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The Conundrum of Follow-Up: Should it be Abandoned?
Surg Oncol Clin N Am 15 (2006) 319–330
The Conundrum of Follow-Up: Should it be Abandoned? Omgo E. Nieweg, MD, PhD*, Bin B.R. Kroon, MD, PhD, FRCS The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Surgery, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
Melanoma is situated on the surface of the body, making it preeminently suitable for early detection. Patients and doctors are increasingly aware of melanoma and the importance of timely treatment. As a result, 95% of patients who have melanoma are now identified at a stage when no evidence of dissemination is present. Among patients undergoing wide excision, 70% are completely relieved of their disease, whereas the remaining 30% eventually experience a recurrence. The melanoma can recur at its original location, but surrounding satellite, in-transit metastases, and lymph node metastases develop more often. About one third of patients who experience recurrence can be cured with additional local–regional treatment. Patients who experience a recurrence beyond the regional lymph nodes have a more grim future. Still, 10% of patients who have distant involvement seem to have no other metastases and are eligible for resection. With a deliberate strategy, this subset of patients can experience a 20% 5-year survival [1]. Some patients develop a second primary melanoma. Doctors follow-up with patients after treating the primary tumor because of the potential for melanoma recurrence. This follow-up is generally accepted and patients are comfortable with this approach [2]. However, in an age when available finances for health care are increasingly constrained, comfort is a poor justification for continuous management of patients. Scientific evidence of what health care workers do is increasingly demanded. Doctors must address the cost/benefit ratio more often.
The authors have no financial relationship with a commercial company. No funding was received for the writing of this manuscript. * Corresponding author. E-mail address: [email protected] (O.E. Nieweg). 1055-3207/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2005.12.005 surgonc.theclinics.com
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The most time doctors devote to patients who have melanoma consists of follow-up visits. No worldwide, accepted, uniform surveillance paradigm exists for patients who have undergone treatment for melanoma. This article takes a critical look at the follow-up of patients who have undergone treatment for a primary melanoma without evidence of metastases. The objectives and methods of follow-up are discussed, and the success of the current strategies is assessed. The findings lead to conclusions and implications that challenge current practice. Objectives of follow-up Early detection of recurrent tumor activity is the principal reason for follow-up. The belief is that early detection results in early treatment, thereby improving the odds of survival and regional disease control, and quality of life. A patient who has experienced melanoma is at an increased risk for a subsequent new melanoma. The follow-up visit offers the doctor an opportunity to diagnose a second primary tumor at an early stage. Patient education is an important additional objective. Following-up patients also enables doctors to evaluate their own results and gather data for scientific work. Incidence of local recurrence, metastases, and second primary melanoma Approximately 30% of patients who have a clinically localized melanoma experience a recurrence of the tumor [3]. Eighty percent of the recurrences become evident within 3 years from diagnosis of the primary tumor [4,5]. A melanoma rarely recurs after more than 10 years, although a recurrence after 46 years has occurred [6]. A few percent of local recurrence, satellite metastases, and in-transit metastases occur [4,7]. Approximately 20% of the patients develop lymph node metastases, and a similar number experience blood-borne metastases [4,7]. A second primary melanoma is seen in a few percent of patients [8]. The risk for an in situ melanoma is four times as high [5]. Follow-up visit After the treatment for a presumably localized melanoma, the patient undergoes a surveillance regimen. The typical follow-up visit commences with a patient history. The physician inquires about regional skin and subcutaneous tissue because detection of a local recurrence or regional metastases has therapeutic implications: approximately 30% of these patients can experience a cure. Such lesions are easily accessible during subsequent physical examination, and the region that drains into the same lymph nodes as the melanoma is scrutinized for signs of tumor deposits.
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Physicians have widely diverging opinions about the need for additional tests. The United Kingdom and Dutch national guidelines recommend routine visits should consist of only a history and physical examination [9,10]. Patients in surrounding countries are subjected to additional tests, as recommended by the World Health Organization [8,11–14]. Not all experts are convinced of the value of this policy [15]. Some physicians in the United States also question the need for routine laboratory and imaging studies [16], although most seem to perform these [17]. This article critically evaluates the published literature on various aspects of posttreatment surveillance.
Frequency of follow-up How frequently should patients be seen for follow-up and for how long? No randomized studies provide direction. Guidelines are typically based on opinions of experts in the field. Physicians generally see their patients every 3 months in the beginning and then gradually increase the intervals until 5 years have passed. Yearly visits are then the general rule. Although this approach is not based on scientific evidence, it seems reasonable because approximately 80% of recurrences occur in the first 3 years [4,5]. Some experts recommend life-long follow-up [6].
Compliance with follow-up recommendations An Austrian study looked at how carefully patients comply with the follow-up guidelines. The mean annual drop-out rate was 11.2% [8]. Only 55% of the patients continued their follow-up examinations after 5 years. Patients apparently do not stick to the guidelines well, but the same can be said for their doctors. Mijnhout and colleagues [18] showed that 76% of physicians did not adhere to the recommended follow-up guidelines. Unwarranted laboratory tests and imaging studies were the most frequent violation of these national guidelines.
