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Prospective evaluation of follow-up in melanoma patients in Germany – Results of a multicentre and longitudinal study

European Journal of Cancer

Abstract

Background

Patient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially.

Methods

In this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis.

Results

Complete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3–4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4 year surveillance of 550 patients without tumour recurrence (stage I–IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3–4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these.

Conclusions

We recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.

Keywords: Melanoma, Guideline, Follow-up, Recurrence, Costs, Psychosocial support, Patient education, Cost-effectiveness, Surveillance.

1. Introduction

In contrast to most other malignancies, melanoma incidence is on a continuous rise especially in fair skinned and young individuals. Due to its prominent location primarily on the visible skin, early detection is – in contrast to many other tumours – possible. Approximately 85% of patients present with clinically localised disease [1] possessing an excellent prognosis with 5-year survival rates as high as 90% for a melanoma with a tumour thickness ⩽1.0 mm [2] . Melanoma, however, remains a deadly disease once metastatic spread has occurred. Subsequently, even though the risk of progression is low in the majority of patients, melanoma surveillance is recommended for more than 5 years or even lifelong by most guidelines[3], [4], [5], [6], and [7].

The value of cancer follow-up care is determined by its ability to earlier detect recurrences and thus improve survival, its cost-benefit ratio and the psychological impact it has on the patient. Due to the increased risk of second primary melanomas [8] , detection of additional melanomas is another important aspect unique to melanoma follow-up. With increasing incidence and decreasing mortality rates [9] and higher life-expectancy in general, the numbers of patients in long-term melanoma surveillance will rise disproportionally posing a significant financial and time burden on the health system. Improved skin cancer screening campaigns will add to the number of incident melanoma with no-/low-risk of metastatic spread expanding the numbers of patients in surveillance even further. Cost- and time-effectiveness of melanoma follow-up care is therefore mandatory but is difficult to assess and determine. The currently available research on melanoma follow-up is mostly based on monocentric experiences and/or of retrospective nature[10], [11], [12], [13], [14], [15], [16], [17], [18], [19], and [20]. The lack of level-one evidence in the literature is reflected by the different surveillance recommendations which vary from country to country and specialty of physician especially with regard to the extent of imaging studies and the frequency of follow-up visits[1], [21], and [22]. The 2005 German melanoma guideline [23] , which was in effect until early 2013, recommended comparatively extensive diagnostic procedures with questionable benefit especially in low-risk melanoma.

This study aims at firstly depicting the current actual practice of melanoma follow-up care and treatment by prospectively following a large and representative cohort of melanoma patients from various centres around Germany for four years since the initial melanoma diagnosis. Secondly, the value of the follow-up care is critically appraised by calculating the costs of the follow-up for patients without tumour recurrence and by assessing the adherence to guideline-recommendations. Thirdly, by means of questionnaires, the psychological impact of melanoma disease on the patient is measured and the need of patients for disease specific information and its significance for the patient are assessed and evaluated.

2. Patients and methods

2.1. Study design and data collection

In this nation-wide project, all patients diagnosed with melanoma and melanoma in situ (MMis) between 1st April 2008 and 30th June 2008, in Germany were eligible for study participation. Patients were registered online by physicians from hospitals and doctor’s offices after the patient had signed informed consent for study participation. Ethics approval was attained from the ethics committee of the medical faculty Mannheim, University of Heidelberg, Germany. Between 2nd July 2012 and 8th November 2012, follow-up data was gathered of all patients with complete initial data entries. An extensive online questionnaire (electronic case reporting form, eCRF) had to be answered by the registering centres asking for data regarding management and surveillance of the melanoma patients at 2 (2010) and 4 years (2012) after initial diagnosis. Supplementary Text 1 gives an overview of all data collected four years after study initiation. The data was combined with information collected at study entry and at the interim analysis 2010.

For each completed follow-up documentation the centres received a reimbursement of 20 €. Centres were subdivided into three groups according to the number of patients registered in 2008: (1) small centres: centres with 1–9 registered patients, (2) medium centres: centres with 10–29 registered patients and (3) large centres: centres with ⩾30 registered patients.

2.2. Patient questionnaires

Patients who had signed a respective informed consent form at the time of melanoma diagnosis (N = 493) were invited to complete a self-report questionnaire battery. Pseudonymised questionnaires were sent out to patients by mail after the closure of the eCRF data base on 8th November 2012 and collected until 14th December 2012. A reimbursement of 20 € was paid to the patients for returning completed questionnaires within the specified time-frame.

Health-related quality of life, anxiety and depression and coping with illness were assessed using validated questionnaires. Briefly, health-related quality of life was measured with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 [25] . The EORTC QLQ-C30 consists of 30 items. For the current study, the variable ‘quality of life’ was based on two questions concerning the overall health and the overall quality of life (QoL) during the past week rated on a 7-point-scale. The EORTC QLQ-C30 has good psychometric properties, with a Cronbach’s alpha coefficient for the ‘quality of life’ scale ranging between 0.86 and 0.89 [25] . According to the manual, raw scores were transformed into a scale ranging from 0 to 100, with higher scores indicating higher quality of life. Anxiety and depression were assessed using the German version [26] of the Hospital Anxiety and Depression Scale [27] . The Hospital Anxiety and Depression Scale (HADS) is a widely accepted questionnaire to assess clinically relevant symptoms of anxiety and depression in patients with somatic diseases. The HADS consists of 14 items that address symptoms of anxiety and depression in the past seven days. The scale can be divided into two subscales (i.e. anxiety and depression), with sum scores ranging from 0 to 21. Higher sum scores indicate increased anxiety and depression, respectively. To indicate clinically relevant symptoms, following cut-off scores were defined: Sum scores <8 indicate normal range (‘non-cases’), scores 8–10 reflect mild alterations (‘doubtful cases’) and scores >10 indicate clinical relevance of symptoms (‘definite cases’) [27] . The sensitivity (83.3%) and specificity (61.5%) for the identification of psychiatric cases are acceptable [26] .

In addition to the validated questionnaires, socio-demographic information (sex, age, marital status, educational level and employment status), use of disease specific health information sources and information on health behaviour were ascertained with self-constructed questions.

2.3. Statistical analysis

All data were analysed in a descriptive manner. Missing data were not imputed; implausible data were recorded as ‘missing’. The chi-square and Fisher’s exact test were used to test for differences between groups for categorical variables, the Wilcoxon test and the one-samplet-test for continuous variables and the Kruskal–Wallis test for ordinal variables. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier estimator, results were compared using the log-rank test. All patients with complete initial data entry and at least one follow-up documentation either in 2010 or 2012 were included in the PFS and OS analyses. PFS was determined from date of melanoma diagnosis to date of first metastasis or end of study period, OS from date of melanoma diagnosis to date of death or end of study period, whichever occurred first.

