

in the University Medical Centre Groningen, to evaluate the value of follow-up

surveillance.

Table 2. Overview on literature of follow-up surveillance and recurrences

Author (year) Design Subjects (time period) AJCC Stage* Follow-up time (median, years)

Recurrences n(%)

Foundation for follow-up recommendation

General recommendation of follow-up

Kelly19 _{(1985) RS 1324 (1971-1984) Clinical Stage I All TT’s 2.7-3.6 (mean) 295(22) Distribution of recurrence}

development Recommendation per TT

Long-term follow-up according to individual risk

Regan38 _{(1985) RS +}

questionnaire

NR (1967-1982) Clinical Stage I All TT’s NR 91 Recurrence detection Better patient education, actively involvement of general practitioner, hospital follow-up for three years Shaw26 _{(1985) RS 1283 (1950-1984) Clinical Stage I All >10 34(3) Analysis of late recurrences Long term follow-up}

Naruns34 _{(1986) RS 649 (1971-1985) Clinical Stage I TT < 0.76 mm NR 30(6) Recurrences in thin melanoma often}

“late”

Careful follow-up for thin melanoma McCarthy39 _{(1988) RS 3171 (1950-1984) Clinical Stage I All TT’s 9.8** 886(28) Distribution of recurrence}

development

Follow-up depending distribution of recurrences, self-detection and individual wishes

Callaway27 _{(1989) RS 536 (1967-1976) Clinical Stage I All TT’s All >10 5(1) Analysis of late recurrences Patient education is essential}

Crowley28 _{(1989) RS 651 (1970-1989) Recurred patients: Pathologic}

Stage I (n=156)

All >10 168(25) - only those with follow-up time >10 years

Analysis of late recurrences Life-long annual follow-up controls with chest x-ray and liver function tests Pathologic Stage II (n=11)

Pathologic Stage III (n=1)

Gutman29 _{(1989) RS 94 (1965-1985) Clinical Stage I All >10 6(6) - only those}

with follow-up time >10 years

Absence of identified risk factors for late recurrences

Long term follow-up

McEwan30 _{(1989) RS 769 (1956-1985) Clinical Stage I All TT’s 11# 14(2)- occurred}

between after 5 years of follow-up

Recurrence rates and the absence of identified risk factors for late recurrences

Follow-up transferred to general practitioner after 5 years. Statistical reasons follow-up maintained until death Brandt35 _{(1990) RS 206 (1964-1988) Clinical Stage I TT < 1.51mm NR 11(5) Analysis of recurrences in thin}

melanoma

Long-term follow-up is not justified, since only benefits 2% of patients

Fusi24 _{(1992) RS 1090 (1960-1981) Clinical Stage I All TT’s 7 302(28) Distribution of recurrences and}

minimum time for clinical trials of recurrence development

3 years of follow-up is sufficient for clinical trials

Tahery31 _{(1992) RS 956 follow-up >}

10 years (1955-1979)

NR All >10 8(1) - only those with follow-up time >10 years

Analysis of late recurrences absence of identified risk factors

Long term annual follow-up

Baughan8 _{(1993) RS 331 (1981-1990) Clinical Stage I TT < 1.51 mm 5 65(20) Distribution of recurrence}

development, recurrence detection and patients preferences

Annual follow-up during 15 years Follow-up by nurse specialist Patient education and counselling

Martini20 _{(1994) RS 840 (1975-1992) Clinical Stage I TT < 1.51 mm 4 202(24) Distribution of recurrence}

development and pattern of recurrence

Follow-up for 10 years

Basseres25 _{(1995) RS 528 (1981-1991) Clinical Stage I TT > 0.4 mm NR 115(22) Risk of recurrences, self-detection Follow-up depending low or high risk}

phenotype and TT Shumate7 _{(1995) RS 1475 (1958-1984) Clinical Stage I Clinical Stage II 6.5# 195(15) Self-detection Symptomatic}

recurrences

Thorough patient education, reduction of follow-up

Weiss11 _{(1995) RS 261 (1984-1990) Regional involved nodes or TT >}

1.69 mm

NR 161(60) Way of detection. Symptomatic recurrences

Only clinical examinations Moloney21 _{(1996) RS 602 (1967-1989) Clinical Stage I TT < 0.76 mm All > 5 24(4) Enormous workload, but little gain}

of routine follow-up

Thorough patient education, reduction of follow-up

Table 2. Overview on literature of follow-up surveillance and recurrences

Author (year) Design Subjects (time period) AJCC Stage* Follow-up time (median, years)