Imaging studies Screening for lymph node metastases Experts have shown recent interest in ultrasound of the lymph nodes. The sensitivity of ultrasound for this purpose was found to be between 87% and 99.2% [19–21]. The specificity ranged from 74% to 99% [19–21]. In one study, ultrasound failed to detect more involved nodes than palpation, although the specificity was better [19]. Another investigator found the opposite [21]. In a German investigation, 12 of 3050 ultrasound examinations were true-positive and 273 were false-positive [15].
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No studies were found that address survival benefit from routine ultrasound at follow-up visits. The risk for false-positive ultrasound results is substantial, but the consequence for the patient is only fine-needle aspiration. Ultrasound surveillance of lymph nodes has enough potential to warrant further examination. Screening for pulmonary metastases The lungs are the most common visceral site of metastatic involvement. Five-year survival with pulmonary involvement is 4% [22]. Of patients who have pulmonary involvement, 12% to 25% can undergo surgery [23], and 80% to 90% of these can undergo complete resection [22,24]. Fiveyear survival in patients who undergo complete resection is 10% to 30% [22–24]. Many patients undergo imaging studies to detect pulmonary involvement. Do these additional tests contribute to better patient management? From a scientific point of view, this question could be answered by results of randomized studies in which half of the patients undergo observation and the other half a specific test, with survival, regional tumor control, and quality of life as end points. Such studies do not exist, but several articles report outcomes from observational studies. Chest radiography is probably the technique most often performed for observation. In four studies using this technique, the chest radiograph did not detect disease [8,18,25,26], but seven other studies showed asymptomatic lung metastases in 0.5% to 6.2% of patients [12,15,16,27–29]. Over half of the recurrences were detected 3 to 5 years after the initial diagnosis [29]. Some of the studies describe the management and outcome of 32 of these patients [16,27,29]; 19 underwent thoracotomy, and only 5 were alive after 18 months, 36 months, 54 months, and 58 months. Mooney and colleagues [29] showed similar overall survival in patients who had symptomatic pulmonary metastases and those who experienced recurrences that were detected by routine chest radiographs. The yield is apparently limited. A German study suggests that the specificity of chest radiograph is also limited [15]; only 7 were true-positive metastases whereas 105 were false-positive. Regular roentgen CT of the lungs did not show metastases in two studies [12,18]. A third study identified metastases in 3 of 364 patients [26]. Two of these patients also had distant metastases elsewhere. Their fate is not described. Screening for intra-abdominal metastases Melanoma frequently spreads to intra-abdominal organs, most often affecting the liver. Liver metastases carry a particularly dismal prognosis. Rose and colleagues [30] described a series of 1750 patients in which
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a mere 34 (2%) underwent exploration with intent to resect the metastases. Of patients undergoing exploratory celiotomy, 24 actually underwent hepatic resection, which was deemed complete in 18. Seven (0.4%) of the patients who underwent resection were alive after 5 years. Melanoma has a tendency to spread to the bowel, more so than other common cancers, but finding a sole bowel lesion at a stage during which complete resection is realistic is uncommon. Median survival in patients who have bowel metastases is 9 months [31]. In a study involving 528 patients who had melanoma, routine use of abdominal ultrasound during follow-up identified only 6 of 115 patients who experienced a recurrence [12]. None of these patients could undergo resection. Another study on ultrasound showed a better sensitivity (53%), but false-positive results occurred in 74 involved sites in 849 patients [32]. The positive predictive value was merely 12%. The high rate of false-positive results was reflected in another study, where a true metastasis was detected in one patient although 101 ultrasounds showed false-positive results [15]. Four other studies failed to show benefit from routine ultrasound of the abdomen [8,18,26,28]. Abdominal CT scans identified metastases with certainty in 20 of 809 cases (2.5%), with a sensitivity of 83% [32]. The positive predictive value was 36%. In a second study, CT uncovered one case of abdominal metastasis in 364 patients [26]. This patient also had lung metastases. Another investigator never found melanoma deposits with abdominal CT scans [12]. These studies show that the yield and specificity of ultrasound and CT in detecting intra-abdominal metastases are inadequate, and identified dissemination is clinically relevant to few patients. Screening for brain metastases Patients who have brain metastases of melanoma also usually have metastases in lung, liver, or bone, making prognosis dismal [33]. Two-year survival is 3% [33]. Treatment with curative intent is considered only in a few highly selected patients. Routine CT scanning of the brain identified two patients who had metastases out of a group of 892 [12,26]. One also had pulmonary metastases; the other patient’s outcome was not disclosed. MRI is now preferred for visualizing brain metastases, but studies analyzing routine MRI surveillance have not been performed. Insufficient evidence exists justifying the use of CT scanning or MRI for surveillance. Screening for bone metastases Compared with some other common neoplasms, melanoma does not spread to bones as often as to other distant sites. A study on the value of bone scintigraphy showed 7 of 116 scintigrams were abnormal, but none
