Biochemical control in intermediate- and high-risk prostate cancer after EBRT with and without brachytherapy boost.

PURPOSE: External beam radiotherapy (EBRT) with or without brachytherapy boost (BTB) has not been compared in prospective studies using guideline-recommended radiation dose and recommended androgen-deprivation therapy (ADT). In this multicenter retrospective analysis, we compared modern-day EBRT with BTB in terms of biochemical control (BC) for intermediate-risk (IR) and high-risk (HR) prostate cancer. METHODS: Patients were treated for primary IR or HR prostate cancer during 1999-2019 at three high-volume centers. Inclusion criteria were prescribed ≥ 76 Gy EQD2 (α/ß = 1.5 Gy) for IR and ≥ 78 Gy EQD2 (α/ß = 1.5 Gy) for HR as EBRT alone or with BTB. All HR patients received ADT and pelvic irradiation, which were optional in IR cases. BC between therapies was compared in survival analyses. RESULTS: Of 2769 initial patients, 1176 met inclusion criteria: 468 HR (260 EBRT, 208 BTB) and 708 IR (539 EBRT, 169 BTB). Median follow-up was 49 and 51 months for HR and IR, respectively. BTB patients with ≥ 113 Gy EQD2Gy experienced a stable, good BC outcome compared with BTB at lower doses. Patients treated with ≥ 113 Gy EQD2Gy also experienced significantly improved BC compared with EBRT (10-year BC failure rates after ≥ 113 Gy BTB and EBRT: respectively 20.4 and 41.8% for HR and 7.5 and 20.8% for IR). CONCLUSIONS: In patients with IR and HR prostate cancer, BTB with ≥ 113 Gy EQD2Gy offered a BC advantage compared with dose-escalated EBRT and lower BTB doses.

Systemic treatment in patients with malignant pleural mesothelioma - real life experience.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural cavity linked to asbestos exposure. The combination of pemetrexed and platinum is a standard first-line therapy for malignant pleural mesothelioma. Despite some progress, almost all MPM patients experience progression after first-line therapy. The second-line treatment is still being under discussion and there are very limited data available on the second-line and subsequent treatments. METHODS: The retrospective analysis included 57 patients (16 females and 41 males) from two Polish oncological institutions treated for advanced mesothelioma between 2013 and 2019. We analysed the efficacy of first-line and second-line therapy: progression-free survival (PFS), overall survival (OS), overall response rate (ORR). RESULTS: In the first-line treatment, 55 patients received pemetrexed-based chemotherapy (PBC) and two cisplatin in monotherapy. Patients' characteristics at baseline: median age was 64.2 years, ECOG PS ≤ 1 (86.2%), epithelial histology (85.7%). Median PFS and OS were 7.6 months and 14 months, respectively. Patients with ECOG PS ≤ 1 vs > 1 had a longer median OS (14.8 months vs 9.7 months, p = 0.057). One-year OS and PFS were 60.9% and 32.0%, respectively. Disease control rate (DCR) was 82.5%. Response to first-line therapy: PFS ≥ 6 months and PFS ≥ 12 months had a significant impact on median OS. Twelve patients received second-line therapy (seven PBC and five other cytotoxic single agents: navelbine, gemcitabine, or adriamycin/vincristine/methotrexate triplet). Median PFS and OS were 3.7 months and 7.2 months, respectively. DCR was 83%. One-year OS and PFS were 37% and 16.7%, respectively. In the group receiving PBC, OS was prolonged by 4.5 months compared to the non-PBC group (6.0 months vs 10.5 months, p = 0.47). CONCLUSION: Patients who benefited from first-line therapy and had prolonged PFS at first-line and achieve PFS longer than 6 months at first-line should be offered second-line treatment. Consideration of retreatment with the same cytotoxic agent could to be a viable option when no other treatment are available.

Quantitative analysis of plasma DNA in anal cancer patients.

