10.1245/s10434-007-9347-2
Annals of Surgical Oncology 14:1924-1933 (2007)
© 2007 Society of Surgical Oncology
Detection of First Relapse in Cutaneous Melanoma Patients: Implications for the Formulation of Evidence-Based Follow-up Guidelines
Anne Brecht Francken, MD1,3,
Helen M. Shaw, PhD1,2,
Neil A. Accortt, PhD4,
Seng-Jaw Soong, PhD4,
Harald J. Hoekstra, MD3 and
John F. Thompson, MD1,2
1 Sydney Melanoma Unit, Sydney Cancer Centre, Royal Prince Alfred Hospital, 1A Eden Street, North Sydney, New South Wales, 2050, Australia
2 Discipline of Surgery, University of Sydney, New South Wales, Australia
3 University Medical Center Groningen and University of Groningen, Hanzeplein 1, postbus 30500, 9700 RB, Groningen, The Netherlands
4 Biostatistics and Bioinformatic Unit, Comprehensive Cancer Center, University of Alabama at Birmingham, 153 Wallace Tumor Institute, 1824 6th Avenue South, Birmingham, Alabama, United States of America
Correspondence: Address correspondence and reprint requests to: John F. Thompson, MD; E-mail: john.thompson{at}smu.org.au
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ABSTRACT
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Background: The value of follow-up surveillance for patients with cutaneous melanoma remains uncertain. In this prospective study the frequency of detection of first melanoma recurrence (FMR) by patient or doctor was analyzed to assist in the future design of evidence-based follow-up guidelines.
Methods: Patients who had a recurrence of a previously treated American Joint Committee on Cancer (AJCC) stage I–III primary melanoma (PM) were interviewed to ascertain how their PM and FMR were detected. Factors predicting the detection of PM and FMR were analyzed.
Results: The study group comprised 211 patients. In 168 patients, information on detection of their PM was available; 102 PMs (61%) were detected by the patient and 18 (11%) by their partner. Higher AJCC stage, visible location for the patient, and female sex were independent predictive factors for patient-detected PM (P = .03, .002, and .02 respectively). The FMR type was local in 28 (13%), in transit in 35 (17%), in regional lymph nodes in 97 (46%), and distant in 51 (24%). Seventy-three percent of all FMRs were detected by the patient. The presence of a symptom was the only independent predictor of a patient-detected FMR (P < .0001). There was no statistically significant survival difference between the patient-detected and doctor-detected FMRs.
Conclusions: Three-quarters of FMRs were detected by patients or their partners, and it should be possible to improve this rate even further by better education. More frequent follow-up visits are thus unlikely to be valuable. Reductions in follow-up frequency may therefore be safe and economically responsible.
Key Words: Melanoma • Recurrence • Follow-up • Self-examination
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INTRODUCTION
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Follow-up recommendations for patients who have been treated for a primary melanoma (PM) are not uniform. Over the past 20 years, various follow-up schedules have been suggested, with large variations in the recommended frequencies of follow-up visits, but with no international consensus having been reached.1
Proposals for follow-up schedules have been based on calculations of the risk of developing a melanoma recurrence (by analysis of retrospective follow-up data), cost-effectiveness considerations, and the possibility of curing some patients who develop a recurrence. Several authors have recommended reductions in the intensity of follow-up regimens on the basis of these factors.2–5 However, some have taken the opposite view, proposing that more intensive follow-up will improve outcomes by earlier detection of recurrences.6–8
In seeking to rationalize follow-up regimens, it is clear that the person detecting the first melanoma recurrence (FMR) should be taken into account. In an earlier Sydney Melanoma Unit (SMU) study,9 proposals for new follow-up intervals were based on the time distribution for developing an FMR, the extent of initial definitive treatment (elective lymph node dissection or no elective nodal treatment), and the probability of FMR detection at a follow-up visit. It was assumed that 50% of FMRs would be detected at a scheduled follow-up visit, although in other studies, all retrospective, this rate of patient FMR detection varied greatly, ranging from 33% to 90%.2,4,5,10–15
The value of a follow-up visit has been expressed as the likelihood of detecting an FMR at a particular consultation.9,12 This allows adjustment of follow-up schedules not only according to stage of disease and PM histology, but also according to the likelihood that the physician will indeed detect an FMR at the follow-up visit. In the current study, all patients in whom an FMR was detected were interviewed shortly after experiencing relapse of disease, with the primary aims being to document the way in which the FMR was detected and to compare this information with the way in which the PMs of the same patients were detected to assist in the design of evidence-based guidelines for follow-up.
