Вашему вниманию предлагается Новостное Письмо от Президента The Melanoma World Society (MWS) профессора Клауса Гарбе, известного международного авторитета и клинициста в области диагностики и лечения меланомы.
Сама Организация была зарегистрирована совсем недавно и является преемницей старейшей международной экспертной группы ВОЗ известной как WHO Melanoma Programme, которая на протяжении почти сорока лет осуществляла координацию всех усилий в борьбе с этим грозным и коварным заболеванием.
Профессор Гарбе обратился ко мне с предложением разместить на нашем сайте данный новостной материал в качестве информации к размышлению относительно перспектив в области ранней диагностики и лечения различных форм меланомы ( не только ее кожной и самой частой формы, но также меланомы хориоидеи и слизистых).
Предполагается выпуск подобных Новостных Писем на постоянной основе с тем чтобы обсуждать быстро меняющиеся взгляды на приоритетные направления и доводить эти изменения и тенденции до широкого круга онкологов,
вовлеченных в современные проблемы меланомы.
Данный материал размещен в своем оригинальном англоязычном варианте. Однако, принимая во внимание тот факт что в нашей профессиональной среде русский язык продолжает оставаться приоритетным, мы планируем далее оригинальный текст сопровождать адаптированным переводом.
Профессор Л. В. Демидов
Председатель Правления Ассоциации специалистов
по проблеме меланомы
Член экспертного совета
The Melanoma World Society (MWS)
Skin Cancer Screening by Smartphones - Nature, January 2017
Claus Garbe, University Department of Dermatology, Tuebingen, Germany
Artificial intelligence can already solve many problems, and computer programs are able to beat the best chess players of the world. We even recently got to know that the best poker players have been beaten by computer algorithms. Why shouldn’t it not be possible to recognize skin cancers, particularly melanoma and also keratinocyte cancers, which are diagnosed by their visual characteristics either with the naked eye or with magnification by dermatoscopy.
Since two decades worked dermatological research groups, mainly in Germany, Austria and Italy, to develop diagnostic devices for melanoma. Several algorithms were developed and also sold on the dermatology market. These computer algorithms were integrated into devices for computer-dermatoscopy, and used by dermatologists in order to improve their diagnostic performance. The algorithms were based on logistic regression analysis or on neuronal networks utilizing image algebra. These computer programs developed already a high diagnostic performance comparable to that of dermatologists. However, these programs were mostly not trained to distinguish seborrheic keratoses from melanocytic lesions and they were not developed for the use of laypersons.
The New Breakthrough
Now seemingly a breakthrough in this field has been achieved. Sebastian Thrun, an adjunct professor in the Stanford Artificial Intelligence Laboratory developed with his coworkers André Esteva and Brett Kuprel in the Thrun laboratories together with dermatologists from the Pigmented Lesion and Melanoma Program at the Stanford Cancer Institute a new algorithm for the diagnosis of skin cancer. It was essential for this project to build large collections of pictures from skin cancer, in the end, the Stanford project group succeeded to collect about 130,000 images of skin lesions representing different disease entities. They started with an algorithm developed by Google that was able to identify more than 1 million images from 1000 object categories. Among these, the program was able to differentiate pictures of cats from those of dogs. The algorithm had been tested in comparison to the diagnostic performance of 21 dermatologists.
Three main key diagnostic tasks were approached: The classification of keratinocyte carcinomas, the classification of melanomas by macroscopic and dermatoscopic pictures. In these three tasks the algorithm matched the performance of the dermatologists. Correct diagnoses were achieved in ~ 90% of the lesions. The results have been published in a research letter in Nature at January 25, 2017 (Esteva et al., 2017).