Multivariate logistic regression analyses were performed to investigate factors associated with the follow-up frequency and additional examinations (divided into lymph node ultrasound, S100 serum tests and other diagnostic imaging) in years 3 and 4 after melanoma diagnosis. Recommendations of the German melanoma guideline [23] were used to define correct stage-dependent follow-up (see Suppl. Table 1 ). For each analysis, factors tested for explicative value belonged to the following: age (<60 years versus ⩾60 years), sex (male versus female), insurance status (private versus public insurance), tumour thickness (⩽1 mm versus >1 mm), location of the tumour (head and neck, upper extremity, lower extremity, trunk and others), region (former East versus West Germany ( Suppl. Fig. 1 ) and Northern versus Central versus Southern Germany ( Suppl. Fig. 2 )), comorbidities (yes or no), type of centre (hospital versus doctor’s office) and centre size (small versus medium versus large). Factors significant at thep < 0.05 level in univariate analyses were included in a stepwise multivariate regression analysis after checking for collinearity using the Pearson correlation coefficient.

All statistical tests were two-sided with a rejection of the null hypothesis atp < 0.05. Analyses were performed using SAS statistical software (SAS Inc., Cary, North Carolina, version 9.2) and SPSS 21.0 (IBM Corp., Armonk, NY, United States of America (USA)).

3. Results

1264 patients had been registered in the data base in 2008, accounting for approximately one quarter of all patients diagnosed with melanoma and 10% of patients diagnosed with MMis in this time period in Germany [24] . Four years later, information was entered into the eCRF for 938 patients by the registering centres. 270 patients were recorded as lost to follow-up or had deceased before the interim analysis 2010 leaving 668 patients (52.8% of all initially registered patients) for final analysis. Despite the loss of patients, patient distribution with regard to sex, age, localisation of the primary tumour, histological subtype and type and size of the registering centre remained stable over the 4-year follow-up course. The change of tumour stages between initial diagnosis, 2- and 4-year follow-up is depicted in Fig. 1 .

gr1

Fig. 1 Distribution of patients (%) among stages at study initiation in 2008, interim follow-up 2010 and at final data collection 2012 according to American Joint Committee on Cancer (AJCC) 2002 classification [2] . Whereas patient numbers remained stable for MMis and stage I (increases due to initially unspecified tumour stage [‘missing’]), a switch from stages II–IIIA to stages IIIB–IV was noted.

The proportion of males and females was comparable (50.9% male, 49.1% female), but men were significantly older (mean 64.3 years, standard deviation [SD] 14.3, versus 59.4 years, SD 16.3,p < 0.0001) and had a significantly higher tumour thickness (mean 1.67 mm, SD 1.9 versus 1.55 mm, SD 2.33,p = 0.046) ( Table 1 ). Median follow-up time was 49.3 months (interquartile range; IQR 5.4). The majority of the 1264 initially registered patients had stage I disease at the time of melanoma detection (59.6%), four years later, 60.3% of patients with complete follow-up pertained to this group. Approximately half of the 668 patients were registered by large centres (54.3%), 77.7% of all patients had initially been registered by a hospital. 24% of all patients suffered from comorbidities, primarily cardiovascular diseases (14.5%) and cancer (9.0%). Eastern Cooperative Oncology Group (ECOG) performance score was 0 for 65.9% of patients.

Table 1 Patient-, tumour- and treatment-specific data.

  2012 (N = 668) %
Stage (AJCC 2002) a
 MMis 61 9.1
 IA 265 39.7
 IB 138 20.7
 IIA 50 7.5
 IIB 32 4.8
 IIC 7 1.1
 IIIA 16 2.4
 IIIB 31 4.6
 IIIC 16 2.4
 IV 43 6.4
 Missing stage 9 1.4
 
Age, mean (SD) 61.9 (15.5) n.a.
 Male b 64.3 (14.3) n.a.
 Female 59.4 (16.3) n.a.
 
Sex
 Male 340 50.9
 Female 328 49.1
Tumour thickness, mm c
 Mean (SD) 1.61 (2.13) n.a. 
 Median (min./max.) 0.90 (0.00–30.0) n.a. 
  Male, mean (median) d 1.67 (1.00)  n.a.
  Female, mean (median) 1.55 (0.80)  n.a.
 
Histological subtype
 Superficial spreading melanoma 347 57.1
 Nodular melanoma 110 18.1
 Lentigo maligna melanoma 43 7.1
 Acrolentiginous melanoma 20 3.3
 Not specified/unknown/others 88 14.5
 Melanoma in situ e 60
 
Location of primary
 Trunk 260 38.9
 Lower extremity 203 30.4
 Upper extremity 119 17.8
 Head/neck 76 11.4
 Other/Missing 10 1.5
 
Size of centre at registration f
 Large 363 54.3
 Medium 192 28.7
 Small 113 17.0
Type of registering centre g
 Hospital 519 77.7
 Doctor’s office 149 22.3
 
Melanoma surveillance
 Yes 641 96.0
 Median FU time since initial diagnosis in months (IQR) 49.3 (5.4) n.a.
 Frequency of surveillance
  Quarterly 226 35.3
  Half-yearly 256 39.9
  Yearly 104 16.2
  Other/Missing 55 8.6
 Centre performing surveillance
  Recruiting centre 455 71.0
  Referred to
   Dermatologist in practice 162 25.3
   GP 8 1.3
   Dermatology hospital 9 1.4
   Oncologist 6 0.9
   Others 1 0.2
 
Staging procedures h
 Yes 573 89.4
Tumour recurrence between 2010 and 2012
 Yes (previously stage I–III only) 56 (44) 8.4 (7.7)
 
Vital status
 Alive 622 93.1
 Dead 44 6.6
 Melanoma specific death 22 50.0
 Unknown 2 0.3
 
Comorbidities 160 24.0
 Cancer 60 9.0
 Cardiovascular diseases 97 14.5
 Diabetes 29 4.3
 Autoimmune disease 8 1.2
 Immunosuppression 0 0.0
 Psych. Diseases 16 2.4
  Depression 11 1.7
  Others 4 0.6
  Anxiety disorder 1 0.2
 
ECOG
 0 440 65.9
 1 90 13.5
 2 26 3.9
 3 10 1.5
 4 3 0.5
 Unknown 99 14.8

a According to AJCC 2002 classification.

b Male patients were significantly older than female patients (p < 0.0001).

c Due to missing tumour thickness, melanoma in situ and melanoma of unknown primary, calculation of tumour thickness was based on a total of 595 patients.

d Male patients had a significantly thicker primary melanoma (p = 0.046).

e Melanoma in situ excluded from percentage as no histological subtype of melanoma.

f At registration in 2008, 13 large centres (⩾30 patients), 20 medium centres (⩾10–29 patients) and 81 small centres (<10 patients) had recruited patients. Of these, 12 large, 19 medium and 36 small centres returned follow-up data in 2012.

g At registration in 2008, 33 hospitals and 81 doctor’s surgeries recruited patients, in 2012, 27 and 40, respectively, returned follow-up data.

h Only patients under regular surveillance (N = 641).

