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© 2003 American Society for Clinical Oncology Prospective Evaluation of a Follow-Up Schedule in Cutaneous Melanoma Patients: Recommendations for an Effective Follow-Up Strategy
From the Department of Dermatology, Skin Cancer Program, Eberhard-Karls-University of Tuebingen; and Central Malignant Melanoma Registry of the German Society of Dermatology, Tuebingen, Germany. Address reprint requests to Claus Garbe, MD, Professor of Dermatology, Department of Dermatology, Eberhard-Karls-University, Liebermeisterstrasse 25, 72076 Tuebingen, Germany; email: claus.garbe{at}med.uni-tuebingen.de.
Purpose: To prospectively examine and evaluate the results of follow-up procedures in a large cohort of cutaneous melanoma patients. Patients and Methods: This was a prospective study in 2,008 consecutive patients with stage I to IV cutaneous melanoma from 1996 to 1998 on the yield of stage-appropriate follow-up examinations according to the German guidelines. Documentation of patient and follow-up data comprised patient demography, primary tumor specifics, and any clinical and technical examinations performed. The detection of metastasis was classified as early or late, and the means of their detection and the resulting overall survival probabilities were examined. Results: A total of 3,800 clinical examinations and 12,398 imaging techniques were documented. Sixty-two second primary melanomas in 46 patients and 233 disease recurrences in 112 patients were detected during this time. In stage I to III disease, physical examination was responsible for the discovery of 50% of all recurrences. In the primary tumor stages, 21% of all recurrences were discovered by lymph node sonography, with the majority being classified as early detection. Forty-eight percent of the recurrences were classified as early detection, and these patients had a significant benefit of overall survival probability. Conclusion: The results of our study suggest that an elaborated follow-up schedule in cutaneous melanoma is suitable for the early detection of second primary melanomas and early recurrences. The intensity of clinical and technical examinations can be reduced during follow-up of patients in the primary tumor stages and may be intensified in locoregional disease. Recommendations for an effective follow-up strategy are outlined.
THERE ARE, AT present, no standardized and universally agreed guidelines in existence for follow-up of patients with cutaneous melanoma. Follow-up protocol recommendations vary from country to country with significant differences in international expert opinion and practice.1–3 Only a small number of retrospective studies exist that scrutinize a follow-up concept or existent strategy. A follow-up protocol was established at the Yale Melanoma Unit in 1987 with the aim of improving the detection rate of disease recurrence in patients with stage I to III melanoma. The protocol consisted of a patient education program and a clinical follow-up schedule. A retrospective evaluation of 419 patients with stage I to III melanoma treated from January 1988 to December 1994 at the unit was conducted. Among 78 patients with disease recurrence, 34 (44%) had clinical symptoms raising suspicion of metastasis and were initially detected by the patients themselves. Fifty-six percent of the recurrences were detected by physician-directed surveillance examinations.4 An assessment of a 5-year follow-up protocol on behalf of the Scottish Melanoma Group revealed that disease recurrences were detected by the patient on self-examination more frequently than by their doctors at follow-up examinations. Almost half (47%) of the recurrences were first observed by the patient, and only 26% were initially detected on follow-up.5 Similar results were reported in two additional studies, which also found that most recurrences were detected by the patients on self-examination.6,7 These retrospective studies suggest that follow-up examinations are of little benefit, because the majority of recurrences seemed to be detected by the patients themselves at a stage when symptoms occurred or the recurrences were recognizable to the patient. To date, no prospective studies to appraise follow-up examinations for cutaneous melanoma have been published. This study was therefore planned to prospectively examine and evaluate the results of follow-up procedures in a large cohort of melanoma patients and to determine their effectiveness in the early detection of developing metastasis. Screening for metastasis was performed according to the guidelines of the German Society of Dermatology,8 which recommend intense follow-up examinations including imaging techniques. The potential benefit for survival was examined by classifying the detection of metastasis as early or late discoveries and by calculation of overall survival probabilities for both categories.
