Citation for published version (APA): Francken, A. B. (2007). Primary and metastatic melanoma: aspects of follow-up and staging s.n.

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1 University of Groningen Primary and metastatic melanoma Francken, Anne Brecht IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Francken, A. B. (2007). Primary and metastatic melanoma: aspects of follow-up and staging s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

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4 Future perspectives Future perspectives As described in this thesis, to optimize the follow-up regimen for melanoma patients we need be informed with respect to the current value of follow-up visits. Although it has been shown that the value of follow-up is limited in terms of survival, there might still be gain in optimizing patient education and society awareness. By improving pathologic staging of the primary melanoma we can enhance prognostic prediction of recurrent disease and survival, which might help us to determine an optimal follow-up regimen. More accurate diagnosis and staging of the metastatic melanoma is feasible with the use of diagnostic modalities as described in this thesis. The following paragraph describes aspects of currently ongoing research and future research in the development of new follow-up guidelines, and also the development of diagnostic devices and strategies of primary and metastatic melanoma staging. The follow-up of melanoma patients Melfo Study In future research the optimal follow-up of melanoma patients needs to be determined, preferably by prospectively randomised controlled research. The Melfo study is a new study for which the protocol was developed at the University Medical Center of Groningen and the University of Groningen (Francken et al., appendix) to investigate the consequences of a reduction of follow-up consultations, based on the calculated chance of recurrence or second primary detection. 1 The study was developed to compare patients in an experimental follow-up schedule, according to the schedule mentioned in Chapter 5 of this thesis, with patients following a conventional follow-up schedule. Differences are to be determined in patients well-being, expressed in health related quality of life, level of anxiety and satisfaction with the follow-up schedule and in the ability to detect recurrences and second primary melanomas. The primary outcome of this study is patient s wellbeing as assessed by several questionnaires. Secondary outcomes are 1. the type of recurrence 2. the person detecting the recurrences 3. the exact method of detection 4. the extent of disease at the time of detection of the first recurrence, recorded as early or late-detected. The experimental follow-up schedule (as defined in chapter 5 of this thesis) results in a 33% reduction of follow-up visits compared with the conventional followup schedule and is derived from the annual risk of recurrence development. The conventional follow-up schedule is derived from the recently developed guidelines 193

5 of the Dutch Melanoma Working Party. Both schedules will be compared in a prospective randomised trial. The final outcome of the study will be determined after a minimum of five years of follow-up surveillance. Patients well-being will be measured at 0, 6, 12, 24, 36, 48 and 60 months after primary diagnosis and inclusion and will be expressed in the health related quality of life (RAND-36), anxiety (STAI- DY), Cancer worry scale and Follow-up satisfaction questionnaires. Primary melanoma staging In 2002 the new American Joint Committee on Cancer staging system was introduced and proposed Breslow tumour thickness and ulceration as the key factors in the prognostic staging system for patients with localized disease. Tumour mitotic rate was not included in the system. Also lymph node staging was newly introduced, and particularly sentinel lymph node biopsy (SLNB), which is now broadly accepted as a sensitive staging procedure. By using this technique we are able to identify not only tumour positive lymph nodes, but also micro-metastases and molecular metastases, the prognostic value of which have not been clarified yet. The third interim analysis of the Multicentre Sentinel Lymph node Trial (MSLT) was published in In this trial observation of the nodal basin and delayed complete lymph node dissection was compared with a SLNB procedure, followed by complete lymph node dissection if the SLNB was found positive. 2 The authors found no survival advantage for patients who underwent SLNB. However, a longer disease-free interval was found for the SLNB patients with intermediate thickness melanoma. The MSLT II is currently under way. In this second trial patients with a SLNB positive result are randomised between complete lymph node dissection and observation of the nodal basin without complete lymph node dissection. 3 In general practice we still query the value of systematic lymph node ultrasonography. The technique is found to be much more sensitive than simple clinical palpation of the lymph node field. However, its influence on survival is not clear and therefore its routine use in follow-up has been questioned. 4 Lymph node ultrasonography might play an extensive role in the future if observation rather than a completion node dissection follows a positive SNLB. Futher research is still needed to determine its role and value. Although the AJCC staging system is sufficient and widely used, we are still searching for more specific and sensitive tests to identify patients at particular risk for recurrence or limited survival. Tumour markers in the serum of melanoma patients may play a role in clinical diagnosis and in prognosis, and also in monitoring of the patients disease and response to therapy. However, the serum markers currently available for melanoma have only limited clinical use. Most widely used in clinical applications are S100-beta, melanoma inhibitory activity (MIA), and 194