Abbreviations:ECOG, Eastern Cooperative Oncology Group; GP, general practitioner; IQR, interquartile range;N, number of patients; SD, standard deviation.

PFS was calculated for 1061 patients based on the tumour stage at the time of melanoma diagnosis in 2008 ( Table 2 a). 118 (11.1%) patients experienced a tumour progression, progression rate increased with tumour stage, but was higher in stage IIC than stage IIIA and IIIB (54.2% versus 42.9% and 43.6%, respectively). Median PFS of stage IIC patients was 34.5 months (95% confidence interval [95%-confidence interval (CI)] 21.8–52.2). Progression rate was highest in stage IV (63.6%, median PFS 5.3 months). In year 3 and 4 of surveillance, 55.6% of locoregionary and 60% of distant metastases were detected during regular follow-up ( Suppl. Table 1 ). Only 33.3% of locoregionary metastases were patient-detected, although 47.2% were described as being clinically visible and 22.2% palpable. The majority of metastases were first diagnosed by a dermatologist in hospital (44.4% and 75.3% for locoregionary and distant metastases, respectively). Metastases identified by diagnostic imaging (30.6% of locoregionary and 96.5% of distant metastases) were commonly detected by lymph node ultrasound (45.5%) in case of locoregionary and by computed tomography (CT) scans (46.3%) in case of distant metastases. 94.4% of locoregionary and 24.7% distant metastases were surgically removed, 22.4% of distant but no locoregionary metastases were treated by radiotherapy.

Table 2 (a) Progression-free survival time according to stage at diagnosis in 2008 (AJCC 2002) [2] . 118 patients experienced a disease progression. Disease progression rate was higher in stage IIC than stage IIIA and IIIB disease (54.2% versus 42.9% and 43.6%, respectively). (b) Overall survival according to AJCC stage 2002 [2] at diagnosis in 2008. Death rate for patients with stage IIC at diagnosis was higher than for stage IIIA and IIIB.

(a)
Stage 2008 N Progression Progress (%) Censored Median time to progression (months)
MMis 94 2 a 2.1 92
IA 430 4 0.9 426
IB 195 5 2.6 190
IIA 88 16 18.2 72
IIB 59 20 33.9 39 52.8
IIC 24 13 54.2 11 34.5
IIIA 42 18 42.9 24 50.4
IIIB 39 17 43.6 22 50.0
IIIC 19 10 52.6 9 15.1
IV 11 7 63.6 4 5.3
Missing 60 6 10.0 54
Total 1061 118 11.1 943
 
(b)
Stage 2008 N Death Death (%) Censored Median time to death (months)
MMis (0) 94 3 3.2 91
IA 430 10 2.3 420
IB 195 7 3.6 188
IIA 88 7 8.0 81
IIB 59 9 15.3 50 54.3
IIC 24 7 29.2 17
IIIA 42 6 14.3 36
IIIB 40 11 27.5 29
IIIC 19 9 47.4 10 37.3
IV 13 10 76.9 3 18.9
Missing 60 6 10.0 54
Total 1064 85 8.0 979

a In one patient, revision of primary tumour histology after patient demonstrated with locoregional metastases showed incorrect initial diagnosis, correct T-stage was T2a. One patient with local tumour recurrence.

Abbreviations:MMis, melanoma in situ.

Of 1064 patients included in the OS analysis 85 patients had died (8%), Table 2 b. In 51 patients melanoma was the known cause of death. The death rate of stage IIC patients exceeded that of stage IIIA and IIIB patients (29.2% versus 14.3% and 27.5%, respectively); median OS had not been reached for either stage. For stage IV patients, median OS was 18.9 months (95%-CI 10.2–33.5), 76.9% of patients had died during the follow-up time.

In the third and fourth year of follow-up, 4.5% of patients (N = 30) received a systemic therapy ( Suppl. Table 2 ). 42 different therapeutic regimens were administered, 81% in a palliative setting. Monotherapy with DTIC (29.4%) was the most commonly used regimen followed by vemurafenib (20.6%) in the palliative situation, whereas it was low-dose interferon (85.7%) in the adjuvant situation.

3.1. Adherence to follow-up recommendations and costs of follow-up

The majority of patients (N = 641, 96%) were in regular melanoma surveillance primarily by the recruiting centre ( Table 1 ). After ⩾2 years since initial diagnosis, only 25.3% of patients had been referred to a dermatologist in doctor’s office for surveillance, few patients were seen by general practitioners (GPs) (1.3%) or medical oncologists (0.9%). For patients under surveillance with stage MMis and I–IIC in 2012 (i.e. by definition no tumour progression detected during the follow-up period) (N = 550), 8672 individual staging procedures including clinical examination, lymph node ultrasound, abdominal ultrasound, chest X-rays, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans, bone scintigraphy, S100 blood tests and other blood tests had been documented ( Table 3 ). The total costs accumulated to 228,155.75 € forN = 550 patients. Amount of staging procedures and subsequently costs increased with tumour stage.

Table 3 Costs of diagnostic imaging for MMis and stages I–IIC in the first four years of melanoma surveillance.

Stage 2012 (N of patients per stage) Procedure and revenues according to GOÄ (€) Number of patients receiving procedure Number of procedures a Total costs (€) Costs per patient in surveillance
Stage 0 (N = 60) Clinical examination (19.82 €) 51 285 5648.70 94.15
  Lymph node ultrasound (25.64 €) 14 35 897.40 14.96
  Abdominal ultrasound (25.64 €) 11 28 717.92 11.97
  Chest X-ray (26.23 €) 7 9 236.07 3.93
  S-100 (26.23 €) 11 36 944.28 15.74
  Other blood tests (30.31 €) 9 28 848.68 14.14
  Total 103 421 9293.05 154.88
 
Stage IA (N = 263) Clinical examination (19.82 €) 246 1431 28362.42 107.84
  Lymph node ultrasound (25.64 €) 121 345 8845.80 33.63
  Abdominal ultrasound (25.64 €) 86 187 4794.68 18.23
  CT abdomen (151.55 €) 11 15 2273.25 8.64
  MRI abdomen (256.46 €) 1 1 256.46 0.98
  Chest X-ray (26.23 €) 55 99 2596.77 9.87
  CT chest (134.06 €) 11 14 1876.84 7.14
  CT head (116.57 €) 7 8 932.56 3.55
  MRI head (256.46 €) 3 4 1025.84 3.90
  PET scan (437.15 €) 2 2 874.30 3.32
  Bone scintigraphy (131.15 €) 3 4 524.60 1.99
  S-100 (26.23 €) 76 223 5849.29 22.24
  Other blood tests (30.31 €) 58 145 4394.95 16.71
  Total 680 2478 62607.76 238.04
 
