ORIGINAL ARTICLES: Clinical research
Costs of the detection of metastases and follow-up examinations in cutaneous melanoma
Leiter, Ulrikea; Marghoob, Ashfaq A.c; Lasithiotakis, Konstantinosa; Eigentler, Thomas K.a; Meier, Friedegunda; Meisner, Christophb; Garbe, Clausa
aDepartments of Dermatology, Skin Cancer Program, Eberhard Karls University
bInstitute of Medical Biometrics, Eberhard Karls University, Tübingen, Germany
cMemorial Sloan-Kettering Cancer Center, 800 Veterans Memorial Highway, Hauppauge, New York, USA
Correspondence to Claus Garbe, MD, Professor of Dermatology, Head, Division of Dermatooncology, Eberhard Karls University, Liebermeister Strasse 25, 72076 Tuebingen, Germany
Tel: +49 07071 2987110; fax: +49 07071 295187;
Received 14 January 2008 Accepted 1 October 2008
At present, no universally accepted recommendations exist for cutaneous melanoma follow-up. Various surveillance strategies, some associated with significant cost, others of uncertain value, are routinely used. This study aimed to evaluate of the costs incurred for varied surveillance strategies practiced in Europe and the USA. One thousand nine hundred and sixty-nine cutaneous melanoma patients with stage I–III disease attending the Department of Dermatology, University of Tuebingen for follow-up between 1996 and 1998 participated in the study. Routine surveillance consisted of cutaneous examination, lymph node and abdomen sonography, chest radiograph (CR) and blood tests. The costs incurred were based upon the 2004 German official scale for medical reimbursement and the 2004 Medicare fee reimbursement schedule (USA). The total charges were based on the number of recurrences detected per stage. Recurrences were detected in 1.5% of patients with stage I, 18.0% in stage II, and 68.6% in stage III. Physical examination was the most effective method, detecting 50.0% of recurrences. Lymph node sonography was effective in stage II–III, detecting 13.2% of recurrences; CR and abdominal sonography, detecting 4.5 and 3.4% of recurrences, were deemed beneficial in stage III. Blood tests detected 1.4% of recurrences and were deemed to be ineffective. Computed tomography scans were valuable in clarifying ambiguous findings and helping to detect 22.5% of recurrences (1.9% in stage I, 1.9% in stage II, and 18.6% in stage III). A risk-adapted surveillance strategy for stage I–II including thorough history, physical examination and lymph node sonography but omitting CR, blood work and abdomen sonography, seems appropriate and cost effective.
At present, the follow-up recommendations for the surveillance of patients with cutaneous melanoma (CM), with the aim of detecting recurrent disease, varies from country to country. This is, in part, on account of differences in the opinions of international experts and, in part, on account of the prevailing medical and legal atmosphere of the country. Various surveillance strategies, some associated with significant cost and others with uncertain value, are routinely used. Statistics reveal that up to 30% of patients with stage I or II melanoma and over 60% of patients with stage III melanoma will ultimately develop metastatic disease . Efficient and cost-effective surveillance strategies, dependent on tumor stage, are required. On the basis of the results of several retrospective and one prospective study [2,3], German guidelines recommend physical examinations, blood tests (full and differential blood count, serum analysis including alkaline phosphatase and lactate dehydrogenase), abdomen sonography, chest radiograph (CR) and sonography of the regional lymph nodes on all melanoma patients every 3–12 months . Additional imaging studies such as computed tomography (CT) scans, MRI scans, bone scintigraphy, and PET scans are obtained only in cases with a suspicion of tumor progression on the basis of the aforementioned tests [1,3–5]. The practice of surveillance and follow-up in melanoma was studied by Bart et al. [6,7] in the late 1990s and similar procedures have been described to be performedin Germany for follow-up of melanoma patients. Furthermore, Sober et al.  recommended in the guidelines of primary melanoma that the follow-up one–four times per year, dependent on the tumor thickness of the lesion and other risk factors for 2 years after diagnosis and once or twice per year thereafter, should be performed based on suspicious findings, imaging studies, and blood tests. Thus, there are undoubtedly clear similarities in follow-up procedures, blood examination, and imaging examinations between Germany and the United States.
