Cutaneous melanoma
Section 7: Patient follow up in stage I, II and III disease

7.1 Introduction

The purpose of the follow up clinic is to

• provide reassurance and psychological counselling
• provide comprehensive information about all aspects of the patient’s melanoma
• detect recurrent disease
• teach patients techniques of self examination for discovery of local and nodal recurrence
• detect new primary melanomas.

Follow up is an opportunity to provide relevant information to patients, carers and family members.

No RCTs on follow up methods were identified. Eight retrospective studies^{179, 180, 181, 182, 183, 184, 185, 186} and one prospective cohort study¹⁸⁷ were identified which highlight the following issues:

• who should be followed up?
• how frequently should patients be followed up?
• for how long should patients be followed up?
• how are recurrences detected?

These questions are addressed in this section.

7.2 Who should be followed up?

Current practice is that all patients with an invasive melanoma who are at risk of recurrent disease have a period of follow up and all patients with stage III disease have a prolonged follow up, often for the rest of their life. Patients with melanoma in situ have no risk of recurrence.¹⁷⁹ Patients with a pure radial growth phase tumour have a very low chance of recurrence.⁸² Evidence level 3

Patients who have had melanoma in situ do not require follow up.

Patients with an invasive melanoma should have a period of follow up; stage III patients with lymph node metastases should have longer, possibly lifelong, follow up.

7.3 Site of initial recurrence

Large retrospective studies show that between 60 and 80% of first recurrences are local and/or nodal.^{180, 181, 182, 183, 184, 185, 186, 187, 188, 189} Evidence level 4

7.4 Timing and rate of recurrence

The timing and rate of recurrence of melanoma is well recognised (see Figure 1 & Table 7).^{185, 188} Evidence level 3

Table 7: Timing and rate of recurrence of melanoma

Tumour thickness	Recurrence rate	Median recurrence time
<1.5 mm	2-19%	25-32 months
>1.5 mm	47-66%	12-16 months

The annual risk of recurrence for tumours <1.5 mm thick remains <6% for the first five years dropping to under 1% for the next five years. Tumours >1.5 mm thick have a higher risk of recurrence in the first year, dropping to <2% after year five.^{179, 184, 185} Overall most studies indicate that about 80% of recurrences occur within the first three years^{179, 188, 189} but up to 16% of first recurrences have been reported to occur after five years185 and late recurrence (more than ten years) is well recognised.^{190, 191, 192, 193} Evidence level 3

Figure1: Breslow thickness plotted against recurrence rates, years 1 to 10 following surgery. Graph compiled from data from McCarthy et al, 1988¹⁸⁵

7.5 Frequency and duration of follow up: variation in current practice

Many follow up frequencies and durations have been suggested but there is no overall consistency in the recommendations made for either follow up frequency or duration. Examples of the variation in recommendations are given below.

7.5.1 THIN TUMOURS

The variation in the management of tumours <0.75 thick mm is considerable. Three studies recommend follow up at yearly intervals for between 15 years and life. ^{184, 185, 186} Two studies advocated six-monthly reviews for five years or ten years,^{187, 188} reducing to yearly for a further five years¹⁸⁷ or for life;¹⁸⁸ and another suggested that tumours less than 0.6 mm needed no follow up but those over 0.6 mm needed three-monthly reviews for eight years.¹⁸¹ Another study recommended three-monthly follow up for three years only.¹⁷⁹ Evidence level 4

7.5.2 THICK TUMOURS

For thick tumours > 4 mm the recommendations are equally varied. Five papers propose an initial three-monthly follow up for three,^{179, 188} four,¹¹⁷ five¹⁸⁷ or eight years.¹⁸¹ Two papers suggest one-monthly follow up for the first two years.^{185, 186} One advocated six-monthly visits for the third year and then yearly for life,¹⁸⁵ whilst the other recommended two-monthly visits for the third year, six-monthly visits for the fourth year and then yearly visits until year 15.¹⁸⁶ Evidence level 4

A further study recommended two-monthly follow up for the first year, three-monthly for year two, four-monthly for year three, five-monthly for year four, six-monthly for year five to ten and then yearly for life.¹⁹⁴ Evidence level 4

7.5.3 LIFELONG SURVEILLANCE

One aspect of follow up recommended by both Australian and North American authors is lifelong surveillance of all patients with the aim of detecting late recurrences and picking up second primaries.^{184, 185} Similar follow up practice has been advocated by Italian authors.¹⁸⁸ The risk of recurrence after eight years was considered to be too low for French authors to recommend follow up after this time.¹⁸¹ British authors, while acknowledging the benefits of a lifelong follow up, suggest limiting the follow up period to five years due to limited resources.¹⁷⁹ Another UK group suggests follow up for 15 years but accept that a five year period may be more manageable.¹⁸⁶ Evidence level 4

The specific frequency and duration of follow up should be determined from the timing and rate of recurrence of the individual patient’s melanoma.

7.6 Psychological and emotional support

None of the studies identified explored patients’ psychological and emotional needs when determining the frequency or length of follow up.

Follow up frequency and duration should take account of patients’ psychological and emotional needs.