Recurrences n(%)

Foundation for follow-up recommendation

General recommendation of follow-up

Kelly19 _{(1985) RS 1324 (1971-1984) Clinical Stage I All TT’s 2.7-3.6 (mean) 295(22) Distribution of recurrence}

development Recommendation per TT

Long-term follow-up according to individual risk

Regan38 _{(1985) RS +}

questionnaire

NR (1967-1982) Clinical Stage I All TT’s NR 91 Recurrence detection Better patient education, actively involvement of general practitioner, hospital follow-up for three years Shaw26 _{(1985) RS 1283 (1950-1984) Clinical Stage I All >10 34(3) Analysis of late recurrences Long term follow-up}

Naruns34 _{(1986) RS 649 (1971-1985) Clinical Stage I TT < 0.76 mm NR 30(6) Recurrences in thin melanoma often}

“late”

Careful follow-up for thin melanoma McCarthy39 _{(1988) RS 3171 (1950-1984) Clinical Stage I All TT’s 9.8** 886(28) Distribution of recurrence}

development

Follow-up depending distribution of recurrences, self-detection and individual wishes

Callaway27 _{(1989) RS 536 (1967-1976) Clinical Stage I All TT’s All >10 5(1) Analysis of late recurrences Patient education is essential}

Crowley28 _{(1989) RS 651 (1970-1989) Recurred patients: Pathologic}

Stage I (n=156)

All >10 168(25) - only those with follow-up time >10 years

Analysis of late recurrences Life-long annual follow-up controls with chest x-ray and liver function tests Pathologic Stage II (n=11)

Pathologic Stage III (n=1)

Gutman29 _{(1989) RS 94 (1965-1985) Clinical Stage I All >10 6(6) - only those}

with follow-up time >10 years

Absence of identified risk factors for late recurrences

Long term follow-up

McEwan30 _{(1989) RS 769 (1956-1985) Clinical Stage I All TT’s 11# 14(2)- occurred}

between after 5 years of follow-up

Recurrence rates and the absence of identified risk factors for late recurrences

Follow-up transferred to general practitioner after 5 years. Statistical reasons follow-up maintained until death Brandt35 _{(1990) RS 206 (1964-1988) Clinical Stage I TT < 1.51mm NR 11(5) Analysis of recurrences in thin}

melanoma

Long-term follow-up is not justified, since only benefits 2% of patients

Fusi24 _{(1992) RS 1090 (1960-1981) Clinical Stage I All TT’s 7 302(28) Distribution of recurrences and}

minimum time for clinical trials of recurrence development

3 years of follow-up is sufficient for clinical trials

Tahery31 _{(1992) RS 956 follow-up >}

10 years (1955-1979)

NR All >10 8(1) - only those with follow-up time >10 years

Analysis of late recurrences absence of identified risk factors

Long term annual follow-up

Baughan8 _{(1993) RS 331 (1981-1990) Clinical Stage I TT < 1.51 mm 5 65(20) Distribution of recurrence}

development, recurrence detection and patients preferences

Annual follow-up during 15 years Follow-up by nurse specialist Patient education and counselling