Introduction: The availability and non-invasiveness of circulating cell-free DNA (cfDNA) opens up new possibilities for real-time serial testing. The relationship between cfDNA concentration, clinical factors and suitability for monitoring was analyzed in patients with newly diagnosed anal squamous cell carcinoma (ASCC). Material and methods: Blood samples were collected at several points during and after treatment. Patients were homogeneously treated with chemoradiotherapy. Results: The concentration of cfDNA strongly correlated with the tumor volume (r = 0.9, p = 0.00006) and number of neutrophils (r = 0.706, p = 0.0069). Monitoring of cfDNA levels during treatment showed an increase after initiation of therapy, a peak at the end of treatment with significantly higher values for advanced than in T1/T2 tumors, and a decrease (T3/T4) during follow-up. However, neither the concentration of cfDNA before treatment nor its changes correlated with the response to chemoradiotherapy. There was no association between baseline cfDNA levels and T, N, age and gender. Conclusions: Substantial changes in plasma cfDNA content can be observed after chemoradiotherapy for ASCC. However, the small number of cases studied makes it difficult to assess the usefulness of the cfDNA test.

Chemotherapy and radiotherapy in locally advanced head and neck cancer: an individual patient data network meta-analysis.

BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRTP) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRTP (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (ICTaxPF-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and ICTaxPF followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or ICTaxPF-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Mathematical model predicts response to chemotherapy in advanced non-resectable non-small cell lung cancer patients treated with platinum-based doublet.

We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004-2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers.

Tumor regression grading after preoperative hyperfractionated radiotherapy/chemoradiotherapy for locally advanced rectal cancers: interim analysis of phase III clinical study.

We investigated the tumor regression grading (TRG) as a prognostic marker for disease-free survival (DFS) in patients with advanced rectal cancer treated within phase III randomized study (ClinicalTrials.gov Identifier: NCT01814969). The study is still recruiting prospective trial of preoperative hyperfractionated radiotherapy (HART) compared with concomitant hyperfractionated radiotherapy with co-administration of chemotherapy based on 5-FU (HART-CT) in patients with T2/N+ or T3/any N resectable rectal cancer. This preplanned interim analysis examined the pathological outcome in the group of 136 patients who were randomly assigned to HART (n=69) and HART-CT (n=67). The pelvis was irradiated twice a day (28 fractions of 1.5 Gy), with a minimal interfraction interval of 8 h to a total dose of 42 Gy over 18 days (HART) or mentioned scheme with concurrent chemotherapy: 5-FU 325 mg/m2 (bolus) on days 1-3 and days 16-18 (HART-CT). Surgery was performed 6-7 weeks after HART/HART-CT. Postoperative 5-FU-based chemotherapy was given to ypN positive patients. The TRG was recorded using the following 4-point scale: TRG0 (pCR) denoted no cancer cells; TRG1 was diagnosed when a few cancer foci had been seen in less than 10% of a tumor mass; TRG2 denoted cancer cells seen in 10-50% of a tumor mass; in order to diagnose TRG3, cancer cells had to be seen in more than 50% of a tumor mass. Multivariable analysis was performed using Cox regression models and Cox proportional hazard model was used in the survival analysis. The crude rate of patients with any serious acute 3 toxicity during the follow-up was 16% vs. 25% for HART and HART-CT. Twenty-two patients (16%) presented with postoperative complications. Anterior resection was performed in 52% vs. 62% for HART and HART-CT respectively (p=0.06). Of the 136 patients evaluable for pathologic response, there were 3 (4%) vs. 9 (13%), 16 (23%) vs. 24 (36%), 40 (58%) vs. 30 (45%), and 10 (15%) vs. 4 (6%) patients with TRG 0, 1, 2, and 3, respectively in HART vs. HART-CT, the difference was statistically significant p=0.002. The addition of 5-FU infusion to HART was not associated with statistically significant improved loco-regional relapse-free survival (LRC), metastasis-free survival (MFS), and DFS. Significant differences in the tumor regression grading (TRG) were found. Both LRC and DFS of rectal cancer patients treated with HART vs. HART-CT had favorable outcomes in the HART-CT arm. Also, the sphincter preservation rate tended to favor HART-CT.

Polymorphisms in EGFR Gene Predict Clinical Outcome in Unresectable Non-Small Cell Lung Cancer Treated with Radiotherapy and Platinum-Based Chemoradiotherapy.

