PURPOSE It is hypothesized that cisplatin-based chemotherapy (CBCT) reduces the occurrence of metachronous contralateral (second) germ cell testicular cancer (TC). However, studies including treatment details are lacking. The aim of this study was to assess the second TC risk, emphasizing the impact of previous TC treatment. PATIENTS AND METHODS Based on the Cancer Registry of Norway, 5,620 men were diagnosed with first TC between 1980 and 2009. Treatment data regarding TC were retrieved from medical records. Cumulative incidences of second TC were estimated, and standardized incidence ratios were calculated. The effect of treatment intensity was investigated using Cox proportional hazard regression. RESULTS Median follow-up was 18.0 years, during which 218 men were diagnosed with a second TC after median 6.2 years. Overall, the 20-year crude cumulative incidence was 4.0% (95% CI, 3.5 to 4.6), with lower incidence after chemotherapy (CT) (3.2%; 95% CI, 2.5 to 4.0) than after surgery only (5.4%; 95% CI, 4.2 to 6.8). The second TC incidence was also lower for those age ≥ 30 years (2.8%; 95% CI, 2.3 to 3.4) at first TC diagnosis than those age < 30 years (6.0%; 95% CI, 5.0 to 7.1). Overall, the second TC risk was 13-fold higher compared with the risk of developing TC in the general male population (standardized incidence ratio, 13.1; 95% CI, 11.5 to 15.0). With surgery only as reference, treatment with CT significantly reduced the second TC risk (hazard ratio [HR], 0.55). For each additional CBCT cycle administered, the second TC risk decreased significantly after three, four, and more than four cycles (HRs, 0.53, 0.41, and 0.21, respectively). CONCLUSION Age at first TC diagnosis and treatment intensity influenced the second TC risk, with significantly reduced risks after more than two CBCT cycles.

Lung cancer is the leading cause of cancer related death, and the past years’ improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse‐free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer‐related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA‐repair genes and the total number of mutations in that tumour (p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.

ABSTRACT Background In patients with locally advanced, inoperable NSCLC and negative prognostic factors, treatment will be of palliative intent. Platinum-based chemotherapy and thoracic radiation are both well documented, but the role of chemoradiation has not been established. Objective: Will concomitant radio- and chemotherapy (chemoradiation), when compared to chemotherapy alone, be superior with respect to survival and health-related quality of life (HRQOL) in patients with incurable NSCLC stage III (negative prognostic factors)? Methods Stage III NSCLC patients, not eligible for curative radiotherapy due to tumor size ≥ 8 cm or performance status 2 or weight loss ≥ 10 % during the last 6 months, were randomized to receive either chemoradiation or chemotherapy alone. Chemotherapy consisted of 4 cycles of carboplatin iv day 1 and vinorelbine po day 1 and 8, with 3-week intervals. Patients in the chemoradiation arm also received radiotherapy with fractionation 42 Gy/2.8 Gy, starting at the 2nd chemo course. The primary endpoint was overall survival. Secondary endpoints were HRQOL and toxicity. Results 191 patients from 25 Norwegian hospitals were randomized from Nov 2006 until Nov 2011, when enrollment was terminated due to slow accrual. Median age was 67 years and 20% had PS 2. In the chemotherapy versus the concomitant arm, the median overall survival was 9.7 and 13.3 months, respectively (p Conclusions Of the 2 investigated treatment regimens; chemoradiation was superior to chemotherapy alone with respect to both survival and global HRQOL, at the expense of more hospital admissions due to toxicity. Disclosure All authors have declared no conflicts of interest.

Background: Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination. Methods: Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0–2. Patients received up to three cycles of vinorelbine 60 mg m −2 p.o.+gemcitabine 1000 mg m −2 i.v. day 1 and 8 (VG) or vinorelbine 60 mg m −2 p.o. day 1 and 8+carboplatin area under the curve=5 (Calvert's formula) i.v. day 1 (VC). Patients ⩾75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy. Results: We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P =0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P =0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P <0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups. Conclusion: The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile.