Martini20 _{(1994) RS 840 (1975-1992) Clinical Stage I TT < 1.51 mm 4 202(24) Distribution of recurrence}

development and pattern of recurrence

Follow-up for 10 years

Basseres25 _{(1995) RS 528 (1981-1991) Clinical Stage I TT > 0.4 mm NR 115(22) Risk of recurrences, self-detection Follow-up depending low or high risk}

phenotype and TT Shumate7 _{(1995) RS 1475 (1958-1984) Clinical Stage I Clinical Stage II 6.5# 195(15) Self-detection Symptomatic}

recurrences

Thorough patient education, reduction of follow-up

Weiss11 _{(1995) RS 261 (1984-1990) Regional involved nodes or TT >}

1.69 mm

NR 161(60) Way of detection. Symptomatic recurrences

Only clinical examinations Moloney21 _{(1996) RS 602 (1967-1989) Clinical Stage I TT < 0.76 mm All > 5 24(4) Enormous workload, but little gain}

of routine follow-up

Thorough patient education, reduction of follow-up

Sylaidis40 _{(1997) RS 244 (1969-1985) TT > 4.0 mm All >10 (unless}

died in this period)

176(72) Distribution of recurrences stratified for TT

Follow-up stratified for distribution of recurrences, depending on prognosis For research purposes follow-up maintained until death

Johnson18 _{(1999) RS 306 (1971-1994) TT < 1.5 mm 4(mean) 20(7) Distribution of recurrences stratified}

for TT. Very poor prognosis if development of recurrence

Patients with melanoma < 0.75 do not require follow-up; for those with melanoma 0.75-1.5mm it is less clear Mooney22 _{(1998) RS 1004 (1971-1995) Clinical Stage I and II 6 174(17) Way of detection. Symptomatic}

recurrences

See Table 8 Dicker17 (1999) RS 1568 (1979-1994) Clinical Stage I 961 patients

> 5

293(19) Distribution of recurrences stratified for TT and possibility to cure, detection of second primary melanoma

More frequent and longer follow-up for thicker melanoma, maximum duration 5 years

Poo-Hwu23 _{(1999) RS 373 (1988-1994) Clinical Stage I n=193 Clinical}

Stage II n=117 Clinical Stag III n=63

All minimum 2 78(21) Hazard ratios of recurrence development

Reduced follow-up stratified for hazard risks, patient education

Schmidt-Wendtner33

(2000) RS

6298 (1026 > 10 year follow-up) (1977-1998)

all Stages 4 31(3) Distribution of late metastases Long-term follow-up, self-examination Kittler36 _{(2001) RS 513 (1993-1996) Clinical Stage I TT < 1.5 mm 4 20(4) Difference in recurrence}

development between patients followed-up and drop-outs

Regular follow-up examinations

Hofmann12 _{(2002) RS 661 (1983-1999) Clinical Stage I + II n=630}

Clinical Stage III n=27 Clinical Stag IV n=4

4 (Stage I) 2 (Stage II)

127/630(20) Distribution of recurrences, staging and screening techniques, cost-effectiveness

Physical examination, education and reassurance are indispensable Leman32 _{(2003) RS 3822 (NR) NR NR 25(1) >10 yr after}

primary diagnosis

Distribution of recurrences Long-term follow-up cannot be justified Garbe13 ₍₂₀₀₃₎

Prospective survey

2008 (1983-1996) Clinical Stages I-IV All 2 112(6) Early and late detection, way of detection and distribution of recurrences

Elaborated follow-up

Kalady16 _{(2003) RS 1563 (1973-2002) TT < 1.0 mm 11 140(12) Distribution of recurrences Long-term follow-up}

Schmidt-Wendtner37

(2003) RS

2302 (1977-1998) Clinical Stage Ia 77(3) Male gender, acrolentiginous melanoma and lentigo maligna melanoma are most common at risk

Thorough follow-up for high risk group

Total 32518 2142

RS=retrospective survey

AJCC=American Joint committee on Cancer TT=tumour thickness

* pre-2001 AJCC Staging system ** of recurred patients

Table 2. continued

Author (year) Design Subjects (time period) AJCC Stage* Follow-up time (median, years)

Recurrences n(%)

Foundation for follow-up recommendation

Sylaidis40 _{(1997) RS 244 (1969-1985) TT > 4.0 mm All >10 (unless}

died in this period)

176(72) Distribution of recurrences stratified for TT

Follow-up stratified for distribution of recurrences, depending on prognosis For research purposes follow-up maintained until death