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PATIENTS AND METHODS
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Patient Selection
The following patients were selected: previously treated for a single PM, American Joint Committee on Cancer (AJCC) stage I–III,16 and presenting to the SMU between July 2001 and February 2003 with an FMR. Patients with an occult PM and with an FMR diagnosed at <6 weeks after PM diagnosis were excluded.
Patients were divided into two groups. Group A comprised patients who were able to be interviewed, and group B comprised patients who were unable to be interviewed as a result of death or severe illness, or for some other reason (such as living outside Australia or having no telephone). Patients <18 or >85 years of age were automatically assigned to group B.
Interview
Group A patients were interviewed by telephone. Information was collected regarding the detection of the PM and FMR, whether they recalled receiving instruction on self-examination at the time of initial treatment, and what follow-up arrangements had been made.
All information on group B patients was retrieved from hospital medical records and the SMU database, with patients being included only if these sources gave complete and unambiguous information about their FMR detection.
PM Characteristics and Detection
Age at PM diagnosis was coded as follows: 1, <50 years; 2, 50–59 years; 3, 60–69 years; 4, 
70 years. PM site was coded as: 1, head and neck; 2, trunk; 3, upper extremity; 4, lower extremity. The person detecting the PM was coded as: 1, patient; 2, partner; 3, family physician; 4, specialist physician; 5, other. The PMs were regarded as readily visible by the patient if they were located on any anterior area of the body or on the posterior aspect of the forearm or leg. All other sites were regarded as poorly visible by the patient (e.g., a lesion on the back or posterior thigh, or an internal metastasis). Primary tumor thickness, tumor ulcerative state, and clinical stage were coded according to the current AJCC staging system.16
Variables investigated in relation to the person detecting the PM were: age at PM diagnosis, sex, PM histology (tumor thickness, Clark level of invasion, ulceration), AJCC stage, PM anatomic site, and visibility for the patient. For statistical analysis, the person detecting the PM was coded as 1, patient; and 2, other (consisting of partners, friends, family physician, and others, but not doctors who performed specific skin screening).
First Relapse Characteristics and Detection
Age at diagnosis of FMR was classified as for PM diagnosis. Recurrences were defined as: 1, local (<3 cm from the PM site); 2, in transit; 3, in regional lymph nodes; or 4, distant. The FMR location was classified as: 1, external (potentially detectable by inspection or palpation, including local, in transit, regional lymph node, and distant cutaneous or subcutaneous metastases); or 2, internal. FMRs were regarded as readily visible by the patient according to the same criteria as those used for PMs.
The person detecting the FMR was coded as for PM detection. Patients were considered to have detected the FMR themselves if any symptom or sign relating to the FMR had resulted in a medical consultation (e.g., a lump or skin lesion, but also undefined symptoms such as a cough or neurologic deficit).
Recurrence detection was broadly categorized as being detected by the patient or by a doctor. Patient detection was coded as by: 1, formal self-examination; 2, noting a sign (e.g., accidentally detecting a symptomless lump); 3, symptoms (e.g., noting discomfort from a swollen lymph node). Detection by a doctor was coded as by: 1, physical examination; 2, ultrasound; 3, chest x-ray; 4, computed tomographic scan; or 5, other investigation. Any symptoms or signs noted by the patient were coded as follows: 1, no symptom or sign; 2, a sign, but no symptom (lump/ swelling); 3, external pain or discomfort; 4, an internal and general symptom such as headache, cough, chest pain, abdominal pain, or general malaise.
Variables statistically assessed in relation to the person detecting the FMR were: age at FMR, sex, and AJCC stage at PM diagnosis; symptoms, type, location of FMR; IP visibility, PM thickness, the time since the last follow-up visit (coded as follows: 1, 0–3.0 months; 2, 3.1–6.0 months; 3, 6.1–12.0 months; 4, >12.0 months); the reported patient education; and the person detecting the PM. For statistical purposes, the person detecting the FMR was coded as follows: 1, patient/partner/relative; and 2, doctor at follow-up visit. The few FMRs detected by an unrelated person (e.g., hairdresser) was excluded from the multivariate analysis.