For non-small cell lung cancer (NSCLC), radiotherapy (RT) and platinum-based chemotherapy (CHT) are among the main treatment options. On the other hand, radioresistance and cytotoxic drug resistance are common causes of failure. The epidermal growth factor receptor (EGFR) plays an important role in radioresponse and therapy resistance. We hypothesized that single nucleotide polymorphisms (SNPs) in the EGFR gene might affect individual sensitivity to these treatments, and thus, therapy outcome and prognosis. The association between functional EGFR SNPs and overall (OS), locoregional recurrence-free (LFRS), and metastasis-free (MFS) survival was examined in 436 patients with unresectable NSCLC receiving RT and platinum-based CHTRT. In a multivariate analysis, the rs712830 CC homozygotes showed reduced OS in the whole group (p = 0.039) and in the curative treatment subset (p = 0.047). The rs712829 TT genotype was strongly associated with decreased LRFS (p = 0.006), and the T-C haplotype was a risk factor for locoregional recurrence in our patients (p = 0.003). The rs2227983 GG alone and in combination with rs712829 T was an indicator of unfavorable LRFS (p = 0.028 and 0.002, respectively). Moreover, significant independent effects of these SNPs on OS, LRFS, and MFS were observed. Our results demonstrate that inherited EGFR gene variants may predict clinical outcomes in NSCLC treated with DNA damage-inducing therapy.

Overweight is associated with better prognosis in metastatic colorectal cancer patients treated with bevacizumab plus FOLFOX chemotherapy.

INTRODUCTION: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in metastatic CRC (mCRC). Whether BMI is a prognostic or predictive factor in mCRC is unclear. We aimed to assess efficacy outcomes according to BMI in patient with metastatic colorectal cancer treated with bevacizumab plus FOLFOX chemotherapy regimen in second-line treatment. MATERIAL AND METHODS: The analysis of 237 patients with metastatic colorectal cancer treated with bevacizumab plus FOLFOX in the second line (treated from January 2014 to August 2018) in 4 reference oncological centers in Poland. RESULTS: The median age of the patients was 65 years (range 34-82). The median overall survival (OS) and progression-free survival (PFS) of the all 237 patient was 14.6 and 8.8 months, respectively. Comparison of obese patient (BMI > 30 kg/m2) vs. overweight patients (BMI ≥ 25 to < 30 kg/m2) vs. normal BMI range patients revealed a significant improvement of median OS (17.5 vs. 14.3 vs. 13.1 months, p = 0.01) and median PFS (9.4 vs. 9.1 vs. 7.3 months, p = 0.03). The Cox hazard model showed that the BMI class is an important risk factor. However, the Cox model also showed that the significance of the BMI class applies only to patients with BMI < 25 kg/m2. This rule applies to both OS and PFS. The regression analysis also confirmed that there is a statistically significant relationship between the length of OS and PFS and the BMI value. Higher BMI was associated with a better prognosis. There were no differences in responses to treatment bevacizumab and FOLFOX chemotherapy and number adverse events according to BMI values. CONCLUSIONS: Patients with mCRC treated with chemotherapy with bevacizumab in second-line treatment with higher BMI compared with normal weight patients have better prognosis in terms of PFS and OS. In this group, we found no evidence of changes in safety profile depending on BMI. Nevertheless, further large randomized studies are needed to assess the body weight on the effectiveness of chemotherapy in combination with bevacizumab.

Blood serum proteins as biomarkers for prediction of survival, locoregional control and distant metastasis rate in radiotherapy and radio-chemotherapy for non-small cell lung cancer.

BACKGROUND: Several studies have documented that blood biomarkers can improve basic prognostic models in radiotherapy and radio-chemotherapy for non-small cell lung cancer. The current study evaluated the prognostic impact of six markers focusing on their utility in homogenous subsets, compared to the significance in a large heterogeneous group. METHODS: Blood samples of 337 patients who were referred for curative or palliative external beam thoracic radiotherapy for non-small cell lung cancer were collected. The concentration of osteopontin (OPN), vascular endothelial growth factor (VEGF), erythropoetin (EPO), high mobility group box 1 protein (HMGB1), insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF) in serum were measured by ELISA assay and the prognostic potential was assessed using univariable and multivariable survival models. RESULTS: Multivariable analysis revealed that out of several variables studied six dichotomized features: namely: cigarette smoking, lack of chemotherapy, palliative doses of radiotherapy, high OPN concentration, advanced T stage and high VEGF concentration had a highly significant (p < 0.005) and independent influence on overall survival in the group of 337 patients. In a subset of patients treated with curative radio-chemotherapy or radiotherapy (N = 148) tumor pathology, EPO concentration and VEGF concentration, significantly and independently influenced overall survival. In a subset of patients with squamous cell cancer (N = 206) OPN had a highly significant impact on overall survival. In contrast, in a subset of patients with nonsquamous histology (N = 131) only VEGF had a significant influence on survival. CONCLUSIONS: Blood serum proteins appear to be clinically useful prognosticators of overall survival in radio-chemotherapy and radiotherapy for non-small cell lung cancer. In unselected heterogeneous groups, dichotomized concentrations of OPN and VEGF emerged among the strongest independent prognosticators of overall survival. VEGF and EPO concentration (dichotomized) were found to be independent prognostic factors among the patients treated with curative doses of radiotherapy. The utility of OPN as a prognostic marker appeared restricted to the patients with squamous histology.

