New approaches in palliative systemic therapy of anal squamous cell carcinoma.

BACKGROUND: Metastatic and locally recurrent inoperable anal squamous cell carcinoma (ASCC) belong to rare tumours - ASCC accounts for about 2% of gastrointestinal tumours. Synchronous metastatic involvement is usually confirmed in approximately 15% of patients and about 20 % of patients develop relapse in the form of distant metastases after curative treatment. The current standard palliative systemic treatment is a PF regimen composed of 5-fluorouracil (5-FU) with cisplatin (cDDP) or a combination of carboplatin with paclitaxel. PURPOSE: The aim of this study is to summarize other options for systemic palliative care in ASCC, including the results of relevant clinical trials performed with new or modified regimens. Triple combinations with taxanes have yielded promising treatment results, and in particular, the inclusion of the DCF regimen (cDDP + 5-FU + docetaxel) in first-line treatment results in a significant increase in treatment responses with good treatment tolerance. Another promising option for palliative care is immunotherapy with checkpoint inhibitors PD-1 or PD-L1, which can be successfully used in palliative systemic treatment or in curative regimens. Epidermal growth factor receptor inhibitors remain the subject of research, whose role in the primary or palliative treatment of ASCC is not entirely clear. CONCLUSION: Compared to standard chemotherapy, available data confirm the treatment outcomes improvement in the use of triple combination DCF with docetaxel or immunotherapy with checkpoint inhibitors in the treatment of metastatic ASCC.

Radiotherapy and radiosensitivity syndromes in DNA repair gene mutations.

BACKGROUND: Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment. PURPOSE: The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Most radiosensitivity syndromes are autosomal recessively inherited; examples are ataxia teleangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome and Werner syndrome. CONCLUSION: Radiotherapy is contraindicated in most homozygous patients with recessive radiosensitivity syndromes. Asymptomatic heterozygotes may have an increased risk of tumor incidence and a small part of them slightly increased risk of RT intolerance; however, this does not limit RT treatment. The high risk of secondary malignancies after radiotherapy is a contraindication to adjuvant RT in Li-Fraumeni syndrome.

Chemoradiotherapy in the treatment of cervical cancer - a single institution retrospective review.

BACKGROUND: The aim of this study is a retrospective analysis of treatment outcomes and toxicity in a group of patients with cervical cancer who underwent (chemo) radiotherapy at the Institute of Radiation Oncology in Bulovka University Hospital in Prague in the period 2014-2017. PATIENTS AND METHODS: During this period, 141 patients were treated, 105 (74.5%) of them underwent combined (chemo) radiotherapy with radical intent and palliative radiotherapy was performed in 36 (25.5%) cases. According to the International Federation of Gynecology and Obstetrics (FIGO) 2009 classification, the most numerous stages were IIB in 39 (27.7%) and IIIB in 64 (45.4%) cases; according to FIGO 2018, a significant number of newly established stages is evident: IIIC1 in 55 (39.0%) patients and IIIC2 in 22 (15.6%) cases. RESULTS: The median progression-free survival (PFS) and overall survival (OS) reached 31.3, resp. 40.1 months in the whole group. In the subgroup of patients treated with radical intent, the median PFS was 44.0 months and OS 48.8 months; in the palliative subgroup, the median PFS was 9.4 months and OS 14.8 months. In a radically treated subgroup, 7 (6.7%) patients had gastrointestinal or genitourinary manifestations of G3-4 toxicity, and overall acute toxicity (including skin and haematological reactions) of G3-4 occurred in 18 (17.1%) patients. Late toxicity of G3-4 was reported in 13 (12.4%) cases. Patients who underwent complete brachytherapy (BRT) showed significantly better survival compared to patients with a lower number of BRT fractions. The prognostic potential of PS (performance status) and anemia was confirmed; significantly longer overall survival was observed in patients in good general condition or in those without anemia. CONCLUSION: Our results confirmed the key role of BRT for the delivery of the curative dose to the target volume. The prognostic role of PS and anemia is evident. The side effects were in acceptable limits but we expect improvements because of the use of modern radiotherapy technologies.

Clinical application of time factor principles in radiotherapy in compensation of radiation series interruptions.

BACKGROUND: The time factor plays a key role in radiotherapy. The radiotherapy overall treatment time is one of the most important predictive factors in the treatment effectiveness and is associated with better local control and impact on the overall survival. The length of the time from the dia-gnosis to radical radiotherapy or from surgery to adjuvant radiotherapy or the use of alternative fractionation schemes shortening the total treatment time also play an important role. The prevention of prolongation of the radiation series remains a fundamental and well feasible way of applying the time factor in radiotherapy. PURPOSE: Interruption of radiotherapy usually occurs for technical reasons, due to factors at the patients side or for personnel reasons of the department. Standard procedures for the compensation for treatment breaks are part of the treatment protocols at radiotherapy departments. Possible risks of the discontinuation of radiotherapy are considered on the basis of the type and extent of the disease, the treatment intent and the condition of the patient, and the need of compensation for a break in the treatment is set. Patients are classified into three categories according to the above mentioned parameters. Compensation for the pause in radiotherapy is performed by calculating the equivalent dose in 2 Gy per fraction (EQD2); the preferred method of compensation is the one which enables observation of the planned total time of radiotherapy without extension. The benefit of local tumor control and the risk of increased acute or especially late toxicity should always be considered. In the current epidemiological situation, radiotherapy is often discontinued for COVID-19, and due to longer breaks in the treatment, it is necessary to combine multiple compensation methods in one patient.

