Radioterapija raka glave in vratu

Radioterapija je eden treh stebrov zdravljenja rakov glave in vratu. Začetki segajo v konec 19. stoletja, vsa dosedanja spoznanja pa danes omogočajo uspešno zdravljenje ob sprejemljivi toksičnosti. S sodobnimi obsevalnimi tehnikami lahko pri sluzničnih karcinomih glave in vratu v zgodnjih stadijih dosežemo popolno lokalno kontrolo bolezni, medtem ko je pri lokoregionalni bolezni obsevanje pogosto edino zdravljenje, ki prinaša možnost ozdravitve. V prihodnosti lahko ob tehničnem napredku, kot sta uporaba adaptivnega pristopa k obsevanju in uporaba visokoenergijskih delcev z ugodnejšimi fizikalnimi lastnostmi, ter predvsem ob napredku v razumevanju mehanizmov občutljivosti na obsevanje pričakujemo nadaljnje pomembne korake k izboljšanju uspehov radioterapije ob nespremenjeni ali celo zmanjšani toksičnosti

Možnosti deintenzifikacije zdravljenja HPV pozitivnih ploščatoceličnih karcinomov orofarinksa

Until recently, the major risk factors for development of oropharyngeal squamous cell carcinoma were smoking and alcohol consumption. Prognosis of these patients is poor, thus intensive and often multimodal approach to treatment is warranted if cure is to be hoped for. However, side effects of such treatment are serious. In recent years, there is a steep increase of oropharyngeal cancer, most notably of base of tongue and tonsils, in younger patients who are not heavy smokers or drinkers. In these patients the culprit is infection with high-risk human papillomavirus (HPV). Albeit the response to non-surgical treatment and prognosis are much better in these patients compared to those with non-HPV mediated oropharyngeal cancer, these patients are treated aggressively earlier in their life and will have to live with side effects of such treatment for considerably longer. The legitimate question arises whether we are treating these patients too aggressively. Several strategies to treatment deintensification were proposed and the first results are already available. These confirm that substituting platinum based concomitant chemotherapy in the setting of radical chemoradiotherapy with concomitant cetuximab is equally toxic yet less effective. More promising are the early results of clinical studies utilizing transoral surgical approaches and de-escalation of radiotherapy dose with or without induction chemotherapy used for selection of patients suitable for treatment deintensification. We are still awaiting results of several such studies that could influence the treatment paradigm of these patients. Until then, the treatment of patients with oropharyngeal cancer remains the same regardless of HPV status.Do nedavnega sta bila poglavitna dejavnika tveganja za nastanek ploščatoceličnega karcinoma orofarinksa kajenje in prekomerno uživanje alkohola. Prognoza teh bolnikov je praviloma slaba, zaradi česar je zdravljenje intenzivno in multimodalno, kar edino nudi možnost ozdravitve, a hkrati povzroča resne neželene učinke. V zadnjih letih pa opažamo naraščanje incidence karcinoma orofarinksa, natančneje nebnic in jezične tonzile, pri bolnikih, ki so mlajši od tipičnih bolnikov s tem rakom in niso podvrženi škodljivim razvadam. Pri njih je povzročitelj karcinoma visokorizični podtip človeškega virusa papiloma (HPV). Ti bolniki v primerjavi s prvimi bolje odgovorijo na nekirurško zdravljenje in imajo pomembno daljše preživetje. Obenem to pomeni, da so ti bolniki agresivnega zdravljenja deležni v zgodnejšem življenjskem obdobju in morajo s posledicami tega živeti bistveno dlje. Zato se upravičeno poraja vprašanje, ali morda teh bolnikov s HPV povezanim rakom orofarinksa ne zdravimo pretirano agresivno. Predlaganih je bilo več načinov za zmanjšanje intenzivnosti zdravljenja, znani pa so tudi že prvi rezultati raziskav. Ti potrjujejo, da je način deintenzifikacije zdravljenja s kombinacijo sočasnega obsevanja in cetuximaba, ki je nadomestil cisplatin oz. karboplatin, neuspešen. Bolj obetavni so zgodnji rezultati kliničnih raziskav, ki vključujejo bodisi manj invazivno kirurgijo ali zmanjšanje odmerka radioterapije, z ali brez predhodne izbire bolnikov, primernih za deintenzifikacijo, z uvodno kemoterapijo. Mnoge raziskave so še v teku in morda bodo izsledki že kmalu spremenili paradigmo zdravljenja v tej skupini bolnikov. Do takrat pa ostaja zdravljenje karcinomov orofarinksa enako za vse bolnike, ne glede na etiologijo njihove bolezni