Stage IB (N = 138) Clinical examination (19.82 €) 135 1129 22376.78 162.15
  Lymph node ultrasound (25.64 €) 121 680 17435.20 126.34
  Abdominal ultrasound (25.64 €) 62 191 4897.24 35.49
  CT abdomen (151.55 €) 16 19 2879.45 20.87
  Chest X-ray (26.23 €) 51 108 2832.84 20.53
  CT chest (134.06 €) 15 19 2547.14 18.46
  MRI chest (250.64 €) 1 2 501.28 3.63
  CT head (116.57 €) 14 17 1981.69 14.36
  MRI head (256.46 €) 2 2 512.92 3.72
  PET scan (437.15 €) 3 3 1311.45 9.50
  Bone scintigraphy (131.15 €) 5 5 655.75 4.75
  S-100 (26.23 €) 101 578 15160.94 109.86
  Other blood tests (30.31 €) 82 417 12639.27 91.59
  Total 608 3170 85731.95 621.25
 
Stage IIA (N = 50) Clinical examination (19.82 €) 50 450 8919.00 178.38
  Lymph node ultrasound (25.64 €) 47 253 6486.92 129.74
  Abdominal ultrasound (25.64 €) 30 106 2717.84 54.36
  CT abdomen (151.55 €) 13 19 2879.45 57.59
  MRI abdomen (256.46 €) 1 1 256.46 5.13
  Chest X-ray (26.23 €) 22 59 1547.57 30.95
  CT chest (134.06 €) 12 19 2547.14 50.94
  CT head (116.57 €) 5 9 1049.13 20.98
  MRI head (256.46 €) 2 2 512.92 10.26
  Bone scintigraphy (131.15 €) 1 1 131.15 2.62
  S-100 (26.23 €) 39 249 6531.27 130.63
  Other blood tests (30.31 €) 32 172 5213.32 104.27
  Total 254 1340 38792.17 775.85
 
Stage IIB (N = 32) Clinical examination (19.82 €) 31 312 6183.84 193.25
  Lymph node ultrasound (25.64 €) 30 186 4769.04 149.03
  Abdominal ultrasound (25.64 €) 22 101 2589.64 80.93
  CT abdomen (151.55 €) 8 14 2121.70 66.30
  MRI abdomen (256.46 €) 1 4 1025.84 32.06
  Chest X-ray (26.23 €) 16 52 1363.96 42.62
  CT chest (134.06 €) 9 16 2144.96 67.03
  CT head (116.57 €) 5 8 932.56 29.14
  MRI head (256.46 €) 1 1 256.46 8.01
  PET scan (437.15 €) 2 7 3060.05 95.63
  S-100 (26.23 €) 29 198 5193.54 162.30
  Other blood tests (30.31 €) 26 149 4516.19 141.13
  Total 180 1048 34157.78 1067.43
 
Stage IIC (N = 7) Clinical examination (19.82 €) 7 73 1446.86 206.69
  Lymph node ultrasound (25.64 €) 6 44 1128.16 161.17
  Abdominal ultrasound (25.64 €) 4 13 333.32 47.62
  CT abdomen (151.55 €) 1 2 303.10 43.30
  Chest X-ray (26.23 €) 4 10 262.30 37.47
  CT chest (134.06 €) 2 3 402.18 57.45
  MRI head (256.46 €) 1 1 256.46 36.64
  PET scan (437.15 €) 1 2 874.30 124.90
  S-100 (26.23 €) 5 42 1101.66 157.38
  Other blood tests (30.31 €) 4 25 757.75 108.25
  Total 35 215 6866.09 980.87
 
All patients stage 0–IIC (N = 550) Total 1860 8672 228155.75 414.83

a Multiple entries per patient possible.

Abbreviations:GOÄ,Gebührenordnung für Ärzte(medical reimbursement charges in Germany); CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

Follow-up frequency recommendations in stage I patients under surveillance were heeded in 56.4%, 13.2% were seen at shorter, 30.6% at longer than recommended intervals ( Table 4 ). Regression analysis showed that a shorter than recommended follow-up interval was associated with the region of the registering centre (Central versus Northern Germany, odds ratio (OR) 4.92, Central versus Southern Germany OR 4.43,p < 0.0001), a longer than recommended interval was associated with region (Central versus Southern Germany OR 0.57,p = 0.005), tumour thickness (⩽1 mm versus >1 mm OR 0.41,p = 0.001) and comorbidities (yes versus no OR 0.36,p = 0.002).

Table 4 Multivariate analyses for follow-up frequency (only stage I patients), lymph node ultrasound, S100 measurements and diagnostic imaging (MMis and stage I–IIC). Correct follow-up frequency was defined as half-yearly for patients with stage I, ⩽1 mm tumour thickness and quarterly for patients with stage I, >1 mm tumour thickness according to the German melanoma guideline [23] . Lymph node ultrasound is not recommended for MMis and stage I, ⩽1 mm tumour thickness, but half-yearly for stage I, >1 mm tumour thickness and stage II and quarterly to half-yearly for stage III. S100 level determination is not recommended for MMis and stage I, ⩽1 mm tumour thickness, but quarterly to half-yearly for stage I, >1 mm tumour thickness and stage II–III. Diagnostic imaging is not recommended for MMis and stage I, ⩽1 mm tumour thickness, but half-yearly to yearly for stage I, >1 mm tumour thickness and stage II patients receiving adjuvant therapy and half-yearly for stage III. All variables withp < 0.05 in univariate analysis were included into the multivariate model.

  p-Value OR 95% CI
Frequency of follow-up (stage I only)
Frequency too short
 Region <0.0001    
  Central versus North   4.92 1.83–13.18
  Central versus South   4.43 2.09–9.41
Frequency too long
 Region 0.005    
  Central versus South   0.57 0.33–0.98
 Tumour thickness 0.001    
 ⩽1 mm versus >1 mm   0.41 0.25–0.70
 Comorbidities 0.002    
  Yes versus No   0.36 0.18–0.69
 
Lymph node ultrasound (MMis, stage 0–III)
Tumour thickness <0.0001    
 ⩽1 mm versus >1 mm   3.31 2.31–4.74
 
S100 serum tests (MMis, stage 0–III)
Sex 0.02    
 Male versus Female   0.57 0.35–0.91
Tumour thickness <0.0001    
 ⩽1 mm versus >1 mm   24.15 14.79–39.43
Type of centre 0.003    
 Hospital versus doctor’s office   0.37 0.20–0.71
Region 0.009    
 East versus West   0.21 0.06–0.67
 
Diagnostic imaging (MMis, stage 0–III)
Sex 0.003    
 Male versus Female   0.55 0.37–0.81
Tumour thickness <.0001    
 ⩽1 mm versus >1 mm   4.67 3.17–6.88
Comorbidities 0.002    
 Yes versus No   0.49 0.31–0.76

Abbreviations:CI, confidence interval; MMis, melanoma in situ; OR, odds ratio.

