The Challenges and Opportunities of the Implementation of Comprehensive Genomic Profiling in Everyday Clinical Practice with Non-Small Cell Lung Cancer: National Results from Croatia.

Non-small cell lung cancer (NSCLC) has become the best example of precision oncology's impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1-3) CRGA per patient. From the panel of recommended tests, KRAS, MET, and EGFR were the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.

Real-World Efficacy and Safety of Bevacizumab in the First-Line Treatment of Metastatic Cervical Cancer: A Cohort Study in the Total Population of Croatian Patients.

BACKGROUND: Although today it is almost preventable, cervical cancer still represents a significant cancer burden, especially in some developing parts of the world. Since the introduction of bevacizumab in the first-line treatment of metastatic disease, improvements of the outcomes were noted. However, results from randomized controlled trials are often hard to recreate in the real-world setting. OBJECTIVE: To assess the real-world efficacy and safety of bevacizumab as a first-line treatment of advanced cervical cancer. METHODS: We conducted a retrospective cohort study on the total population of Croatian patients diagnosed with metastatic cervical cancer from 2016 to 2019 who were treated with bevacizumab in combination with cisplatin and paclitaxel (TCB) in the first line. The comparison group was the consecutive sample of patients treated with chemotherapy alone. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate, incidence of adverse events, and the proportion of treatment discontinuation. RESULTS: We enrolled 67 patients treated with TCB and a control group of 62 patients treated with chemotherapy alone. The TCB cohort had significantly longer unadjusted OS with a median of 27.0 (95% CI 18.5; not calculable) months, compared to 15.5 (10.7; 30.1) months in the chemotherapy-alone cohort. Adjusted OS was not significantly different. PFS was significantly longer for the TCB cohort, with a median of 10.6 (95% CI 8.5; 15.4) months, than for the chemotherapy-alone cohort, with a median of 5.4 (95% CI 3.9; 9.1) months, even after adjustment for baseline covariates (HRadjusted = 0.60; 95% CI 0.39; 0.94; p=0.027; false discovery rate <5%). CONCLUSIONS: In a real-world setting, TCB as a first-line treatment of metastatic cervical cancer was associated with longer PFS, better objective disease control rate, and acceptable toxicity profile in comparison to chemotherapy alone. These results may indicate its utility and potential applicability in other parts of the developing world.

Three radiation-induced metachronous pelvic tumors in a patient who underwent radiotherapy for cervical cancer: a case report.

INTRODUCTION: Patients treated with radiotherapy are under increased long-term risk of developing radiation-induced tumors. In this report we present an exceptionally rare case of a patient who, following radiotherapy for cervical cancer, developed 3 radiation-induced metachronous pelvic tumors. CASE PRESENTATION: In 1997, a 37-year-old patient with cervical adenocarcinoma (FIGO stage IB2) was subjected to adjuvant conventionally fractionated external-beam radiation therapy and brachytherapy following surgical treatment. Eleven, 14 and 15 years later, 3 radiation-induced malignant tumors developed: a leiomyosarcoma of the gluteus and 2 separate carcinomas of the rectum. DISCUSSION AND CONCLUSION: Radiotherapy for cervical carcinoma increases the standardized incidence ratios for rectal cancer and soft tissue sarcoma. Unfortunately, the current guidelines on contraindications to radiotherapy appear insufficient as they take into account a very limited number of clinical states and associated conditions, which is in disproportion to the rather high risk of radiation-induced malignancies of 0.45%. Information on the molecular characteristics of human radiation-induced tumors is still of no relevance for everyday clinical practice. Although radiotherapy is one of the most important modalities of oncological treatment, it should be judiciously used in cases where the benefits clearly outweigh the risk of serious untoward effects. In the case of patients undergoing pelvic irradiation, careful follow-up is needed for years.

[CLINICAL RECOMMENDATIONS FOR DIAGNOSIS, TREATMENT AND MONITORING OF PATIENTS WITH ESOPHAGEAL AND ESOPHAGOGASTRIC JUNCTION CANCERS].

