Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis

Hypoxia is a characteristic of many solid tumors and an adverse prognostic factor for treatment outcome. Hypoxia increases the expression of carbonic anhydrase IX, an enzyme that is predominantly found on tumor cells and is involved in maintaining the cellular pH balance. Many clinical studies investigated the prognostic value of carbonic anhydrase IX expression, but most have been inconclusive, partly due to small numbers of patients included. The present meta-analysis was therefore performed utilizing the results of all clinical studies to determine the prognostic value of carbonic anhydrase IX expression in solid tumors. Renal cell carcinoma was excluded from this meta-analysis due to an alternative mechanism of upregulation. 958 papers were identified from a literature search performed in Pubmed and Embase. These papers were independently evaluated by two reviewers and 147 studies were included in the analysis. The meta-analysis revealed strong significant associations between CAIX expression and all endpoints: overall survival (HR=1.76, 95%CI 1.58 – 1.98), disease-free survival (HR=1.87, 95%CI 1.62 – 2.16), locoregional control (HR=1.54, 95%CI 1.22 – 1.93), disease-specific survival (HR=1.78, 95%CI 1.41 – 2.25), metastasis-free survival (HR=1.82, 95%CI 1.33 – 2.50), and progression-free survival (HR=1.58, 95%CI 1.27 – 1.96). Subgroup analyses revealed similar associations in the majority of tumor sites and types. In conclusion, these results show that patients having tumors with high carbonic anhydrase IX expression have higher risk of locoregional failure, disease progression, and higher risk to develop metastases, independent of tumor type or site. The results of this meta-analysis further support the development of a clinical test to determine patient prognosis based on CAIX expression and may have important implications for the development of new treatment strategies

Reversal of the hanging protocol of Contrast Enhanced Mammography leads to similar diagnostic performance yet decreased reading times

Objectives: Contrast-enhanced mammography (CEM) was found superior to Full-Field Digital Mammography (FFDM) for breast cancer detection. Current hanging protocols show low-energy (LE, similar to FFDM) images first, followed by recombined (RC) images. However, evidence regarding which hanging protocol leads to the most efficient reading process and highest diagnostic performance is lacking. This study investigates the effects of hanging-protocol ordering on the reading process and diagnostic performance of breast radiologists using eye-tracking methodology. Furthermore, it investigates differences in reading processes and diagnostic performance between LE, RC and FFDM images. Materials and methods: Twenty-seven breast radiologists were randomized into three reading groups: LE–RC (commonly used hangings), RC-LE (reversed hangings) and FFDM. Thirty cases (nine malignant) were used. Fixation count, net dwell time and time-to-first fixation on malignancies as visual search measures were registered by the eye-tracker. Reading time per image was measured. Participants clicked on suspicious lesions to determine sensitivity and specificity. Area-under-the-ROC-curve (AUC) values were calculated. Results: RC-LE scored identical on visual search measures, t(16)= -1.45, p =.17 or higher-p values, decreased reading time with 31%, t(16)= -2.20, p =.04, while scoring similar diagnostic performance compared to LE-RC, t(13.2)= -1.39, p -.20 or higher p-values. The reading process was more efficient on RC compared to LE. Diagnostic performance of CEM was superior to FFDM; F (2,26)= 16.1, p <.001. Average reading time did not differ between the three groups, F (2,25)= 3.15, p =.06. Conclusion: The reversed CEM hanging protocol (RC-LE) scored similar on diagnostic performance compared to LE-RC, while reading time was a third faster. Abnormalities were interpreted quicker on RC images. A RC-LE hanging protocol is therefore recommended for clinical practice and training. Diagnostic performance of CEM was (again) superior to FFDM

A Phase I Study of Concurrent Individualized, Isotoxic Accelerated Radiotherapy and Cisplatin–Vinorelbine–Cetuximab in Patients With Stage III Non–Small-Cell Lung Cancer

Background:In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non–small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated.Methods:Patients with stage III non–small-cell lung cancer, World Health Organization performance status 0–1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine–carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m2 d1, 8; 40 mg/m2 d22)–vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m2 d1, 8 and 8 mg/m2 d22, 29; (2) 20 mg/m2 d1, 8 and 8 mg/m2 d22, 29; (3) 20 mg/m2 d1, 8; 15 mg/m2 d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography.Results:Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 ± 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients.Conclusion:C-CRT with cetuximab and cisplatin–vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m2 d7 and 250 mg/m2 weekly, cisplatin 50 mg/m2 d1, 8; 40 mg/m2 d22 and vinorelbine 20 mg/m2 d1, 8; 15 mg/m2 d22, 29 for 5 weeks together with RT

Radical Treatment of Non-Small-Cell Lung Cancer Patients with Synchronous Oligometastases Long-Term Results of a Prospective Phase II Trial (Nct01282450)

BackgroundStage IV non–small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available.MethodsA prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450.ResultsForty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44–81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6–19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6–14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and 18F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated.ConclusionIn this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed

What to choose as radical local treatment for lung metastases from cob-rectal cancer: Surgery or radiofrequency ablation?