Immunotherapy for squamous cell carcinoma of the head and neck - experience from Slovenia

Izhodišča: Imunoterapija z zaviralcem imunskih kontrolnih točk nivolumabom, zaviralnim protitelesom proti proteinu programirane celične smrti 1 (PD-1), je za bolnike z neozdravljivo ponovitvijo bolezni ali sistemskimi zasevki ploščatoceličnega karcinoma glave in vratu (P/Z PKGV), pri katerih je bolezen neobčutljiva na preparate platine, pomembna nova možnost zdravljenja. V primerjavi s citostatiki pomembno podaljša njihovo preživetje. Metode: Opravljena je bila retrospektivna analiza zdravljenja z nivolumabom pri slovenskih bolnikih s P/Z PKGV, ki so prejeli prvi odmerek nivolumaba do marca 2020. Zbiranje podatkov je bilo končano septembra 2020. Uporabljene so bile opisne statistične metode in test log-rank. Rezultati: V raziskavo je bilo vključenih 27 bolnikov. Srednji čas sledenja od prve aplikacije nivolumaba do konca opazovanja je bil 7,4 meseca, relativno šestmesečno celokupno preživetje pa 59- odstotno (95-odstotni interval zaupanja pri 41–78 %). Odgovor na zdravljenje je bil pri 85 % bolnikov ocenjen s kliničnim pregledom in rentgenskim slikanjem prsnega koša, pri čemer je bil pri 41 % kot najboljši odgovor ugotovljen delen odgovor na zdravljenje. Imunsko pogojeni neželeni dogodki so se pojavili pri 30 % bolnikov, pri čemer so bili vsi gradusa ≤ 2. En bolnik je bil sočasno z nivolumabom tudi obsevan. Zaključek: Glede na zbrane podatke se je tudi v slovenski populaciji bolnikov s P/Z PKGV zdravljenje z nivolumabom izkazalo za varno. Zaradi kratkega časa sledenja ugotovljene učinkovitosti ni mogoče primerjati z rezultati tujih raziskav. S pričakovano odobritvijo pembrolizumaba bodo zaviralci imunskih kontrolnih točk tudi v Sloveniji dobili mesto v prvem redu zdravljenja P/Z PKGV.Background: Immunotherapy with the immune checkpoint inhibitor nivolumab – an inhibitory antibody against programmed death receptor-1 (anti-PD-1) – represents an important new treatment option for patients with an incurable recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) that is unresponsive to platinum-based chemotherapy. It significantly prolongs survival compared to standard chemotherapy. Methods: A retrospective analysis of treatment with nivolumab in patients with R/M HNSCC in Slovenia who received their first dose of nivolumab by March 2020 was performed. Data collection was completed in September 2020. Descriptive statistics and log rank tests were used. Results: Twenty-seven patients entered the study. The median time of follow-up from the first nivolumab application onward was 7.4 months, and the relative six-month overall survival rate was 59% (95% confidence interval 41–78%). In 85% of patients, the response to treatment was evaluated using clinical examination and chest x-ray only. In 41% of patients the partial response to treatment was declared as the best response achieved. Thirty per cent of patients experienced immune-related adverse events, of which all were grade ≤2. In one patient radiotherapy was delivered concurrently with nivolumab. Conclusion: According to the presented results, treatment with nivolumab has also been shown to be safe in Slovenian patients with R/M HNSCC. Due to the short follow-up time, the observed efficacy cannot be compared with the results of foreign studies. With the expected approval of pembrolizumab, immune checkpoint inhibitors will also be given a place in the first line treatment of R/M HNSCC in Slovenia