This single-center study used a prospective, descriptive design to examine the effectiveness of a specific follow-up strategy. It was planned to include 2,000 patients in this study and to document the results of the follow-up examinations carried out over a 2-year period. It was expected that within this time period, disease recurrences in approximately 100 patients could be noted and recorded. All patients referred to the Department of Dermatology of the University of Tuebingen from August 1996 to August 1998 for follow-up examinations of stage I to IV melanoma were considered for study inclusion. The patients were diagnosed, treated, and prospectively documented in a computerized database established in 1983 at our institution, and all patients were readily retrievable at the start of the observation phase. If primary excision had been performed elsewhere, then the original histologic slides were requested for re-examination in every single case, and patients were only included in the follow-up program after confirmation of the melanoma diagnosis at our department. The majority of these patients were free of any sign of metastasis at the time of study inclusion, with metastases first occurring during the study period. To be eligible for the study, patients were required to have pathologically confirmed malignant melanoma and to attend regular follow-up examinations at the university hospital. Informed consent was obtained in all cases. Patients who had not previously undergone observation of their disease and who were referred with a suspected metastasis to our clinic were excluded from study participation (n = 7). Also excluded from the study were patients who had discontinued previous follow-up and, subsequently, returned with a possible metastasis (n = 5). Staging of patients was performed according to the classification of the American Joint Committee on Cancer (AJCC).9 The AJCC staging system has been slightly modified according to the recommendations of the German Society of Dermatology.8 Classification of the primary tumors was performed primarily according to Breslow’s tumor thickness, as is now recommended by the AJCC,9,10 and the level of invasion was only used in cases of missing reports for tumor thickness. The stage definitions are as follows: stage IA is defined as a Breslow’s tumor thickness up to 0.75 mm (or Clark’s level of invasion II); stage IB is defined as a tumor thickness of 0.76 to 1.5 mm (or level III); stage IIA represents tumor thickness of more than 1.5 up to 4.0 mm (or level IV); stage IIB is defined as a tumor thickness of more than 4 mm (or level V); stage IIIA comprises local recurrences, and satellite and in-transit metastasis; stage IIIB represents regional-node metastasis; and stage IV disease involves distant metastasis. The follow-up protocol was carried out according to the guidelines established in 1994 by the German Society of Dermatology.8 These guidelines recommend follow-up examinations every 3 months in the first 5 years after resection of the primary tumor, continued every 6 months until the 10th postoperative year. During the initial consultations, patients were extensively educated regarding the clinical characteristics of melanoma and its metastases, with particular emphasis on self-examination and the recognition of the signs and symptoms of recurrence. Each examination consisted of a complete history, inspection of the entire skin and the adjacent mucosae, and clinical examination of the scar of primary resection, the lymphatic drainage area(s), and all lymphatic regions. Abdominal sonography and x-ray of the chest were performed every 12 months in stage I to II disease and every 6 months in stage III disease. Similarly, annual blood testing for patients in stages I to II and biannual testing for stage III patients was performed to examine the following parameters: full blood count and differential, erythrocyte sedimentation rate, renal function (urea and creatinine), liver enzymes ALT, AST, alkaline phosphatase (AP), gamma-glutamyltransferase, and lactate dehydrogenase (LDH) as potential markers of metastasis. In patients with a high risk of metastasis, protein S100ß levels also were measured during the second half of the study period.11,12 Furthermore, within the first 5 years, sonographic examination of the resected tumor scar, lymphatic drainage area(s), and regional node region(s) was performed once a year in patients with stage I melanoma, every 6 months in patients with stage II melanoma, and every 3 to 6 months in patients with stage III melanoma. The examinations were alternated between the university Department of Dermatology and dermatology practices, with imaging procedures performed only at the university hospital. All examinations were prospectively documented and evaluated within the frame of this study. Prospective data documentation was carried out with the use of a special computer program that was developed using the Visual Objects 1.1 development system (Computer Associates International, Islandia, NY). A data sheet was created for each patient, which consisted of patient demography, primary tumor specifics, and the treatment received after the initial diagnosis, with an account of disease development from the establishment of the diagnosis to the time of inclusion in the study. Clinical and technical examinations performed during the 25-month study period and the results obtained were also recorded in this program. The occurrence of metastasis or second primary melanomas, if any, the means of their detection, ensuing therapy, and a description and assessment of the disease progression were documented. Metastasis was further classified as an early or late discovery according to the status at the time of documentation. Organ or lymph node metastases of no more than 2 cm in diameter, with less than 10 individual nodes being affected (mainly accounting for in-transit metastasis) and, simultaneously, with an indication for surgery with a curative intent were graded as early discoveries. More advanced metastases were considered to be late discoveries. To obtain complete follow-up of the entire cohort, patients who did not appear at the appointed follow-up examination were addressed by letter proposing a new appointment or were traced by contacting their local attending physician. If no answer was obtained, inquiries at the regional authorities were performed to find out if the patient was deceased.