So far, only a few retrospective studies have addressed the effectiveness of physical, laboratory, and imaging examinations, and even fewer studies have evaluated the costs incurred for the follow-up of melanoma patients [9–11]. However, what is clear is that most recurrences are not detected solely because of findings in laboratory or imaging studies. In fact, approximately 44–56% of recurrences are detected by physician-directed surveillance examinations or by patient's self-examination [12,13]. A retrospective study from Germany revealed that history and physical examination led to the detection of first or second recurrences in 47 and 52%, respectively. This study also stated that routine lymph node sonography of the regional nodal basins consumed 24% of the total follow-up healthcare costs for stage I–II patients but that, in return, it was able to detect 13% of first relapses, which were not detectable through physical examination alone .
Our earlier report evaluated the outcome of a specific surveillance strategy and reported that physical examination discovered 50% of all recurrences in stage I–III (American Joint Committee on Cancer 2002). Of interest was the fact that in stage I–II, 21% of all recurrences were discovered solely by lymph node sonography. Very few metastases were detected by CR (0.6%), abdomen sonography (0.8%), and blood tests (0.07%) . Herein, by using data obtained from the same patient cohort , we aimed to evaluate the costs incurred from follow-up examinations performed on melanoma stage I–III patients. Monitory charges for the detection of metastasis per stage and examination method and costs incurred for clarifying suspicious findings were calculated, and, for comparison, given for the US system. Total costs for a 5-year surveillance were determined on the basis of the risk-adapted surveillance schedule reported earlier .
Patients and methods
This monocenter study used a prospective design to investigate the effectiveness of a specific follow-up strategy for detecting recurrence  and calculated the approximate medical costs incurred during a 2-year follow-up period. One thousand nine hundred and sixty-nine patients with stage I–III CM were included in the study. A detailed description of this cohort has been published earlier . The surveillance was performed in the Department of Dermatology, University of Tuebingen according to the guidelines of the German Society of Dermatology [3,5]. Informed consent was obtained from all patients. Tumor characteristics and case histories were recorded in a standardized manner and patients were restaged retrospectively at the time of diagnosis according to the American Joint Committee on Cancer 2002 staging system . All patients underwent an excision of the primary tumor with safety margins depending on tumor thickness. Sentinel lymph node biopsies (SLNB) were routinely performed in CM greater than 1.0 mm tumor thickness since 1996. Stage III patients were tumor free at the time of study inclusion . In this study, a total of 108 patients underwent SLNB (5.5%): of these, 11 (0.6%) showed a positive sentinel lymph node and underwent elective lymph node dissection (ELND) and 129 patients had primarily an ELND (6.5%). Of the 27 patients with nodal recurrences of the regional lymph nodes detected by lymph node ultrasound, 15 had SLNB or primary ELND at primary diagnosis with positive results in six patients.
Follow-up examinations were performed three times a month for 1–5 years after resection of the primary tumor and continued six times a month until the 10th postoperative year. Physical examinations were performed four times a year in all stages: abdomen sonography and CR once a year in stage I–II and twice a year in stage III. Blood tests (full and differential blood count and serum analysis including alkaline phosphatase and lactate dehydrogenase) were obtained annually for patients with stage I–II and biannually for those with stage III disease. Lymph node sonography of the regional lymph nodes was performed once a year in stage I, twice a year in stage II, and 3–6 times a month in stage III. CT and MRI scanning, bone scintigraphy, skeletal radiographs, and PET scans were obtained only to clarify ambiguous findings noted from aforementioned tests.
Evaluation of costs of detection of metastases
Prospective data documentation was carried out as described earlier . Data evaluation was performed by using the statistical package SPSS 13.0 for Windows (SPSS-Inc., Headquarters, Chicago, USA). The results of all examinations (true positives, true negatives, false positives, and false negatives) were also documented. All subsequent imaging examinations performed to clarify suspicious findings were considered. A suspicion of metastases was classified as a false-positive finding, when the suspicion of metastases was not confirmed by further investigations. Further investigations were additional imaging examinations [magnetic resonance tomography (MRT) or CT scans] or subsequent follow-up examinations.
The calculation of costs was based on the 2004 official scale of medical reimbursement charges in Germany (Gebührenordnung für Ärzte, GOÄ). The corresponding American costs were estimated on the basis of the 2004 Medicare fee reimbursement schedule by using a quantity and price approach (Table 1). Thus, a comparison of costs incurred in the US and in Europe is possible.
The cost accrued to detect one recurrence per stage combined with the 95% confidence intervals were calculated. The total costs for examinations performed in stage I–III and the costs for each examination method were evaluated. The number of examinations required to detect a single recurrence was also determined.
