MELANOMA CRITICAL DEBATES - PART 6 pot

mended. The authors calculated that the cost to detect one metastasis was 9, 20 or 36 times higher when chest radiograph, abdominal ultrasound or both were used, as compared to regular clinical examination. Weiss et al. [3] investigated how recurrence was diagnosed in 145 patients treated in a clinical study. In 99 patients (68%) symptoms signalled the recurrence of disease, and physical examination of asymptomatic patients led to the detection of recurrence in 37 patients (26%). Only nine patients (6%) with recurrent disease had abnormal chest radiographs. A retrospective analysis of 1004 patients with stage I or II malignant melanoma treated at Roswell Park Cancer Institute between 1971 and 1995 analysed impact of method of recurrence detection on survival [5]. Of note in this series only 7% of patients had AJCC pT4 tumours. Constitutional symptoms heralded 17% of 154 recurrences, physical examination 72% (over half patients detected) and chest radiograph 11% (17 patients). Overall survival curves were superimposable for patients who detected their recurrence themselves and those whose recurrence was detected by the physician. Survival was identical in patients whose pulmonary recurrence was picked up by chest radiograph or by symptoms. However, nine of the 17 patients with recurrences detected by chest radiograph alone underwent curative surgical excision with median survival of 24 months from diagnosis of recurrence, compared to 15 months in patients who received chemotherapy for unresectable disease. We estimate that, for the 1004 patients followed up according to protocol for a median of 6.1 years, with 174 recurring at a median of 2.5 years and 830 patients not recurring during reported follow-up, over 10000 chest radiograph investigations would have been performed to detect the 17 recurrences. Although the patient dose from a single chest radiograph is minimal, the cumulative dosage over the study period for say 10 radiographs is not. Unfor- tunately, no information was provided about false-positive chest radiograph results and the follow-up investigations to clarify those further. The risk of recurrence and death from melanoma can be calculated for patients according to the thickness of their primary lesion, and has been reported as a function of time since diagnosis [23–29]. For all melanomas, the risks of first recurrence and death are highest in the first years following excision and fall gradually over the next 10 years. However, a small risk of death from melanoma relapse persists at 10 years for even the thinnest melanomas. Most recurrences are diagnosed by physical examination and the patients can be taught to perform this proficiently themselves [26]. To date there are no prospective studies to assess the use of imaging in follow-up, and so the use of imaging in surveillance will ultimately depend on clinicians’ interpretation of the published retrospective data and available financial resources. The published evidence argues strongly against follow-up imaging of any sort in patients with stage I and II disease. 140 CHAPTER 11 Stage III melanoma Staging Sentinel node dissection (SND) is increasingly used to determine pathological nodal status in patients with intermediate or thick primaries. The rationale of SND is the demonstration of orderly progression of melanoma nodal metastases, coupled with the ability to identify the first draining node using intraoperative lymphatic mapping guided by vital blue dye or radiolymphoscintigraphy. SND is now variously accepted as standard practice in Europe and the USA, but most studies of the value of imaging in stage III patients have included patients that were conventionally staged, rather than by SND. Patients with clinical lymph node involvement by melanoma often have thicker primaries and their risk of harbouring further metastases is substan- tially higher than for stage I and II patients. Buzaid et al. [30] were the first to analyse the value of staging CT scans in patients with lymph node involvement at diagnosis or first recurrence. They reviewed the records of 89 asymptomatic patients with stage III disease and with normal LDH and chest radiograph who underwent staging CTs. A further 10 patients were described who were excluded from analysis based on either symptoms suggestive of distant disease, raised LDH or positive chest radiograph. Overall, even in group of ‘high risk’ patients, the positive predictive value of CT was less than 25%. True-positive findings were seen in six patients, false-positive in 20 and true-negative in 63 patients. Kuvshinoff et al. [31] published the Memorial Sloan Kettering experience with 347 asymptomatic patients, of which 136 had CT scans of chest, abdomen and pelvis. A total of 788 scan results were analysed retrospectively, with 33 (4.3%) confirmed instances of metastatic melanoma and 66 (8.4%) false-positives. Body CT scans further identified five second primaries, four at early stages. When only the patients who had combined scans of chest, abdomen and pelvis were analysed separately, the overall yield was of 11 true- positive scans (8.1%) for melanoma and three for second primaries. When patients with abnormal LDH or chest radiograph were excluded, the diagnostic yield for melanoma was 4.4% (or for melanoma and second primaries 5.9%). Management of nine of 14 patients with positive findings was altered by the CT findings, and in three patients a complete resection of identified tumour was