Clinical recommendations for diagnosis, treatment and monitoring of patients with bladder cancer

Rak mokraćnog mjehura (RMM) jest, u skladu s podatcima hrvatskog Registra za rak iz 2015. godine, drugi prema učestalosti tumor urinarnog sustava, odmah nakon raka prostate. U 90% slučajeva radi se o urotelnom karcinomu, a razlika u preživljenju kod bolesnika s mišićnoinvazivnim RMM-om (MIRMM) i nemišićnoinvazivnim RMM-om (NMIRMM) znatna je. Liječenje NMIRMM-a usmjereno je na smanjenje recidiva i sprječavanje napredovanja bolesti, a sastoji se od transuretralne resekcije (TUR) tumora i primjene intravezikalne terapije ovisno o procjeni rizika od povrata bolesti. Temelj liječenja bolesnika s MIRMM-om jest radikalno kirurško liječenje, tj. cistektomija kojoj u bolesnika koji su sposobni primiti cisplatinu prethodi neoadjuvantna kemoterapija (NKT). U trenutku postavljanja dijagnoze bolest je kod 4 – 6% bolesnika proširena, dok će se u 50% bolesnika razviti povrat bolesti nakon cistektomije. Metode liječenja proširenje bolesti uključuju: kemoterapiju temeljenu na cisplatini, imunoterapiju, palijativnu radioterapiju te simptomatsko i potporno liječenje. Važno obilježje RMM-a jest prisutnost visoke stope somatskih mutacija koje su omogućile promjenu paradigme u liječenju proširenog RMM-a i dovele do odobravanja niza novih lijekova koji pripadaju inhibitorima PD-1 i PD-L1, tj. inhibitorima nadzornih točaka imunosnog odgovora posredovanog T-stanicama .Bladder cancer is the second most common malignancy of urinary system according to data from the Croatian National Cancer Registry for 2015. In 90% of cases the underlying histology is urothelial carcinoma. Difference in survival in patients with muscle-invasive disease (MIBC) compared to the survival of patients with non-muscle invasive disease (NMIBC) is enormous. Management of NMIBC, traditionally, has been focused on the reduction of subsequent bladder recurrence and prevention of disease progression and is primarily based on transurethral resection (TUR) of the tumor, followed by intravesical therapy based on estimated individual risk of recurrence. Conversely, in patients with MIBC radical cystectomy remains the corne stone of the treatment, optimally in conjunction with neoadjuvant platinum-based chemotherapy in cisplatin-eligible patients. At the moment of diagnosis, 4–6% of patients already have distant metastases, and post cystectomy recurrence could be expected in 50% of patients. Treatment options in metastatic disease range from cisplatin-based chemotherapy, immunotherapy, palliative radiotherapy and finally supportive care. Landmark feature of bladder cancer is the high prevalence of somatic mutations which enabled profound change for decades held treatment paradigm for advanced bladder cancer leading to regulatory approval of whole array of novel immunotherapy agents. These emerging therapeutics (programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1)) belong to the class of inhibitors of checkpoint proteins, which are key targets that regulate T-cell mediated immune response

Clinical Recommendation for Diagnostics, Treatment and Monitoring of Patients with Prostate Cancer

Adenokarcinom prostate najčešća je zloćudna neoplazma u muškaraca u Republici Hrvatskoj. Klinički je često asimptomatski, a najčešće se otkriva na osnovi povišenih vrijednosti PSA u serumu. Odluka o liječenju donosi se na temelju TNM-klasifikacije, gradusne skupine i vrijednosti PSA. Klinički lokalizirana bolest vrlo se uspješno liječi radikalnom prostatektomijom ili radikalnom radioterapijom s hormonskom terapijom ili bez nje. Klinički lokalno uznapredovala bolest najčešće se liječi združenom primjenom radikalne radioterapije i hormonske terapije. Metastatska bolest godinama se može kontrolirati androgenom deprivacijom, a nakon razvoja kastracijski rezistentne bolesti opravdani su kemoterapija ili dodatni oblici hormonske terapije. U radu su prikazane kliničke upute radi ujednačenja postupaka i kriterija postavljanja dijagnoze, liječenja i praćenja bolesnika s rakom prostate u Republici Hrvatskoj.Prostate adenocarcinoma is the most common solid neoplasm in male population in Croatia. It is often asymptomatic. The finding of PSA rise is the most common reason for diagnostic workout. Treatment plan is based on TNM classification, grade group and PSA. Clinically localized disease is successfully treated by radical prostatectomy or radiotherapy with or without hormonal therapy. Locally advanced disease is treated with radiotherapy and hormonal therapy. Metastatic disease can be controlled for many years by androgen deprivation. For castration resistant metastatic disease appropriate treatment is chemotherapy or secondary hormonal therapy. The following paper presents the clinical guidelines to standardize procedures for the diagnosis, treatment and follow-up of patients with prostate cancer in the Republic of Croatia