The evaluation of data was performed using the statistical package SPSS 9.0 for Windows (SPSS Inc, Chicago, IL) and S-Plus 4.0 (MathSoft Inc, Seattle, WA). Statistical testing was performed using the
Patient Characteristics From August 1996 to August 1998, a total of 2,008 patients participated in this study; 56.7% of participants were female, and 43.3% were male. The median age of female patients was 52 years and the median age of male patients was 56 years. The distribution of age and sex is generally representative of melanoma patients in Germany at the present time.
Tumor data are listed in Table 1
Detection of Recurrences and Second Melanomas During and Outside of Regular Follow-Up Examinations Within the frame of this study, the results of 3,800 clinical examinations and 12,398 imaging procedures were documented. Over the 25-month study period, 233 disease recurrences were detected in 112 patients with stage I to III melanoma (Table 2  ). Seventy-one percent of all metastases (165 cases) were primarily diagnosed and confirmed on scheduled follow-up examinations at the University Department of Dermatology or in a cooperating dermatology practice. In 39 (17%) of 233 recurrences, the patients themselves initially suspected a metastasis, and in 31 of these recurrences, the diagnosis was established during subsequent regular follow-up examinations. In 29 patients (12%), the metastases were first discovered by physicians not participating in the melanoma follow-up schedule who were consulted for other reasons (Table 3).
In 46 of the 2,008 patients, 62 newly developed second primary melanomas were identified. Three lesions were primarily discovered by the patients themselves, the remainder were detected by their attending physicians in a dermatology practice or at the university hospital. A single second primary melanoma was identified in 36 patients, two second primary melanomas were discovered in six patients, and three or four second primary melanomas were diagnosed in an additional four patients. The distribution of second primary melanoma occurrence according to stage is listed in Table 4 , reflecting the numbers of patients in the respective tumor stages.
Contribution of History and Physical Examination Almost half of all recurrences were discovered on case history and physical examination. A complete history and physical examination was carried out at each visit. A total of 3,800 clinical examinations were performed and documented at the Department of Dermatology in Tuebingen during the study period, whereas a similar number were performed during this time period by cooperating physicians in dermatology practices. One hundred eleven of the 3,800 clinical examinations performed at the Department of Dermatology in Tuebingen revealed a suspicion of metastasis, which was confirmed in 78 (70.3%) of these 111 examinations. In nine patients, two different metastases were discovered during a follow-up physical examination. Eighty percent of metastases detected on clinical examination consisted of local recurrences, satellite or in-transit metastasis, or regional lymph node metastasis.
Lymph Node Sonography
Chest X-Ray and Abdominal Sonography Throughout the 25-month surveillance period, 2,396 chest x-rays were performed with a suspicion of metastasis in only 14 patients (0.6%), 12 of which were confirmed as true-positives. Of the 1,676 x-rays taken, a suspicious finding resulted on only two occasions in stage I patients, no occasions in stage II patients, and three occasions in stage III patients. A high rate of chest x-ray findings (13%) that were inferential for a metastasis was noted in patients with a positive history of distant metastasis (Table 6 ). Thirty chest x-rays revealed potentially abnormal findings that demanded more frequent radiographic control, six of them were subsequently confirmed to be metastatic lung disease, and in one patient, a concomitant lung carcinoma was diagnosed. No additional lung metastasis among these cases was detected in stage I to II disease.
Abdominal sonography was carried out annually in patients with stage I or II disease and biannually in patients with stage III disease, with 2,464 examinations documented over the course of this study. However, only 0.8% of examinations resulted in a suspicion of metastasis, and when the results of examinations performed in stage IV patients are omitted, this value decreases to 0.3%. Three findings suspicious for metastasis and 37 findings necessitating further investigation were established from the 2,034 examinations implemented in stages I and II (Table 7 ). Fifteen of the 19 findings suggestive of metastasis were found to be true-positives, with two of these positive results occurring in stage I and II disease. No metastases were confirmed during the subsequent monitoring of the 37 findings requiring control in stages I and II.