possible. Pertinently, the authors also analysed the diagnostic yield of scans as affected by the location of the primary tumour. Pelvic scans were of no use for primaries above the diaphragm, and the yield of chest scans was lowest for patients with lower extremity primaries and inguinal lymphadenopathy. IMAGING AND INVESTIGATION OF MELANOMA PATIENTS 141 A further study analysed the value of CT in detecting neck node metastases in patients with thin and intermediate thickness head or neck melanoma [32]. Twenty-six patients, of whom 18 had clinically involved lymph nodes, had CT evaluation before undergoing neck dissections. Although the diagnostic accuracy was greater than palpation, in seven patients small nodal metastases were missed on the scan when pathology data were reviewed. Recently, the use of 2-fluoro-2-deoxyglucose (FDG)-PET scanning was reported for detection of melanoma metastases [33,34]. Although access to PET is at present limited, it is a promising tool in staging of melanoma which ap- pears to have a higher sensitivity and specificity than CT. Between 1994 and 1996, 100 patients with melanomas thicker than 1.5mm underwent an extensive staging programme [33], consisting of chest radiograph, abdominal ultrasound and high-resolution sonography of regional nodes, CT of chest and abdomen and MRI of the brain, together with whole body PET scans. Overall, sensitivity, specificity and accuracy of PET (91.8, 94.4 and 92.1%, respectively) were significantly higher than for conventional imaging, the other modalities combined (57.5, 45 and 55.7%, respectively). PET was superior in imaging of lymph nodes, abdomen and mediastinum, while CT was superior for definition of lung nodules. The authors concluded that a single PET scan would replace all other conventional imaging techniques for staging malignant melanoma. One reason for the superiority of PET is that metabolic changes often precede morphological changes, and foci of melanoma smaller than the threshold above which disease is considered present on CT already are visualized by PET imaging. Superior sensitivity (94.2%) and specificity (83.3%) for PET scans compared to CT (55.3 and 84.4%, respectively) is also claimed by another group [34], who indicated 5mm as the threshold of detection melanoma size. FDG-PET staging of regional lymph nodes prior to SND was investigated. In contrast to an earlier report [35], Wagner et al. [36] claimed that PET was an insensitive indicator of occult nodal disease in 70 patients when compared to histological results of SND and clinical course. Sensitivity was merely 16.7%, with median tumour volume of 4.3mm 3 . However, specificity was very good (95.8%), which may be of relevance in those centres where SND is not routinely performed, as this makes FDG-PET still the most accurate non- invasive method of lymph node assessment. Surveillance Patients with AJCC stage III melanoma have a chance of relapse of approxi- mately two-thirds, with two-thirds of those occurring at distant sites [37]. Furthermore, the majority of relapses occur early. Surveillance practice varies widely [2] and involves use of chest radiograph, CT of chest, abdomen, pelvis 142 CHAPTER 11 and brain or MRI. There may be benefits in early detection of recurrence, and preliminary reports on earlier identification of relapse in high-risk patients followed up by PET scans than conventional imaging are encouraging. It is to be hoped that prospective randomized studies evaluating clinical and survival impact of PET surveillance compared to conventional follow-up will be forthcoming. Stage IV melanoma Staging and response assessment As curative approaches to patients with extensive melanoma spread are lack- ing, for some patients receiving conventional treatment assessment by chest radiograph or abdominal ultrasound may be sufficient. Differential responses are rare, and extrapolation of response in the imaged metastases to the others is reasonable. For monitoring of response, reproducibility is of key importance, and thus repeat imaging should be the same as initial evaluation. More extensive imaging may be required for patients treated in the context of clinical studies. The ability to examine large tissue volumes rapidly and reproducibly makes CT the preferred option. MRI may be useful as a problem solving tool or for specific indications (e.g. cord compression, leptomeningeal metastasis). The role of PET is unclear in patients with evident metastases. For some treatment regimens, toxicity may result from treatment of unsuspected brain metastases. These patients will usually be investigated with contrast enhanced CT of the body and examination of the brain at the end of the body examination suffices to assess metastatic disease. Problem solving by multidisciplinary meeting For most patients the information provided from imaging will confirm the clinical impression of disease activity and extent. For a few there are discrep- ancies or other problems requiring clinicopathoradiological discussion. Such discussion works best within a multidisciplinary team which meets regularly to review problem cases. An understanding of the sites and appearance of melanoma metastases is key to their recognition (e.g. advanced melanoma may spread to uncommon sites, such as spleen and muscle) (Figs 11.2 and 11.3). Familiarity with these patterns avoids investigation for alternative causes. What are the options for dealing with uncertainty? Often the fuller discussion within the multidisciplinary