Johnson18 _{(1999) RS 306 (1971-1994) TT < 1.5 mm 4(mean) 20(7) Distribution of recurrences stratified}

for TT. Very poor prognosis if development of recurrence

Patients with melanoma < 0.75 do not require follow-up; for those with melanoma 0.75-1.5mm it is less clear Mooney22 _{(1998) RS 1004 (1971-1995) Clinical Stage I and II 6 174(17) Way of detection. Symptomatic}

recurrences

See Table 8 Dicker17 (1999) RS 1568 (1979-1994) Clinical Stage I 961 patients

> 5

293(19) Distribution of recurrences stratified for TT and possibility to cure, detection of second primary melanoma

More frequent and longer follow-up for thicker melanoma, maximum duration 5 years

Poo-Hwu23 _{(1999) RS 373 (1988-1994) Clinical Stage I n=193 Clinical}

Stage II n=117 Clinical Stag III n=63

All minimum 2 78(21) Hazard ratios of recurrence development

Reduced follow-up stratified for hazard risks, patient education

Schmidt-Wendtner33

(2000) RS

6298 (1026 > 10 year follow-up) (1977-1998)

all Stages 4 31(3) Distribution of late metastases Long-term follow-up, self-examination Kittler36 _{(2001) RS 513 (1993-1996) Clinical Stage I TT < 1.5 mm 4 20(4) Difference in recurrence}

development between patients followed-up and drop-outs

Regular follow-up examinations

Hofmann12 _{(2002) RS 661 (1983-1999) Clinical Stage I + II n=630}

Clinical Stage III n=27 Clinical Stag IV n=4

4 (Stage I) 2 (Stage II)

127/630(20) Distribution of recurrences, staging and screening techniques, cost-effectiveness

Physical examination, education and reassurance are indispensable Leman32 _{(2003) RS 3822 (NR) NR NR 25(1) >10 yr after}

primary diagnosis

Distribution of recurrences Long-term follow-up cannot be justified Garbe13 ₍₂₀₀₃₎

Prospective survey

2008 (1983-1996) Clinical Stages I-IV All 2 112(6) Early and late detection, way of detection and distribution of recurrences

Elaborated follow-up

Kalady16 _{(2003) RS 1563 (1973-2002) TT < 1.0 mm 11 140(12) Distribution of recurrences Long-term follow-up}

Schmidt-Wendtner37

(2003) RS

2302 (1977-1998) Clinical Stage Ia 77(3) Male gender, acrolentiginous melanoma and lentigo maligna melanoma are most common at risk

Thorough follow-up for high risk group

Total 32518 2142

RS=retrospective survey

AJCC=American Joint committee on Cancer TT=tumour thickness

* pre-2001 AJCC Staging system ** of recurred patients

Table 2. continued

Author (year) Design Subjects (time period) AJCC Stage* Follow-up time (median, years)

Recurrences n(%)

Foundation for follow-up recommendation

Table 6. Overview on literature of follow-up surveillance and subsequent primary melanoma Author (year) Design Subjects (time period) Median follow-up time (years) SPM n(%) Time-interval between IPM and SPM (years)

AJCC Stage of IPM and SPM respectively

Mean TT of IPM and SPM respectively (p-value)

General conclusion General recommendation of follow-up

Kang41 _{(1992) RS 2032 (1965-1989) 7 (patients with}

SPM only)

41(2) 3.0(median) NR 1.21 mm (+/-0.28) and 0.51 mm (+/-0.08) (p=0.038)

Subsequent primary melanoma as long as 31 years after initial melanoma.