Esophageal and esophagogastric junction cancers comprise histologically and biologically different malignant tumors in which the progress in the understanding of the disease has not been followed by the improvement in the survival. Diagnosis is set by tumor biopsy during endoscopy. Multimodal approaches containing surgery, radiotherapy and chemotherapy are frequently applied in the treatment of locoregionally advanced disease. However, the optimal sequence of the treatment options is still the issue of numerous clinical trials and meta-analyzes. Metastatic disease is treated with palliative chemotherapy and best supportive care. Treatment decisions should be individualized according to patients' characteristics and made after multidisciplinary team discussion. The following text presents the clinical guidelines in order to standardize the diagnostic procedures, treatment and monitoring of patients with esophageal and esophagogastric junction cancers in the Republic of Croatia.

[CLINICAL GUIDELINES FOR DIAGNOSING, TREATING AND MONITORING OF ADULT PATIENTS WITH GLIOMAS OF CENTRAL NERVOUS SYSTEM]. / KLINICKE UPUTE ZA DIJAGNOZU, LIJECENJE I PRACENJE ODRASLIH BOLESNIKA OBOLJELIH OD GLIOMA SREDISNJEGA ZIVCANOG SUSTAVA.

Gliomas of the central nervous system are glial cell tumors that are divided in low and high grade group. Multidisciplinary approach to treatment consists of surgery, radiotherapy and chemotherapy. The type and order of treatment depend on the characteristics of the tumor and the patient. We present the clinical guidelines for diagnostic procedures, surgical treatment, oncological treatment and follow up of patients with this type of tumor in the Republic of Croatia.

[Clinical recommendations for diagnosing, treatment and monitoring patients with non-small cell lung cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od karcinoma pluca nemalih stanica.

In Croatia, lung cancer is the most common malignant disease among male population and the third common among female population where 85% of patients have non-small cell lung cancer. Due to significance of this disease it is necessary to define and implement standardized approach for diagnostic and treatment algorithm as well to patients monitoring. Several multidisciplinary sessions were organized in achieving this goal. The sessions' results are given in the form of the Clinical guidelines.

[Clinical recommendations for diagnosis, treatment and monitoring of patients with colorectal cancer]. / Klinicke upute za dijagnozu, lijecenje i pracenje bolesnika oboljelih od kolorektalnog raka.

Colorectal cancer is the third most common malignant tumour in males and the fourth most common malignancy in women in the Republic of Croatia. It is usually manifested as stool forming disorders, feeling that bowel does not empty completely, finding blood in the stool, weight loss and fatigue. In-time diagnosis, confirmed by pathohistological findings, is cornerstone of successful treatment. The decision about treatment is made based on clinical assessment of disease stage and other risk factors, after completion of the diagnostic process. Depending on that, treatment options include surgery, the application of systemic therapy (chemotherapy, immunotherapy) and radiotherapy. The following text presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, treatment and monitoring of patients with colorectal cancer in the Republic of Croatia.

Phase II study of bevacizumab in combination with capecitabine as first-line treatment in elderly patients with metastatic colorectal cancer.

The relative survival of elderly patients with metastatic colorectal cancer (mCRC) is generally worse than that of younger patients because of more advanced stage at presentation, comorbidity and reduced use of optimal therapy. We conducted a prospective phase II trial of the combination of bevacizumab and capecitabine in elderly patients with mCRC. In total 41 patients aged more than or equal to 70 years with mCRC, who had not received chemotherapy earlier for metastatic disease, were enroled. Patients received capecitabine (1000 mg/m twice daily on days 1-14) and bevacizumab (7.5 mg/kg of body weight on day 1). The treatment cycles were repeated every 3 weeks. The overall response rate was 65%, including 13% of patients with a complete response and 53% of patients with a partial response. A further 13% of patients maintained stable disease. The median progression-free survival was 11.5 months and the median overall survival was 21.2 months. Despite the advanced age of participants, the rate of bevacizumab-related and capecitabine-related adverse events was consistent with that reported earlier in the general mCRC population. The combination of bevacizumab and capecitabine is effective and has a favourable tolerability profile and should be considered as an option for the initial treatment of mCRC in elderly patients.

Long-lasting partial regression of glioblastoma multiforme achieved by edotecarin: case report.

We describe the response to a new chemotherapy agent, topoisomerase I inhibitor edotecarin in an 18-year-old woman with recurring glioblastoma. The therapy was administered for 17 months. The radiological partial response and clinical improvement have been achieved, with minor toxicity. Median survival of patients with glioblastoma is 10 months. With edotecarin we have achieved promising result, which should encourage further investigations to develop more efficient therapy for such a deadly disease.