Haematotoxicity in IMRT/VMAT curatively treated anal cancer.

INTRODUCTION: Curative chemoradiotherapy of squamous cell carcinoma achieves long-term complete remissions in most patients and minimizing treatment toxicity becomes crucial issue. The aim of the retrospective analysis was to determine an acceptable dose to the bone marrow for radiotherapy planning not leading to increased haematological toxicity. PATIENTS AND METHODS: In the period 2013-2019, 40 patients with squamous cell carcinoma were curatively treated at the Department of Oncology of the University Hospital Motol using intensity modulated radiotherapy (IMRT) /volumetric modulated arc radiotherapy (VMAT) technique. Women make up 90% of the group, the average age at the time of dia-gnosis was 65 years (47-81). Chemotherapy mitomycin C and 5-fluorouracil was given to 68% of patients. The bone marrow was contoured in the Varian Eclipse planning system, version 15.6. RESULTS: Acute hematotoxicity (G3, 4, 5 according to Common Terminology Criteria for Adverse Events - CTCAE) was significantly associated with the concomitant chemoradiotherapy (P = 0.002) and the average dose to the bone marrow 27 Gy (P = 0.011). Late haematological toxicity was mild (maximum grade 1), asymptomatic, and no dependence of late haematotoxicity on any risk factor (age, gender, WHO performance status, bone marrow dose, CHT, BMI, smoking, stage) was proved. The overall survival at 5 years was 100% in stage I, 83% in stage II, 61% in stage III and 0% in stage IV. Local control at 5 years is 100% in stage I, 92% in stage II, 87% in stage III and 0% in stage IV. Local recurrence developed in 5% of radically treated patients. Distant metastases occurred in 8% of radically treated patients. Local recurrences or metastases occurred only during the first 2 years after the treatment. CONCLUSION: Radical chemoradiotherapy in the treatment of squamous cell anal carcinoma is highly effective. IMRT/VMAT enabled to apply a sufficiently effective dose to the tumor and elective areas and reduced not only acute skin, GI and GU toxicity, but also acute haematological toxicity in cases with the dose Dmean to bone marrow lower than 27 Gy. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical, papers.

Improved survival in patients with FDG-PET/CT-based radiotherapy treatment planning for squamous cell anal cancer.

The aim of this retrospective analysis was to evaluate the impact of FDG-PET/CT-based target volume definition on locoregional control and survival, compared to conventional CT-based target volume definition and dose prescription. One hundred and twenty-two patients with squamous cell anal cancer were treated with curative radiotherapy (RT) alone (27%) or with RT with concurrent chemotherapy (73%) and analyzed. Forty-six percent had the early disease (stage I+II) and 54% were stage III. FDG-PET/CT-based staging was performed in 21% of the patients. The mean follow-up time was 60 months. Other risk factors affecting survival were investigated. According to initial staging in both groups (FDG-PET/CT and conventional CT) were 10% of stage IV disease, and they were excluded from radical radiotherapy and treated with palliative intent. Ninety-two percent of the patients achieved complete remission. Significant favorable factors in univariate analysis associated with disease-free survival (DFS) were PET/CT staging, T1/2 and N0 stage, and clinical stage I and II. Locoregional control (LRC) correlated with the T1/2 stage and initial performance status (PS) 0. There were no significant factors affecting overall survival (neither in univariate nor multivariate analysis). In multivariate analysis, the factor associated with better DFS was PET/CT staging and for LRC, PS 0 and concomitant chemoradiation. Acute toxicity was increased in the concurrent chemo-radiotherapy group. Two-, five- and ten-year overall survival rates were 83%, 69%, and 60%; disease-free survival rates were 76%, 73%, 73%; local control rates were 91%, 90%, and 90% and colostomy-free survival was 89%, 86%, and 81%, respectively. PET/CT staging allowed targeted dose escalation to the primary tumor and nodal metastases while decreasing dose to uninvolved regions, resulting in significantly improved DFS without compromising locoregional control.

Three-dimensional conformal radiotherapy versus intensity modulated radiotherapy with simultaneous integrated boost in the treatment of locally advanced head and neck carcinoma.