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because of melanoma [27]. One patient who had a normal image had bone metastases. Relevance of laboratory tests Laboratory studies of blood are often performed as part of routine surveillance and are recommended by some experts [17,34]. Studies have shown simple laboratory tests, such as a blood count, blood chemistry panel, and liver enzymes, are useless in the detection of recurrences [8,16,18,25,27–29]. False-positive test results will lead to other futile tests [29]. Serum lactate dehydrogenase has prognostic relevance and is now incorporated in the staging classification for stage IV, but the value of this enzyme in routine follow-up seems limited. Few blood tests have been designed to specifically detect melanoma. Neuron-specific enolase is a glycolysis enzyme specific for cells derived from the neuroectoderm, such as melanocytes. This enzyme has a sensitivity of 27% and a specificity of 70% [35]. Lipid-bound sialic acid has a sensitivity of 65% and a specificity of 76% [35]. The S-100 protein is produced by melanoma cells and used as tumor marker. The value of S-100 was evaluated in a group of 141 patients followed for 15 months after undergoing surgery for a clinically localized melanoma [36]. Seven of these patients experienced a recurrence. In six patients, the increased S-100 preceded the detection of the metastases location by 4 to 21 months. In a group of patients who had a tumor-free sentinel lymph node, the sensitivity to detect a recurrence was 33% and the specificity 100% [37]. The polymerase chain reaction for melanoma characteristics in the blood has shown potential in identifying patients who are at increased risk [38]. Signs of melanoma may be detectable in the blood after patients undergo treatment for a clinically localized melanoma, but the sensitivity to detect a recurrence was limited (64%) in an initial study [39]. Only few studies have been published of patients who had specific blood tests performed in a surveillance program, and the numbers of patients are small. Whether early detection of recurrence using these tests contributes to an improved prognosis, and false-positive results harm the patients through unnecessary examinations and instigated fear, is unclear. Relevance of follow-up per se Five studies showed that recurrence is usually detected by the patient between office visits [25,27,29,40,41], and three showed the opposite [12,15,42]. Two of these eight studies possibly involve overlapping patient populations, but show different outcomes [25,42]. Some experts believe that more than 90% of the recurrences are now detected by patients and not their doctors because of patient education and self-examination [34].
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These observations cast doubt on whether follow-up is really relevant. Does follow-up lead to an increased probability of survival? No studies on survival are available in which patients were randomized to either follow-up or no follow-up. So, the question can only be answered indirectly. Several points seem to support the argument for follow-up. Lymph node metastases discovered by the patient are on average larger than those discovered by the doctor [41]. Poo-Hwu and colleagues [42] showed that patients who experienced asymptomatic recurrence that is found at the regular follow-up visit have a 5.8% better survival rate after 80 months compared with patients who discovered the recurrence themselves. Concluding from this study that follow-up improves survival is premature for several reasons. This study not only involved patients who had clinically localized melanoma but also patients who had regional involvement. Furthermore, the difference in outcomes could also be explained by a lead-time bias. Another possibility is that metastases identified by the physician have a more protracted growth pattern with a more favorable biology, resulting in a better survival rate (length-time bias). Also, three other studies showed no survival difference when comparing who first spotted the recurrence [15,29,41]. To increase the confusion, a fifth study surprisingly showed that the likelihood of survival is less if recurring tumor activity is discovered by a melanoma specialist [40]. In addition to survival, regional tumor control and quality of life are end points that deserve assessment, but no studies elucidate these aspects. Detection of a subsequent primary melanoma The risk for developing a second primary melanoma is a few percent [8]. The risk for an in situ melanoma is four times as high [5]. A second invasive melanoma usually has more favorable characteristics than the initial lesion [42]. For instance, the Breslow thickness is about half of the first melanoma [8]. Like a recurrence of the original tumor, a new melanoma is often discovered by the patient [27]. Patient education Patients and their family have many questions particularly in the phase after the treatment. They have often received conflicting information from various sources and struggle with the uncertainties associated with the unpredictable disease. They consider the doctor the definitive source of reliable information. Many patients want to know what they can do to detect a new primary melanoma or recurrence in an early phase. Doctors can explain signs of primary melanoma and regional metastases and teach them how to perform self-examination. The dissemination pattern of melanoma is unpredictable and sometimes bizarre. Doctors can explain that a recurrence can take
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many forms. Symptoms that remain for more than a few weeks and cannot be explained unequivocally in another way are reasons to schedule an appointment. Patients’ ability to detect renewed tumor development is inconsistent. Some individuals consistently and correctly identify recurrent metastases that are not yet discernible to the doctor, whereas other patients are unaware of a subcutaneous metastasis 5 cm in size.
Evaluation of results, scientific clinical study Follow-up and well-documented files enable evaluation of diagnosis and treatment results. Follow-up data can be gathered for current or future scientific studies. Few doctors exploit these opportunities, but this article could not have been written without the ones who did.