Immune checkpoint inhibitors therapy in older patients (≥ 70 years) with metastatic melanoma: a multicentre study.

INTRODUCTION: The use of immunotherapy in older patients remains challenging due to very few data on the efficacy and safety of treatment in this group. AIM: To analyse the efficacy and safety of immunotherapy with checkpoint inhibitors in older patients (≥ 70 years) with metastatic melanoma. MATERIAL AND METHODS: In the Maria Sklodowska-Curie Institute - Oncology Centre, between 2011 and 2017, 318 non-resectable or metastatic melanoma patients were treated with immune checkpoint inhibitors: anti-CTLA-4 or/and anti-PD-1. Eighty-two patients were ≥ 70 years (median age: 76 years; range: 70-90 years). Among this group 10% of patients had brain metastases, 24% of patients had BRAF mutant melanoma, and co-morbidities were present in 86% of patients (mainly hypertension, cardiovascular diseases and/or diabetes). RESULTS: Median PFS and OS were similar in patients < 70 years and ≥ 70 years. In the group of patients ≥ 70 years old, the 2-year OS rate (from the start of immunotherapy) was 27%, and in patients aged < 70 it was 28% (p = NS). Two-year progression-free survival was 13.7% in the group of patients ≥ 70 years old and in patients aged < 70 it was 13% (p = NS). Patients ≥ 70 years of age were significantly less likely to have a BRAF mutation (p = 0.020). The presence of co-morbidities was not associated with an increased risk of immunotherapy (p = 0.790). CONCLUSIONS: The survival and toxicity profile in the older patients treated with immune checkpoint inhibitors are similar to younger patients. Therefore, the age as a clinical factor should not exclude this population from the most effective therapy used nowadays in melanoma treatment.

Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis.

BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11 423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8). INTERPRETATION: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. FUNDING: Institut National du Cancer; and Ligue Nationale Contre le Cancer.

The VEGFR2, COX-2 and MMP-2 polymorphisms are associated with clinical outcome of patients with inoperable non-small cell lung cancer.

Certain common inherited variations in genes involved in tumor angiogenesis, progression and metastasis may contribute to cancer therapy outcome and prognosis by altering the gene expression and protein activity. In this report, we examined the effect of functional polymorphisms in MMP-1, MMP-2, MMP-3, VEGF, VEGFR2, FGFR4 and COX-2 genes on overall (OS) and progression-free survival (PFS) of 350 Caucasian patients with inoperable non-small cell lung cancer (NSCLC). The results of multivariate analysis indicated that VEGFR2 -906C and COX-2 -1195G alleles were strongly associated with poor OS and PFS (p = 0.002 and 0.015, respectively, for OS; p = 0.009 and 0.015, respectively, for PFS), while MMP-2 -1306 T allele carriers had significantly reduced PFS (p = 0.010). Moreover, an increased risk of death and progression was significantly associated with the number of adverse alleles for VEGFR2/COX-2 (p = 0.0005 for OS and 0.0006 for PFS in >1 adverse allele carriers) and VEGFR2/COX-2/MMP-2 combinations (p = 0.0003 for OS and 0.0001 for PFS in patients with >2 adverse alleles). Finally, VEGFR2 TC/CC, COX-2 AG/GG and MMP-2 CT/TT genotypes as well as "at risk" allele combinations were identified as independent predictors of unfavorable OS and PFS in the group. In conclusion, the data suggest that selected VEGFR2, COX-2 and MMP-2 polymorphisms may be potential prognostic markers in unresectable NSCLC treated with radiotherapy with or without chemotherapy, although further validation studies are warranted to confirm our observations.

The SIPA1 -313A>G polymorphism is associated with prognosis in inoperable non-small cell lung cancer.