This is now the breakthrough for diagnostic algorithms, which can be transferred to devices with ability to analyze smartphone pictures. A number of questions have probably still to be solved, like a kind of standardization of photography, and also the marketing strategy for such an offer in healthcare. Nevertheless, there are few doubts that such a diagnostic algorithm may be a perfect precondition for new forms of skin cancer screening. What does this mean for dermatologists? Will they become needless? Probably we have to expect the contrary outcome: Laypersons using such computer programs will have urgent needs for explanation and management of their suspected skin cancer lesions! In conclusion, let us support the development of such computer programs beating the diagnostic performance of dermatologists. Esteva A, Kuprel B, Novoa RA, Ko J, Swetter SM, Blau HM, et al. Dermatologist-level classification of skin cancer with deep neural networks. Nature 2017;542(7639):115-8.
Skin Cancer Screening by Smartphones - Nature, January 2017 – Comment by Iris Zalaudek Iris Zalaudek
University Department of Dermatology, Graz, Austria, President of the International Dermoscopy Society
Who in the age between 40 to 60+ did not watch Star Track in television? And those who did, remember certainly the Tricorder (tri-function-recorder) of Dr. McCoy, a portable instrument able to measure several vital parameters and even making a specific diagnosis. What sounded like a science-fiction in the 70 and 80ies becomes reality in the 21st century. According to the study published in this January issue in Nature, we seem to move away from an era of human skin imaging and diagnosis to an era of computerized skin imaging and diagnosis in skin cancer detection. So will artificial intelligence and smart phone devices or apps substitute the human dermatologist in the future? This is one of the “fear” key questions that both, clinicians as well as researchers try to answer. I admit, I do not have a definitive answer, but let us look at the data from two different – pro and cons - view points: The data promise quite good news for all, the patients, the dermatologists, and for research in general: First, if mobile devices will allow an accurate diagnosis, we might be able to better triage patients requiring medical action. We might be able to reduce waiting time and provide immediate adequate treatment.
Second, if mobile devices do equally good or even better than dermatologists, we move a big step forward in improving medical care for remote geographic areas where a dermatologist is not available. Third, we will gain enormous amounts of data in very little time, aiding to move forward other research and developments in both human and computer research. Fourth, mobile devices may also function as teaching tools: Users might receive useful information or even may improve their own diagnostic capacities in skin cancer recognition. On the other hand, there is even a longer list of unsolved problems that need to be ad-dressed: First, machines will be just as good as the data (currently created by humans) they are provided with. We all know the problem related to so-called grey zone lesions, which accurate diagnosis is challenging, if sometimes only possible in retrospect. This means there is no 100% accuracy in medicine and this is currently true also for artificial intelligence. Second, some melanomas cannot be detected at baseline but just due to changes over time (i.e., by digital dermoscopic monitoring). Accordingly, new technology will requires to learn also assessment over time. Third, while good dermoscopists recognize almost 95% of skin cancers in their daily routine, about 10% of suspicious lesions are just diagnosed by applying management rules. Also this is an issue that requires further research. My believe is that that artificial intelligence and future apps will not substitute a dermatologist but they may move dermatologists into another gate keeper role in the whole process from diagnosis to treatment. Finally, it is amazing to notice that although research groups developed the idea of computerized skin cancer diagnosis about 2 decades ago, these first technology pioneers were hampered by the available technology of that time. Now it seems that time has come for artificial intelligence to follow a humans’ brain vision.