Blood Tests and Additional Technical Investigations An additional 4,048 technical investigations consisting predominantly of blood examinations were carried out. In 1,492 patients, 2,719 blood tests were performed annually in the earlier stages of melanoma and twice yearly in patients with more advanced stages of disease. However, blood tests were rarely the first proof of metastasis, and a first diagnosis was made in only three patients by further investigation after the detection of an elevated LDH value. However, in patients developing metastasis, LDH and AP were found to be elevated in 16.4% and 12.5% of this cohort, respectively. Both percentages were significantly higher than in patients without metastasis (4.2% for LDH and 3.5% for AP, P < .0001). Serum protein S100ß was determined in approximately half of all patients with stage II and III disease and was elevated in approximately 50% of patients with distant metastasis. In those patients with developing locoregional metastasis, only a few were found to have an elevated protein S100ß. Computed tomography (CT) and magnetic resonance imaging (MRI) scanning, bone scintigraphy, skeletal x-ray, and positron emission tomography (PET) were used to further investigate findings suspicious for metastasis. CT scanning played a major role in the diagnosis of metastatic disease, with 14% of metastasis in stage II disease, 23% in stage III disease, and 40% in stage IV disease being diagnosed by this method. CT scanning was revealed to be much more effective in the detection of metastasis in these stages than chest x-ray or abdominal sonography.
Impact of Various Examination Methods on Relapse Detection
Hazard Rates for the Development of Recurrences Hazard rates for the development of recurrences were calculated according to clinical stages of melanoma patients as classified at the time of study inclusion. Calculation commenced from the time of the diagnosis of the respective clinical stage. Hazard rates decreased during the follow-up time and, after 5 years (more precisely, after 53 months), reached a nearly invariable low level in primary tumor stages (stages I and II). In stage III patients, a low hazard rate had already been observed after 3 years (more precisely, after 32 months) (Fig 1 ).
Early and Late Detection of Recurrences and Their Impact on Overall Survival Once detected, a metastasis was categorized as an early or late discovery (as described in Patients and Methods). Forty-eight percent of all metastases were classified as early discoveries, with the remaining 52% of cases being discovered at a more advanced stage. An assessment of the timing of the discovery of metastasis for each stage reveals a similar pattern, except for those recurrences in stage IV disease, for which 90% of all positive findings were late discoveries. The rate of detection of metastasis at an early stage of development varied according to the examination method used, with 71% of lymph node sonography findings and 56% of clinical examination findings being classified as early discoveries. Among the other imaging techniques, 30% of recurrences detected by CT scans were discovered at an early stage of development; chest x-rays and abdominal ultrasound only detected 25% of recurrences.
The overall survival probability of all patients in whom metastases were discovered at an early or late stage of development was determined according to the Kaplan-Meier method. Survival probabilities were calculated from the time of diagnosis of metastatic recurrence to death or last time of regular follow-up (3-month intervals of follow-up examinations). Patient follow-up was continued until June 2002, and the median follow-up time of patients who had developed recurrences after the date of their diagnosis was 43 months. Patients with metastasis detected early and at the later stages were estimated to have highly significant overall survival rates (P < .0001). The early discovery of melanoma metastasis was clearly beneficial to patients with stage I or II disease (76% overall survival rate after 3 years for early detection v 38% for late detection). In patients with stage III disease, the difference between overall survival rates is also clearly distinct (60% overall survival rate after 3 years for early detection v 18% for late detection). The patient overall survival probability curves are shown in Fig 2
This study is, to the best of our knowledge, the first prospective cohort study conducted that evaluates the various procedures used in follow-up of cutaneous melanoma and, in addition, that provides recommendations for the follow-up protocol for melanoma on the basis of the extensive data collected. Two hundred thirty-three metastatic recurrences and 62 second or multiple primary melanomas were discovered in our 2,000-strong patient cohort during the 25-month study period. More than 70% of all recurrences were primarily detected on scheduled follow-up examinations, and only 17% of all recurrences were first discovered by the patients themselves after a thorough educational program on self-detection of metastasis. Approximately half of all recurrences were classified as early discoveries at the time of diagnosis and considered to be curable by surgery. Interestingly, a highly significant difference in overall survival was observed between those patients with recurrences classified as early discoveries and those that were classified as late discoveries. The study design of the present trial is that of a prospective cohort study, with all patients retrievable in the existing database or being newly diagnosed during the study period and newly added to the database. For the