Discussion Few randomized studies are available examining a survival benefit from imaging studies and laboratory tests. The studies published carry less scientific weight but are numerous, and many involve large groups of patients. These studies indicate that insufficient benefit is gained from imaging and blood testing. Only few patients who have metastases are identified using these techniques, and even fewer survive just because they underwent these tests. A false-positive result most often occurs, which invariably causes unnecessary concern, leads to additional unnecessary testing, and may even result in needless surgery. Ultrasound, tumor markers, and the polymerase chain reaction can possibly improve detection of regional metastases, but this has not been proven. More than other imaging techniques, ultrasound seems to depend on the technical skills and experience of the person who performs the examination. Given the fact that lymph node surveillance is a novel application of this imaging technique, capable radiologists are few. Based on the evidence available, the relevance of follow-up per se must be challenged. The articles reviewed do not provide convincing evidence that regional control, survival, and quality of life improve through surveillance. Even if a study shows that a patient lives longer if a metastasis is detected by the doctor at a routine visit rather than by the patient, that this occurred because of the follow-up would be hard to prove. Interpretation of the data is thwarted by possible lead-time and length-time biases. Whether the sobering conclusions in this article are relevant for today’s patients can be argued. Several of the studies contain many patients who have undergone elective lymph node dissection, a procedure that is not performed anymore. Nowadays, many patients undergo sentinel lymph node biopsy, a new procedure that is not considered in these studies. Another factor is that better imaging techniques, in particular positron emission
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tomography, enable better selection of patients who have distant metastases who have the best prospects for benefitting from aggressive treatment. Physicians should not immediately abolish posttreatment surveillance for several reasons. Cancer patients appreciate being followed-up by their physicians [41]; they generally dread having to go to the doctor but experience relief if no abnormality is found [41,43]. The doctor’s task is not only to pursue a cure but also provide patients with peace of mind. Patients in Great Britain prefer structured follow-up appointments rather than walk-in visits when they have a complaint [41]. A randomized study shows that a structured psychiatric group intervention after 6 weeks improves the prognosis [44]. Keeping options open for evaluation of results and participation in scientific projects are other advantages of structured follow-ups, but these may be insufficient reasons for the average doctor to follow-up with patients. From a scientific viewpoint, the value of follow-up should be determined through a randomized study. One practical problem of a randomized study on follow-up, however, is that it would require a huge number of patients because any differences in end points would likely be small. Patients must also be monitored for many years, and results would not be available for at least 15 years, during which time imaging and new blood tests would be developed. A fundamental problem would be determining the recurrence rate, survival, and incidence of new melanomas and their characteristics in patients not undergoing follow-up. Furthermore, patients may be reluctant to accept a 50% ‘‘risk’’ of being assigned to the arm without follow-up. These problems hinder a successful randomized study. Perhaps a systematic review to collect sufficient circumstantial evidence would be the best method to clarify the value of follow-up. Follow-up became relevant when new Dutch national guidelines on the management of melanoma patients had to be developed. The idea was that patients would be followed in a manner scientifically proven to be beneficial. Review of the available data revealed no scientific evidence that follow-up improves survival, regional tumor control, or quality of life. The obvious conclusion was that follow-up should be abandoned, but the guidelines committee was not prepared to recommend this complete departure from common practice. The scientific evidence conflicted with the intuitive desire of doctors to provide continuing care for their patients. After much deliberation, the committee settled on a compromise wherein patients who have melanoma of Breslow thickness 1 mm or smaller need not be followed. These patients receive sufficient information about their disease and are instructed to perform self-examination. They are counseled regarding the lifetime risk for a second primary melanoma and are guaranteed quick access to their doctor when they perceive a potential recurrence or new melanoma. Patients who have a thicker melanoma and those at increased risk for a second melanoma continue to be followed-up according to the existing system, which does not allow additional routine tests. Although various groups of physicians in the Netherlands that care for patients who have
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melanoma found this recommendation acceptable, the governing body that pushes for science-based guidelines was skeptical of this admittedly halfhearted position. Whether this radical approach will be a huge disaster or forebode the future of follow-up for patients who have cancer remains to be seen.
Summary This article critically evaluates the practice of follow-up for patients who have undergone treatment for a primary melanoma without evidence of metastases. One conclusion from this analysis is that the benefits of routine imaging and blood testing are insufficient to warrant a place in routine follow-up. Few patients who have metastases are identified in this fashion and even fewer survive because they underwent these tests. Far more often, false-positive results occur, which invariably cause unnecessary concern, lead to additional unnecessary testing, and may even result in needless surgery. Based on the evidence available, the relevance of follow-up per se must even be challenged. No convincing evidence exists that regional control, survival, and quality of life improve through surveillance. Other reasons for surveillance may be present, but these are less imperative. The present findings challenge current practice.