Patient Follow-up Advice and Education
The follow-up recommendations given to patients before and during the study were based on the guidelines previously proposed by the SMU.9 In general, all patients with tumors >1.0 mm thick were advised to return for review at least twice a year for the first 5 years after treatment of their PM, and at least annually thereafter. During the interview, patients were asked whether they recalled having received instructions on self-examination at the time of PM diagnosis and/or treatment. This was coded as follows: 1, yes; and 2, no. They were also asked to give their preference in regard to follow-up frequency during the first year after PM diagnosis. This was coded as follows: 1, every month; 2, every 3 months; 3, every 6 months; 4, after 1 year; 5, only if medical reassurance was desired.
Analyses and Statistics
Differences in distribution between group A (interviewed patients) and group B (those unable to be interviewed) were tested by the Mann-Whitney U-test for primary tumor thickness, AJCC stage, and type of FMR. Differences in distribution of the person who detected the FMR between groups A and B were determined by the Fisher exact test. 
2 and Fisher exact tests were performed to determine the univariate relations between variables and the person detecting the PM or the FMR.
A multivariate logistic regression model was used to determine which variables had an independent relationship with the person who detected the 1, PM and 2, FMR. Only variables that had a P value of <.2 in the univariate analysis were brought into the regression model.
A survival analysis was performed by the Kaplan-Meier method and the log rank test to compare patients with nonsymptomatic and symptomatic FMRs and patients with patient-detected and doctor-detected FMRs. Statistical significance for all tests was considered to exist if the P value was <.05.
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RESULTS
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Patient Selection
In total, 262 SMU patients with an FMR detected were identified between July 2001 and February 2003. A total of 211 were eligible for inclusion in the study (Fig. 1
).
Clinical and Pathologic Variables and Detection of PM
Clinical and pathologic features of the PM are detailed in Table 1 (n = 211). The median time interval between PM detection and interview (group A) was 34 months (range, 5–336 months). Because 43 patients were unable to be interviewed, completely reliable information about the person who detected the PM was available for only 168 patients (Table 2). Seventy-one percent of the PMs were detected by the patient or their partner and 18% by a doctor. Distributions of clinical and pathologic factors according to the person detecting the PM are listed in Table 3 (this analysis excluded 10 patients whose PM was detected by a physician undertaking routine skin screening).
Univariate analysis showed a statistically significant relationship between the person detecting the PM and ready visibility of the PM site, clinical stage at PM diagnosis, tumor thickness, and sex. Multivariate logistic regression showed the same variables to be statistically significant, except for tumor thickness (Table 4).
FMR Characteristics and Detection
The median time to detection of an FMR was 28 months (range, 2–322 months). Characteristics of the person detecting the FMR are listed in Table 5. Recurrences in regional lymph node and at distant sites were most common. The distribution of distant metastases was: intrathoracic (lung or mediastinum) 18 (35%), at multiple sites 11 (22%), hematogenous intradermal or subcutaneous 9 (17%), lymph node at a distant site 5 (10%), brain 4 (8%), bone 2 (4%), and other sites 2 (4%).
Symptoms were present in 157 patients (74%). In 61 patients (39%), FMR detection was reported as a consequence of symptoms. Of 56 FMRs detected at a follow-up visit, 35 were by physical examination (63%), 8 were by chest x-ray (14%; 4% of the total number of FMRs), and 6 (11%) by lymph node ultrasound examination (Table 6).
The median time between FMR diagnosis and interview was 5.3 months (range, .6–17.5 months). In 154 patients (73%), the detection was by patient, partner, or relative (67% by the patients themselves). In 57 patients, detection was by a doctor (27%), but in only 50 (24%) was this at a routine follow-up visit (Table 6
). The last follow-up interval before FMR detection was known in 201 patients (Table 7). Although most patients had attended regular follow-up visits, 20 (10%) had not attended for follow-up 2 years before FMR detection. Multivariate analysis revealed that only the presence of symptoms seemed to be an independent variable predicting the person detecting the FMR. Thus, symptomatic patients were more likely to detect their own FMR (odds ratio, .004) (Table 8). This analysis excluded seven patients whose FMR was detected accidentally by someone not related to the patient.
Survival Analysis
The mean survival time was 23.8 months. Ninety-six patients (47%) had died of melanoma in this period. Survival analysis comparing patients with nonsymptomatic and symptomatic FMRs showed no statistically significant difference, nor was there any survival difference when patients with patient-detected and doctor-detected FMRs were compared (Figs. 2 and 3).
