Follow up after initial definitive treatment for each stage of melanoma

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Systematic review evidence

A systematic review was performed for the following question How should patients at each stage of melanoma be followed after initial definitive treatment?. The review did not identify any randomised trials. The recommendations are based on level III and IV evidence.

Self-examination

A review of nine clinical practice guidelines by Marciano et al (2014)[1] reveals consensus that patients should be taught skin self-examination and education, which was based primarily on consensus and/or clinical experience. For this recommendation, four guidelines varied in evidence content while five guidelines did not provide any evidence to support this. Education on sun-smart behaviour was recommended by four guidelines.[1]

Successfully implementing self-examination requires patient education on whole-body skin examination with particular attention given to melanoma surgical scars and the corresponding lymphatic drainage areas for in-transit and lymph node recurrence. Patients should also be given education regarding persistent symptoms that may warrant further investigation. In addition, the use of brochures or videos, and the engagement of relatives in the education process may be helpful.[2][3][4][5][6] Randomised controlled trials do not exist. In Australia, patients themselves detect up to 75% of recurrences, while in other countries this can be as low as 20%.[3][4][7][8][9] These data highlight that even with education, there are great differences in patients’ individual ability to detect recurrences.[4] Self-examination is recommended following definitive local treatment for melanoma patients of any stage

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History and physical examination during follow-up

There is general consensus that the most cost-effective component of a strategy resulting in the detection of the majority of recurrences is careful history taking and physical examination. The detection of distant metastases in patients with early localised disease is unusual and hence a recurrence-risk adjusted approach should be undertaken with patients with higher disease stages undergoing more frequent follow up (see follow-up duration and frequency). For high-risk patients, the history should include questions regarding the existence of persistent symptoms that may warrant further investigation, such as pain, fatigue, weight loss, nausea and vomiting, dyspnoea and headache. Moreover, history and physical skin examination is important for the detection of second primary melanoma following the treatment of stage I/II melanoma.

As with self-examination, history and physical examination includes specific history taking, a full skin examination looking for new primaries, palpation of melanoma surgical scars, and lymphatic drainage areas for in-transit and lymph node recurrence. Apart from patient self-detected relapses, most relapses and secondary melanomas are detected during physical exams.[8][10] In one large prospective study[8], roughly 50% of recurrences were identified by history taking/physical examination, 80% of which were local recurrences, in-transit metastases, and regional lymph node metastases.[8] Indeed, the vast majority of operable recurrences (96%) are those detected by physical examination.[10][11] In summary, history and physical examinations for patients with stage I to stage III melanoma are the most effective procedure for early recurrence detection.[12][13][11]

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Imaging techniques and blood tests during follow-up

Very few patients have metastases identified by the routine use of imaging techniques and blood tests.[14][15] There are no randomised trials indicating that such tests are of value and in any case it would be difficult to prove that the few who survive did so merely because they underwent these tests.

All current clinical guidelines recommendations are based on low-level evidence (case series, diagnostic accuracy or prognostic cohort studies). One guideline reports low yield and significant rates of false-positives, yet still recommends imaging in some cases. Two guidelines recommend using ultrasound in high-risk patients, while another two guidelines with similar evidence do not.[1]

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Ultrasonography during follow-up

Ultrasonography is a technique that is being used increasingly for high-risk patients with the goal of detecting regional lymph node metastases. However, its usefulness depends entirely on the technical skill and experience of the personnel involved. There is a consensus of opinion that ultrasound is superior to clinical examination of regional lymph nodes, although its survival advantage is unproven.[16] One group obtained a sensitivity of 92.9% for ultrasound compared with only 71.4% for the clinical examination of regional lymph nodes.[17] Their specificity was equally high for both procedures (>98%). Despite the superiority of ultrasound, very few patients benefited by the addition of ultrasound to clinical examination. The reasons cited for this were that although ultrasound was useful in the earlier detection of regional disease or avoidance of unnecessary surgery in 7.2% of patients, 5.9% had deleterious effects such as unnecessary stress caused by repetition of ultrasounds for benign lymph nodes or useless removal of benign lymph nodes. Therefore, the use of ultrasound was advantageous in only 1.3% of patients. Only from a large prospective randomised clinical trial could the efficacy of ultrasound be established, but this would be hardly feasible since about 3000 patients would have to be enrolled. Hence, the routine use of ultrasound in the follow-up of melanoma patients of any clinical stage cannot be recommended.