Clinical guidelines for diagnostics, treatment and monitoring of patients with kidney cancer

Svjetlostanični karcinom bubrežnih stanica najčešći je oblik raka bubrega. Klinički je uglavnom asimptomatski, a samo se kod manjeg postotka bolesnika očituje hematurijom, tupom boli i palpabilnom masom u trbuhu. Najčešće se otkrije slučajno tijekom radioloških pregleda zbog nekoga drugog razloga. Dijagnoza raka bubrega potvrđuje se patohistološkim nalazom nakon provedene dijagnostičke obrade. Odluka o liječenju donosi se temeljem kliničke procjene stadija bolesti i drugih čimbenika rizika. Ovisno o tome, mogućnosti liječenja uključuju kirurški zahvat, sustavnu terapiju malim molekulama, imunoterapiju, kemoterapiju u odabranih bolesnika te palijativnu radioterapiju. U tekstu koji slijedi predstavljene su kliničke upute radi standardizacije postupaka i kriterija postavljanja dijagnoze, liječenja i praćenja bolesnika s rakom bubrega u Republici Hrvatskoj.Clear cell cancer is the most common form of kidney cancer. Clinically, it is mostly asymptomatic, and only a small proportion of patients present with hematuria, pain, and palpable abdominal mass. It is most commonly detected incidentally during radiological examinations for other causes. Diagnosis of kidney cancer is confirmed by pathohistological findings after the radiological imaging procedures. The decision on optimal treatment is based on a clinical assessment, stage of the disease and the presence of other risk factors. Depending on this, treatment options include surgical procedure, systemic treatment with small molecules, immunotherapy, chemotherapy in selected patients, and palliative radiotherapy. In the following text clinical guidelines have been presented to standardize procedures and criteria for diagnosing, treating and monitoring kidney cancer patients in the Republic of Croatia

CLINICAL RECOMMENDATIONS FOR DIAGNOSING, TREATMENT AND MONITORING OF PATIENTS WITH OVARIAN CANCER – CROATIAN ONCOLOGY SOCIETY AND CROATIAN SOCIETY FOR GYNECOLOGY AND OBSTETRICS AS CROATIAN MEDICAL ASSOCIATION UNITS AND CROATIAN SOCIETY OF GYNECOLOGICAL ONCOLOGY