Lymph node ultrasound was performed according to guideline recommendations in 56.9% of MMis and stage I–III patients. In MMis and tumour stage I, ⩽1 mm tumour thickness, 102 patients received lymph node ultrasound examinations even though not recommended, in stage I >1 mm tumour thickness to stage III frequency of lymph node ultrasound was too low (107 patients) or patients did not undergo ultrasound at all (28 patients), whereas in only 18 patients frequency was too short. In the multivariate model, only tumour thickness showed to be associated with adherence to lymph node ultrasound recommendations (⩽1 mm versus >1 mm OR 3.31,p < 0.0001).

S100 serum levels were determined correctly in 55.8% patients. 57 MMis and tumour stage I, ⩽1 mm tumour thickness patients received unnecessary examinations, in 146 stage I >1 mm tumour thickness to stage III patients frequency of S100 serum level checks was too low, in 53 patients S100 levels were never checked. Female patients, patients with a tumour thickness ⩽1 mm, patients treated in a doctor’s office and patients in West Germany were more likely to get guideline-corresponding S100 level checks ( Table 3 ).

Diagnostic imaging in melanoma surveillance was correct in 65.5% of patients. In 150 patients diagnostic imaging procedures were done even though not recommended. In patients in whom the guideline recommends diagnostic imaging, 33 had too many investigations, 14 too few and seven never underwent diagnostic imaging. Female patients, patients with a tumour thickness ⩽1 mm and patients without comorbidities were more likely to receive correct diagnostic imaging treatment.

3.2. Psychological impact of melanoma disease

348 patients with complete follow-up data entry in 2012 returned evaluable questionnaires (response rate 70.6%). Patient- and tumour-specific data of this sub-cohort (see Suppl. Table 3 ) were comparable to the total melanoma cohort, but participating patients were more often from large centres (88.5%) and had less comorbidities (10.3%). The majority of patients were in a relationship (80.7%). 5.5% experienced a tumour recurrence between 2010 and 2012.

HADS score for anxiety was statistically significantly lower than for German cancer patients in general [28] (5.37, SD 4.07 versus 7.19, SD 4.15,p < 0.0001) but higher than for the general German population [29] (4.74, SD 3.26,p = 0.001) ( Table 5 ). Mean anxiety score was higher in females than males (5.95, SD 4.22 versus 4.83, SD 3.9) and in younger patients (<60 years) compared to older patients (5.98, SD 4.3 versus 4.94, SD 4.21) ( Table 5 ). 12.1% of patients reached a HADS anxiety score >10 indicating clinically relevant symptoms of anxiety. HADS depression score was significantly lower (i.e. better) in comparison to both the general population [29] (4.03, SD 4.06 versus 4.68, SD 3.83,p = 0.007) and cancer patients in general [28] (6.44, SD 4.45,p < 0.0001) ( Table 5 ). Older patients (⩾60 years) had higher depression scores (4.21, SD 4.01 versus 3.86, SD 4.19). 11.6% of patients displayed HADS depression scores > 10, indicating clinically relevant symptoms of depression. QoL was significantly lower than in the general EORTC population (67.8%, SD 21.9 versus 71.2%, SD 22.4,p = 0.005) but comparable to the EORTC melanoma cohort [30] (68.2%, SD 21.0) ( Table 5 ).

Table 5 HADS mean scores and percentages of cases for anxiety, depression and QoL of questionnaires cohort, general German cohort [29] , general German cancer cohort [28] , general EORTC population and EORTC melanoma cohort [30] .

  Mean (SD) 0–7 (non-case) 8–10 (doubtful case) >10 (definite case) p-Value a
Anxiety
Questionnaires cohort
All patients (N = 346) b 5.37 (4.07) 71.4% 16.5% 12.1%  
Male (N = 180) 4.83 (3.90) 75.0% 15.6% 9.4%  
Female (N = 166) 5.95 (4.22) 67.5% 17.5% 15.1%  
0–<60 years (N = 143) 5.98 (4.30) 66.4% 20.3% 13.3%  
⩾60 years (N = 203) 4.94 (4.21) 74.1% 13.7% 11.2%  
 
General German population
All patients (N = 2037) 4.74 (3.26) 80.7% 13.5% 5.9% 0.001
Male (N = 1929) 4.4 (3.3) 81.9% 12.9% 5.2% 0.1
Female (N = 2481) 5.0 (3.6) 76.8% 15.1% 8.1% 0.001
 
Cancer population
All patients (N = 1529) 7.19 (4.15) 55.9% 23.5% 20.6% <0.0001
Male (N = 905) 6.6 (4.4) n.a. n.a. n.a. <0.0001
Female (N = 642) 8.0 (4.3) n.a. n.a. n.a. <0.0001
           
Depression
Questionnaires cohort
All patients (N = 346) b 4.03 (4.06) 80.6% 7.8% 11.6%
Male (N = 180) 4.07 (4.16) 80.0% 7.8% 12.2%
Female (N = 166) 4.07 (4.01) 81.3% 7.8% 10.8%
0–<60 years (N = 143) 3.86 (4.19) 80.4% 6.3% 13.3%
⩾60 years (N = 203) 4.94 (4.21) 80.0% 8.8% 10.2%
 
General German population
All patients (N = 2037) 4.68 (3.83) 78.3% 13.3% 8.5% 0.007
Male (N = 1929) 4.8 (4.0) 76.1% 14.3% 9.6% 0.020
Female (N = 2481) 4.7 (3.9) 76.5% 14.2% 9.3% 0.044
 
Cancer population
All patients (N = 1529) 6.44 (4.45) 63.4% 18.5% 18.1% <0.0001
Male (N = 905) 6.2 (4.4) n.a. n.a. n.a. <0.0001
Female (N = 642) 6.7 (4.5) n.a. n.a. n.a. <0.0001
           
Global Health (QoL)
Questionnaires cohort
All patients (N = 345) b 67.8 (21.9) n.a. n.a. n.a.  
Male (N = 179) 68.3 (21.5) n.a. n.a. n.a.  
Female (N = 166) 67.2 (22.3) n.a. n.a. n.a.  
0- < 60 years (N = 143) 70.1 (20.4) n.a. n.a. n.a.  
⩾60 years (N = 202) 66.1 (22.7) n.a. n.a. n.a.  
 