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Chest X-ray during follow-up

The use of routine chest X-ray (CXR) exams for the detection of small pulmonary metastases has been investigated. However, false-positive and false-negative findings are frequent. The sensitivity of CXR is poor with reports varying from 7.7% to 48%. A large study of 1969 patients with stage I to stage III melanoma undergoing routine follow up found that only 10/204 relapses were discovered by CXR: the majority (7/10) of which were observed in patients with stage III disease.[13] A large prospective study of 1,235 patients found that only 0.9% of CXRs identified pulmonary metastases, less than 10% of which were amenable to resection, with a false positive rate of 3.1%.[18] A cost-effectiveness analysis using data from the Roswell Park Cancer Institute and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program found that the cost of CXR screening per quality-adjusted life year was $165,000, respectively, in 1996 US dollars.[19] Based on these findings, the investigators suggested reducing the frequency of screening CXR.

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CT/MRI

Computed tomography and magnetic resonance imaging (MRI) are key investigations for the detection of suspected metastasis based on clinical, lab, or sonographic findings. In addition, they are useful in the monitoring treatment response for patients with stage IV disease.[20] It should be remembered that more than 50% of recurrences are detected by patients themselves or physical examination, hence the use of cross-sectional imaging screening should only be considered for patients at high of systemic recurrence.[2][21][8][22] Indeed, the detection rates for cross sectional imaging of asymptomatic distant metastases vary between 15 and 72%.[8][9][12][23] It should be noted that cerebral metastases are more readily detected by magnetic resonance imaging (MRI) than by CT or FDG-PET/CT.[24]

FDG-PET

Positron emission tomography (PET) utilises the uptake of radioactively labelled glucose in metabolically active areas to identify metastatic disease. PET scanning is usually combined with computed tomography in a PET/CT scanner, facilitating spatial mapping of metabolically active lesions thereby increasing the diagnostic utility.[25][26] PET/CT exams reveal a high sensitivity (80%) and specificity (87%) for the detection of distant melanoma metastases, compared with conventional CT (51% and 69%, respectively).[26] A recent systematic review by Danielson et al[27] of seven studies was undertaken to assess the diagnostic value of PET as a tool for surveillance in the regular follow-up program of asymptomatic cutaneous malignant melanoma patients. The majority of the 739 patients in the studies were stage IIB and III. The authors concluded that the mean sensitivity of PET was 96% (95% CI: 92-98) and the specificity was 92% (95% CI: 87-95). Overall, PET has a high diagnostic value. However, there were no data available to demonstrate better survival outcomes for patients as a result of routine PET surveillance.[27] A small non-randomised study by Baker et al (2014)[28] in 38 asymptomatic stage IIIA melanoma patients examined the contribution of routine restaging PET/CT scans in detecting initial recurrence in routine follow-up. After median follow up of 27.5 months, there were 7 relapses: all in transit and regional nodes (n=3) were found by the patients; PET/CT detected 2 asymptomatic recurrences and MRI found 1.[28] There were no data provided to demonstrate whether early detection of asymptomatic recurrences improved survival.[28][11]

Recently, Australian investigators studied the utility of routine PET/CT for 170 patients with stage IIIA-C melanoma using schedules based on sub-stage-specific relapse probabilities.[11] Relapses were identified in 38% patients, of which 69% were asymptomatic. Positive predictive values of individual scans were 56–83%, while negative scans had predictive values of 89–96% for true non-recurrence. A negative PET at 18 months had negative predictive values (NPVs) of 80–84% for true non-recurrence at any time in the 47-month (median) follow-up period. Of relapsed patients, 33 (52%) underwent potentially curative resection was undertaken for 52% patients, although few patients (16%) remained disease-free after 24 months. While the NPV of a negative PET may be reassuring, these data do not conclusively demonstrate that survival was improved by routine PET/CT scanning.[11]

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Measurement of S100B serum levels during follow-up