Rak jajnika i jajovoda po učestalosti je peta zloćudna bolest žena u Hrvatskoj. Histološki je rak jajnika najčešće epitelnog podrijetla, i to seroznog podtipa. Rjeđi su različiti neepitelni malignomi jajnika, a posebnu skupinu čine epitelni karcinomi niskoga zloćudnog potencijala karakterizirani neinvazivnošću, klinički indolentnim tijekom i dobrom prognozom te primarni rak potrbušnice i rak jajovoda. Klinički su ovi zloćudni tumori u ranim stadijima razvoja uglavnom asimptomatski, zbog čega se najčešće dijagnosticiraju u kasnijim stadijima bolesti. Dijagnoza se potvrđuje patohistološkim nalazom, a iznimno citološkim nalazom nakon provedene dijagnostičke obrade. O liječenju odlučuje multidisciplinarni tim uzimajući u obzir dob, opće stanje i komorbiditete bolesnice, kao i obilježja samog tumora uključujući stadij bolesti, histološki tip i gradus tumora. Principi liječenja primarnog raka potrbušnice i jajovoda temelje se na principima liječenja epitelnog raka jajnika koji obuhvaćaju primjenu kirurških zahvata, kemoterapije, imunoterapije i hormonske terapije, kao i suportivno-simptomatskih mjera tijekom cijelog liječenja. Razlikuje se terapijski pristup rjeđim, neepitelnim histološkim tipovima tumora koji se češće dijagnosticiraju u ranim stadijima bolesti, imaju indolentniji tijek pa se kod ovih bolesnica češće primjenjuju poštedni kirurški zahvati s ciljem očuvanja plodnosti. U tekstu koji slijedi predstavljene su kliničke upute s ciljem standardizacije postupaka i kriterija postavljanja dijagnoze, liječenja te praćenja bolesnica s rakom jajnika, jajovoda i potrbušnice u Republici Hrvatskoj.Ovarian cancer together with fallopian tube represents the fifth most common female cancer in the Republic of Croatia. Epithelial ovarian cancer, serous subtype, encompasses most of malignant ovarian neoplasms. Less common are various non-epithelial ovarian malignancies. A special group consists of epithelial carcinomas of low malignant potential with clinically indolent flow, good prognosis and no invasion, and primary cancer of the peritoneum and fallopian tube cancer. Clinically, these malignant tumors are generally asymptomatic in early stages, and usually diagnosed in advanced stages. The diagnosis is confirmed by pathological examination, and occasionally, cytological findings after completing diagnostic procedures. Multidisciplinary team makes treatment decisions, taking into account age, general condition and comorbidities of the patient and characteristics of the tumor itself, including disease stage, histological type and grade of the tumor. The principles of treatment of primary peritoneal and fallopian tube cancer are based on the principles of treatment of epithelial ovarian cancer involving surgery, chemotherapy, immune and hormone therapy, and symptomatic-supportive care throughout the treatment. Less common histological types have a different treatment approach being more frequently diagnosed in the early stages of the disease, have more indolent flow, so in these patients conservative surgeries with the goal of preserving fertility are more often employed. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, management, treatment and monitoring of patients with ovarian carcinoma, fallopian tube and primary peritoneal cancer in the Republic of Croatia

CLINICAL RECOMMENDATIONS FOR DIAGNOSING, TREATMENT AND MONITORING OF PATIENTS WITH UTERINE CERVICAL CANCER – CROATIAN ONCOLOGY SOCIETY AND CROATIAN SOCIETY FOR GYNECOLOGY AND OBSTETRICS AS CROATIAN MEDICAL ASSOCIATION UNITS AND CROATIAN SOCIETY OF GYNECOLOGICAL ONCOLOGY

Rak vrata maternice, u odnosu na malignome drugih ginekoloških sijela, jest bolest mlađih žena koja se može redovitim kontrolama i zdravstvenim odgojem prevenirati, a u slučaju pojave bolesti učinkovito liječiti. Metode liječenja uključuju kirurgiju, radioterapiju i kemoterapiju, ovisno o stadiju bolesti i općem stanju bolesnica. Odluku o liječenju donosi multidisciplinarni tim. S obzirom na važnost ove bolesti, potrebno je definirati i provoditi standardizirani pristup u dijagnostici, liječenju i praćenju ovih bolesnica. U tekstu koji slijedi iznesene su kliničke smjernice s ciljem implementacije standardiziranih postupaka u radu s bolesnicama s rakom vrata maternice u Republici Hrvatskoj.Cervical cancer, in comparison with other gynecological malignancies, mainly affects younger women. It can be prevented trough educational programs, screening and early detection. It also can be efficiently treated when it appears. Treatment modalities include surgery, chemotherapy and radiotherapy, according to the stage of the disease and patient condition. Treatment decisions should be made after multidisciplinary team discussion. Due to the significance of this disease it is important to define and implement standardized approach for diagnostic, treatment and monitoring algorithm as well. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, management, treatment and monitoring of patients with uterine cervical cancer in the Republic of Croatia