evaluation of follow-up results, we decided to examine our cohort during a 25-month period and to include all patients of our cohort matching the inclusion criteria and being presently under follow-up. Thereby, we did not change the already more than 10 years of previously established follow-up strategy, but we supplemented a comprehensive and thorough computerized documentation of follow-up results. The documentation was performed by scientific assistants not involved in medical care using a newly developed computer program for this purpose. There were several reasons for the evaluation of follow-up results during a limited time period of 25 months and for inclusion of the entire cohort under follow-up. First, this study design is best suitable to reflect the natural situation of patient management within follow-up clinics. All patients were recorded who were considered to require follow-up examinations. Second, we did not limit the time span for establishment of first diagnosis to avoid excluding patients developing tumor progression after a longer time span. Thirty percent of our cohort had a diagnosis of 6 to 10 years’ standing, and 6% had a disease history of 10 years or longer, the latter all having developed recurrences in between those years. Third, the computerized documentation of follow-up results requires enormous efforts because of the great amount of data generated by the multiple examination techniques. Therefore, documentation should be performed at the same time as receipt of examination results and not retrospectively. Furthermore, in view of the costs of the extensive documentation work and the great amount of data to be evaluated, a clearly limited time span for the observation period should be preferred. The main end points of our study were the yield of different examination techniques for detection of recurrences and their potential impact on the course of the disease. We were able to demonstrate that our study design was suitable to address these questions. There is not yet much trial experience published according to different study concepts designed to evaluate follow-up examinations of cancer patients. Previous studies in melanoma patients followed a retrospective study design determining the yield of different examination procedures and probably did not record the total follow-up examination results. In all of these studies, the entire cohort of a given institution has been evaluated and frequently been defined by a certain time span for establishment of the first diagnosis.4–7,13–16 Similarly, in more frequent cancer entities such as breast cancer and colorectal cancer, there are mainly studies of the same retrospective type as those published on melanoma follow-up.17–21 In breast cancer, some prospective cohort study types have been performed that share similarities with the present study.22,23 Furthermore, in breast cancer, two randomized prospective trials were conducted already with great impact on the present practice of breast cancer follow-up.24,25 Future studies on melanoma follow-up may likewise apply a randomized prospective design, taking into account the results of this trial. Physical examination was responsible for the discovery of approximately 50% of all disease recurrences; the remaining 50% were detected by the various imaging techniques available. In only 17% of all cases, the metastasis was first discovered by the patient on self-examination. Previous studies, however, have reported a much higher rate of metastasis discovery on physical examination by both the physician and the patients themselves. The Scottish Melanoma Group found that almost half (47%) of the recurrences were first observed by the patient, with only 26% being initially detected on follow-up.5 Other similar published surveys describe detection of 50% or more of symptomatic recurrences by the patients on self-examination.4,6,7,14,16 The lower rate of detection of disease recurrence by means of patient self-examination may be explained by the intense follow-up protocol implemented in this study. Metastases that were discovered at an early stage by imaging techniques were, to a large extent, detected by lymph node sonography. We and others showed that one third of lymph node metastases not yet palpable on physical examination were detectable by sonography.26–29 In our study, as opposed to the other retrospective studies, imaging techniques detected a considerably larger proportion of metastasis.4,5,30 This may be a result of the greater use of imaging techniques throughout this study in comparison with other similar studies, not only as means of investigating suspicious findings on physical examination but also as part of the standard follow-up procedure. Therefore, it is possible that concerted use of imaging techniques leads to a decrease in the number of metastases discovered on physical examination by a physician or the patient themselves. Several studies have been performed to assess the benefit of the various imaging techniques used in screening for metastasis of cutaneous melanoma. In our study, it was observed that the rate of metastasis detection by the different imaging techniques was varied for each stage of disease. There is to date no general consensus on the role and efficacy of imaging techniques, such as chest x-ray, lymph node and abdominal sonography, CT or MRI scans, and scintigraphy, in patient follow-up. In stage I and II patients, 1,981 chest x-rays were performed, with a resultant suspicion of lung metastasis in just 0.1% of examinations, and 3% of the 415 chest x-rays carried out in stages III and IV patients were suggestive of metastasis. Overall, 