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[32] Kaufmann PM, Crone-Munzebrock W. Tumornachsorge mittels Sonographie und Computertomographie im Bereich des Abdomens bei Patienten mit malignem Melanom [Tumor follow-up using sonography and computed tomography in the abdominal region of patients with malignant melanoma]. Aktuelle Radiol 1992;2:81–5 [in German]. [33] Saha S, Meyer M, Krementz ET, et al. Prognostic evaluation of intracranial metastasis in malignant melanoma. Ann Surg Oncol 1994;1:38–44. [34] Hoekstra HJ, Schraffordt Koops H. Diagnosis of systemic melanoma metastases: general principles. In: Thompson JF, Morton DL, Kroon BBR, editors. Textbook of melanoma. London: Martin Dunitz; 2004. p. 459–63. [35] Reintgen DS, Cruse CW, Wells KE, et al. The evaluation of putative tumor markers for malignant melanoma. Ann Plast Surg 1992;28:55–9. [36] Jury CS, McAllister EJ, Mackie RM. Rising levels of serum S100 protein precede other evidence of disease progression in patients with malignant melanoma. Br J Dermatol 2000;143: 269–74. [37] Smit LHM, Nieweg OE, Korse CM, et al. Significance of serum S-100B in melanoma patients before and after sentinel node biopsy. J Surg Oncol 2005;90:66–9. [38] Hoon DS, Bostick P, Kuo C, et al. Molecular markers in blood as surrogate prognostic indicators of melanoma recurrence. Cancer Res 2000;60:2253–7. [39] Curry BJ, Myers K, Hersey P. Utility of tests for circulating melanoma cells in identifying patients who develop recurrent melanoma. Recent Results Cancer Res 2001;158:211–30. [40] Ruark DS, Shaw HM, Ingvar C, et al. Who detects the first recurrence in stage I cutaneous malignant melanoma: patient or doctor? Melanoma Res 1993;3(Suppl 1):44. [41] Baughan CA, Hall VL, Leppard BJ, et al. Follow-up in stage I cutaneous malignant melanoma: an audit. Clin Oncol (R Coll Radiol) 1993;5:174–80. [42] Poo-Hwu WJ, Ariyan S, Lamb L, et al. Follow-up recommendations for patients with American Joint Committee on Cancer Stages I–III malignant melanoma. Cancer 1999;86:2252–8. [43] Ross MI. Staging evaluation and surveillance for melanoma patients in a fiscally restrictive medical environment. A commentary. Surg Clin North Am 1996;76:1423–32. [44] Fawzy FI, Fawzy NW, Hyun CS, et al. Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch Gen Psychiatry 1993;50:681–9.
The Conundrum of Follow-Up: Should it be Abandoned? Omgo E. Nieweg, MD, PhD*, Bin B.R. Kroon, MD, PhD, FRCS The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Surgery, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
Melanoma is situated on the surface of the body, making it preeminently suitable for early detection. Patients and doctors are increasingly aware of melanoma and the importance of timely treatment. As a result, 95% of patients who have melanoma are now identified at a stage when no evidence of dissemination is present. Among patients undergoing wide excision, 70% are completely relieved of their disease, whereas the remaining 30% eventually experience a recurrence. The melanoma can recur at its original location, but surrounding satellite, in-transit metastases, and lymph node metastases develop more often. About one third of patients who experience recurrence can be cured with additional local–regional treatment. Patients who experience a recurrence beyond the regional lymph nodes have a more grim future. Still, 10% of patients who have distant involvement seem to have no other metastases and are eligible for resection. With a deliberate strategy, this subset of patients can experience a 20% 5-year survival [1]. Some patients develop a second primary melanoma. Doctors follow-up with patients after treating the primary tumor because of the potential for melanoma recurrence. This follow-up is generally accepted and patients are comfortable with this approach [2]. However, in an age when available finances for health care are increasingly constrained, comfort is a poor justification for continuous management of patients. Scientific evidence of what health care workers do is increasingly demanded. Doctors must address the cost/benefit ratio more often.
The authors have no financial relationship with a commercial company. No funding was received for the writing of this manuscript. * Corresponding author. E-mail address: [email protected] (O.E. Nieweg). 1055-3207/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2005.12.005 surgonc.theclinics.com
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The most time doctors devote to patients who have melanoma consists of follow-up visits. No worldwide, accepted, uniform surveillance paradigm exists for patients who have undergone treatment for melanoma. This article takes a critical look at the follow-up of patients who have undergone treatment for a primary melanoma without evidence of metastases. The objectives and methods of follow-up are discussed, and the success of the current strategies is assessed. The findings lead to conclusions and implications that challenge current practice. Objectives of follow-up Early detection of recurrent tumor activity is the principal reason for follow-up. The belief is that early detection results in early treatment, thereby improving the odds of survival and regional disease control, and quality of life. A patient who has experienced melanoma is at an increased risk for a subsequent new melanoma. The follow-up visit offers the doctor an opportunity to diagnose a second primary tumor at an early stage. Patient education is an important additional objective. Following-up patients also enables doctors to evaluate their own results and gather data for scientific work. Incidence of local recurrence, metastases, and second primary melanoma Approximately 30% of patients who have a clinically localized melanoma experience a recurrence of the tumor [3]. Eighty percent of the recurrences become evident within 3 years from diagnosis of the primary tumor [4,5]. A melanoma rarely recurs after more than 10 years, although a recurrence after 46 years has occurred [6]. A few percent of local recurrence, satellite metastases, and in-transit metastases occur [4,7]. Approximately 20% of the patients develop lymph node metastases, and a similar number experience blood-borne metastases [4,7]. A second primary melanoma is seen in a few percent of patients [8]. The risk for an in situ melanoma is four times as high [5]. Follow-up visit After the treatment for a presumably localized melanoma, the patient undergoes a surveillance regimen. The typical follow-up visit commences with a patient history. The physician inquires about regional skin and subcutaneous tissue because detection of a local recurrence or regional metastases has therapeutic implications: approximately 30% of these patients can experience a cure. Such lesions are easily accessible during subsequent physical examination, and the region that drains into the same lymph nodes as the melanoma is scrutinized for signs of tumor deposits.
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Physicians have widely diverging opinions about the need for additional tests. The United Kingdom and Dutch national guidelines recommend routine visits should consist of only a history and physical examination [9,10]. Patients in surrounding countries are subjected to additional tests, as recommended by the World Health Organization [8,11–14]. Not all experts are convinced of the value of this policy [15]. Some physicians in the United States also question the need for routine laboratory and imaging studies [16], although most seem to perform these [17]. This article critically evaluates the published literature on various aspects of posttreatment surveillance.