Description of sample
Between 1996 and 1998, a total of 3651 physical examinations, 8753 imaging studies (technical), and 2872 blood tests were performed in 1969 patients. Of these patients, 1554 (78.9%) were classified as stage I, 205 as stage II (10.4%), and 210 as stage III (10.6%). During this surveillance period, 204 recurrences were discovered in 112 patients. The recurrence rates were 1.5% in stage I, 18.0% in stage II, and 68.6% in stage III. Most of the recurrences were detected by physical examination (N=101, 50.0%) and lymph node sonography (N=27, 13.2%), whereas the recurrence rates were much lower for CR (N=10, 4.5%), abdomen sonography (N=7, 3.4%) and blood tests (N=3, 1.5%). In 29.5% (N=33) of patients, the patient's history was suspicious for recurrences [stage I (N=6, stage II (N=8), stage III (N=19)], which was confirmed by physical examination in all cases. Recurrences detected in patients following the examination guidelines for stage I–III are shown in Table 2. One hundred and ninety-two false-positive results led to further imaging examinations.
Costs were calculated for all tests routinely obtained for patients in stage I–III (Table 2). Total costs for routine melanoma follow-up during this 2-year period accounted for 236.30€ per patient. In the USA, in contrast, where patients are customarily evaluated by a radiologist who performs and interprets the sonography examinations and where the patient is billed separately by both the primary treating physician and the radiologist, the costs would be much higher (757.60$).
Follow-up examinations in stage I showed the highest costs in total (307 914€/887 261$), in stage II total costs were 62 673€/252 292$ and in stage III total costs accounted for (89 651€/352 214$) (Table 3).
Costs for the detection of one recurrence per stage and examination method
Physical examination was the most efficient diagnostic test to detect metastases in routine follow-up (Tables 2 and 3). Between laboratory and imaging examinations, lymph node sonography was the most successful method to detect metastases. In stage I patients, costs for the detection of one recurrence were the highest (4289€/4391$ for physical examination and 18 035€/131 423$ for lymph node sonography). Costs decreased in stage II to 500€/512$ for physical examination and to 1333€/9712$ for lymph node sonography, in stage III to 168€/171$ and to 1250€ /9112$, respectively.
CR generated the highest costs in stage I to detect one recurrence (22 886€/20 512$) according to German revenues. For the US system, lymph node sonography generated more costs because of the reasons mentioned above. No metastases could be detected by abdomen sonography and blood tests in stage I disease and accounted for a total cost of 46 108€/182 076$ and 83 732€/99 127$, respectively. In stage II, 0.4% of CR examinations were positive for metastasis (6453€/5783$). No metastases were found on abdomen sonography, generating costs of 6151€/24 290$. In stage III, 2.2% of CR examinations and 2.1% of abdomen sonography examinations led to the detection of metastases, with costs of 1199€/1075$ and 1238€ /4887$, respectively. In stage II and III, the metastasis detection rate through blood tests was 0.3 and 0.4% (Table 2) and accounted for 15 728€/18 620$ and 19 412€/22 981$ per metastases, respectively, Table 3.
Physical examinations and lymph node sonography showed the highest recurrence detection rates in all stages, whereas CR and abdomen sonography showed a detection rate of more than 2% only in stage III. Blood tests generated the highest costs for the detection of metastasis and were not effective in any of the stages.
In cases of suspected visceral metastases, CT scans were performed to confirm the diagnosis of metastases. CT scans are separately counted for the different body regions and therefore a whole-body CT screening consists of five separate CT scans (head, neck, chest, abdomen, and pelvis). Thus, a number of CT scans had to be performed to clarify false-positive findings, 640 CTs in 192 patients, further 57 MRT scans, 19 PET scans, and 23 bone scintigraphy (Table 2). In addition, in a subgroup of patients, only ultrasound controls were performed during the follow-up. Costs generated to clarify suspicious findings amounted to a total of 41 007€ /306 557$ for CT scans and 27 514€/50 518$ for others (MRT, PET, bone scintigraphy). Twenty-four false-positive findings were made through physical examinations and were succeeded by an average cost of 2721.6€/16104$. Fifty-two false-positive diagnoses resulted from lymph node ultrasound and subsequent examination cost on average 4742.7€/41079$. Ninety-one ambiguous findings resulted from elevated blood levels of alkaloid phosphatate and lactate dehydogenase and resulted in average costs of follow-up examinations of 2129.6€ /15160.7$. Costs per recurrences detected were highest in stage I (3993€/24 743$ for CT and 5377€/9651$ for others) and decreased in stage II (2478€/20 825$ for CT, 2354€/4656$ for others) and stage III (398€/3297$ for CT, 1940€/3484$ for others), Table 3.