Age and Metastatic Potential - NEJM, August 2016
Iris Zalaudek, University Department of Dermatology, Graz, Austria,
The Spectrum of Melanomas
It is well known that the term melanoma stands as umbrella for a different spectrum of malignant melanocytic tumors that differ significantly in relation to their morphology, epidemiology, growth patterns and genetic signature. Testing for mutations in BRAF, NRAS and c-KIT are nowadays standard for the treatment choice of advanced melanoma. However, despite the enormous progresses in the treatment of metastatic melanoma, there are still patients that do not respond to any of the targeted, immuno- or cytotoxic therapies. The article by Claudia Wellbrock picks up a novel and intriguing view on this problem as it focusses on the age-dependent changes of the microenvironment and melanoma progression.(Wellbrock, 2016)
Aging, Oxidative Stress and Metastasis
In her commentary, Claudia Wellbrock highlights the possible clinical implications of a recent study by Kaur et al, who demonstrated that fibroblasts from young individuals protect melanocytes (as well as melanoma cells) better from oxidative stress than fibroblasts of older persons.(Kaur et al., 2016) In particular, it has been shown that BRAF V600E mutated melanoma cells, which are injected into older mice with an aging environment, grow more slowly, produce smaller tumors, but have a higher metastatic potential than cells growing in young mice. A similar observation was made by human fibroblasts in a 3D model. Moreover, the authors tested whether age was associated with response to BRAF-targeted therapy in a small cohort of patients. They found that response to therapy was significantly different between patients aged 65+ years and the ones aged 65- years. Clinical studies indeed support that older persons express lower levels of oxidative-stress regulators and higher expression of DNA-damage markers in their serum than younger patients.
Although the clinical relevance of these findings still to be determined, the exploration of oxidative-stress regulators as potential biomarkers for response or the role of anti-oxidants to enhance response to various treatments is certainly worth to be investigated in future clinical research. Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH, 3rd, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 2016;532(7598):250-4. Wellbrock C. Melanoma and the Microenvironment--Age Matters. The New England journal of medicine 2016;375(7):696-8.
Adjuvant Melanoma Therapy with Ipililumab Improves Overall Survival – NEJM, October 2016
Claus Garbe, University Department of Dermatology, Tuebingen, Germany,
Adjuvant Treatment of Melanoma
There have been numerous studies performed for the adjuvant treatment of melanoma with chemotherapeutic drugs and also with unspecific immune stimulants like BCG, GM-CSF and other compounds without any positive results. Interferon-alpha has been established as an adjuvant treatment in high-risk melanomas with a rather low efficacy. In the US, a high dose schedule with a very high-dose induction phase of one month and a high-dose maintenance phase for another 11 months was approved by the FDA. This schedule has been likewise approved for Europe and, additionally, a low dose schedule for 18 months was approved in Europe. In most countries in Europe, only the low dose schedule is still offered to patients. In some European countries systemic treatment of melanoma is done by medical oncologists and still high dose interferon is offered in countries like Spain, Italy etc..
Adjuvant Treatment with Ipilimumab
The EORTC 18071 phase III trial evaluated ipilimumab as adjuvant therapy for patients with high risk stage III melanoma. 951 patients were randomized to ipilimumab or placebo. First results were already reported in 2015, the study found a significant benefit for primary endpoints of improving recurrence-free-survival after median follow-up of 2.3 years (Eggermont et al, 2015). The drug was subsequently approved by the US Food & Drug Administration as adjuvant therapy for stage III melanoma. Now, after a median follow-up of 5.3 years, the impact on overall survival is reported and represented 28% reduction of the relative risk of death (Hazard ratio 0.72, p= 0.001). The overallsurvival rate at 5 years was 11% higher in the ipilimumab arm (65%) than in the placebo arm (54%)(Eggermont et al, 2016). Five therapy associated deaths were already reported in the first publication. Now, 40% of patients developed grade III-IV adverse events most frequently gastrointestinal (16%) hepatic (11%) and endocrine (8%). These adverse events were managed by immune suppressive treatments and usually resolved within 4-8 weeks. Endocrine adverse events required usually permanent hormonal replacement therapies.
The EORTC 18071 study showed for the first time that checkpoint blockade is an effective treatment for the adjuvant therapy of melanoma. The survival benefit is clearly better than ever achieved with interferons. Therefore, introduction of such a treatment into the management of melanoma would have been expected.
However, there are several obstacles. First, the toxicity was substantial. It is further questionable whether the long treatment period is really justified. Given the fact, that only 42% of patients received one or more dosages beyond the induction phase and that only 29% went beyond one year of treatment, the question arises whether the induction phase would be sufficient for the adjuvant effect.