Background: Long-term survival can be obtained with local treatment of lung metastases from colorectal cancer. However, it is unclear as to what the optimal local therapy is: surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SBRT). Methods: A systematic review included 27 studies matching with the a priori selection criteria, the most important being &gt;= 50 patients and a follow-up period of &gt;= 24 months. No SBRT studies were eligible. The review was therefore conducted on 4 RFA and 23 surgical series. Results: Four of the surgical studies were prospective, all others were retrospective. No randomized trial was found. The reporting of data differed between the studies, which led to difficulties in the analyses. Treatment-related mortality rates for RFA and surgery were 0% and 1.4-2.4%, respectively, whereas morbidity rates were reported inconsistently but seemed the lowest for surgery. Conclusion: Due to the lack of phase III trials, no firm conclusions can be drawn, although most evidence supports surgery as the most effective treatment option. High-quality trials comparing currently used treatment modalities such as SBRT, RFA and surgery are needed to inform treatment decisions

The impact of late treatment-toxicity on generic health-related quality of life in head and neck cancer patients after radiotherapy

SummaryTo examine the impact of late treatment-related xerostomia and dysphagia on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients after radiotherapy. A multi-center cross-sectional survey was performed. Patients with a follow-up of at least 6months after curative radiotherapy, without evidence of recurrent disease were eligible for inclusion. The Euroqol-5D questionnaire (EQ-5D) was filled out and toxicity was scored and converted to the RTOG scale. The EQ-5D measures generic HRQOL in terms of utility and visual analogue scale (VAS) scores. Missing data on the EQ-5D were imputed using multiple imputation. HRQOL was compared between subgroups of patients with and without toxicity. Subsequently, the impact of xerostomia and dysphagia on HRQOL was analyzed using multivariate regression analyses. Both analyses were performed separately for utility scores and VAS scores. The study population was composed of 396 HNC patients. The average utility and VAS scores were 0.85 (scale 0–1) and 75 (scale 0–100). Subgroups of patients with xerostomia and/or dysphagia showed statistically significantly lower utility and VAS scores (P=0.000–0.022). The multivariate regression model showed that xerostomia and dysphagia were negative predictors of both utility and VAS scores. Other factors which influenced HRQOL in at least one of the two regression models were: sex, tumor location and the addition of surgery to radiotherapy. Xerostomia and dysphagia diminish generic HRQOL. Moreover dysphagia affects patients’ HRQOL stronger than xerostomia

Proton and photon radiotherapy in stage III NSCLC:Effects on hematological toxicity and adjuvant immune therapy

Background and purpose: Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. Materials and methods: Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. Results: 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0–4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9–12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16–0.79, P = 0.01). Conclusion: IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab.</p

The usefulness and feasibility of a screening instrument to identify psychosocial problems in patients receiving curative radiotherapy: a process evaluation

<p>Abstract</p> <p>Background</p> <p>Psychosocial problems in cancer patients are often unrecognized and untreated due to the low awareness of the existence of these problems or pressures of time. The awareness of the need to identify psychosocial problems in cancer patients is growing and has affected the development of screening instruments. This study explored the usefulness and feasibility of using a screening instrument (SIPP: Screening Inventory of Psychosocial Problems) to identify psychosocial problems in cancer patients receiving curative radiotherapy treatment (RT).</p> <p>Methods</p> <p>The study was conducted in a radiation oncology department in the Netherlands. Several methods were used to document the usefulness and feasibility of the SIPP. Data were collected using self-report questionnaires completed by seven radiotherapists and 268 cancer patients.</p> <p>Results</p> <p>Regarding the screening procedure 33 patients were offered to consult a psychosocial care provider (e.g. social worker, psychologist) during the first consultation with their radiotherapist. Of these patients, 31 patients suffered from at least sub-clinical symptoms and two patients hardly suffered from any symptoms. Patients' acceptance rate 63.6% (21/33) was high. Patients were positive about the content of the SIPP (mean scores vary from 8.00 to 8.88, out of a range between 0 and 10) and about the importance of discussing items of the SIPP with their radiotherapist (mean score = 7.42). Radiotherapists' perspectives about the contribution of the SIPP to discuss the different psychosocial problems were mixed (mean scores varied from 3.17 to 4.67). Patients were more positive about discussing items of the SIPP if the radiotherapists had positive attitudes towards screening and discussing psychosocial problems.</p> <p>Conclusions</p> <p>The screening procedure appeared to be feasible in a radiotherapy department. In general, patients' perspectives were at least moderate. Radiotherapists considered the usefulness and feasibility of the SIPP generally to be lower, but their evaluations were mixed. A positive attitude to using screening instruments like the SIPP needs to be encouraged among radiotherapists, as this may not only improve the usefulness of a screening instrument, but also patients' satisfaction with care.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00859768">NCT00859768</a></p