False-positive results accounted for 1.25% (192 of 15 276) of all examinations, of these 87 of 10 526 (0.8%) in stage I, 39 of 2038 (1.9%) in stage II, and 66 of 2712 (2.4%) in stage III. Blood tests showed the highest rate of false positives (3.1%) in stage I and II (3.9%), with a decrease in stage III (2.9%). Lymph node sonography showed the highest number of false-positive results of routine imaging techniques (1.6%), especially in stage III (4.2%), Table 2.
Costs for surveillance during a 5-year period
The follow-up schedule performed in Tuebingen from 1996 to 1998 provided the basis for the calculation for a 5-year surveillance program. Total costs amounted to 990.8€/2208$ per patient in stage I and up to 1841€/4009$ per patient in stage III, Table 4.
On the basis of this study and our earlier published study , we recommend a risk-adapted follow-up schedule (Table 4). On the basis of this schedule, the 5-year surveillance costs could be reduced to 198€/203$ for stage I patients, remain similar in stage II 1329€/2518$ and increase to 2775€/6361$ in stage III on account of intensified examinations and blood tests, including the tumor marker S100β. The total costs during the 5-year follow-up for the entire patient population in this study (planned examinations) would decrease from 2 155 813€/4 917 216$ (old schedule) to 1 163 340€/2 167 286$ (new schedule).
Costs in melanoma follow-up
No consensus exists regarding the most appropriate frequency of follow-up examinations in patients diagnosed with melanoma. Furthermore, the frequency of obtaining laboratory and imaging examinations in melanoma patients is even more controversial [4,13]. In many cancers, other than melanoma, researchers have created numerous models designed to estimate the costs and cost effectiveness of cancer care treatments and follow-up [15–19]. Only a few have evaluated the economic impact of melanoma [4,9,20,21]. Currently, many laboratory and imaging studies, some of which are quite expensive, are routinely performed in the surveillance of melanoma patients. The effectiveness of the surveillance methods in melanoma is still unproven; therefore real cost-effectiveness analyses cannot yet be performed .
In many studies, cost effectiveness is calculated in relation to life years saved by the respective diagnostic or therapeutic strategies. Until now, we do not have a clear knowledge of the number of life years gained by follow-up examinations and the early detection of recurrences in melanoma. Therefore, this study focuses on the total costs, on the relationship between costs of examinations performed and the number of recurrences detected during follow-up of stage I–III melanoma patients.
The costs for the detection of one recurrence were found to be extremely high in stage I, accounting for 13 388€/38 574$. Compared with the high number of examinations, only a few recurrences were detected (Table 2). Physical examinations showed the highest detection rate for recurrences in stage I–III disease, ranging from 0.5 to 11.8%, respectively. Lymph node sonography proved to be the most effective screening examination in stage II and III disease. CR and abdomen sonography were inefficient in detecting recurrences in stage I and II, but may be of benefit in stage III disease (Table 2). Blood tests were ineffective in detecting recurrences in stage I–III, generating the highest costs and showing the lowest detection rate for recurrences (0.4% and lower). Blood tests are not routinely performed during follow-up in many US centers . However, as the analysis of the tumor marker S100β was not routinely performed during the study period, it was not included in this evaluation. The value and significance of S100β were, however, considered separately in a cohort of 500 patients . The diagnostic utility of S100β as a tumor marker has been reported as being at most useful in stage II and III patients [23,23–27].
Similar results were reported by Basseres et al.  in an evaluation of follow-up examinations of 528 stage I/II patients. Ninety-five percent of surgically removable metastases were detected by physical examination and thus the clinical examination was deemed to be most cost-effective. Blood tests were described as inefficient methods for detecting subclinical metastatic disease. Physical examinations had the lowest costs associated with the detection of metastasis, whereas the costs were 10-fold higher for CR and 20-fold higher for abdomen sonography. The authors opinion was that abdomen sonography and CR should be used routinely only in patients at high risk for recurrence (tumor thickness of more than 1.5 mm) . The high cost–benefit ratio of physical examinations compared with technical examinations in stage I/II patients has also been reported in other studies [2,10,28,29].