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FIG. 2. Survival curves comparing patients with symptomatic and nonsymptomatic first melanoma recurrence (FRM).
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FIG. 3. Survival curves comparing patients with patient- and doctor-detected first melanoma recurrence (FRM).
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Patient Education and Preferences
Of the 165 patients for whom this information was available, 94 (57%) recalled having received instruction about examining their skin and regional lymph node fields for recurrence at the time of PM diagnosis and treatment. Of the 96 interviewed patients, 57% expressed a preference for follow-up visits once every 3 months in the first year after diagnosis.
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DISCUSSION
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The primary aim of this prospective study was to document how FMR was detected in melanoma patients. It was found that the patient or a partner or relative detected 73% of FMRs. Because of the study design, this information is likely to have been more accurately determined than in previous studies. We found that the detector could not be predicted on the basis of clinical or pathologic PM features, and our high proportion of patient-detected FMRs casts doubt on the value and cost-effectiveness of frequent follow-up checks. Thus, our study could contribute to the development of more rigorously evidence-based recommendations than currently exist for follow-up of melanoma patients.
PM Detection
Several previous studies have documented the person who detects a PM. Blum et al.17 found that 247 (58%) of 429 PMs were patient detected, and the findings of Brady et al.18 were similar: 270 (57%) of 471. The proportion of patient-detected PMs in the current study (61%) was slightly higher than previously reported,17–20 possibly because only patients who had developed a recurrence were included. Previous reports have indicated that physicians are more likely to detect thinner lesions.17–20 In our study, the median tumor thickness was 2.1 mm and a relatively small proportion of patients interviewed had AJCC stage I disease. Skin cancer education programs, such as are carried out extensively in Australia, seem to be important in improving the ability of patients to detect malignant lesions.21
In this study, the PMs most likely been detected by persons other than the patient were those in men, those of advanced stage, and/or those in poorly visible sites, thus confirming previous findings of two factors associated with the detection of a PM: stage and sex.17–19,22 Site has not been reported previously to be a predictor for the detecting PMs. Brady et al.18 considered the possibility but did not find that a readily visible site was a predictor for detection. Finally, it must be noted that there was a long time interval between PM detection and the interview in some patients, so that recall bias may have influenced the results in this group.
FMR Characteristics, Detection, and Follow-up
Three-quarters of the patients (or their partners or relatives) detected their own FMR, in agreement with some earlier studies on recurrence detection,2,13,14 but the rate is much higher than in other studies.11,12,23 In the latter, methodology used to assess the information on FMR detection was mainly retrospective, the design sometimes was not rigorous, and there was little methodological consistency between them.1
The current study shows a strong relationship between the person detecting the FMR and the existence of symptoms. However, more patients detected their own FMR than those who reported that they had detected the recurrence as a result of symptoms. Therefore, the confounding influence of the use of symptomatic lesions for patient-detected FMR is not likely to cause an overestimation, but rather a lower estimate. Thus, patients may detect an FMR without the presence of a symptom (e.g., a painless lump).
Fewer patients reported detection of their FMR as a result of self-examination (n = 39, 23%) than did those who reported receiving instruction about self-examination (n = 94, 57%). Information on this aspect of FMR detection is subjective, and to verify the value of self-examination for FMR detection, a more detailed study would be required. Ideally, every patient would be thoroughly instructed, remember these instructions, and perform self-examination regularly. However, the fact that only 23% of the patients reported detecting the FMR by self-examination emphasizes the need to stress the value of self-examination to patients in future. At the time of initial treatment of their PM, all SMU patients are routinely given explicit advice about regular examination of their skin and regional lymph nodes for recurrence between scheduled follow-up visits. It was therefore disappointing to find that only 57% recalled receiving this information. Clearly, more effective ways of communicating and reinforcing this advice are required. Use of a suitable printed brochure is one strategy that is currently being considered.
The median time between last follow-up visit and FMR diagnosis was 4.5 months (range, .3–64 months). It was expected that the longer the follow-up interval, the greater the chance the FMR would be detected by the patient. However, this variable was not found to be statistically significantly related to the person detecting the FMR. The recurrence detection was not primarily determined by the frequency of scheduled follow-up visits. Forty-six patients (24%) exceeded the maximum 12-month follow-up interval currently recommended by the SMU. On the basis of a previous study, follow-up has been recommended for at least 10 years, because after this, only 3% of patients had experienced recurrence, and follow-up surveillance was therefore considered difficult to justify on the basis of cost-effectiveness.9 Nevertheless, in the current study, the PM of 23 patients (11%) was diagnosed more than 10 years before FMR detection.