The importance of hypoxia in radiation therapy

Uspešnost zdravljenja z radioterapijo (RT) je odvisna od številnih dejavnikov, med katerimi je tudi oksigenacija tumorskih celic. Tumorske celice, ki so dobro preskrbljene s kisikom, so namreč na obsevanje tudi do 3-krat bolj občutljive kot hipoksične tumorske celice. Poleg tega deluje hipoksija v tumorjih kot selekcijski pritisk, zaradi katerega preživijo le bolj maligne celice, z manjšim apoptotskim potencialom. V prisotnosti hipoksije se povečata genomska nestabilnost in metastatski potencial tumorskih celic, zveča pa se tudi odpornost celic na kemoterapijo, kar vse vpliva na uspešnost zdravljenja z RT. Hipoksija je posledica neskladja med celičnim dihanjem, koncentracijo kisika v krvi in perfuzijo tumorja, pri čemer so najpogostejši patogenetski mehanizmi neustrezna ožiljenost, motena difuzija kisika ter anemija, ki je lahko posledica rakave bolezni ali zdravljenja. Z uporabo invazivnih in novejših neinvazivnih diagnostičnih metod lahko ocenimo delež hipoksičnih celic v tumorju in temu prilagodimo terapevtski pristop. Boljši učinek obsevanja slabše oksigeniranih tumorjev lahko dosežemo z uporabo radiosenzibilizatorjev, z izboljšanjem tumorske oksigenacije, s selektivnim uničenjem hipoksičnih celic s citotoksini ter z obsevanjem hipoksičnih predelov z višjimi obsevalnimi odmerki ob pomoči radioprotektorjev in z uporabo sodobnih obsevalnih tehnik.The success of radiation therapy (RT) treatment depends on numerous factors, one of which is also tumour cell oxygenation. Tumour cells which are well-supplied with oxygen can be up to 3 times more sensitive to radiation than hypoxic tumour cells. In addition, hypoxia functions as selective pressure in tumours, which results in the survival of only more malignant cells with diminished apoptotic potential. Presence of hypoxia increases the genomic instability and metastatic potential of tumour cells, while also increasing cell resistance to chemotherapy, all of which affects the success of treatment with RT. Hypoxia is a result of an imbalance between cellular respiration, concentration of oxygen in the blood and tumour perfusion, with the most common pathogenic mechanisms being inappropriate vascularization, disturbed oxygen diffusion and anaemia which may be a consequence of cancer or treatment. Using invasive and most recent non-invasive diagnostic techniques, we can assess the proportion of hypoxic cells in the tumour, adapting the therapeutic approach accordingly. A better effect of irradiation of less oxygenated tumours can be achieved using radio sensitizers, by improving tumour oxygenation, through selective destruction of hypoxic cells, and with irradiation of hypoxic areas using higher doses of radiation and with the help of radio protectors or using modern irradiation techniques

Pomen hipoksije pri obsevanju

The success of radiation therapy (RT) treatment depends on numerous factors, one of which is also tumour cell oxygenation. Tumour cells which are well-supplied with oxygen can be up to 3 times more sensitive to radiation than hypoxic tumour cells. In addition, hypoxia functions as selective pressure in tumours, which results in the survival of only more malignant cells with diminished apoptotic potential. Presence of hypoxia increases the genomic instability and metastatic potential of tumour cells, while also increasing cell resistance to chemotherapy, all of which affects the success of treatment with RT. Hypoxia is a result of an imbalance between cellular respiration, concentration of oxygen in the blood and tumour perfusion, with the most common pathogenic mechanisms being inappropriate vascularization, disturbed oxygen diffusion and anaemia which may be a consequence of cancer or treatment. Using invasive and most recent non-invasive diagnostic techniques, we can assess the proportion of hypoxic cells in the tumour, adapting the therapeutic approach accordingly. A better effect of irradiation of less oxygenated tumours can be achieved using radio sensitizers, by improving tumour oxygenation, through selective destruction of hypoxic cells, and with irradiation of hypoxic areas using higher doses of radiation and with the help of radio protectors or using modern irradiation techniques.Uspešnost zdravljenja z radioterapijo (RT) je odvisna od številnih dejavnikov, med katerimi je tudi oksigenacija tumorskih celic. Tumorske celice, ki so dobro preskrbljene s kisikom, so namreč na obsevanje tudi do 3-krat bolj občutljive kot hipoksične tumorske celice. Poleg tega deluje hipoksija v tumorjih kot selekcijski pritisk, zaradi katerega preživijo le bolj maligne celice, z manjšim apoptotskim potencialom. V prisotnosti hipoksije se povečata genomska nestabilnost in metastatski potencial tumorskih celic, zveča pa se tudi odpornost celic na kemoterapijo, kar vse vpliva na uspešnost zdravljenja z RT. Hipoksija je posledica neskladja med celičnim dihanjem, koncentracijo kisika v krvi in perfuzijo tumorja, pri čemer so najpogostejši patogenetski mehanizmi neustrezna ožiljenost, motena difuzija kisika ter anemija, ki je lahko posledica rakave bolezni ali zdravljenja. Z uporabo invazivnih in novejših neinvazivnih diagnostičnih metod lahko ocenimo delež hipoksičnih celic v tumorju in temu prilagodimo terapevtski pristop. Boljši učinek obsevanja slabše oksigeniranih tumorjev lahko dosežemo z uporabo radiosenzibilizatorjev, z izboljšanjem tumorske oksigenacije, s selektivnim uničenjem hipoksičnih celic s citotoksini ter z obsevanjem hipoksičnih predelov z višjimi obsevalnimi odmerki ob pomoči radioprotektorjev in z uporabo sodobnih obsevalnih tehnik