6 Future perspectives lactate dehydrogenase (LDH); there are close correlations between the serum concentrations of these markers and tumour load. Regular determination of S100- beta and MIA levels during follow-up can therefore be used for early detection of a tumour relapse in melanoma patients, increased serum concentrations being indicative of tumour growth. However, in terms of early detection, only a minority of the patients can be surgically resected to a disease free status. The majority will be diagnosed with wide-spread disease, when no curative systemic treatment available. Patients with distant metastases from melanoma who present with elevated serum levels of S100-beta, MIA, or LDH have poorer overall survival than patients whose serum concentrations are within normal ranges. These three markers can also be used to monitor the course of disease and therapy outcome in patients with distant metastases. Since there are no marker proteins for melanoma that are not dependent on tumour load, it is currently not possible to forecast the survival of patients who are tumour free after surgery. Serum markers are also not found to be suitable for screening or for the diagnosis of primary melanomas. 5,6 Next to serum tumour markers there is a relatively new and upcoming field in melanoma research involving the definition of genetic aberration. Genetic mutations are responsible for the development of neoplastic potential in a number of malignancies. These DNA alterations result in significant changes in gene expression that can now be determined and catalogued. The microarray technique screens and identifies expressed genes that may be responsible for tumour genesis. 7 The microarray technique is in its initial development for clinical application in a variety of tumour models. The research on micro-arrays in the field of melanoma is still premature, but might be an ideal system to study the genetic changes associated with the stepwise progression of malignancy. It may be possible to efficiently screen the entire human genome to identify the particular aberrations in gene expression responsible for tumour genesis in melanoma. This technique might play a role in the future in the identification of patients with a particular prognostic profile. Metastatic melanoma staging Imaging studies represent a major component of the staging work-up of melanoma patients. Many techniques are used to facilitate preoperative planning and intraoperative management. Study benefits are not clear, and evidence does not support any particular protocol for their use. Developments in imaging technology are moving forward extremely fast. As a result, clinical diagnostic studies are out of date once results are released. Particular interest has been focused on Positron Emisson Tomography in the last decade, but has been elipsed by the development 195

7 of PET-CT scanning which is now widely used. The exact indications for the latter in melanoma management have yet to be defined. 8 Another diagnostic technique in the nuclear physics field is the Single Positron Emission Tomography (SPECT), ideally combined with CT scanning. This technique is still in its infancy, but initial results are promising and its use might particularly be interesting in the field of detecting sentinel lymph nodes. 9 Adjuvant therapies Adjuvant radiation treatment following lymph node dissection in melanoma patients has been suggested and investigated in an attempt to gain regional control and improve survival. From retrospective studies, adjuvant radiotherapy after lymph node dissection for metastases of melanoma seems to improve locoregional control without improving overall survival. 10 However, the true value of adjuvant radiation therapy has yet to be defined. Currently, a randomised clinical trial is under way to determine the role of adjuvant radiation therapy in Stage III and IV melanoma patients. 11 In recent decades several different chemotherapy regimens have been studied in the hope of improving the poor survival of AJCC Stage IV melanoma patients. Unfortunately, all of these regimens, of which dacarbazine is the most widely used, show low response rates without any survival benefit. Also immunotherapy studied in the nineties showed promising results initially. However, several randomised controlled trials that followed, showed no benefits of adjuvant immunotherapy, such as interferon. 12,13 New approaches are being developed continuously. Some of them are thought to be potentially effective, targeting newly discovered pathways in the disease. Most advanced of these agents is probably sorafenib (BAY , Nexavar TM ), acting as a RAF kinase and VEGFR inhibitor. It has also been found to have activity against the oncogenic B-RAF and to induce apoptosis. This agent has shown promising results in phase I trials and is now being extensively tested in phase II and III trials. 14

8 Future perspectives References 1. Francken AB, Bastiaannet E, Hoekstra-Weebers J.E.H.M., Schaapveld M., Hoekstra HJ. MELFO: Prospective Randomized Trial for the Evaluation of a Theoretical Follow-up schedule in Cutaneous Melanoma Patients Ref Type: Internet Communication 2. Morton DL, Thompson JF, Cochran AJ et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 2006; 355: Morton DL. Sentinel node mapping and an International Sentinel Node Society: current issues and future directions. Ann Surg Oncol 2004; 11:137S-143S. 4. Bafounta ML, Beauchet A, Chagnon S et al. Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis. Lancet Oncol 2004; 5: Ugurel S. [Serum markers for melanoma]. Hautarzt 2005; 56: Smit LH, 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: Kim CJ, Reintgen DS, Yeatman TJ. The promise of microarray technology in melanoma care. Cancer Control 2002; 9: von Schulthess GK, Steinert HC, Hany TF. Integrated PET/CT: current applications and future directions. Radiology 2006; 238: Belhocine TZ, Scott AM, Even-Sapir E et al. Role of nuclear medicine in the management of cutaneous malignant melanoma. J Nucl Med 2006; 47: Bastiaannet E, Beukema JC, Hoekstra HJ. Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications. Cancer Treat Rev 2005; 31: Stevens G, Hong A. Radiation therapy in the management of cutaneous melanoma. Surg Oncol Clin N Am 2006; 15: Moschos S, Kirkwood JM. Present role and future potential of type I interferons in adjuvant therapy of high-risk operable melanoma. Cytokine Growth Factor Rev. 2007; 18(5-6): Epub 2007 Aug Eggermont AM, Suciu S, MacKie R et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005; 366(9492): Kasper B, D Hondt V, Vereecken P et al. Novel treatment strategies for malignant melanoma: a new beginning? Crit Rev Oncol Hematol 2007; 62:

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