0.6% of all chest x-rays were responsible for the detection of metastasis, and as many as 75% of recurrences detected by chest x-ray were first discovered at an advanced phase of development. The results of some studies suggest that the practice of routine radiographic tests to screen for distant metastasis is of little value because patient survival is rarely prolonged as a result.14,31,32 It was also observed that few cases of curable metastasis were detected by chest x-ray,14 and only a small number of patients with recurrent disease had an abnormal finding on chest x-ray.7 Other studies found that chest x-ray, among other technical examinations, was of no value in a multiple staging program for asymptotic patients.15,33,34 Therefore, it is questionable whether routine chest x-ray is of any benefit in the screening of asymptotic patients, particularly in stage I and II disease, and it may be possible to restrict its use to follow-up of patients with more advanced stages of disease. During the course of this study, a total of 2,464 abdominal sonography examinations were carried out with a subsequent suspicion of metastasis in just 0.8% of investigations. Similar to the results obtained for chest x-ray, this value was 0.1% for stage I and II patients and approximately 4% for stage III and IV patients. In the literature, the use of abdominal sonography in screening for metastasis is seldom examined, with some authors claiming that it is of marginal value in the detection of curable metastasis but should be implemented to improve patient compliance with the follow-up protocol.14 Because of the results of our study, we feel that abdominal sonography in routine follow-up examinations is of little use in stage I and II patients and should, therefore, be omitted in these patients. It would be reasonable to confine its application to the examination of stage III and IV patients. Lymph node sonography was carried out on 3,490 occasions, with a suspicion of metastasis arising from 5% of the total examinations and almost 2% of examinations in stage I and II and 15.5% in stage III and IV disease. Other authors report a high rate of true-positive results obtained using lymph node sonography and recommended this method for follow-up procedures because it is easy to perform, less time is required for its execution, and it is less expensive than PET scanning.35 Moreover, lymph node sonography was shown to be highly effective in the early identification of lymph node and in-transit metastasis, and approximately one third of all recognizable metastases could already be identified by this method before they became palpable.26–29 This study confirmed lymph node sonography to be the examination method with the highest rate of early detection of metastasis, with 71% of early detection on average compared with 48% of early detection on average for all examination methods. Hence, lymph node sonography should be included as part of a regular follow-up protocol in patients with primary melanomas of higher tumor thickness and in patients with regional metastasis. The value of additional imaging techniques is also disputed, and practices vary greatly. In our study, CT and MRI scanning, bone scintigraphy, skeletal x-ray, and PET were used to further investigate a suspicious finding. Three percent of CT scans of stage I and II patients and 7% of CT scans of stage III and IV patient were suggestive of metastasis. The utility of CT scans has been studied by many groups. It was discovered that, in general, CT scanning is the technique of choice for areas inaccessible by physical examination. It is more sensitive than chest x-ray in the detection of pulmonary metastasis but tends to be less specific because it also detects small benign nodules;36 some authors claim that chest CT scans are of no prognostic benefit.16,37 In other studies, it was found that CT scans are not advantageous in the detection of occult metastases.15,37 However, CT scans usually reveal more extensive disease than anticipated, which has an influence on the succeeding treatment, and therefore, they provide a means of measuring disease progression and evaluating the effectiveness of therapy.36,38,39 In our study, CT scanning was responsible for the detection of 27.7% and 40% of all stage III and IV metastases, respectively; and as a result, it seems to be of greatest benefit to patients in these stages of disease. Therefore, it should be integrated into a stage-appropriate routine follow-up strategy for advanced stages of cutaneous melanoma. Routine blood tests contributed to the detection of metastasis in only a few patients. The percentage of patients at the time of detection of metastatic disease showing elevated values of LDH (16.4%) and AP (12.5%) was significantly increased compared with patients without recognizable metastasis. However, these percentages also demonstrate the low sensitivity of these markers, as already described in the literature.40–43 Nevertheless, increasing values of both markers may be the first hint of developing metastasis and direct attention to appropriate staging examinations. Serum protein S100ß was determined during the second half of the study period and was found to be elevated in approximately half of all patients developing distant metastasis, being the first indication of metastasis in around one fourth of these patients. Therefore, the sensitivity of this marker clearly seems to be higher than that of LDH and AP.44–46 Future investigations are needed to clarify whether protein S100ß is a suitable substitute for the other blood values or whether it should be used as a supplementary examination method.