Secondly, the pricing for such a therapy is not yet defined.(Eggermont, 2016) Ipilimumab is dosed in the treatment of distant metastases with 3mg/kg bodyweight and 200mg costs 15,659 € and additional 50mg 3,958 € (German market). Thus, four cycles of treatment with a total of 12mg/kg bodyweight will cost between 64,000 and 80,000 €. In the EORTC trial patients received infusions of 10mg/kg bodyweight ipilimumab four times for the initiation phase and then every three months for up to 3 years. These are 15 doses of 10mg/kg bodyweight and sum up to 150mg/kg bodyweight.
That means, the price would be 12-times higher than for the treatment in stage IV disease. As a recent trial comparing 3mg and 10mg ipilimumab in the setting of stage IV disease showed a superiority of the higher dosage.(Ascierto et al., 2016) Therefore, it is questionable whether the survival benefit with adjuvant ipilimumab treatment can also be achieved by a lower dosage. Thus, changing to the lower dosage of 4 x 3mg/kg bodyweight cannot be recommended. Other adjuvant trials are on the way and programed cell death inhibitors (PD-1) are already tested in the adjuvant setting. There are two trials evaluating the adjuvant benefit of PD-1- inhibitors and both of these trials have reached full accrual.
One trial is comparing nivolumab with ipilimumab and the other trial is comparing pembrolizumab with placebo. The results are already expected in 2018. Therefore, probably the adjuvant treatment with ipilimumab may not be further developed and the results of adjuvant PD-1-inhibitors are awaited.
Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Arance Fernandez M, et al. Overall survival and safety results from a phase 3 trial of ipilimumab at 3 mg/kg vs. 10 mg/kg in patients with metastatic melanoma. Ann Oncol 2016;27(Suppl. 6). abstract1106O. Eggermont AM. Adjuvant ipilimumab in stage III melanoma: New landscape, new questions. European journal of cancer (Oxford, England : 1990) 2016;69:39-42. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. The New England journal of medicine 2016;375(19):1845-55. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. The Lancet Oncology 2015;16(5):522-30.
Mucosal Melanoma: Checkpoint Inhibition as the new treatment standard? – JCO, January 2017
Axel Hauschild, University Department of Dermatology, Kiel,
Systemic treatment of metastatic mucosal melanoma
The treatment of mucosal melanomas is still a dilemma. Although in roughly 15% of patients with mucosal melanomas treatment-relevant mutations (CKIT and BRAF) have been identified, only a minority of them will have a significant benefit from a targeted therapy. The recent clinical studies on CKIT inhibitors like imatinib, nilotinib or dasatinib remained disappointing. The response rate is in a range of 15-25% with mainly short-lasting responses and no clear impact on overall survival. Therefore, targeted therapies for mucosal melanomas remain as a suitable option, but a treatment with better efficacy is highly appreciated.
Systemic Treatment with Nivolumab alone or in Combination with Ipilimumab
Pooled data from 889 patients, who received nivolumab alone, and 361 patients, with combined nivolumab and ipilimumab, revealed a total of 121 patients (10%), who were suffering from mucosal melanomas.(D'Angelo et al., 2017)
Among these mucosal melanoma patients the median PFS (progression-free survival) with nivolumab single-agent treatment was 3.0 months compared to 6.2 months for cutaneous melanomas. The corresponding response rates were 23% (mucosal melanomas) and 40.9% (cutaneous melanomas). For the combination of the two checkpoint inhibitors nivolumab (PD1 antibody) and ipilimumab (CTLA-4 antibody) the median PFS was longer (11.7 months versus 5.9 months), too. Also, the objective response rate was 37.1% compared to 60.4% in favor of the combination. There were no obvious differences in the toxicity, when patients with mucosal and cutaneous melanomas have been treated. As expected, the number of CTC grade 3/4 treatment-related adverse events with nivolumab alone was relatively low (8.1% for mucosal and 12.5% for cutaneous melanomas, respectively) and relatively high for the combined schedule (40.0% versus 54.9%).