Polymorphism in signal-induced proliferation-associated 1 (SIPA1) gene may contribute to the development of metastasis in human cancers. In this preliminary study, we examined the association of the SIPA1 -313A>G (rs931127) polymorphism with overall survival (OS) and progression-free survival (PFS) in 351 inoperable patients with non-small cell lung cancer (NSCLC) treated with radiotherapy or radiochemotherapy (curative or palliative). The GG homozygotes had significantly shorter PFS under codominant and recessive models in all patients (hazard ratio (HR) 1.47, p = 0.035, and HR 1.47, p = 0.022, respectively) and in advanced stage subgroup (HR 1.49, p = 0.037, and HR 1.48, p = 0.023, respectively). The GG genotype was also associated with reduced OS and PFS (codominant model: HR 2.41, p = 0.020, and HR 2.34, p = 0.020, respectively; recessive model: HR 2.16, p = 0.026, and HR 2.18, p = 0.022, respectively) in radiotherapy alone subgroup. Moreover, the SIPA1 -313GG was identified as an independent adverse prognostic factor for PFS in the cohort. Our results indicate, for the first time, that the SIPA1 -313A>G may have a prognostic role in unresected NSCLC making it a potential predictor of poor survival due to earlier progression.

Does routine clinical practice reproduce the outcome of large prospective trials? The analysis of institutional database on patients with limited-disease small-cell lung cancer.

We performed the analysis of database on 409 patients with LD-SCLC to evaluate as to what extent the clinical outcome of large prospective trials was reproduced in routine practice. The analysis has shown that the hazard rate of death in the absence of prophylactic cranial irradiation (PCI) adjusted for the effects of confounding factors, appeared larger than that reported in the trials on PCI in LD-SCLC, and was comparable to that estimated for extensive disease. Less intense routine staging procedures, compared to the trial settings, contributed for such outcome. Hyperfractionated thoracic radiotherapy provided survival advantage similar to that reported in the literature.

Early closure of phase II prospective study on acute and late tolerance of hypofractionated radiotherapy in low-risk prostate cancer patients.

AIM: To assess acute and late toxicity of hypofractionated radiotherapy, its efficacy and impact on quality of life in patients with low-risk prostate cancer. MATERIALS AND METHODS: Since August 2006 to October 2007, 15 prostate cancer patients with favorable clinical features, aged 54-74 years (mean 67 years) entered the study. Tumor stage in the majority (73%) of patients was T2a, the mean pretreatment PSA value was 7.2 ng/ml (range 5-10.9 ng/ml). The study group was treated 3 times a week with 4 Gy per fraction to the total dose of 60 Gy within 5 weeks. 3D conformal treatment planning was used with no fiducial markers. Acute and late toxicity was evaluated using modified EORTC/RTOG/LENT scoring systems. Patients regularly filled the EORTC QLQ-PR25 questionnaires. RESULTS: All patients completed radiotherapy according to the plan. During radiotherapy, 26% of patients had grade 1-2 rectal symptoms. The incidence of acute urinary toxicity score was 26%, 60%, and 14% for grade 0-1, 2 and 3, respectively. One year after RT, the incidence of grade 2 GI toxicity was 27%, which was the reason for an early closure of the accrual. Grade 2 late urinary toxicity was noted in 20% of patients. The mean PSA level was 0.61 ng/ml after 24 months and 0.47 ng/ml after 36 months (range: 0.06-1.54 ng/ml). CONCLUSIONS: Low number of patients does not allow to determine the influence of hypofractionation on unsatisfactory tolerance of this regimen. Suboptimal (from the present day's perspective) target localization (no fiducial markers) could potentially explain higher than expected late GI reactions in our series.

Pretreatment plasma osteopontin level as a marker of response to curative radiotherapy and hormonal treatment for prostate cancer.

