Акценти от 3-ти ден

Management of difficult to treat carcinomas, Non melanoma skin cancer, Melanoma, Cutaneous lymphoma

Prof. Olivier Dereure

Dermatologist, Montpellier, France

Cases: management of difficult to treat carcinomas

Multiple scalp SCCs in a patient with chronic lymphocytic leukemia

Dr. Chrysalyne D. Schmults (Dermatologist, United States)

Ms Schmults (USA) emphasised the particular and increasingly often occurring problem of recurrent and/or multiple squamous cell carcinoma of the scalp in humans. It primarily spreads locally but can often be dangerous, as it recurs particularly often and is susceptible to acute exacerbations. Its curative surgical treatment proves to be especially delicate because of the frequent infiltration depth and nerve sheath invasion that represent fast pathways for contaminants.

The presence of multiple tumours that appear sequentially but sometimes in close succession clearly illustrates the concept of a cancer field that requires the most comprehensive treatment strategy.

These tumours are all the more dangerous and progressive as they affect immunosuppressed patients, particularly in the context of organ transplantation or underlying hematologic disease (CLL) as well as patients treated with JAK inhibitors with a possible class effect with these molecules. It is therefore crucially important to examine all the margins, particularly using horizontal and not vertical cuts (that are commonly made), which allows for a much more accurate vision of actual margins in all directions.

Interestingly, in these situations, unlike in basal cell carcinomas, Mohs microscopic surgery has not (yet?) really proved to be superior to “standard” wide excision, particularly in terms of relapse. Beyond 10 squamous cell carcinomas of the skin, the speaker recommends to consider the retinoid treatment. The role of the sentinel node in these situations is still very much debated but, for the moment, cannot be highly recommended, as this procedure does not seem to improve the overall evolution of the lesions, which remains essentially local.

Finally, the role of PD-1 suppressor needs to be better defined in adjuvant or neoadjuvant contexts, whereas these molecules have proven their performance in locally advanced or metastatic stages with promising results in recent therapeutic trials. Organ transplant patients, however, represent a very particular case, since the use of immunotherapy clearly correlates with a risk of organ transplant rejection. The risk reaches 50% with a fatal risk in cases of liver, heart or lung transplants in which it is not possible to revert to substitution treatment, such as dialysis.

What is a "difficult to treat" BCC?

Prof. Jean-Jacques Grob (Dermatologist, France)

Jean-Jacques Grob has also attempted to better define the fairly intuitive and pragmatic concept of “difficult to treat” basal cell carcinoma.

The trouble may be related to different factors that depend on the basal cell carcinoma itself (because of its size, number lesions, topography, uncertain clinical limits, certain histological characters) as well as on the patient history (relapse, previous treatments), practitioner and comorbidities.

The TNM staging system is entirely inadequate in these situations. It should be noted that there is also no clear definition of the so-called “locally advanced” basal cell carcinomas, which represent a slightly different situation and should not be confused with difficult to treat basal cell carcinomas.

The latter case is often evaluated intuitively and subjectively, in fact, in a rather cognitive manner and, in order to better standardise situations, particularly in view of epidemiological studies and therapeutic trials, a pragmatic classification system for difficult to treat basal cell carcinomas was developed by a panel of European experts based on the analysis of nearly 200 cases according to a consensual clustering method for cluster identification. Thus, five relatively personalised groups responding to this type of situation have been identified, whose typology can be used by other practitioners. The identification of these situations has resulted in an EADO-supported “operational” classification of basal cell carcinomas in general into six stages: I, IIa, IIb, IIIa, IIIb and IV (metastatic), and it is quite clear that the so-called difficult to treat basal cell carcinomas identified by this classification do not exactly overlap with locally advanced basal cell carcinomas, even if the two concepts can be confused in some situations.

What's new?

What's new in non melanoma skin cancer?

Prof. Brigitte Dréno (Dermatologist, France)

The focus of attention this morning was on the classic and eagerly awaited exercise of “what’s new”, where Brigitte Dréno opened the debate on non-melanoma skin cancer.

With regard to basal cell carcinoma, she mentioned that the meta-analysis comparing the hedgehog, sonidegib and vismodegib signalling pathway inhibitors presents similar response rates and spectrum of side effects but with significantly more complete responses for vismodegib.

