D. Schallier

Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu

Human epidermal growth factor receptor (HER)2/neu kinase domain mutations are found in approximately 1-4% of lung adenocarcinomas with a similar phenotype to tumors with epidermal growth factor receptor (EGFR) mutations. Afatinib is a potent irreversible ErbB family blocker. We determined the tumor genomic status of the EGFR and HER2 genes in non- or light smokers with lung adenocarcinoma in patients who were entered into an exploratory Phase II study with afatinib. Five patients with a non-smoking history and metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene were identified, three of which were evaluable for response. Objective response was observed in all three patients, even after failure of other EGFR- and/or HER2-targeted treatments; the case histories of these patients are described in this report. These findings suggest that afatinib is a potential novel treatment option for this subgroup of patients, even when other EGFR and HER2 targeting treatments have failed.

Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC)

BACKGROUND 18FDG-PET and multislice computerized axial tomography (CT) scan are used for diagnosis, staging and response evaluation in NSCLC patients. The correlation between the response assessment by both imaging techniques and survival was assessed in patients with unresectable stage III NSCLC treated with induction chemotherapy followed by consolidation radiotherapy. METHODS Thirty-one patients, enrolled in a phase II study evaluating the efficacy and toxicity of a novel triplet induction chemotherapy (paclitaxel, carboplatin and gemcitabine) (PACCAGE) before consolidation radiotherapy, were evaluated by CT and 18FDG-PET at baseline and after three cycles of chemotherapy. The correlation between CT and 18FDG-PET response and time to progression and overall survival was analyzed using the Kaplan-Meier estimates of survival and the log rank test. RESULTS Ten patients with a complete response (CR) on 18FDG-PET had a significantly longer time to progression and overall survival than patients with a non-CR (median 19.9 months versus 9.8 months, p=0.026, and median >49 months versus 14.4 months, p=0.004, respectively). Twenty patients with a partial CT response (PR) had a significantly longer time to progression (median 15 months versus 9.4 months, p=0.001) than patients with a non-PR but the difference in overall survival only showed a trend (23.3 months versus 14.4 months, p=0.093). CONCLUSIONS A CR on 18FDG-PET following induction chemotherapy for locally advanced, unresectable NSCLC seems to be a more powerful prognostic marker for survival compared to PR on CT.

Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients

BACKGROUND Stereotactic body radiotherapy (SBRT) has emerged as a treatment modality in patients presenting with oligometastatic nonsmall-cell lung cancer (NSCLC). SBRT is used as a local consolidative treatment to metastatic disease sites. The majority of patients included in SBRT trials for oligometastatic NSCLC have controlled primary tumors and brain metastases. PATIENTS AND METHODS Oligometastatic NSCLC patients with ≤5 metastatic lesions were included in a prospective phase II trial to evaluate efficacy and toxicity of SBRT to all disease sites, primary tumor and metastatic locations. SBRT to a dose of 50 Gy in 10 fractions was delivered. Positron emission tomography-computed tomography (PET-CT) was carried out at baseline and 3 months after SBRT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST). The progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method from start of chemotherapy or radiotherapy. Side-effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. RESULTS Twenty-six patients received SBRT after induction chemotherapy (n = 17) or as a primary treatment (n = 9). Median follow-up was 16.4 months. Overall metabolic response rate was 60% with seven patients (30%) achieving a complete metabolic remission and 7 (30%) a partial metabolic response. Any acute grade 2 toxicity was observed in four patients (15%) and grade 3 pulmonary toxicity in two patients (8%). Median PFS and OS were 11.2 and 23 months. The 1-year PFS and 1-year OS rate were 45% and 67%, respectively. CONCLUSION SBRT to all disease sites, primary tumor and metastatic locations, in oligometastatic NSCLC patients produced an acceptable median PFS of 11.2 months.

Tolerance of adjuvant letrozole outside of clinical trials

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

Methylprednisolone as an antiemetic drug

SummaryTo evaluate the antiemetic efficacy of high-dose methylprednisolone (MP) in previously untreated cancer patients receiving cisplatin (CPDD) for the first time, we performed a randomized double blind study. MP or a placebo (PLB) was administered six times during each course of chemotherapy. The first dose was 500 mg and all others, 250 mg. A total of 30 patients were included and studied during three chemotherapy courses. No significant differences were found between the MP- and PLB-treated group with respect to the number of emetic episodes and degree of nausea. There was also no difference for pain, appetite, nausea, vomiting, sleep, weakness, or energy level as analyzed by the use of a Linear Analog Self-Assessment (LASA) scale up to 7 days after chemotherapy. On the other hand, the assessment of well-being, anxiety, and mood favored the PLB group.We conclude that high-dose MP used as a single antiemetic medication against CPDD-induced nausea and vomiting is of only limited value or none at all.