Lifelong follow-up skin examinations

Slingsluff42 _{(1993) RS 7816 (1972-1990) >10 (1191)}

>15 (321)

283(4) 52% <1yr 76% <5yr NR Single T1-2: 51% Multiple T1-2:61% (p>0.001)

(1) Risk is 5% in 10 years (FH 14%). (2) Most in first 3 months after IPM diagnosis. (3) Prognosis not worsened by SPM

Aggressive surveillance for patients with risk factors

Burden50 _{(1994) RS 3818 (1979-1991) NR 35(1) NR NR 2.1 mm and 1.2 mm (sign.) Most SPM within two}

years. FH and atypical moles are risk factors, but will not predict SPM development in most cases

Risk of SPM should be considered in follow-up proposal

Table 5. Proposed follow-up schedules in the last 20 years for T1-4 or AJCC stage I-III tumors (all

pre-2001 Staging System)

T1 (<0.75mm) T2 (0.8-1.5mm) T3 (1.6-4.0mm) T4 (> 4.0mm) Years after primary diagnosis Years after primary diagnosis

Author Year 1 2 3 4 5 6-10 1 2 3 4 5 6-10 1 2 3 4 5 6-10 1 2 3 4 5 6-10 Method Number of visits per year Number of visits per year

Kelly19 _{1985 2 1 1 1 1 1 2 2 2 2 2 2 4 3 3 3 2 2 5 4 4 4 2 2 distribution of recurrences by time}

McCarthy39 _{1988 1 1 1 1 1 1 3 3 2 1 1 1 8 6 4 2 1 1 distribution of recurrences by time +}

patient detection

Baughan8 _{1993 1 1 1 1 1 1 4 4 2 2 1 1 12 12 6 2 1 1 12 12 6 2 1 1 distribution of recurrences by time}

Martini20 _{1994 2 2 2 1 1 1 2 2 2 1 1 1 4 4 4 1 1 1 4 4 4 1 1 1 distribution of recurrences by time +}

pattern

Weiss11 _{1995 >1.69mm 6 3 2 2 2 2 6 3 2 2 2 2 6 3 2 2 2 2 distribution of recurrences by time}

Mononey21 _{1996 no follow-up not examined not examined not examined distribution of recurrences by time}

Sylaidis40 _{1997 not examined not examined not examined 6 4 3 2 2 2 distribution of recurrences by time}

Dicker17 _{1999 4 4 4 - - - 4 4 4 1 1 - not examined not examined distribution of recurrences by time}

Kittler36 _{2001 2 2 2 2 2 1 2 2 2 2 2 1 not examined not examined compared fu with no fu}

Hofmann12 _{2002 1 1 1 1 1 - 2 2 2 1 1 - 2 2 2 1 1 1 2 2 2 1 1 1 distribution of recurrences by time}

Stage I Stage II Stage III Stage IV

Hofmann12 _{2002 4 4 4 2 2 1 distribution of recurrences by time}

Poo-Hwu23 _{1999 2 2 2 1 1 1 3 3 3 2 2 1 4 4 4 4 4 1 not examined hazard ratios}

Garbe13 _{2003 2 2 2 2 2 2* 4 4 4 4 4 2# 4 4 4 4 4 2 individually determined prospective evaluation}

AJCC = American Joint Committee on Cancer fu=follow-up

*Pre-2001 AJCC Stage I and < 1.01mm Breslowthickness # Pre-2001 AJCC Stage I and II > 1mm Breslow thickness

Table 6. Overview on literature of follow-up surveillance and subsequent primary melanoma Author (year) Design Subjects (time period) Median follow-up time (years) SPM n(%) Time-interval between IPM and SPM (years)

AJCC Stage of IPM and SPM respectively

Mean TT of IPM and SPM respectively (p-value)

General conclusion General recommendation of follow-up

Kang41 _{(1992) RS 2032 (1965-1989) 7 (patients with}

SPM only)

41(2) 3.0(median) NR 1.21 mm (+/-0.28) and 0.51 mm (+/-0.08) (p=0.038)

Subsequent primary melanoma as long as 31 years after initial melanoma.