BACKGROUND AND PURPOSE: Osteopontin is a known marker for tumour hypoxia with relevance for the outcome of radiotherapy. We analysed the plasma concentration of OPN in prostate cancer patients receiving RT with or without ADT to evaluate OPN as a potential marker of treatment response. MATERIALS AND METHODS: Between 2012 and 2014, 274 patients with prostate cancer qualifying for RT were enrolled to the study. SCADT received 34.3 % of patients, LCADT 46.3 %. The median OPN concentration was 83.9 ng/mL. We analysed the groups by OPN level: group A with OPN below and group B with OPN above the median. RESULTS: There was a significant difference in OPN between the Gleason score (p = 0.005), the D'Amico risk (p = 0.002), the ADT (p < 0.001) and the RT (p = 0.019) groups. We found a positive correlation between OPN and clinical stage (p = 0.042). There were no significant effect of OPN on bRFS, RFS and MFS. The 10-year OS rate for group A was 81 % and for group B 60 % (p < 0.001). Cox analysis showed that low OPN level (p < 0.001), low age (p = 0.002) and low Gleason score (p = 0.038) were associated with higher OS. The prognostic influence of OPN on survival decreased with duration of ADT with the strongest effect of OPN (HR=3.93) observed when RT alone was used, weakest effect (HR=2.48) for SCADT and the smallest effect (HR=2.09) for LCADT. CONCLUSIONS: Based on the obtained results, we assume that the level of OPN measured before the start of radiotherapy may be an independent predictor of OS of patients with prostate cancer treated with radiotherapy with and without ADT.

Randomized clinical trial on accelerated preoperative hyperfractionated radiotherapy versus preoperative hyperfractionated radio-chemotherapy in locally advanced rectal cancer.

OBJECTIVES: The aim of this study was to compare pathological response rates after preoperative hyperfractionated radiotherapy with co-administration of chemotherapy based on 5FU (HART-CT) versus preoperative hyperfractionated radiotherapy (HART) in patients with resectable rectal cancer. METHODS: Patients with T2/N+ or T3/any N rectal cancer were randomized either to HART twice a day (28 fractions of 1.5 Gy) to total dose 42 Gy or to HART-CT. Tumour regression grade was postoperatively assessed according to the 4-point scale as recommended by the American Joint Committee on Cancer (AJCC). The secondary endpoints included overall survival (OS), disease-free survival (DFS), toxicity of preoperative treatment, locoregional, and distant failure rates. There were 187 patients eligible for analysis: 95 in HART and 92 in the HART-CT. Median follow-up was 5.6 years. RESULTS: The analysis demonstrated a significantly higher chance of achieving pathologic complete response in HART-CT arm: complete response was achieved in 4/95, 4% (HART) and 11/92, 12% (HART-CT) (P = .045). The differences in OS and DFS, while tending to favour HART-CT, were not significant: OS (P = .13, hazard ratio [HR] = 0.82, 95% CI, 0.63-1.06) and DFS (P = .32; HR = 0.88, 95% CI, 0.69-1.13). The locoregional failure and distant metastases rates did not statistically differ between the trial arms. The rate of late complications was similar (P = .51), grade 3+ being 8% versus 11% in the HART/HART-CT group, respectively. CONCLUSIONS: The hyperfractionated preoperative radiotherapy with concurrent 5-Fu-based chemotherapy (HART-CT) improved pathological response rate compared to HART. This translated into favourable OS and DFS in HART-CT, but the differences did not reach the threshold for significance. ADVANCES IN KNOWLEDGE: A new hyperfractionated chemo-RT scheme is proposed. Histopathological major response (TRG 0-1) is associated with better clinical outcome.

Distribution characteristics and prognosis of tumor-infiltrating lymphocytes in the brain metastases of small cell lung cancer: a retrospective cohort study.