The treatment of locally advanced head and neck cancer (LAHNC) requires a multimodality approach. Radiotherapy with combination of chemotherapy are demonstrated to be effective, however, the treatment intensification leads to increased toxicity at the same time. The implementation of three-dimensional conformal radiotherapy (3D-CRT) allowed to irradiate the treatment volume more precisely with better surrounding healthy tissue sparing. Intensity modulated radiotherapy (IMRT) facilitated higher conformity in dose shaping to target volume. IMRT with simultaneous integrated boost (IMRT-SIB) offered the possibility to deliver individualized dose levels within one fraction and enabled escalation of the dose per fraction and radiotherapy acceleration. The aim of our study was to compare the technique of 3D-CRT and IMRT-SIB in the treatment of LAHNC and evaluate the treatment outcome and the treatment-related toxicity. 262 patients in 3D-CRT group and 263 patients in IMRT-SIB group underwent the radical treatment for LAHNC between 1/1998 and 12/2016. No statistically significant differences in locoregional control (LCR) and overall survival (OS) were found between the two groups. Acute toxicity and xerostomia were significantly reduced in the patients treated by IMRT-SIB. IMRT-SIB is a safe radiotherapy method where less toxicity was proven without compromising local control and overall survival.

Preoperative radiotherapy for locally advanced rectal cancer and prognostic factors influencing outcome.

The aim of presented study was to evaluate the impact of different factors on survival, local recurrence and development of metastatic disease in patients with rectal cancer treated with preoperative radiotherapy or 5-fluorouracil (5-FU) based concurrent chemoradiation. Retrospective clinical evaluation was performed in 165 patients (33% women and 67% men) with locally advanced rectal adenocarcinoma treated with preoperative radiotherapy or chemoradiotherapy in the period January 1998 - March 2003. Tumor extent was evaluated by CT and/or MRI and/or TRUS examination and tumor biopsy was performed during colonoscopy. The median follow up is 21 month. All patients received preoperative external beam radiation to primary tumor, adjacent lymphnodes and presacral region. Computed tomography localisation of target volume was used for 3D radiotherapy treatment planning. Accelerated short term regimen (25 Gy/5 fraction/1 week) was performed in 14% of patients especially in year 1998-2000 and normofractionated regimen (40-50 Gy/20-25 fractions/4-5 weeks) was performed in 86% of patients. Chemoradiotherapy with 5-FU was carried out in 22% of patients. Radical resection underwent 85% of patients, inoperable tumor persisted in 7% and distant metastases were detected peroperatively in 8%. The 2-year overall survival (OS) was 84% and 5-year OS was 60% following radical resection. The important prognostic factors affecting survival were postradiotherapy determined pathological staging (p=0.005), postradiotherapy tumor grade (p<0.001) and the presence of angioinvasion and/or perineural spread (p=0.023). Prognostic factors for disease-free survival were identical with those for OS. Higher local recurrence rate was associated in preradiotherapy tumor staged T4 (p=0.048) and in presence of angioinvasion and/or perineural spread (0.049). Age, tumor location, histological grade before radiotherapy and tumor downstaging were not statistically significant for survival and/or for local recurrence rate. The best survival rates were obtained in patients with postradiotherapy grade 1 tumors (5-years survival 100%), tumors without angioinvasion and perineural spread (5-years survival 65%) and in patients who obtained complete remission after preoperative radiotherapy (5-years survival 86%).

Predictors of local failure in early laryngeal cancer.

The aim of the study was to assess the impact of factors that could predict the probability of local failure in early laryngeal squamous cell carcinoma treated with curative radiotherapy. Sixty seven patients (12 women and 55 men) with laryngeal cancer stage I (47 patients) and stage II (20 patients) were treated from 1998 to 2003 with curative radiotherapy and retrospectively evaluated. Median follow-up was 36 months (3-80). Local relapse occurred in 10 patients (15%), regional lymphnodes relapse affected 2 patients. The median time between start of radiotherapy to recurrence was 13 months (3-48). Death due to cancer occurred in 4 patients (2 died from locoregional progression of the recurrence and 2 from distant metastases), whereas 7 patients died from non-cancer related causes. The 2-year overall survival rate was 90% and 5-year OS was 79%. The 2-year local control rate was 82% and 5-year local control was 79%. In the univariate analysis there was a statistically significant decrease in local control influenced by grading (p < 0.0001). High risk group of relapse encompassed patients with at least two negative factors: supraglottic tumor, women, radiotherapy prolongation by 3 or more days and high grade tumor and has 3 times worse local control than low risk group (p=0.0125). The highest risk of local recurrence was in the first three years after radiotherapy than later (p=0.0057). On multivariate analysis unfavourable prognostic factors for local control were gender (p=0.022), presence of 2 or more negative risk factors (p=0.018) and lengths of follow up (p=0.005). Radiation dose, stage, age, hemoglobin level and anterior commissure involvement were not significant factors for local control. Overall survival was affected both in the univariate and multivariate analysis by presence of local relapse (p < 0.005) and follow up duration (p < 0.02). Anemia had borderline significance for overall survival in univariate analysis (p=0.064), but in the multivariate analysis was significant unfavourable factor (p=0.008). Other studied factors (radiation dose, anterior commissure involvement and age) were not reaching level of statistical significant value for overall survival. Close follow up strategy is recommended for high risk group of patients with two or more risk factors especially in the first three years after radiation therapy.

Somatic mutations of KIT in familial testicular germ cell tumours.

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.