In this analysis, the overall rate of false-positive results was 1.25%; of these 126 of 12 564 (1.0%) in stage I and II and 66 of 2712 (2.4%) in stage III. Lymph node sonography showed the highest number of false-positive results (1.6%), followed by physical examination (0.66%).
A few studies have been published examining the costs associated with a false-positive result or indeterminate findings. High numbers of false-positive results were found in the follow-up examinations in stage I–II disease (4.1%), and 4.9% false-positive results in stage III, which led to further technical examinations . Lymph node sonography had the highest false-positive rate for all stages, followed by physical examination and abdomen sonography . However, lymph node sonography revealed the highest sensitivity (85.7%) in routine follow-up examinations, followed by physical examination (68.4%) . Thus, many of the true positive lymph node metastases were detected early , allowing early surgical intervention . Blood tests revealed a high number of false-positive values (3.7%) and had a low sensitivity (11.2%) .
Mooney et al.  showed that the costs for the evaluation of false-positive results reached 30% of the total screening costs by CR and were regarded as ineffective in stage I and pT2 tumors. Imaging techniques such as CT scan, MRT and bone scintigraphy became more cost-effective and of increased medical importance in stage II and III disease . As CT scans and other imaging techniques (MRT, PET) showed the highest rates of detecting recurrences of all imaging techniques, these examinations should be performed in patients suspected of having recurrences. Concordant to these results, Brady et al.  showed CT and PET scans to be the most appropriate form of management in the screening for occult metastatic disease in high-risk melanoma patients, and discussed whether PET scans should be the standard of care in the preoperative evaluation of patients. However, these examination techniques are expensive and are not suitable for routine follow-up.
Costs in risk-adapted follow-up schedules
A calculation of a risk-adapted 5-year follow-up program revealed a possible reduction of costs in stage I, similar costs in stage II, and an increase in stage III (Table 4). As the majority of melanoma patients are diagnosed with early-stage disease, it is reasonable to assume that the savings in the follow-up of stage I and II patients would be substantial if we adhered to the findings of this study. As CR and abdomen sonography were not routinely performed in stage I–II and lymph node sonography was only performed in stage II, the total follow-up costs could be reduced from 990.80€ for a 5-year period to 198.20€ for stage I, Table 4. As 70.6% of all recurrences were detected in stage III, the costs of detecting one recurrence with an intensified follow-up schedule including physical examinations, lymph node ultrasound, and blood tests performed four times a year and CR and abdomen ultrasound obtained twice a year may be reasonable in this stage. A similar analysis was performed by Hengge et al.  for a cohort of 526 stage I–III melanoma patients. Savings of more than 100 000 EUR annually would be obtained when a reduced-yet-adequate follow-up scheme eliminating blood tests at early stages and reducing CRs and abdomen ultrasound examinations was to be implemented.
Blood tests were not found to be cost effective at all because they did not contain the determination of the tumor marker S100β. The analysis of S100β showed the highest sensitivity and specificity of all tumor markers examined in melanoma [23,25]. Therefore, the determination of S100β has now been included into the new follow-up recommendations at Tuebingen and is performed twice yearly in stage II and four times yearly in stage III.
A risk-adapted, less-frequent follow-up schedule has been proposed earlier [10,28,32]. The frequency of CR was reduced to twice yearly without any changes in the sensitivity or specificity of the screening regimen, although no stage-dependent analysis was included . Hofmann recommended only physical examinations once to twice a year in stage I–II and four times a year in stage III, and lymph node sonography once to twice a year as adequate surveillance methods . Further technical examination methods were reported to be cost ineffective and were not included in the follow-up recommendations. A risk-adapted follow-up schedule was proposed based on the premise of not lowering the quality of medical care but still achieving significant savings .
Regarding the costs for the follow-up examinations as a function of the number of detected recurrences, physical examination was the most effective method in routine follow-up. Lymph node sonography was a reasonably effective method in detecting recurrences in stage II and III, and CR and abdomen sonography were effective only in stage III disease. As CT scans and other imaging techniques (MRT, PET) showed the highest rates to detect recurrences of all imaging techniques, these examinations should be performed in patients suspected of having recurrences.
A risk-adapted surveillance schedule with reduced imaging and laboratory examinations performed in stage I/II and a more intensified schedule in stage III seems a reasonable strategy in the follow-up of melanoma patients. Significant reductions in costs, without compromising excellent patient care, can be achieved if the results of this study are considered when planning melanoma follow-up guidelines.
Supported by grant no. M3/95/Ga I from the Deutsche Krebshilfe, 53111 Bonn, Germany
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