General population
All patients (N = 7802) 71.2 (22.4) n.a. n.a. n.a. 0.005
Male (N = 4046) 72.7 (22.2) n.a. n.a. n.a. 0.009
Female (N = 3749) 69.2 (21.9) n.a. n.a. n.a. 0.255
 
Melanoma population
All patients (N = 1200) 68.2 (21.0) n.a. n.a. n.a. 0.728
Male (N = 671) 68.7 (21.5) n.a. n.a. n.a. 0.804
Female (N = 529) 67.6 (20.5) n.a. n.a. n.a. 0.838

a Referent is according group in questionnaires cohort.

b Not all patients filled out HADS questionnaires, anxiety, depression and QoL scores could therefore not be calculated for the whole questionnaires population (N = 368).

Abbreviations:EORTC, European Organisation for Research and Treatment of Cancer; HADS, Hospital Anxiety and Depression Scale.

Most patients reported they had received detailed oral disease-specific information by a physician (68.1%) and information in written form (51.7%), but only a small proportion recalled receiving patient education (12.9%), psychosocial support (8.6%) or were in contact with a self-help group (1.7%) ( Suppl. Table 4 ). The majority of patients found the various information sources very or rather important for emotional coping, health protection and knowledge acquisition ( Fig. 2 ). For all areas, lack of offer was the main reason why the information source had not been used. Utilisation of the sources was independent of sex or age, it only differed significantly between younger (<60 years) and older patients (12.6% versus 5.9%,p = 0.04) for psychosocial support.

gr2

Fig. 2 Patient evaluation of the significance of different forms of disease specific information for their emotional coping, health protection and knowledge acquisition. To assess which sources of disease-specific and health behaviour-related information were used, patients were asked if they had gained information from one or more of the following information sources: Detailed oral disease-specific information by physician, information in written form, patient education, psychosocial support and self-help group. If participants answered that they had not used an information source, they were asked if they had had no interest or if it had not been offered.

4. Discussion

The foremost objective of follow-up care in cancer is the early detection of tumour recurrence with the aim of improving OS. In melanoma, most patients develop tumour recurrences within the first three years after diagnosis[10], [31], [32], and [33]. In our cohort, in years three and four of surveillance only 7.7% of patients with stage I–III disease developed first or additional metastases and only 55.6% of the locoregionary metastases were detected during regular melanoma surveillance. These low recurrence rates and the low detection rate during surveillance visits are confronted with actual costs of 228,155.75 € of follow-up care in 550 stage I–IIC and MMis patients, in whom no tumour progression was detected during the study period of four years. For a reduced, but still rather rigorous follow-up scheme Leiter et al. [34] had calculated costs of 198.20 € per stage IA patient for 5-year surveillance. Our data, however, show that the costs in actual practice exceed these estimates. We calculated that on average 238.04 € were spent per stage IA patient in 4 years of follow-up – a patient group in which only 0.9% of initially registered patients developed a tumour recurrence.

The benefit of frequent follow-up visits in the low-risk patient group is therefore doubtful, especially when considering that most recurrences are locoregionary and thus amenable to visual or palpatory detection even by the patient himself. Patient-detected recurrences are believed to be as high as 60–75%[17], [32], [35], and [36]. In our cohort, however, only one third of locoregionary metastases were documented as being detected by the patient. This is especially surprising as some patients might have had previous locoregionary metastases or multiple metastases and should thus be experienced with the appearance of metastases. Moreover, 69.4% were described as being either palpable or clinically visible. The interim analysis 2010 demonstrated that only 6.0% of first recurrences in stage I–III patients were patient-detected. Even if bias was introduced as centres rather than patients themselves stated who detected the metastasis, patient-detection rate in Germany is low and requires urgent improvement. Reason might be a lack of patient education on the necessity and the procedure of self-examination itself. Interestingly, another study showed that the frequency of patient skin self-examinations is higher in Australia, the US and Southern Europe than Central Europe [37] .

Apart from the general costs of follow-up, frequent variation from guideline recommendations in clinical practice is another critical aspect. We could already demonstrate guideline deviations with regard to treatment and staging procedures at the time of initial melanoma diagnosis [24] . Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and other diagnostic imaging was only approximately 60% in our cohort in years 3 and 4 of surveillance. Non-adherence with guideline recommendations has been associated with several factors including specialty of follow-up provider, tumour thickness, patients’ reassurance and sex[18], [19], and [38]. Our data show that in Germany, with increasing tumour stage/tumour thickness more guideline deviations occurred due to a higher rate of missing examinations or follow-up intervals being too long. Significant regional differences exist with regard to follow-up frequency of stage I patients. Patients in Central Germany, the most densely populated area, have too many excess visits; the reason might be the comparatively easy access to a medical specialist. In patients with documented comorbidities, the interval between follow-up visits was less often too long compared to patients without comorbidities, but incorrect diagnostic imaging occurred significantly more often. Comorbidities might affect the patients’ health more than the melanoma progression risk and thus diagnostic imaging forgone as not deemed necessary. At the same time, patients with comorbidities are used to frequent doctor’s visits and might keep them better then patients without comorbidities. Female patients were more likely to receive guideline-corresponding treatment with regard to S100 level tests and diagnostic imaging. In general, S100 serum level often was not determined even though recommended. Interestingly, apart from female patients, patients treated in a doctor’s office and patients in Western Germany were more likely to receive S100 guideline-corresponding checks.

Over the course of 4 years, systemic treatment of metastatic disease was impacted by the development and approval of new drugs. Between 2010 and 2012, DTIC was still the most commonly applied substance in the palliative setting in Germany, but after few months of its use within clinical trials and even before its FDA/EMA approval, vemurafenib ranked second for palliative systemic treatment in our cohort. Ipilimumab, in contrast, was still rarely used.