It is important to ascertain whether the effort necessary to implement this quality of follow-up protocol is actually of benefit to the patient in prolonging his or her survival time. This study design is not suitable to provide a definitive answer to this question because comparative cohorts with different follow-up schedules are required. An indirect evaluation of the protocol was nevertheless attempted with the classification of metastasis as early or late discoveries. Despite the intensity of the study surveillance protocol, approximately 50% of all metastases were deemed to be late discoveries. The overall survival time of patients with early- or late-detected metastasis is compared and shown in Fig 2 In the frame of this study, no specialized investigation on the cost-effectiveness of this surveillance was performed. However, in primary melanoma, physical examinations and lymph node sonography are inexpensive procedures that lead to early detection of second primary melanomas and recurrences in the majority of the cases in whom these develop. The cost-effectiveness of additional radiologic examinations, such as chest x-ray or abdominal sonography, however, is low in comparison, as shown in this study and by other investigators.13,14 Therefore, these additional radiologic examinations should be restricted to advanced stages of disease. The early detection of developing metastasis, enabling the surgical removal of all lesions with curative intention, may be at least as effective as adjuvant therapeutic strategies involving interferon alfa for which cost-effectiveness has been claimed.47–49 The cost-effectiveness of follow-up strategies deserves future, specifically aimed studies.32,50,51 On the basis of the data of the present study, we developed the following recommendations for the follow-up of cutaneous melanoma, including a stage-appropriate surveillance strategy. Approximately 75% of all patients in this study had stage I disease, with metastasis occurring in 1.5% of these cases. The majority of metastases were discovered on clinical examination, and almost half of these were categorized as late discoveries. Thus, it is clear that the use of certain technical examinations for metastasis screening in this stage of disease is of little benefit, and therefore, we suggest that chest x-ray and abdominal sonography be omitted from the standard follow-up protocol for stage I disease and used only to further investigate symptoms indicative of metastasis. With re-enforced patient collaboration, it should be possible to limit follow-up in the first 5 years to biannual examinations for stage I disease. In this study, the risk of metastasis development for patients with stage II disease was 8.5%. Lymph node sonography was responsible for the early detection of 22.4% of stage II recurrences and should remain part of the standard follow-up examinations. Additional technical examinations ought to be confined to further clarification of suspicious symptoms or abnormal blood results. We therefore recommend that clinical examination be performed every 3 months and lymph node sonography and blood tests every 6 months in the first 5 years, in which the hazard rates for recurrences are highest. Blood tests should consist of a measurement of LDH, AP, and protein S100ß levels.
Follow-up of patients in stage III should be carried out with an intensification of technical examinations during the first 3 years. Clinical examination, lymph node sonography, and blood tests, including protein S100ß, should be carried out at 3-month intervals, and technical examinations should be performed every 6 months. This strategy may result in an increase in the detection rate of metastasis at an early phase of development. For each patient with stage IV disease, an individual follow-up strategy according to the patient requirements is created. A summary of a stage-appropriate surveillance strategy that is based on our data is given in Table 9
In conclusion, the surveillance strategy examined in this study yielded a high proportion of detection of metastasis and second primary melanomas by the physicians carrying out the follow-up examinations. The patients themselves first recognized signs of recurrence in only 17% of all recurrences, whereas in previous studies this percentage reached or exceeded 50% of the patients. Furthermore, approximately half of all the discoveries of recurrences were classified as early detection, indicating the possibility of surgical resection with curative intention in the cases of small tumor masses. A benefit in terms of overall survival resulted for early-detection recurrences compared with those patients in whom recurrences were classified as late detected. The survival benefit of such a surveillance strategy, however, has to be established in comparative prospective trials. The present data may serve as a solid basis for planning and conducting future randomized trials on the value of surveillance strategies in cutaneous melanoma.
Supported by grant no. M3/95/Ga I from the Deutsche Krebshilfe, Bonn, Germany.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test and Mann-Whitney U test. The overall survival curves were calculated according to the Kaplan-Meier product-limit method, and significance was evaluated with the log-rank test. The hazard curves were estimated using nonparametric regression smoothers (Gray’s HAZCOV library for S-Plus; Gray RJ, Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA). In each statistical analysis, a P value of less than .05 was regarded as statistically significant. 