Frequency of follow-up How frequently should patients be seen for follow-up and for how long? No randomized studies provide direction. Guidelines are typically based on opinions of experts in the field. Physicians generally see their patients every 3 months in the beginning and then gradually increase the intervals until 5 years have passed. Yearly visits are then the general rule. Although this approach is not based on scientific evidence, it seems reasonable because approximately 80% of recurrences occur in the first 3 years [4,5]. Some experts recommend life-long follow-up [6].
Compliance with follow-up recommendations An Austrian study looked at how carefully patients comply with the follow-up guidelines. The mean annual drop-out rate was 11.2% [8]. Only 55% of the patients continued their follow-up examinations after 5 years. Patients apparently do not stick to the guidelines well, but the same can be said for their doctors. Mijnhout and colleagues [18] showed that 76% of physicians did not adhere to the recommended follow-up guidelines. Unwarranted laboratory tests and imaging studies were the most frequent violation of these national guidelines.
Imaging studies Screening for lymph node metastases Experts have shown recent interest in ultrasound of the lymph nodes. The sensitivity of ultrasound for this purpose was found to be between 87% and 99.2% [19–21]. The specificity ranged from 74% to 99% [19–21]. In one study, ultrasound failed to detect more involved nodes than palpation, although the specificity was better [19]. Another investigator found the opposite [21]. In a German investigation, 12 of 3050 ultrasound examinations were true-positive and 273 were false-positive [15].
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No studies were found that address survival benefit from routine ultrasound at follow-up visits. The risk for false-positive ultrasound results is substantial, but the consequence for the patient is only fine-needle aspiration. Ultrasound surveillance of lymph nodes has enough potential to warrant further examination. Screening for pulmonary metastases The lungs are the most common visceral site of metastatic involvement. Five-year survival with pulmonary involvement is 4% [22]. Of patients who have pulmonary involvement, 12% to 25% can undergo surgery [23], and 80% to 90% of these can undergo complete resection [22,24]. Fiveyear survival in patients who undergo complete resection is 10% to 30% [22–24]. Many patients undergo imaging studies to detect pulmonary involvement. Do these additional tests contribute to better patient management? From a scientific point of view, this question could be answered by results of randomized studies in which half of the patients undergo observation and the other half a specific test, with survival, regional tumor control, and quality of life as end points. Such studies do not exist, but several articles report outcomes from observational studies. Chest radiography is probably the technique most often performed for observation. In four studies using this technique, the chest radiograph did not detect disease [8,18,25,26], but seven other studies showed asymptomatic lung metastases in 0.5% to 6.2% of patients [12,15,16,27–29]. Over half of the recurrences were detected 3 to 5 years after the initial diagnosis [29]. Some of the studies describe the management and outcome of 32 of these patients [16,27,29]; 19 underwent thoracotomy, and only 5 were alive after 18 months, 36 months, 54 months, and 58 months. Mooney and colleagues [29] showed similar overall survival in patients who had symptomatic pulmonary metastases and those who experienced recurrences that were detected by routine chest radiographs. The yield is apparently limited. A German study suggests that the specificity of chest radiograph is also limited [15]; only 7 were true-positive metastases whereas 105 were false-positive. Regular roentgen CT of the lungs did not show metastases in two studies [12,18]. A third study identified metastases in 3 of 364 patients [26]. Two of these patients also had distant metastases elsewhere. Their fate is not described. Screening for intra-abdominal metastases Melanoma frequently spreads to intra-abdominal organs, most often affecting the liver. Liver metastases carry a particularly dismal prognosis. Rose and colleagues [30] described a series of 1750 patients in which
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a mere 34 (2%) underwent exploration with intent to resect the metastases. Of patients undergoing exploratory celiotomy, 24 actually underwent hepatic resection, which was deemed complete in 18. Seven (0.4%) of the patients who underwent resection were alive after 5 years. Melanoma has a tendency to spread to the bowel, more so than other common cancers, but finding a sole bowel lesion at a stage during which complete resection is realistic is uncommon. Median survival in patients who have bowel metastases is 9 months [31]. In a study involving 528 patients who had melanoma, routine use of abdominal ultrasound during follow-up identified only 6 of 115 patients who experienced a recurrence [12]. None of these patients could undergo resection. Another study on ultrasound showed a better sensitivity (53%), but false-positive results occurred in 74 involved sites in 849 patients [32]. The positive predictive value was merely 12%. The high rate of false-positive results was reflected in another study, where a true metastasis was detected in one patient although 101 ultrasounds showed false-positive results [15]. Four other studies failed to show benefit from routine ultrasound of the abdomen [8,18,26,28]. Abdominal CT scans identified metastases with certainty in 20 of 809 cases (2.5%), with a sensitivity of 83% [32]. The positive predictive value was 36%. In a second study, CT uncovered one case of abdominal metastasis in 364 patients [26]. This patient also had lung metastases. Another investigator never found melanoma deposits with abdominal CT scans [12]. These studies show that the yield and specificity of ultrasound and CT in detecting intra-abdominal metastases are inadequate, and identified dissemination is clinically relevant to few patients. Screening for brain metastases Patients who have brain metastases of melanoma also usually have metastases in lung, liver, or bone, making prognosis dismal [33]. Two-year survival is 3% [33]. Treatment with curative intent is considered only in a few highly selected patients. Routine CT scanning of the brain identified two patients who had metastases out of a group of 892 [12,26]. One also had pulmonary metastases; the other patient’s outcome was not disclosed. MRI is now preferred for visualizing brain metastases, but studies analyzing routine MRI surveillance have not been performed. Insufficient evidence exists justifying the use of CT scanning or MRI for surveillance. Screening for bone metastases Compared with some other common neoplasms, melanoma does not spread to bones as often as to other distant sites. A study on the value of bone scintigraphy showed 7 of 116 scintigrams were abnormal, but none