The most commonly reported psychological comorbidities in melanoma patients are anxiety and depression[39], [40], and [41]. Even though the true association between psychological stress, coping and melanoma survival or recurrence is uncertain [42] , psychological distress in general has been related with patient delay in seeking medical advice[43] and [44]decreased adherence to treatment regimes [45] , lower health-related quality of life [46] , greater medical costs[47] and [48]and reduced engagement in post-treatment screening and preventive behaviours [49] . In the surveyed sub-cohort of melanoma patients, anxiety, depression and QoL mean scores were found to be comparable to the general population. Even thoughstatisticallysignificant differences in mean anxiety, depression and QoL scores were observed, the absolute differences between the melanoma cohort and the general population were marginal (e.g. difference in QoL was <5 points), which should not be clinically meaningful [50] . The significantly lower depression and anxiety scores in our melanoma cohort compared to German cancer patients in general are in line with previous investigations on long-term cancer survivors, in which melanoma and prostate cancer survivors compared best to the general non-cancer population [51] . Striking is the high rate of patients exceeding published cut-off scores [27] , which indicate a high risk of clinically relevant anxiety and depression symptoms. Thus, despite of lowmeananxiety and depression scores in the total patient sample, a considerable number of patients report symptoms of anxiety (12.1% of patients) and depression (11.6%), which may require psychological or psychiatric treatment. However, the registering centres had documented depression in only 11 patients (1.7%) and an anxiety disorder in only one patient (0.2%). We therefore have to assume that many patients with severe anxiety and depression symptoms go undetected even though they require treatment and it might subsequently also affect their melanoma prognosis. Additionally, psychological comorbidities also impact the choice of therapeutic substances, specifically interferon. Better screening for these patients is therefore mandatory. As not only clinical characteristics of the disease determine stress responses, other potential predictors such as sex, age, social disadvantage and support and previous mental health problems need to be considered.

Information needs are one of the greatest areas of unmet need for people with cancer [52] . Despite most melanoma guidelines recommending psychosocial interventions and education for all patients, its implementation in clinical practice is limited. Research has consistently demonstrated that patients who receive medical information according to their preferences report improved emotional, social and physical well-being [53] , but patients are often dissatisfied with the quality and quantity of cancer-related information they receive [54] . Schofield et al. [55] found that patients generally have strong preferences for receiving full and clear information about melanoma, discussing their prognosis and receiving emotional support from their treating team. Our data clearly show the existing information need also in our sub-cohort and the importance that the patients ascribe to the different forms of counselling, education, information and support for their emotional coping, health protection and knowledge acquisition. No significant differences were found between sex and age groups regarding utilisation of the several forms of disease specific information except for older patients (⩾60 years), who stated significantly more often that education in written form was not offered than younger patients.

This study is not without limitations. The majority of patients were registered by hospital based dermatological centres. The validity of our results is therefore limited for patients treated by e.g. GPs or oncologists. In Germany, however, melanoma patients are generally treated by dermatologists (including all surgical and medical procedures), the results of this study thus reflect actual treatment procedures in Germany. Survival figures especially for stage IV patients are higher than expected (18.9 months in our population compared to a median survival of 6–10 months). The longer observed OS rates may be a reflection of survival being defined from the date of diagnosis of advanced melanoma, rather than from the point of registration in a clinical trial [56] . The costs of staging procedures are most likely underestimated as for some patients the exact amount of procedures they underwent was not given and subsequently only one procedure was taken account of.

In conclusion, we feel that for low-risk melanoma patients with stage I–IIB and MMis patients, follow-up frequency and investigations can be reduced in Germany as partially already recommended in the new guideline [4] and thus expenses saved. Instead, patient education in any form and psychosocial support are areas that urgently require more attention and funding. A supportive care programme incorporating different educational techniques, behavioural or skills training, social support and psychotherapy tailored to the specific needs and circumstances of the individual should be offered to every melanoma patient. These measures provided, patients with high psychological stress will hopefully be better identified, the self-assurance and independence of patients improved and the rate of patient-detected second primaries and metastases increased while costs of melanoma surveillance sink despite the increasing number of long-term melanoma survivors.

Conflict of interest statement

Livingstone:Consultancies and Honoraria: Bristol Myers Squibb GmbH & Co KG, Munich; Boehringer-Ingelheim Pharma GmbH & Co KG, Ingelheim; Speakers bureau: Amgen GmbH, Munich; Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim; Roche GmbH, Grenzach-Wyhlen; Bristol-Myers Squibb GmbH & Co KG, Munich; MSD SHARP & DOHME GmbH, Haar; Merck KGaA, Darmstadt.

Eigentler:Consultancies and Honoraria: Bristol Myers Squibb GmbH & Co KG, Philogen; Delcath Systems Inc., Speakers bureau: Roche GmbH, Bristol-Myers Squibb GmbH & Co KG, Leo Pharma GmbH, GSK GmbH & Co KG.

Kähler:serves as consultant to Roche GmbH, Bristol Myers Squibb GmbH & Co KG, Delcath Systems Inc., Almirall Hermal, MSD SHARP & DOHME GmbH, Haar, and received travel grants and speaker fees from Roche GmbH, Bristol Myers Squibb GmbH & Co KG, Almirall Hermal, MSD SHARP & DOHME GmbH, Haar, Amgen GmbH, Munich, GSK GmbH & Co KG, Munich.

Benson/Dippel/Elsenbruch/Kilian/Krajewski/Mauerer/Möllenhoff/Rompel/Windemuth-Kieselbach: no conflicts of interest.

Hauschild:Consultancies and Honoraria: Bristol Myers Squibb GmbH & Co KG, Munich; Roche GmbH, Grenzach-Wyhlen; Amgen, Munich; GSK GmbH & Co KG, Munich; Novartis Pharma GmbH, Nuremberg; MSD SHARP & DOHME GmbH, Haar; Merck KGaA, Darmstadt; Celgene; Eisai; MedImmune; MelaSciences; Novartis; Oncosec.

Mohr:Consultancies, honoraria and ad boards: Bristol Myers Squibb GmbH & Co KG, Munich; Roche GmbH, Grenzach-Wyhlen; GSK GmbH & Co KG, Munich; Novartis Pharma GmbH, Nuremberg; MSD SHARP & DOHME GmbH, Haar; SciBase Stockholm; TEVA GmbH Berlin.

Meiss:Honoraria, ad-boards, speaker fees, travel grants: Bristol Myers SquibbGmbH & Co KG, Munich; Roche GmbH, Grenzach-Wyhlen; GSK GmbH & Co KG, Munich; MSD SHARP & DOHME GmbH, Haar.

Utikal:Consultancies and Honoraria: Roche GmbH, Grenzach-Wyhlen Speakers bureau: Roche GmbH, Bristol-Myers Squibb GmbH & Co KG, Leo Pharma GmbH, GSK GmbH & Co KG, MSD SHARP & DOHME GmbH, Haar.

Schadendorf:Consultancies, honoraria and ad boards : Bristol Myers Squibb GmbH & Co KG, Munich; Roche GmbH, Grenzach-Wyhlen; Amgen, Munich; GSK GmbH & Co KG, Munich; Novartis Pharma GmbH, Nuremberg; Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim; Delcath Systems Inc., MSD SHARP & DOHME GmbH, Haar; Merck KGaA, Darmstadt.