The authors concluded that this is the largest analysis of anti PD1 antibody treatment data in mucosal melanomas so far. The efficacy of the combined schedule seems to be greater than either agent alone. However, the efficacy in mucosal melanomas is much lower than in cutaneous melanomas. No differences in the safety profile became apparent.
The publication of D´Angelo and co-workers on the pooled analysis on nivolumab-based treatment regimens showed a promising response rate and median PFS for nivolumab alone and for the immunotherapy combination. Although it is not a randomized trial comparing headto-head nivolumab to the combination of nivolumab and ipilimumab and other drugs like TKIs, this is an early evidence about the superiority of immunotherapy over targeted therapies in these extracutaneous melanomas.
Although this is promising for our patients with mucosal melanomas of all origins, we need to wait for overall survival data. Before they are mature, it is too early to speculate about new standards of care and a significant improvement in the overall survival of this dismal disease. An early diagnosis of mucosal melanomas by all involved medical specialties, an aggressive surgery of the primary tumor, and adjuvant irradiation remain essential. Chemotherapy showed almost no efficacy as ipilimumab alone. PD1 antibodies with or without ipilimumab could become standard of care for advanced local mucosal melanomas and metastatic disease in the near future.
D'Angelo SP, Larkin J, Sosman JA, Lebbe C, Brady B, Neyns B, et al. Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017;35(2):226-35.
Checkpoint inhibition in uveal melanoma: poor outcome – Acta Oncol. January 2017
Claus Garbe, University Department of Dermatology, Tuebingen, Germany,
Uveal melanomas occur in more or less the same incidence in the different ethnical human populations, in Caucasians, Asians, Africans etc. They are rare tumors, but their incidence is increasing with age and we see increasing numbers of metastatic melanoma patients deriving from uveal melanomas. Hereditary predispositions may play a role for the development of these tumors. No other causes of carcinogenesis for these tumors are known. There are some characteristic chromosomal abnormalities in uveal melanomas.
The most common is monosomy 3 in ~ 50% of uveal melanomas which is associated with metastatic disease. Common mutations in uveal melanomas are GNAQ und GNA-11, both activating the MAP kinase pathway. So far, there are no inhibitors for these mutations available.
Treatment of Metastatic Uveal Melanoma with PD-1 and CTLA-4 antibodies
In January 2017, a report about anti-PD-1 treatment in metastatic uveal melanoma was published by Dutch cancer centers. They evaluated a series of 17 patients treated either with pembrolizumab or with nivolumab and they did not observe a single objective response. Two of 17 patients showed a stable disease over four treatment cycles.(van der Kooij et al., 2017) This is close to the results of treatment with ipilimumab. A phase II DeCOG study in 53 patients with metastatic uveal melanoma found not a single, partial or complete response. Some patients were testified as stable disease, but also this was short lasting.(Zimmer et al., 2015) Thus, obviously treatment results from cutaneous melanoma cannot be transferred to ocular melanoma.
Presently, no systemic therapy is available in order to prolong survival in metastatic uveal melanoma. As an alternative, local treatments of liver metastases like radiofrequency ablation, transarterial chemoembolization and chemosaturation are chosen as a therapeutic alternative. However, it is noteworthy to state that none of these local treatments was ever shown to prolong overall survival. Thus, the present reality is we do not have effective treatments for uveal melanoma. In the age of great progress of immunotherapy of cutaneous melanoma, treatment strategies for ocular have still to be developed. There is not yet any progress in the treatment of ocular melanoma. We should proceed to larger international studies for these rare tumors.
van der Kooij MK, Joosse A, Speetjens FM, Hospers GA, Bisschop C, de Groot JW, et al. AntiPD1 treatment in metastatic uveal melanoma in the Netherlands. Acta oncologica (Stockholm, Sweden) 2017;56(1):101-3. Zimmer L, Vaubel J, Mohr P, Hauschild A, Utikal J, Simon J, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naive patients with metastatic uveal melanoma. PloS one 2015;10(3):e0118564.