Background: The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still unknown. Therefore, we investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastases from SCLC to explore the tumor microenvironment of SCLC brain metastases. Methods: A retrospective analysis was performed on 12 surgical specimens of brain metastases from patients with SCLC treated in the Department of Neurosurgery of The First Affiliated Hospital of Anhui Medical University from June 2017 to June 2022. The inclusion criteria for this study were the following: (I) a pathologically confirmed diagnosis of SCLC brain metastases; (II) surgical resection of brain metastases; (III) age >18 years; (IV) and complete clinical data. Patient-related data were retrieved from the inpatient medical record system, telephone follow-up of patients date of death, and overall survival (OS). The immunofluorescence-based tissue microenvironment analysis panel (MAP) was utilized for the detection of TILs, including CD3, CD8, programmed cell death 1 (PD-1), and PD-L1, in formalin-fixed and paraffin-embedded archival specimens of brain metastases. The expression levels of PD-L1 in tumor cells were detected by immunohistochemistry. The correlation between the OS and the above-mentioned markers was analyzed in the 12 patients. Results: Twelve patients were included in the study. The patients' ages ranged from 51-78 years with a median of 68 years, with 1 female and 11 males. Among 12 patients with SCLC brain metastases: positive rates of CD3+ TILs in the tumor parenchyma vs. tumor stroma were 0.60%±0.94% vs. 1.76%±2.72% (P=0.01), respectively; positive rates of CD8+ TILs in the tumor parenchyma vs. tumor stroma were 0.80%±0.78% vs. 2.46%±3.72% (P=0.02), respectively. There was no co-expression of CD8+ and PD-1+ TILs in the tumor parenchyma of 11 cases, and the infiltration density of coexpressed CD3+ and PD-1+ TILs was more than 10/mm2 in only 1 case. There was no coexpression of CD3+ and PD-1+ TIL in the stroma of 10 cases, and the infiltration density of CD8+ and PD-1+ TILs was more than 10/mm2 in 2 cases. Immunohistochemistry was used to detect the expression of PD-L1 in 12 cases of SCLC metastatic lesions, and 3 cases (25%) were positive. Survival analysis showed that patients with positive intraepithelial CD3+ TILs had significantly longer OS [hazard ratio 3.383, 95% confidence interval (CI): 0.959-11.940; P=0.04]. Conclusions: Our study further demonstrated the immune microenvironment of SCLC brain metastases. The distribution of TILs in SCLC brain metastases is low and mainly distributed in the stroma, with the expression of PD-L1 in these tumor tissues being low. Further exploration of the immune microenvironment of SCLC brain metastases is of great significance for potential treatment.

Circulating HPV16 DNA in Blood Plasma as Prognosticator and Early Indicator of Cancer Recurrence in Radio-Chemotherapy for Anal Cancer.

BACKGROUND: Implementation of anal squamous cell carcinoma (ASCC) treatment modifications requires reliable patient risk stratification. The circulating tumor-related human papillomavirus type 16 (ctHPV16) may play a role in predicting survival or assessing treatment response. METHODS: The study included 62 ASCC patients treated with chemoradiotherapy. A threshold of 2.5 was used to determine the maximum standardized uptake value (SUVmax). The ctHPV16 viral load (VL) was quantified by qPCR. RESULTS: In the multivariate Cox analysis, lower SUVmax (p = 0.047) and ctHPV16-positive (p = 0.054) proved to be independent prognostic factors for favorable overall survival (OS). In the subgroup with the higher SUVmax, ctHPV16 and nodal (N) status were independent prognostic factors with p = 0.022 for ctHPV16 and p = 0.053 for N. The best survival rate (95%) presented ctHPV16-positive/N-negative patients. High ctHPV16 VL tended to be slightly specific for patients younger than 63 years (p = 0.152). The decrease in ctHPV16 VL to undetectable level after the end of treatment correlated with the overall clinical response. CONCLUSIONS: A prognostic stratification by SUVmax, ctHPV16 and N-positive status allows consideration of more aggressive treatment in high-risk patients (those with high SUVmax, ctHPV16-negative, and N-positive) or de-intensification of therapy in low-risk patients (those with low SUVmax, ctHPV16-positive and N-negative). However, prospective clinical trials on a large group are needed.

Common Variants in Osteopontin and CD44 Genes as Predictors of Treatment Outcome in Radiotherapy and Chemoradiotherapy for Non-Small Cell Lung Cancer.

Osteopontin (OPN)-CD44 signaling plays an important role in promoting tumor progression and metastasis. In cancer, OPN and CD44 overexpression is a marker of aggressive disease and poor prognosis, and correlates with therapy resistance. In this study, we aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in the OPN and CD44 genes with clinical outcomes in 307 non-small cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. The potential impact of the variants on plasma OPN levels was also investigated. Multivariate analysis showed that OPN rs11730582 CC carriers had a significantly increased risk of death (p = 0.029), while the CD44 rs187116 A allele correlated with a reduced risk of locoregional recurrence (p = 0.016) in the curative treatment subset. The rs11730582/rs187116 combination was associated with an elevated risk of metastasis in these patients (p = 0.016). Furthermore, the OPN rs1126772 G variant alone (p = 0.018) and in combination with rs11730582 CC (p = 7 × 10-5) was associated with poor overall survival (OS) in the squamous cell carcinoma subgroup. The rs11730582 CC, rs187116 GG, and rs1126772 G, as well as their respective combinations, were independent risk factors for unfavorable treatment outcomes. The impact of rs11730582-rs1126772 haplotypes on OS was also observed. These data suggest that OPN and CD44 germline variants may predict treatment effects in NSCLC.