Oligometastatic cancer

Oligometastatska bolezen (OMB) predstavlja vmesno stanje med lokalno napredovalo boleznijo in obsežnejšo metastatsko boleznijo. Zaenkrat ne poznamo specifičnih biomarkerjev, ki bi nam pomagali opredeliti bolnike z majhnim bremenom bolezni, zato diagnoza OMB temelji na slikovni diagnostiki. V zadnjih letih narašča zanimanje za optimizacijo zdravljenja OMB predvsem zaradi obetavnih rezultatov dodatka lokalnega k obstoječemu sistemskemu zdravljenju. S takšnim načinom zdravljenja se je prvič pokazala možnost doseganja dolgotrajnih zazdravitev ali redko celo ozdravitev teh bolnikov. Razlikovanje posameznih vrst OMB in njihovo enotno poimenovanje je pomembno zlasti v kliničnih raziskavah, saj nam omogoča medsebojno primerjavo rezultatov različnih raziskav.Oligometastatic disease (OMD) is a stage between locally advanced disease and polymetastatic disease, a group of diseases that are used interchangeably based on treatment history, ongoing treatment status, and imaging findings. The diagnosis of OMD is based on imaging because, as of yet, we are not aware of any specific biomarkers that would enable us to recognize patients with a low disease burden. In recent years, there has been an increasing interest in optimizing the treatment of OMD, owing mostly to the promising outcomes of combining local and systemic treatment. For the first time, the prospect of achieving long-term cures or possibly curing these individuals was established using this form of treatment. The standard name of OMD subgroups allows for the comparison of diverse circumstances in everyday clinical work, as well as the classification for clinical study comparability

Stereotactic Body Radiotherapy as a Curative Treatment for De Novo Mucosal Carcinoma of the Head and Neck: A Feasible Alternative Option for Fragile Patients with Small Lesion: A Systematic Review †

Stereotactic body radiotherapy (SBRT) is characterized by a high dose per fraction, well-defined small targets, superior dose conformity, and a steep off-target dose gradient. A literature search was conducted to examine the experience with SBRT as a curative treatment for newly diagnosed mucosal carcinoma of the head and neck (MCHN). Four retrospective case series and one prospective phase I clinical trial published between 2012 and 2020 described 124 patients. SBRT was mainly performed in older patients with different tumor sites. The median size of the planning target volumes ranged from 5.3 to 41 cm3. Different approaches were used to create margins. In two studies, limited elective nodal irradiation was performed. The equivalent doses used were 60–83.33 Gy delivered in five fractions. Considerable heterogeneity was observed in the radiation dose specification. The incidence of grade ≥3 late toxicity was 0–8.3%, with local and regional control ranging from 73% to 100%. Improved or stable quality of life after SBRT was reported in two studies. Curative-intent SBRT for de novo MCHN appears to be an effective and relatively safe treatment for small tumor targets, preferably without concomitant elective tissue irradiation. Standardization of SBRT practice and well-designed prospective clinical trials are needed to better define the role of SBRT in this setting