7.8 Second primaries

Three retrospective studies found second primaries in 1.2%, 2% and 7% of their patients.^{179, 185, 195} The timing of discovery ranged from synchronous with the initial melanoma to more than 10 years later. The second primaries were usually thinner. One paper estimated that the Scottish melanoma patients in their study had a 200-fold increase in risk of developing a second melanoma compared to the general population,¹⁹⁵ (see Table 2, section 2.4.2). Evidence level 4

7.9 How are recurrences detected?

Large retrospective studies have shown that 90% of recurrent disease in patients with stage I and II is detected solely by signs or symptoms noted either by the patient or the physician, with imaging techniques (usually chest X-ray) detecting the remainder.^{180, 181, 183, 196, 199} Patients’ own detection rates in between clinic visits are generally in the range of 33 - 72% ^{179, 181, 183, 186, 199, 197} but in one study where patients with stage I-III melanoma were meticulously educated in self examination techniques the rate of self detection rose to 100%.¹⁹⁸ The rate of self detection in one prospective trial was much lower at 17%.¹⁸⁷ Three retrospective studies indicate that the overall survival time is the same for patient-detected recurrences as for those detected in the clinic.^{183, 186, 199} Evidence level 3

7.9.1 ROUTINE LABORATORY TESTS

Routine laboratory tests (full blood count and liver function tests) do not detect asymptomatic recurrent disease in stages I-III.^{156, 180, 181, 182, 198} Evidence level 3

Lactate dehydrogenase (LDH) is a marker of liver metastases and tumour burden in patients with stage IV disease that indicates a poor prognosis with a median survival of six months.^{199, 200, 201} Two studies have looked at LDH as a first indicator of metastases. In stage III disease an elevated LDH was the first indicator in 12.5% of patients (with a sensitivity of 73%) when tested for every three months.¹⁵⁷ In a prospective cohort study of stages I-IV disease an elevated LDH was the first indicator in 2% of recurrences when patients were tested every 12 months (stages I and II melanoma) or every six months (stages III and IV melanoma).¹⁸⁷ Evidence level 3

7.9.2 TUMOUR MARKERS

A variety of new tumour marker blood tests have been developed:

• S100B protein
• Melanoma Inhibitory Activity (MIA) protein
• Tyrosinase mRNA.
  Evidence level 1+

None of these tests is currently sensitive or specific enough to be used in clinical practice.²⁰² Evidence level 1+

7.9.3 IMAGING

• Chest X-ray
  
  In stages I and II, four retrospective^{18, 183, 198, 203} and one prospective study¹⁸⁷ have reported the percentage of metastases detected by routine chest X-ray to be 0%^{198, 203} (frequency of examination six-monthly203 or 12-monthly¹⁹⁸), 4.5%¹⁸⁷ (frequency of examination 12-monthly), 5%¹⁸¹ (frequency of examination six-monthly) and 11%¹⁸³ (frequency of examination three-monthly in year one, four-monthly in year two, six-monthly in years three to five and yearly thereafter). There is evidence that the identification by chest X-ray of treatable asymptomatic pulmonary metastases gives no overall survival advantage when compared to symptomatic pulmonary disease.¹³⁴ In stage II and III melanoma, one retrospective study detected 6% of recurrences by chest X-ray (frequency of examination two-monthly for year one, four-monthly for year two, six-monthly for year three and yearly thereafter).¹⁸⁰ In stage III melanoma, one prospective study detected 4.4% of recurrences by chest X-ray (frequency of examination six-monthly).¹⁸⁷ Evidence level 3
• Ultrasound (US)
  
  In stage I and II melanoma, two retrospective studies were identified which used abdominal US routinely during follow up in asymptomatic patients. One study found that 5% of metastases were detected (frequency of examination six-monthly)¹⁸¹ and the other found that none were detected using this modality (frequency of examination six-monthly).²⁰³ A single prospective trial found a detection rate of 1.5% (frequency of examination 12-monthly).¹⁸⁷ Evidence level 3
  
  In stage III melanoma a single prospective trial found a detection rate of 4.4% of all detected metastases using abdominal ultrasound (frequency of examination six-monthly).¹⁸⁷ In this study 21% of all metastases in stages I and II; and 9.5% in stage III were detected by using ultrasound to examine regional nodes. Evidence level 3
• Computed tomography (CT)
  
  In stage I and II melanoma, two retrospective studies were identified that used CT routinely for examination of brain, chest and abdomen during follow up in asymptomatic patients.^{181, 203} The first study detected less than 1% of metastases using CT, the second reported a detection rate of 21% (frequency of examination in both studies six-monthly). In stage III, four retrospective studies were identified which looked at the usefulness of CT as a staging exercise upon a patient being diagnosed as stage III. One study found that CT offered a 2% chance of finding further metastases.¹⁸³ The other three studies found a true positive rate of detecting further metastatic disease of 4% (false positive rate of 8%),²⁰⁴ 7% (false positive rate of 22%)¹⁵⁵ and 16% (false positive rate of 12%).²⁰⁵ Evidence level 3

Routine full blood counts, liver function tests, tumour markers, chest X-rays, ultrasound scans, computed tomography and lactate dehydrogenase are not recommended as part of a follow up schedule in the asymptomatic patient.

Patients should be educated in self assessment techniques to detect local and nodal recurrent disease and secondary lesions and appraised of the possibility of late recurrence There should be an easy route into the clinic if problems occur between clinic visits or after discharge.

 

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