Lifelong follow-up skin examinations

Slingsluff42 _{(1993) RS 7816 (1972-1990) >10 (1191)}

>15 (321)

283(4) 52% <1yr 76% <5yr NR Single T1-2: 51% Multiple T1-2:61% (p>0.001)

(1) Risk is 5% in 10 years (FH 14%). (2) Most in first 3 months after IPM diagnosis. (3) Prognosis not worsened by SPM

Aggressive surveillance for patients with risk factors

Burden50 _{(1994) RS 3818 (1979-1991) NR 35(1) NR NR 2.1 mm and 1.2 mm (sign.) Most SPM within two}

years. FH and atypical moles are risk factors, but will not predict SPM development in most cases

Risk of SPM should be considered in follow-up proposal

Table 5. Proposed follow-up schedules in the last 20 years for T1-4 or AJCC stage I-III tumors (all

pre-2001 Staging System)

T1 (<0.75mm) T2 (0.8-1.5mm) T3 (1.6-4.0mm) T4 (> 4.0mm) Years after primary diagnosis Years after primary diagnosis

Author Year 1 2 3 4 5 6-10 1 2 3 4 5 6-10 1 2 3 4 5 6-10 1 2 3 4 5 6-10 Method Number of visits per year Number of visits per year

Kelly19 _{1985 2 1 1 1 1 1 2 2 2 2 2 2 4 3 3 3 2 2 5 4 4 4 2 2 distribution of recurrences by time}

McCarthy39 _{1988 1 1 1 1 1 1 3 3 2 1 1 1 8 6 4 2 1 1 distribution of recurrences by time +}

patient detection

Baughan8 _{1993 1 1 1 1 1 1 4 4 2 2 1 1 12 12 6 2 1 1 12 12 6 2 1 1 distribution of recurrences by time}

Martini20 _{1994 2 2 2 1 1 1 2 2 2 1 1 1 4 4 4 1 1 1 4 4 4 1 1 1 distribution of recurrences by time +}

pattern

Weiss11 _{1995 >1.69mm 6 3 2 2 2 2 6 3 2 2 2 2 6 3 2 2 2 2 distribution of recurrences by time}

Mononey21 _{1996 no follow-up not examined not examined not examined distribution of recurrences by time}

Sylaidis40 _{1997 not examined not examined not examined 6 4 3 2 2 2 distribution of recurrences by time}

Dicker17 _{1999 4 4 4 - - - 4 4 4 1 1 - not examined not examined distribution of recurrences by time}

Kittler36 _{2001 2 2 2 2 2 1 2 2 2 2 2 1 not examined not examined compared fu with no fu}

Hofmann12 _{2002 1 1 1 1 1 - 2 2 2 1 1 - 2 2 2 1 1 1 2 2 2 1 1 1 distribution of recurrences by time}

Stage I Stage II Stage III Stage IV

Hofmann12 _{2002 4 4 4 2 2 1 distribution of recurrences by time}

Poo-Hwu23 _{1999 2 2 2 1 1 1 3 3 3 2 2 1 4 4 4 4 4 1 not examined hazard ratios}

Garbe13 _{2003 2 2 2 2 2 2* 4 4 4 4 4 2# 4 4 4 4 4 2 individually determined prospective evaluation}

AJCC = American Joint Committee on Cancer fu=follow-up

*Pre-2001 AJCC Stage I and < 1.01mm Breslowthickness # Pre-2001 AJCC Stage I and II > 1mm Breslow thickness

Ariyan43 _{(1995) RS 423 (1983-1993) 3.3(median) 27(6) 2.4(median) NR 1.0 and 0.5 mm SPM does not worsen}

the prognosis

Patients with FH should have 3 monthly examinations

Brobeil9 _{(1997) RS 2600 (1987-1995) NR 41(2) NR NR 2.3 and 0.9 mm (p=0.008) Melanoma patients}

are at high-risk to develop subsequent melanomas 93% of SPM detected by physician Intensive follow-up is important (history and physical examination)

Johnson44 _{(1998) RS 1482 (1990-1995) 4 (patients with}

SPM only)

60(4) 5(median) NR 1.0 and 0.9 (p=0.7) SPM often occur in different regional areas, several years after diagnosis IPM

Lifelong follow-up and skin self-examinations

DiFronzo46 _{(1999) RS 3310 (1971-1998) 10 113(3) NR NR NR Patients age 15-39 and}