meeting of the clinical problem suffices. As discussed, imaging involves first detection of abnormalities and then their IMAGING AND INVESTIGATION OF MELANOMA PATIENTS 143 characterization. However, the characterization has a clinical context and management impact. Thus, if a lesion is detected which might be metastatic in a patient already committed to systemic chemotherapy, its characterization would not alter management. However, its characterization is important to determine context; would such treatment be in an adjuvant or metastatic setting? Definitive characterization requires histological analysis following surgical excision or image guided biopsy. Only a positive biopsy result is reliable, as sampling error as well as technical failure may result in false-negative findings. In certain circumstances, addition of another imaging test may be diagnostic. In staging it is usual to use the best and most rapid methods for detection and characterization of metastatic disease but there is a compromise to be reached between using many specialized tests or a single multipurpose examination (e.g. CT). MRI is a valuable supplementary test for melanoma metastases as they may have characteristic high signal on T1-weighted images (Fig. 11.4). 144 CHAPTER 11 Fig. 11.2 Contrast enhanced upper abdominal CT showing splenic metastases (arrows). Fig. 11.3 Contrast enhanced pelvic CT showing left inguinal nodal metastases (arrows) and unsuspected bilateral buttock metastases. If the nature of abnormalities cannot be ascertained by any of these methods — or if biopsy is considered too invasive — the other option is a wait and watch policy. This is particularly suitable when a patient is asymptomatic or when active management would not be prejudiced by a delay in characterization — during which interval the lesion may grow or others may appear. Small pulmonary nodules can cause problems of characterization for CT (Fig. 11.5) as well as chest radiography. Other common indeterminate lesions are subcentimetre liver nodules which could represent benign entities (cyst, haemangioma) and adrenal nodules. Recommendations for use of imaging in melanoma patients For patients not treated or followed up in the context of clinical trials, imaging IMAGING AND INVESTIGATION OF MELANOMA PATIENTS 145 Fig. 11.4 (a) Contrast enhanced upper abdominal CT showing hyperdense liver metastases (arrows); and (b) contemporaneous T1-weighted MRI of the liver at a similar level showing high signal change within these and additional lesions not seen with CT. Diagnosis: melanoma metastases in a patient with a previous breast cancer and melanoma. (a) (b) protocols should be based on the prevalence of metastases in the correspond- ing risk group, based on pathological criteria for the primary lesion and in- transit, satellite and locoregional lymph node metastases (Table 11.1). There are few prospective trials that allow estimates of sensitivity and specificity of imaging modalities in the various risk groups, and these are urgently needed. In the past, increasing availability and perceived higher sensitivity of newer imaging techniques led to their use in many patients with melanoma in the absence of any evidence that they improve staging and outcome in early stage melanoma. There is little evidence to support use of any radiological investigations in patients with thin melanoma. For stage I and IIA melanomas (primary tumours <4mm thickness), chest radiograph and CT scans have a poor ratio of true-positive:false-positive findings. Stage I patients do not benefit from any form of imaging for staging, while use of chest radiograph and 146 CHAPTER 11 Fig. 11.5 Lung CT showing: (a) indeterminate subpleural nodules; and (b) after 2 months of observation showing an increase in the size and number of nodules suggesting metastatic disease. (a) (b) CT scans for stage II is controversial and both diagnostic accuracy and yield are poor. We thus recommend that these patients have a baseline chest radiograph only, against which future suspected relapse can be assessed. Occa- sionally, clear-cut pulmonary metastases will be revealed. More likely, indeterminate nodules will be found and will require a repeat radiograph in 2–3 months. Patients with melanomas thicker than 4mm (stage IIB) have a higher risk of subclinical metastases. There are thus grounds to investigate them similarly to clinical stage III but at present principally in the context of clinical trials. More data are required on the use of imaging in staging and surveillance of stage IIB disease. For asymptomatic stage III patients with normal baseline blood tests, chest radiograph and CT tailored to the primary site seem warranted, given that these investigations will pick up clinically occult disease in 10–20% of patients. This is the group of patients who may be offered adjuvant interferon therapy, a toxic and expensive treatment, justifying the need to exclude metastatic disease. PET scans, where available, may be a better tool than CT for staging and surveillance in these high-risk patients. Choice of imaging modality in patients with distant metastases will be in- formed by the goals of treatment, either radical or palliative. IMAGING AND INVESTIGATION OF MELANOMA PATIENTS 147 Table 11.1 Practical recommendations for initial staging investigations Stage Location of primary tumour Recommendation I, IIA Any Chest radiograph as baseline If abnormal repeat in 2–3 months. 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