Gefitinib monotherapy in advanced nonsmall cell lung cancer: a large Western community implementation study

Epidermal growth factor receptor tyrosine kinase inhibitors represent a new treatment option for patients with advanced nonsmall cell lung cancer (NSCLC). This retrospective study examined to what extent previous clinical trial experience matches large-scale Western community implementation of this treatment. In the Belgian expanded access programme, the data from 513 patients with advanced or metastatic NSCLC, not suitable for further chemotherapy and receiving oral gefitinib 250 mg·day-1 until disease progression, death or unacceptable toxicity, were analysed. The median (range) duration of gefitinib treatment was 2.3 months (0.0–32.7). Its use was predominantly in second- or third-line treatment. The overall response and disease control rates were 8.9 and 41.2%, respectively. In univariate analysis, response was more common in females and never-smokers. In multivariate analysis, female sex was the only significant predictive factor (odds ratio (OR) (95% confidence interval (CI)) 0.329 (0.129–0.839)). Symptom improvement was reported in 108 patients of whom 32 (29.6%) had an objective response, 66 (61.1%) experienced disease stabilisation and 10 (9.3%) progressed. Gefitinib was well tolerated; only 7.8% of the patients reported grade 3 or 4 toxicity. The overall median survival was 4.7 months, with a 1-yr survival rate of 21%. Survival was strongly influenced by a better performance status (PS) (good PS: hazard ratio (HR) (95%CI) 0.110 (0.077–0.157)) and adenocarcinoma with bronchioloalveolar carcinoma features histology (HR (95%CI) 0.483 (0.279–0.834)). In conclusion, the activity of gefitinib was confirmed in the present large Western community implementation study. Response, present in a small subgroup, led to a rewarding survival and could be predicted by sex only. Baseline performance status and adenocarcinoma with bronchioloalveolar carcinoma features histology were significant factors for survival.

Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastasis in limited squamous cell lung cancer? A randomized study

In order to study the usefulness of treatment with vinblastine (VLB) in the prevention of cancer metastasis in squamous cell lung cancer, 50 patients with locoregional disease were randomized to receive either locoregional RT alone (group A) or a weekly intravenous bolus injection of VLB (6 mg/m2) concurrently with and after locoregional radiotherapy (RT) (55 Gy in 6 weeks) until the appearance of metastases (group B). Neither the incidence of death with metastases, metastasis-free survival (MFS) nor overall survival (S) were significantly affected by treatment with the drug. However, due to the limited number of patients in each group, the power of the statistical test was such to allow only the detection of differences in MFS and S to or more than 80 per cent at theP=0.05 level. Local tumor response was significantly superior in group B (P<0.05). Acute toxicity (dysphagia, myelosuppression) during RT was significantly worse in group B. During long-term therapy with VLB, mild polyneuropathy developed in the majority of patients in group B. Furthermore, seven patients discontinued treatment with VLB during maintenance due to compliance (4) and excessive neurotoxicity (3).This treatment schedule with VLB is not recommended for patients with locoregional squamous cell lung cancer as significant toxicity is present during and after RT and significant increase in MFS and S is lacking. Because of an apparent increase in local response, the combination of VLB and RT merits further investigation in those tumors where local tumor control is crucial.

Abiraterone acetate post-docetaxel for metastatic castration-resistant prostate cancer in the Belgian compassionate use program