Patients’ preferences for follow-up frequency varied widely, but most (n = 96, 57%) wished to have visits every 3 months, perhaps indicating some anxiety and a lack of confidence in their ability to detect their own FMRs.
FMR Detection and Outcome
Multivariate analysis revealed that only symptoms of an FMR independently predicted patient detection of an FMR, implying that no distinction for follow-up recommendations can be made between patients on the basis of demographic, clinical, or PM features. Moreover, the results of this prospective study confirm previous retrospective studies. Most patients detected their FMR themselves despite frequent follow-up, and this will need be taken into account in the development of evidence-based follow-up schedules.
Garbe et al.7 classified FMRs as early and late detected, and related this to survival, finding a far higher survival rate among patients who had early detected FMR. However, they included patients with not only first relapses, and they did not relate this information to the person detecting the recurrence. In the current study, we found that patients with doctor-detected recurrences or nonsymptomatic recurrences had a worse prognosis, which is not surprising because most of these recurrences were distant metastases. Patients with patient-detected recurrences or symptomatic recurrences fared slightly better. However, the survival outcomes were not statistically significantly different. Therefore, we do not think that this is a reason to modify follow-up frequency. Our results correspond with the findings of some other authors, who have found no difference in survival for symptomatic and nonsymptomatic recurrences,2,10 whereas results regarding survival and patient-initiated visits before the scheduled visit have been inconclusive and controversial.4,15
Follow-up Recommendations
Follow-up in the management of melanoma patients has several purposes. It serves to detect FMRs, allows the physician or surgeon to assess treatment efficacy, and plays an important role in the detection of second PMs, which develop in approximately 2%–6% of the melanoma patient population.24–26 Also of great importance are patient reassurance and documentation of outcome for research purposes.
Over the last two decades, strategies for the follow-up of melanoma patients have become a matter of increasing relevance as a result of increasing incidence rates in many countries. Currently recommended follow-up protocols are often of high frequency and intensity,1 and resources in many centers have become insufficient to deal with the ever-increasing patient load. In the present study, attempts were made to determine the value of follow-up consultations and to document the actual detection rate of FMRs in a more detailed and realistic way. With the results of this study, combined with comprehensive documentation of the risk of developing a melanoma recurrence (data not shown), we hope to be able to recommend a follow-up schedule that is truly evidence based. A supplementary study on the detection of second PMs in SMU patients is in progress.
In summary, patients, partners, or relatives detected almost three-quarters of the FMRs evaluated in this study. The presence of one or more symptoms was the only factor predicting FMR detection. This indicates that the frequency of follow-up visits proposed in an earlier SMU study9 and by other groups2,3,6,10,12,15,27–29 could be reduced for most patients. However, individual patient-related factors such as physical and mental health, travel distance, and personal preferences will always need to be considered, and the extent of resources available to conduct follow-up programs may also be of relevance. Follow-up visits at a specialist center alternating with clinical checks by the patient’s local family physician may be a rational solution. Finally, this study emphasizes the need for effective patient education and instruction. This aspect of follow-up will undoubtedly contribute to earlier detection of FMRs and is likely to play an increasingly important role in melanoma patient surveillance.
Our concluding recommendations are that patient education should be improved and that consideration be given to reducing the frequency of follow-up visits. Specific proposals in relation to follow-up visit frequencies will be reported separately.
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ACKNOWLEDGMENTS
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Supported in part by Stichting VSB Fonds, Stichting Dr. Hendrik Muller’s Vaderlandsch Fonds, Stichting Fonds Doctor Catherine van Tussenbroek—Nell Ongerboer Fonds, Stichting Groninger Universiteits Fonds, Stichting De Korintiers, KWF Kankerbestrijding, Marco Polo Fonds, and the Melanoma Foundation of the University of Sydney.
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FOOTNOTES
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Presented at the American Society of Clinical Oncology annual meeting June 5–8 2004, New Orleans, Louisiana.
Received for publication April 19, 2006.
Accepted for publication October 20, 2006.
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ABSTRACT
INTRODUCTION