CLINICAL RECOMMENDATIONS FOR DIAGNOSING, TREATMENT AND MONITORING OF PATIENTS WITH ENDOMETRIAL CANCER – CROATIAN ONCOLOGY SOCIETY AND CROATIAN SOCIETY FOR GYNECOLOGY AND OBSTETRICS AS CROATIAN MEDICAL ASSOCIATION UNITS AND CROATIAN SOCIETY OF GYNECOLOGICAL ONCOLOGY

Rak trupa maternice javlja se u većini slučajeva u poslijemenopauzalnih žena, a najčešće se očituje ginekološkim krvarenjem. Nakon raka jajnika i vrata maternice treći je uzrok smrti žena od raka spolnog sustava. Dijagnoza se postavlja patohistološkim pregledom kiretmana ili bioptata, a definitivni stadij bolesti utvrđuje se analizom uzoraka dobivenih histerektomijom i obostranom salpingoovariektomijom sa zdjeličnom i paraaortalnom limfadenektomijom. U tekstu koji slijedi sadržane su kliničke upute s ciljem standardizacije postupaka i kriterija postavljanja dijagnoze, liječenja i praćenja bolesnica s rakom trupa maternice u Republici Hrvatskoj.Uterine cancer occurs mainly in postmenopausal women, usually as vaginal bleeding. Following ovarian and cervical cancer it is the third most common cause of female reproductive system cancer death. Diagnosis is set by analyzing samples obtained via hysterectomy with salpingo-oophorectomy and pelvic / paraaortal lymphadenectomy. The following text presents the clinical guidelines in order to standardize the procedures and criteria for the diagnosis, treatment and monitoring of patients with uterine cancer in the Republic of Croatia

Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation shemotherapy in the treatment of locally advanced carcinoma of the uterine cervix

U ovom radu prikazali smo rezultate liječenja šezdeset i dvije bolesnice s lokalno uznapredovalim rakom vrata maternice FIGO stadija IB2 do IVA novim kemoradioterapijskim protokolom - konkomitantnom kemobrahiradioterapijom ifosfamidom i cisplatinom praćenom ordinacijom konsolidacijske kemoterapije istom kombinacijom citostatika. Većini bolesnica dijagnosticiran je uznapredovali karcinom pločastih stanica, a manjem broju adenoskvamozni, odnosno adenokarcinom vrata maternice. Svim uključenim bolesnicama ordinirana je puna doza eksterne radioterapije s dvije brahiradioterapijske aplikacije niske brzine doze konkomitantno s kemoterapijom cisplatinom i ifosfamidom, a polovica bolesnica je primila svih planiranih šest ciklusa kemoterapije. Kompletan odgovor na terapiju postignut je kod svih bolesnica, uz prihvatljivu akutnu i kasnu toksičnost liječenja te očuvanu kvalitetu života tijekom i nakon završetka liječenja. Nakon razdoblja praćenja od pet godina ukupno preživljenje iznosi 83.8%, što je za oko 20% bolji rezultat od rezultata drugih dosad objavljenih istraživanja. Konkomitantna kemobrahiradioterapija ifosfamidom i cisplatinom praćena konsolidacijskom kemoterapijom istom kombinacijom lijekova pokazala se kao učinkovit i siguran način liječenja bolesnica s lokalno uznapredovalim rakom vrata maternice. Pravu vrijednost navedenog protokola vrijedilo bi ispitati u kliničkom istraživanju faze III, s većim brojem uključenih bolesnica te usporedbom sa standardnom kemoradioterapijom temeljenom na cisplatinu.Herein, we presented results of the treatment of sixty-two female patients diagnosed with locally advanced carcinoma of the uterine cervix, FIGO stages IB2 to IVA with our investigatory protocolchemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy with the same drugs. Most of these patients were diagnosed with planocellular and less with adenosquamous or adenocarcinoma of the uterine cervix. All the patients received the full course of external radiotherapy with two lowdose brachyradiotherapy applications concomitantly with chemotherapy consisted of ifosfamide and cisplatin. Half of the patients received all six courses of combination chemotherapy. Complete response to therapy was achieved in all the patients, with expected rate of acute and late side effects of therapy. Quality of life was preserved during and after the treatment. After the follow up period of five years, the overall survival is 83.8%, which is approximately 20% better result in comparison to the results of similar researches published so far. Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy is efficacious and safe way of treatment of patients with locally advanced cervical cancer. The true value of this investigatory protocol should be confirmed in larger phase III clinical trial in comparison with standard chemoradiotherapy with cisplatin

Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation shemotherapy in the treatment of locally advanced carcinoma of the uterine cervix

U ovom radu prikazali smo rezultate liječenja šezdeset i dvije bolesnice s lokalno uznapredovalim rakom vrata maternice FIGO stadija IB2 do IVA novim kemoradioterapijskim protokolom - konkomitantnom kemobrahiradioterapijom ifosfamidom i cisplatinom praćenom ordinacijom konsolidacijske kemoterapije istom kombinacijom citostatika. Većini bolesnica dijagnosticiran je uznapredovali karcinom pločastih stanica, a manjem broju adenoskvamozni, odnosno adenokarcinom vrata maternice. Svim uključenim bolesnicama ordinirana je puna doza eksterne radioterapije s dvije brahiradioterapijske aplikacije niske brzine doze konkomitantno s kemoterapijom cisplatinom i ifosfamidom, a polovica bolesnica je primila svih planiranih šest ciklusa kemoterapije. Kompletan odgovor na terapiju postignut je kod svih bolesnica, uz prihvatljivu akutnu i kasnu toksičnost liječenja te očuvanu kvalitetu života tijekom i nakon završetka liječenja. Nakon razdoblja praćenja od pet godina ukupno preživljenje iznosi 83.8%, što je za oko 20% bolji rezultat od rezultata drugih dosad objavljenih istraživanja. Konkomitantna kemobrahiradioterapija ifosfamidom i cisplatinom praćena konsolidacijskom kemoterapijom istom kombinacijom lijekova pokazala se kao učinkovit i siguran način liječenja bolesnica s lokalno uznapredovalim rakom vrata maternice. Pravu vrijednost navedenog protokola vrijedilo bi ispitati u kliničkom istraživanju faze III, s većim brojem uključenih bolesnica te usporedbom sa standardnom kemoradioterapijom temeljenom na cisplatinu.Herein, we presented results of the treatment of sixty-two female patients diagnosed with locally advanced carcinoma of the uterine cervix, FIGO stages IB2 to IVA with our investigatory protocolchemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy with the same drugs. Most of these patients were diagnosed with planocellular and less with adenosquamous or adenocarcinoma of the uterine cervix. All the patients received the full course of external radiotherapy with two lowdose brachyradiotherapy applications concomitantly with chemotherapy consisted of ifosfamide and cisplatin. Half of the patients received all six courses of combination chemotherapy. Complete response to therapy was achieved in all the patients, with expected rate of acute and late side effects of therapy. Quality of life was preserved during and after the treatment. After the follow up period of five years, the overall survival is 83.8%, which is approximately 20% better result in comparison to the results of similar researches published so far. Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy is efficacious and safe way of treatment of patients with locally advanced cervical cancer. The true value of this investigatory protocol should be confirmed in larger phase III clinical trial in comparison with standard chemoradiotherapy with cisplatin

Experience of Department of oncology and radiotherapy in threedimensional conformal chemoradiotherapy of non-small cell lung cancer - dosimetric study