BACKGROUND Abiraterone acetate (AA) is licensed for treating metastatic castration-resistant prostate cancer (mCRPC). Real-world data on oncological outcome after AA are scarce. The current study assesses efficacy and safety of AA in mCRPC patients previously treated with docetaxel who started treatment during the Belgian compassionate use program (January 2011-July 2012). PATIENTS AND METHODS Records from 368 patients with mCRPC from 23 different Belgian hospitals who started AA 1000mg per day with 10mg prednisone or equivalent were retrospectively reviewed (September 2013-December 2014). Prostate-specific antigen (PSA) response (decrease≥50%), time to PSA progression (increase>50% over PSA nadir in case of PSA response/>25% in absence of PSA response), time to radiographic progression (on bone scans or for soft tissue lesions using Response Evaluation Criteria In Solid Tumors 1.1), overall survival and adverse event rate (Common Terminology Criteria for Adverse Events v4.03) were analyzed. Kaplan-Meier statistics were applied. RESULTS Overall, 92 patients (25%) had an Eastern Cooperative Oncology Group performance status≥2. Median age was 73 years, median PSA was 103ng/dl. PSA response was observed in 131 patients (37.4%). Median time to PSA and radiographic progression was 4.1 months (95% CI: 3.6-4.6) and 5.8 months (5.3-6.4), respectively. Median overall survival was 15.1 months (13.6-16.6). Most common grade 3 to 4 adverse events were anemia (13.9%), hypokalemia (7.3%), fatigue (6.8%), and pain (6.3%). Median duration of AA treatment was 5.3 months (interquartile range: 2.8-10.3). The main study limitation is its retrospective design. CONCLUSIONS These real-world data on post-docetaxel AA efficacy are in line with the COU-AA-301 trial. Importantly, incidence of severe anemia and hypokalemia is up to 50% higher than reported in previous studies.

Idiopathic familial hemochromatosis: limited disease extent with prolonged survival and arthritis

SummaryThree siblings with idiopathic hemochromatosis are presented. They are remarkable because of the particularly benign disease and absence of typical HLA phenotype in the index case. In only one of the patients is the glucose tolerance disturbed. This case also has an HLA A3 phenotype. A typical hemochromatosis arthropathy is described in two patients. Following venesection a subjective improvement of the arthritis was reported by one patient.

Abstract P1-13-06: Correlation between aromatase-induced arthralgia and inflammatory cytokines in postmenopausal patients with early breast cancer treated with surgery followed by adjuvant hormone therapy: A prospective open-label single center study

Introduction: Nine randomized trials in early breast cancer(EBC) have demonstrated an advantage of aromatase inhibitors(AI’s) over tamoxifen in disease-free survival. Joint symptoms are common toxicities and lead to treatment interruption in up to 20% in case of severe aromatase-induced arthralgia(AIA). During menopause levels of markers of inflammation such as IL-1b, TNF-alpha and IL-6 increase. We hypothesized that estrogen deprivation by aromatase inhibition could be associated with similar changes in these markers and that this could play a role in AIA. In an earlier study, similar toxicities were observed in patients(pts) treated with a recombinant form of IL-6. In several cell types it has been shown that ligand activated estrogen receptor blocks nuclear factor kappa beta controlled gene transcription of IL-6. Aim of the study: We initiated a prospective open-label study to examine the role of inflammatory cytokines and other serum markers(CRP and hormones) in the pathogenesis of AIA. Methods: 29 evaluable postmenopausal pts with hormone sensitive, Her 2 negative EBC stage I-III, with baseline G0-1 arthralgia were included. Before chemotherapy, at baseline, at month 3, 6, 9, 12 and 18 after AI initiation, serum samples were taken for CRP and hormones (estradiol, androstenedion) and cytokines were analyzed with a human cytokine 25-plex panel. A detailed rheumatologic questionnaire and Visual Analog Scale(VAS) was performed at each visit. Arthralgia grading was assessed using the CTCAE criteria 4.0. The T-test and the Wilcoxon Signed Rank test were used to look for the difference in terms of IL-6, Il-1b, IL-8, TNF, CRP, estradiol and androstenedion between G0 versus G1-2-3 arthralgia. Results: The mean age was 56 yrs. (34-72yrs). All patients were treated with surgery followed by concomitant chemoradiation and letrozole (31) or anastrazole (1). In 16 pts G1 arthralgia was present before the start of the chemotherapy. Grade 2 and 3 arthralgia appeared at mth 3. The proportion of pts with grade 2 remained more or less the same, while grade 3 pts declined from month 6 onwards and disappeared at month 18. There was a significant correlation between the grade of arthralgia and the VAS score at all-time points (p Conclusion: This study indicates that both menopause and AIA have inflammatory mediators (IL6 and CRP) that correlate with the degree of lowering of estradiol levels. This is consistent with the regulation of IL-6 by the ligand activated ER through NFkB in vitro. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-06.