Serum levels of S100B correlate with tumour load and the evidence has been reviewed previously.[20] In summary, increasing S100B levels over time may signify disease progression. However, delayed processing and warm storage temperatures of blood samples can result in falsely elevated levels. Thus, it is recommended to first repeat the test when elevated before undertaking investigations in search of regional nodal and distant metastases. As tumour marker, S100B displays a sensitivity of 86–91%, specificity[29][30] and its use has been recommended elsewhere.[20] While serum S100B levels may portend recurrence, there are no data demonstrating superior survival outcomes for patients undergoing routine S100B testing in follow-up. The use of serum LDH or melanoma-inhibitory activity (MIA) protein in follow-up for the detection of asymptomatic melanoma recurrence has been reviewed by Fields and Coit (2011).[31] Abnormal blood tests were rarely the first sign of metastases. Low sensitivity, specificity, and accuracy for general laboratory profiles make them futile in the detection of subclinical recurrence and their roles are yet to be defined. Hence, routine serum S100B, LDH or other blood testing for asymptomatic stage I to stage III melanoma patients cannot be recommended.

FNA, core biopsy and lymph node biopsy

FNA is the current standard method to confirm the presence of suspected nodal metastases for lymphadenopathy identified after definitive local treatment of cutaneous melanoma.[32][33] Ultrasound guidance should be used as the diagnostic yield is superior, particularly for small lymph nodes <10mm in size. Core biopsy has higher sensitivity and specificity compared with FNA and should be considered where FNA is negative but clinical suspicion remains high. There is no role for routine lymph node biopsy during follow-up of asymptomatic patients.[34] Routine ultrasound for clinically negative lymph node basins cannot be recommended.

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Evidence summary and recommendations

Evidence summary Level References
The majority of patients detect their own recurrence if they have received a thorough explanation of the signs and symptoms of recurrences and new primary melanomas. IV [7], [5], [6]
* History and physical examination are the most effective methods for the detection of early, treatable melanoma recurrence.
  • Ultrasound is most effective way to detect nodal recurrence.
  • FNA and core biopsy are accurate tests to confirm regional melanoma recurrence.
  • PET/CT is a useful test for the detection of melanoma recurrence during follow-up.
  • There are no data demonstrating superior survival outcomes as a result of routine imaging, even for patients at high risk of melanoma recurrence.
  • Low sensitivity, specificity, and accuracy for general laboratory profiles, S100, and MIA make them futile in the detection of subclinical recurrence and their roles are yet to be defined.
IV [7], [5], [6]
Studies examining the benefit of routine cross-sectional imaging or blood tests over self-examination or physical examination alone include heterogeneous patients groups and are characterized by low evidence levels. III-3, IV [8], [9], [12], [13], [16], [17], [29], [30], [18], [23], [27], [28]
Evidence-based recommendationQuestion mark transparent.png Grade
Self-examination is recommended following definitive local treatment for melanoma patients of any stage.
C


Evidence-based recommendationQuestion mark transparent.png Grade
History and physical examination by a patient’s preferred medical practitioner should be undertaken for the detection of early, treatable recurrence following definitive treatment of stage I to stage III melanoma.
C


Evidence-based recommendationQuestion mark transparent.png Grade
Routine blood or radiological investigations are not recommended for the follow-up of asymptomatic stage I to stage IIB melanoma patients after definitive local treatment.
C


Evidence-based recommendationQuestion mark transparent.png Grade
Routine radiological investigations every 3-12 months may be considered for the first three years of follow up after definitive local treatment of stage IIC and III melanoma where detection of recurrence would allow early commencement of systemic therapy. However, there are currently no high-quality data that early detection and treatment of recurrence improves survival.
C



Practice pointQuestion mark transparent.png

Skin self-examination by patients is essential and they should be taught the process. Routine follow-up by the patient’s preferred health professional may be appropriate to emphasise sun smart behaviour and perform skin checks, especially in ‘hard to see’ areas.


Practice pointQuestion mark transparent.png

Routine radiological imaging PET/CT or CT may be considered for patients with stage IIC or III melanoma for the early detection of recurrence, particularly in the context of a clinical trial. However, patients should be counselled regarding the potential risks of false positives, anxiety, and the risks of radiation including thyroid cancer and cataracts.

Go to next section: Ideal settings, duration and frequency of follow-up for patients with melanoma

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References

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  34. Bohelay G, Battistella M, Pagès C, de Margerie-Mellon C, Basset-Seguin N, Viguier M, et al. Ultrasound-guided core needle biopsy of superficial lymph nodes: an alternative to fine-needle aspiration cytology for the diagnosis of lymph node metastasis in cutaneous melanoma. Melanoma Res 2015 Apr 29 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25933210.

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