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because of melanoma [27]. One patient who had a normal image had bone metastases. Relevance of laboratory tests Laboratory studies of blood are often performed as part of routine surveillance and are recommended by some experts [17,34]. Studies have shown simple laboratory tests, such as a blood count, blood chemistry panel, and liver enzymes, are useless in the detection of recurrences [8,16,18,25,27–29]. False-positive test results will lead to other futile tests [29]. Serum lactate dehydrogenase has prognostic relevance and is now incorporated in the staging classification for stage IV, but the value of this enzyme in routine follow-up seems limited. Few blood tests have been designed to specifically detect melanoma. Neuron-specific enolase is a glycolysis enzyme specific for cells derived from the neuroectoderm, such as melanocytes. This enzyme has a sensitivity of 27% and a specificity of 70% [35]. Lipid-bound sialic acid has a sensitivity of 65% and a specificity of 76% [35]. The S-100 protein is produced by melanoma cells and used as tumor marker. The value of S-100 was evaluated in a group of 141 patients followed for 15 months after undergoing surgery for a clinically localized melanoma [36]. Seven of these patients experienced a recurrence. In six patients, the increased S-100 preceded the detection of the metastases location by 4 to 21 months. In a group of patients who had a tumor-free sentinel lymph node, the sensitivity to detect a recurrence was 33% and the specificity 100% [37]. The polymerase chain reaction for melanoma characteristics in the blood has shown potential in identifying patients who are at increased risk [38]. Signs of melanoma may be detectable in the blood after patients undergo treatment for a clinically localized melanoma, but the sensitivity to detect a recurrence was limited (64%) in an initial study [39]. Only few studies have been published of patients who had specific blood tests performed in a surveillance program, and the numbers of patients are small. Whether early detection of recurrence using these tests contributes to an improved prognosis, and false-positive results harm the patients through unnecessary examinations and instigated fear, is unclear. Relevance of follow-up per se Five studies showed that recurrence is usually detected by the patient between office visits [25,27,29,40,41], and three showed the opposite [12,15,42]. Two of these eight studies possibly involve overlapping patient populations, but show different outcomes [25,42]. Some experts believe that more than 90% of the recurrences are now detected by patients and not their doctors because of patient education and self-examination [34].
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These observations cast doubt on whether follow-up is really relevant. Does follow-up lead to an increased probability of survival? No studies on survival are available in which patients were randomized to either follow-up or no follow-up. So, the question can only be answered indirectly. Several points seem to support the argument for follow-up. Lymph node metastases discovered by the patient are on average larger than those discovered by the doctor [41]. Poo-Hwu and colleagues [42] showed that patients who experienced asymptomatic recurrence that is found at the regular follow-up visit have a 5.8% better survival rate after 80 months compared with patients who discovered the recurrence themselves. Concluding from this study that follow-up improves survival is premature for several reasons. This study not only involved patients who had clinically localized melanoma but also patients who had regional involvement. Furthermore, the difference in outcomes could also be explained by a lead-time bias. Another possibility is that metastases identified by the physician have a more protracted growth pattern with a more favorable biology, resulting in a better survival rate (length-time bias). Also, three other studies showed no survival difference when comparing who first spotted the recurrence [15,29,41]. To increase the confusion, a fifth study surprisingly showed that the likelihood of survival is less if recurring tumor activity is discovered by a melanoma specialist [40]. In addition to survival, regional tumor control and quality of life are end points that deserve assessment, but no studies elucidate these aspects. Detection of a subsequent primary melanoma The risk for developing a second primary melanoma is a few percent [8]. The risk for an in situ melanoma is four times as high [5]. A second invasive melanoma usually has more favorable characteristics than the initial lesion [42]. For instance, the Breslow thickness is about half of the first melanoma [8]. Like a recurrence of the original tumor, a new melanoma is often discovered by the patient [27]. Patient education Patients and their family have many questions particularly in the phase after the treatment. They have often received conflicting information from various sources and struggle with the uncertainties associated with the unpredictable disease. They consider the doctor the definitive source of reliable information. Many patients want to know what they can do to detect a new primary melanoma or recurrence in an early phase. Doctors can explain signs of primary melanoma and regional metastases and teach them how to perform self-examination. The dissemination pattern of melanoma is unpredictable and sometimes bizarre. Doctors can explain that a recurrence can take
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many forms. Symptoms that remain for more than a few weeks and cannot be explained unequivocally in another way are reasons to schedule an appointment. Patients’ ability to detect renewed tumor development is inconsistent. Some individuals consistently and correctly identify recurrent metastases that are not yet discernible to the doctor, whereas other patients are unaware of a subcutaneous metastasis 5 cm in size.