With regard to squamous cell carcinomas of the skin, Brigitte Dréno reviewed the different clinical trials with PD-1 inhibitors as well as the predictive factors for aggressiveness that could encourage to use these molecules in adjuvant or neoadjuvant situation in order to limit the risk of subsequent relapse. These aggressiveness criteria are divided into fairly standard and well-known clinical or histological criteria as well as into more innovative criteria, in particular the expression of the inositol phosphate type 1 molecule, with a clear correlation between a weak expression of this molecule and reduced overall survival.

Dréno also discussed the use of PD-1 inhibitors in organ transplant patients with the possibility of using oral prednisone 40 mg/day and sirolimus treatment in these situations.

Finally, she mentioned a number of interesting findings in Merkel cell carcinoma including the long-term results of using pembrolizumab in advanced stages and the fact that there is a correlation between the response and a rather weak viral load and, on the contrary, with a larger number of CD8 lymphocytes present in the tumour, especially when these lymphocytes are not peripheral but well inside the tumour with a good positive predictive value of response in this case. In addition, trials of avelumab show that an early response before 6 or 13 weeks is predictive of prolonged response and overall survival. Other immunological targets will most likely be usable in the future in this terrible tumour to further improve response levels and overall survival.

What's new in melanoma?

Prof. Olivier Michielin (Dermatologist, Switzerland)

Olivier Michielin (Lausanne), who had the difficult task of outlining the current and future challenges of melanoma treatment, chose to focus his presentation on treatment combinations, concentrating on two fundamental issues: improved selection of patients who can truly benefit from combined immunotherapies and better understanding of how to combat primary or secondary resistance mechanisms, in particular, by “turning up the heat” on immunologically “cold” tumours and restoring an interferon-gamma inflammatory signature.

Another unresolved issue is that of the benefit of sequential strategies compared to combined strategies, particularly when it comes to the interest of using combination treatment in case of primary or secondary resistance to a PD-1 inhibitor.

For the speaker, the basis of immunotherapy combinations most likely lies in PD-1 inhibitors that can be associated with multiple elements, such as other checkpoint inhibitors, immune activators (GITR and NKTR214 which is none other but a PEGylated form of IL2 that activates effector T lymphocyte cells and NK cells, but not Treg cells) or molecules allowing to reverse the “exhausted” phenotype state of lymphocytes such as LAG-3 and TIM-1 inhibitors. They may also include molecules interfering with tumour metabolism even if the use of IDO inhibitors has not provided great results so far, perhaps for lack of a better selection of patients who could benefit from it. These combinations can also be trebled with the association of a PD-1 inhibitor with a targeted combination therapy, a PD-1 inhibitor, a LAG-3 inhibitor and an iHDAC or IDO inhibitor.

Four therapeutic trials are currently underway or are being finalised with the association of PD-1 inhibitor with targeted combination therapy, the results will be available shortly.

Finally, the combinations with local treatments presenting a wide variety of mechanisms of action (in particular allowing to recreate an immunologically favourable microenvironment) are very promising since they are often well tolerated.
However, the essential question is whether we can obtain a systemic effect with these strategies, which was possible in some cases, especially in microenvironment (T-VEC and other oncolytic viruses, PAMP, cytokines, stimulation of innate immunity with TLR agonists including TLR-9, etc.). The latter strategies are likely to develop but will surely be limited depending on whether or not there are any lesions available for intralesional product injection...

What's new in cutaneous lymphoma?

Prof. Marie Beylot-Barry (Dermatologist, France)

In conclusion, Marie Beylot performed a complete review of primary cutaneous lymphomas with a focus on classification and therapeutic strategies in primary cutaneous lymphomas, including mycosis fungoides and Sézary syndrome, highlighting recent therapeutic advances (Brentuximab vedotin, Mogamulizumab, anti-KIR3DL2, iDHAC, anti-CD70, allogeneic stem cell transplantation) as well as PD-1 inhibitor immunotherapies with 7 ongoing trials, particularly in aggressive lymphomas where allogeneic stem cell transplantation finally proved to be the only treatment that allows to achieve true healing. Cutaneous large B-cell lymphomas, particularly of “leg” type, should not be left out, especially with the use of anti-NF-kB strategies (lenalidomide in particular) as well as PD-1 inhibitors in case of a post R-CHOP relapse; the use of ibrutinib (BTK inhibitor) by analogy with ABC-type lymphocyte-predominant lymphoma is also possible.