65-79 years of age are at particularly high risk of SPM

Careful surveillance for SPM in addition to routine screening for recurrences DiFronzo45 _{(2001) RS 3310 (1971-1999) all > 1 114(3) NR 48% decreased}

50% unchanged 2% increased 1.3 mm (1.0 mm) 0.6 mm (0.5 mm) (p=0.0001) SPM significantly thinner Evidence that careful follow-up allows earlier diagnosis

Counselling and lifelong follow-up at biannual intervals for all patients

Stam-Posthuma47 _{(2001) RS 840 (1983-1995) NR 60(7) 2.9 (mean) NR 1.1 and 0.9 mm (mean)}

(males 1.1 versus 1.2 mm)

Genetic factors are involved in patients with SPM

Regular follow-up for at least 5 years, annual for lifetime

Garbe13 _{(2003) Prospective}

survey

2008 (1983-1996) all > 2 46(2) NR mostly Stage Ia NR Nearly all SPM detected by physicians.

No guidelines for specific SPM detection. Twice a year physical examination Nashan48 _{(2003) RS 533 (NR) 6 (mean) 30(6) 4.3(SD=4.7) NR NR, but 16 SPM in situ and}

of remaining 14 SPM: 0.59-0.62 mm Relative risk >30 compared to general population Careful follow-up is required Goggins49 _{(2003) RS 61245} (1973-1997) NR 1421(2) NR NR NR Risk to develop SPM highest in first few months after IPM diagnosis NR IPM=initial primary melanoma FH=family history NR=not reported

SPM=second primary melanoma TT=tumour thickness

AJCC=American Joint Committee on Cancer RS=retrospective survey Author (year) Design Subjects (time period) Median follow-up time (years) SPM n(%) Time-interval between IPM and SPM (years)

AJCC Stage of IPM and SPM respectively

Mean TT of IPM and SPM respectively (p-value)

General conclusion General recommendation of follow-up

Ariyan43 _{(1995) RS 423 (1983-1993) 3.3(median) 27(6) 2.4(median) NR 1.0 and 0.5 mm SPM does not worsen}

the prognosis

Patients with FH should have 3 monthly examinations

Brobeil9 _{(1997) RS 2600 (1987-1995) NR 41(2) NR NR 2.3 and 0.9 mm (p=0.008) Melanoma patients}

are at high-risk to develop subsequent melanomas 93% of SPM detected by physician Intensive follow-up is important (history and physical examination)

Johnson44 _{(1998) RS 1482 (1990-1995) 4 (patients with}

SPM only)

60(4) 5(median) NR 1.0 and 0.9 (p=0.7) SPM often occur in different regional areas, several years after diagnosis IPM

Lifelong follow-up and skin self-examinations

DiFronzo46 _{(1999) RS 3310 (1971-1998) 10 113(3) NR NR NR Patients age 15-39 and}

65-79 years of age are at particularly high risk of SPM

Careful surveillance for SPM in addition to routine screening for recurrences DiFronzo45 _{(2001) RS 3310 (1971-1999) all > 1 114(3) NR 48% decreased}

50% unchanged 2% increased 1.3 mm (1.0 mm) 0.6 mm (0.5 mm) (p=0.0001) SPM significantly thinner Evidence that careful follow-up allows earlier diagnosis

Counselling and lifelong follow-up at biannual intervals for all patients

Stam-Posthuma47 _{(2001) RS 840 (1983-1995) NR 60(7) 2.9 (mean) NR 1.1 and 0.9 mm (mean)}

(males 1.1 versus 1.2 mm)

Genetic factors are involved in patients with SPM

Regular follow-up for at least 5 years, annual for lifetime

Garbe13 _{(2003) Prospective}

survey

2008 (1983-1996) all > 2 46(2) NR mostly Stage Ia NR Nearly all SPM detected by physicians.

No guidelines for specific SPM detection. Twice a year physical examination Nashan48 _{(2003) RS 533 (NR) 6 (mean) 30(6) 4.3(SD=4.7) NR NR, but 16 SPM in situ and}