Cilj: Ispitati dozimetrijske trendove na organe od rizika i akutnu toksičnost u pacijenata s karcinomom pluća nemalih stanica liječenih trodimenzionalnom konformalnom kemoradioterapijom u jednom onkološkom centru. Metode: Ovo je retrospektivna studija provedena na Klinici za onkologiju i radioterapiju KBC-a Split. Prikupljeni su podatci oboljelih od lokalno uznapredovalog nesitnostaničnog karcinoma pluća liječenih trodimenzionalnom konformalnom radioterapijom od 2011. godine do početka 2019. godine. Prikupljeni su podatci pacijenata koji su se zračili primarno, adjuvantno i/ili neoadjuvantno. Uključeni pacijenti primili su najmanje jedan ciklus kemoterapije. Ciljni volumeni i organi od rizika ocrtani su prema radioterapijskim smjernicama. Rezultati: Medijan doze na “planing treatment volume” bio je 56 Gy. Najčešća akutna radijacijska toksičnost bila je akutni ezofagitis. Nije zabilježen nijedan slučaj akutnog radijacijskog pneumonitisa. Nije pokazana korelacija između prekoračenja doze na zadane volumene organa od rizika i toksičnosti istih, te smo ukazali na trend poboljšanja dozimetrijskih rezultata kroz godine liječenja. Zaključak: Toksičnost liječenja 3D KRT-om lokalno uznapredovalog raka pluća u Klinici za onkologiju i radioterapiju KBC-a Split usporediva je s objavljenim rezultatima drugih svjetskih institucija. S duljim vremenom primjene trodimenzionalne konformalne radioterapije u kliničkoj praksi postiže se optimalna raspodjela doza zračenja na rizične organe.Aim of the study: To investigate organs-at-risk toxicity with concomitant chemo radiotherapy in non-small cell lung cancer patients, and to explore dosimetry trends for organs-at-risk over the years. To investigate the rates of acute toxicities and to compare the results with the worldwide literature. Subjects and methods: This is a retrospective study conducted at the Department of Oncology and Radiotherapy at University Hospital of Split. Data were collected from patients with locally advanced non-small cell lung cancer treated with three-dimensional conformal chemo radiotherapy from 2011 to early 2019. Data were collected from patients who were treated with primary, adjuvant, and/or neoadjuvant radiotherapy. The patients received at least one cycle of chemotherapy. The target volumes and organs of risk were delineated according to radiotherapy guidelines. Results: The median dose on planning treatment volume was 56 Gy. The most common acute radiation toxicity was radiation esophagitis. No cases of acute radiation pneumonitis were noted. No correlation has been noted between dose override on organsat- risk volumes and toxicity, and we have shown a trend of improved dosimetry results through the years. Conclusion: The toxicity of treatment with 3D conformal radiotherapy for locally advanced lung cancer at the Department of Oncology and Radiotherapy at University Hospital of Split is comparable to the published results of other worldwide institutions. With longer use of 3D conformal radiotherapy we have seen improved dosimetry results over the years

Is There a Place for Adjuvant Chemotherapy in the Treatment of Locally Advanced Cervical Cancer?

Findings on the efficacy of adjuvant chemotherapy (ACT) of locally advanced cervical cancer (LACC) after the concurrent chemoradiation (CCRT) therapy were inconsistent, and the OUTBACK trial was expected to shed some light regarding the topic. Its results on ACT in LACC were negative, with the conclusion of not to use it. The objective of this review was to present the inconsistencies of previous studies, along with the OUTBACK trial in more detail, and to rethink whether its results provide an unambiguous and definite answer to the optimal position of ACT in the treatment of LACC. To critically appraise the OUTBACK trial and understand the consequences of its results, we used only randomized controlled studies (RCTs) on ACT in LACC that have been included in high-quality systematic reviews and meta-analyses. We calculated the pooled prediction intervals using a random effects meta-analysis of all published randomized studies including the OUTBACK trial. After combining the OUTBACK trial with the results of four previous randomized trials, the pooled hazard ratio for overall survival benefit of CCRT + ACT was 0.95 (95% CI 0.75; 1.20). The pooled hazard ratio of the four previous trials was 1.00 (95% CI 0.69; 1.44). The OUTBACK trial improved the precision of the pooled estimate, but the clinical heterogeneity and the consequent prediction intervals are still very wide, and with 95% reliability, we can expect that if the new study, using a similar approach to the ACT, on a randomly selected patient population from the presented five trials is conducted, its hazard ratio for overall survival after ACT would be between 0.47 and 1.93. In conclusion, there is an absolute need for further research in order to optimally define the position of ACT in the treatment of LACC