Evaluation of results, scientific clinical study Follow-up and well-documented files enable evaluation of diagnosis and treatment results. Follow-up data can be gathered for current or future scientific studies. Few doctors exploit these opportunities, but this article could not have been written without the ones who did.
Discussion Few randomized studies are available examining a survival benefit from imaging studies and laboratory tests. The studies published carry less scientific weight but are numerous, and many involve large groups of patients. These studies indicate that insufficient benefit is gained from imaging and blood testing. Only few patients who have metastases are identified using these techniques, and even fewer survive just because they underwent these tests. A false-positive result most often occurs, which invariably causes unnecessary concern, leads to additional unnecessary testing, and may even result in needless surgery. Ultrasound, tumor markers, and the polymerase chain reaction can possibly improve detection of regional metastases, but this has not been proven. More than other imaging techniques, ultrasound seems to depend on the technical skills and experience of the person who performs the examination. Given the fact that lymph node surveillance is a novel application of this imaging technique, capable radiologists are few. Based on the evidence available, the relevance of follow-up per se must be challenged. The articles reviewed do not provide convincing evidence that regional control, survival, and quality of life improve through surveillance. Even if a study shows that a patient lives longer if a metastasis is detected by the doctor at a routine visit rather than by the patient, that this occurred because of the follow-up would be hard to prove. Interpretation of the data is thwarted by possible lead-time and length-time biases. Whether the sobering conclusions in this article are relevant for today’s patients can be argued. Several of the studies contain many patients who have undergone elective lymph node dissection, a procedure that is not performed anymore. Nowadays, many patients undergo sentinel lymph node biopsy, a new procedure that is not considered in these studies. Another factor is that better imaging techniques, in particular positron emission
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tomography, enable better selection of patients who have distant metastases who have the best prospects for benefitting from aggressive treatment. Physicians should not immediately abolish posttreatment surveillance for several reasons. Cancer patients appreciate being followed-up by their physicians [41]; they generally dread having to go to the doctor but experience relief if no abnormality is found [41,43]. The doctor’s task is not only to pursue a cure but also provide patients with peace of mind. Patients in Great Britain prefer structured follow-up appointments rather than walk-in visits when they have a complaint [41]. A randomized study shows that a structured psychiatric group intervention after 6 weeks improves the prognosis [44]. Keeping options open for evaluation of results and participation in scientific projects are other advantages of structured follow-ups, but these may be insufficient reasons for the average doctor to follow-up with patients. From a scientific viewpoint, the value of follow-up should be determined through a randomized study. One practical problem of a randomized study on follow-up, however, is that it would require a huge number of patients because any differences in end points would likely be small. Patients must also be monitored for many years, and results would not be available for at least 15 years, during which time imaging and new blood tests would be developed. A fundamental problem would be determining the recurrence rate, survival, and incidence of new melanomas and their characteristics in patients not undergoing follow-up. Furthermore, patients may be reluctant to accept a 50% ‘‘risk’’ of being assigned to the arm without follow-up. These problems hinder a successful randomized study. Perhaps a systematic review to collect sufficient circumstantial evidence would be the best method to clarify the value of follow-up. Follow-up became relevant when new Dutch national guidelines on the management of melanoma patients had to be developed. The idea was that patients would be followed in a manner scientifically proven to be beneficial. Review of the available data revealed no scientific evidence that follow-up improves survival, regional tumor control, or quality of life. The obvious conclusion was that follow-up should be abandoned, but the guidelines committee was not prepared to recommend this complete departure from common practice. The scientific evidence conflicted with the intuitive desire of doctors to provide continuing care for their patients. After much deliberation, the committee settled on a compromise wherein patients who have melanoma of Breslow thickness 1 mm or smaller need not be followed. These patients receive sufficient information about their disease and are instructed to perform self-examination. They are counseled regarding the lifetime risk for a second primary melanoma and are guaranteed quick access to their doctor when they perceive a potential recurrence or new melanoma. Patients who have a thicker melanoma and those at increased risk for a second melanoma continue to be followed-up according to the existing system, which does not allow additional routine tests. Although various groups of physicians in the Netherlands that care for patients who have
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melanoma found this recommendation acceptable, the governing body that pushes for science-based guidelines was skeptical of this admittedly halfhearted position. Whether this radical approach will be a huge disaster or forebode the future of follow-up for patients who have cancer remains to be seen.
Summary This article critically evaluates the practice of follow-up for patients who have undergone treatment for a primary melanoma without evidence of metastases. One conclusion from this analysis is that the benefits of routine imaging and blood testing are insufficient to warrant a place in routine follow-up. Few patients who have metastases are identified in this fashion and even fewer survive because they underwent these tests. Far more often, false-positive results occur, which invariably cause unnecessary concern, lead to additional unnecessary testing, and may even result in needless surgery. Based on the evidence available, the relevance of follow-up per se must even be challenged. No convincing evidence exists that regional control, survival, and quality of life improve through surveillance. Other reasons for surveillance may be present, but these are less imperative. The present findings challenge current practice.
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