Funding sources

This study was supported by educational grants from MSD SHARP & DOHME GmbH, Haar (formerly: Essex Pharma), Medac Onkologie, Wedel, Bayer Health Care AG, Leverkusen, Bristol-Myer Squibb GmbH & Co KG, Munich, Swedish Orphan Biovitrum GmbH, Langen.

Acknowledgments

We are indebted to all patients who participated in this study and who completed the study questionnaire. We thank all investigators who documented patient follow-up data for this study:

Prof. Dr. Rompel, Dept. of Dermatology, Kassel Hospital; Ms. Petersen, Dept. of Dermatology, University Hospital Tübingen; Dr. F. Meiss, Dept. of Dermatology, University Medical Centre Freiburg; Dr. A. Mauerer, Dept. of Dermatology, University Hospital Regensburg; Dr. K. Kähler, Dep. Of Dermatotology, University Hospital Kiel; Prof. Dr. E. Dippel, Dept. of Dermatology, Hospital of Ludwigshafen; Dr. K. Möllenhoff, Dept. of Dermatology, University Hospital Bochum; Dr. K. Kilian, Dept. of Dermatology, LMU University Hospital Munich; Dr. P. Mohr, Dept. of Dermatology, Elbe-Hospital Buxtehude; Prof. J. Utikal, Dept. of Dermatology, University Hospital Mannheim; Prof. Dr. Kretschmer, Dept. of Dermatology, University Hospital Göttingen; Dr. Feldmann-Böddeker, Dept. of Dermatology, DRK-Hospital Chemnitz-Rabenstein; Prof. Dr. M. Tronnier, Dept. of Dermatology, Hildesheim Hospital; Dr. Vehring/Amann, Medizinisches Versorgungszentrum Lingen; Dr. Krapf, Dept. of Dermatology, SLK-Hospital Heilbronn; Dr. Koch/Hildebrand, Krefeld; Dr. Kreuzberg, Dept. of Dermatology, University Hospital Cologne; Dr. Terheyden, Dept. of Dermatology, University Hospital Lübeck; Prof. Dr. Zouboulis, Dept. of Dermatology, Municipal Hospital Dessau; Dr. N.M. Gerhardus, Dept. of Dermatology, Municipal Hospital of Karlsruhe; Dr. Pföhler, Dept. of Dermatology, University Hospital Homburg/Saar; Dr. H. Bruckbauer/Dr. S. Karl, Neufahrn; Prof. Dr. Lehmann, Dr. A. Larisch, Dept. of Dermatology, Helios Hospital Wuppertal; Dr. Debus, Dept. of Dermatology, University Hospital Nuremberg; Dr. Trefzer, Dept. of Dermatology, Charité University Hospital Berlin; Dr. K. Jäger, Wörth; Dr. Viehmann, Dept. of Dermatology, University Hospital Gießen; Dr. Bockhorst/Dr. Dominicus, Praxisklinik Hautzentrum Dülmen; Prof. Dr. A. Rübben, Dept. of Dermatology, University Hospital Aachen; Dr. Wengenroth-Zinn/Klose, Wiesbaden; Prof. Dr. Welzel, Dept. of Dermatology, Augsburg Hospital; Dr. Platschek/Karches/Thielert, Hannover; Dr. Kingreen, Dept. of Dermatology, General Hospital Hagen; Dr. U. Schwäbleinsprafke/U. König, Hohenstein-Ernstthal; Dr. Belloni, Dept. of Dermatology, University of Technology Hospital Munich; Dr. Ockenfels, Dept. of Dermatology, Municipal Hospital Hanau; Dr. Ziegler/Philipp/Denfeld, Stuttgart; Dr. Türk, Nuremberg; Dr. Hahne, Siegsdorf; Dr. S. Gönner, Mainz; Dr. Happ, Dept. of Dermatology, University Hospital Frankfurt/Oder; Dr. Lustig/Meyer, Hameln; Dr. K. Kilian/U. Begemann, Marktredwitz; Dr. Peterburs, Paderborn; Dr. Buck, Hamburg; Dr. van Weersch, Wesel; Dr. U. Zell, Erfurt; Dr. Onsa, Leverkusen; Dr. Maurer/Krebs-Posingies, Emsdetten; Dr. K. Ehrich, Hannover; Dr. Gerfelmeyer/Friedmann, Bremerhaven; Dr. Häger, Marne; Dr. Figl, Karlsruhe; Dr. R. Salzmann, St. Wendel; Dr. Ludolph-Hauser, Ergolding; Dr. Skarabis, Berlin; Dr. Ullmann, Passau; Dr. Tentrup/Koch-Schulte/Offers, Ibbenbüren; Dr. M. Hoffmann, Witten; Prof. Dr. Knopf, Dept. of Dermatology, Zwickau Hospital; Dr. Otte, Bad Oyenhausen; Dr. Balz, Northeim; Dr. Durani, Heidelberg; Dr. Weber, Berlin; Dr. A. Leibing, Selm; Dr. Bernsdorff/Seefried, Neusäß; Dr. Paul, Gera.

Appendix A. Supplementary data

 

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Footnotes

a Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Hufelandstr. 55, 45122 Essen, Germany

b Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany

c Dept. of Dermatology, University Tübingen, Liebermeisterstr. 25, 72076 Tübingen, Germany

d Alcedis GmbH, Winchesterstr. 3, 35394 Gießen, Germany

e Dept. of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 7, 24105 Kiel, Germany

f Dept. of Dermatology Kassel, Clinical Centre Kassel, Mönchebergstr. 41, 34125 Kassel, Germany

g Dept. of Dermatology, University Medical Centre Freiburg, Hauptstr. 7, 79104 Freiburg, Germany

h Dept. of Dermatology, University Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany

i Dept. of Dermatology, Clinical Centre Ludwigshafen, Bremserstr. 79, 67073 Ludwigshafen, Germany

j Dept. of Dermatology, Ruhr-University Bochum, Gudrunstr. 56, 44791 Bochum, Germany

k Dept. of Dermatology, Ludwig-Maximilians University Munich, Frauenlobstrasse 9-11, 80337 München, Germany

l Dept. of Dermatology, Elbekliniken Stade-Buxtehude GmbH, Am Krankenhaus 1, 21614 Buxtehude, Germany

m Skin Cancer Unit, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

n Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht-Karl University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany

lowast Corresponding author at: Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany. Tel.: +49 2017234342; fax: +49 2017235935.

Joint project of the Arbeitsgemeinschaft Dermatologische Onkologie (Dermatologic Cooperative Oncology Group, DeCOG) the Deutsche Dermatologische Gesellschaft (German Society of Dermatologists DDG) and the Berufsverband der Deutschen Dermatologen (Professional Organization of German Dermatologists BVDD).

STROBE statement fulfilled.