Introduction: To compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting HER2 alterations and to investigate the prevalence and prognostic significance of Erb family members in non-small cell lung cancer (NSCLC).Methods: Stage I to IIIA tumors from 335 patients with NSCLC were immunohistochemically tested for protein expression of all Erb family members. Membranous HER2 expression was compared with its gene copy number by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with clinicopathological variables.Results: Synchronous high immunohistochemical expression of all Erb family members was seen in 8% of tumor samples. There was a significant correlation between the HER2 gene copy number and HER2 protein expression (p = 0.003). High nuclear HER3 expression correlated significantly with high HER2 gene copy numbers (p = 0.015). In univariate analyses, high HER2 gene copy number was a highly significant negative prognostic indicator for disease-specific survival in women (p = 0.005), whereas it did not show prognostic influence in men (p = 0.9). Neither polysomy of chromosome 17 nor the IHC expression of Erb family member proteins as singles or pairs correlated significantly with survival. In the multivariate analysis, high HER2 gene copy number in tumor epithelial cells (p = 0.03) was an independent prognostic factor for disease-specific survival in female patients.Conclusions: IHC does not consistently identify patients likely to have a poor prognosis, whereas SISH provides superior prognostic information for female patients with NSCLC. High HER2 gene copy number in tumor epithelial cells is an independent predictor of inferior survival in female patients with primary NSCLC.

Unsere Studie wurde durchgeführt, um die Ergebnisse einer japanischen Studie mit Irinotecan+Cisplatin versus Etoposid+Cisplatin zu reproduzieren.

7517 Background: A prospective, randomized, multicentre study was conducted to compare pemetrexed + carboplatin (PC) with a standard regimen, gemcitabine + carboplatin (GC). Methods: Chemonaive patients with verified non-small cell lung cancer, stage IIIB (ineligible for curative radiotherapy) or stage IV, WHO performance status (PS) 0–2, adequate hematology and creatinine-clearance > 45 ml/min were eligible. All patients were supplemented with folic acid 0.4 mg OD and vitamin B12 1 mg IM every 9 weeks, from >= 5 days before and through the treatment period. Patients were randomized to receive either pemetrexed 500 mg/m2 + carboplatin AUC=5 (Calvert) day 1 or gemcitabine 1,000 mg/m2 day 1 & 8 + carboplatin AUC=5 (Calvert) day 1. Maximum 4 courses every 3 weeks were given. Primary endpoints: QoL defined as global health status, nausea/vomiting, dyspnea and fatigue - measured by the EORTC QLQ-C30 and LC13 before every cycle and 3 & 11 weeks after the last cycle. Secondary endpoints: Overall survival (OS) and toxicity measured by the CTCAE v3.0. Stratification was done for age (−75 vs +75 years), stage (IIIB vs IV) and PS (0–1 vs 2). 190 evaluable patients in each arm were required to detect a 15% improvement on predefined QoL parameters with an a of 0.05 and β of 0.80. A 15% loss to follow up was expected. Results: 446 patients were included from Apr 05 - Jul 06. The two arms were well balanced with respect to age, sex, stage, PS and histological classification. 436 patients were eligible for the primary QoL-analyses. No statistical significant differences in mean score of the QoL-scales were observed between the arms. So far, 384 patients have been analysed for toxicity. Significantly more patients in the GC arm experienced grade 3–4 thrombocytopenia (48 vs 107, p<0.001), leucopenia (44 vs 89, p<0.001) and granulocytopenia (78 vs 98, p=0.02). No difference in the frequency of neutropenic fever was recorded. More patients in the GC arm received transfusion of platelets (5 vs 19, p=0.02). At present, 291 patients are deceased. We expect to present complete OS analyses for a minimum of 380 patients at the annual meeting. Conclusions: No differences were detected between the two arms with respect to the primary QoL outcome. Patients in the PC arm experienced less toxicity. No significant financial relationships to disclose.

127 men with previously untreated non-seminomatous germ cell tumours (NSGCT) of the testis were given BEP chemotherapy (bleomycin, etoposide and cisplatin) between 1979–1986. Long-term follow-up (median 65 months) has shown an overall 5 year survival of 87.2% (95% confidence limits 81.1%–93.3%). Outcome was related to both tumour volume and serum marker levels of alpha-fetoprotein (αFP) and beta human chorionic gonadotropin (HCG), with 5 year actuarial survivals of 97.8%, 72.2% and 26.7% respectively for small, large and very large volume disease defined by Medical Research Council criteria, and 91.2% and 60.8%, respectively, for men with low (αFP≤500 kU/l and HCG≤1000iU/l) or high serum marker levels. 79 men (62%) had a complete radiological and serum marker response to chemotherapy alone; residual masses postchemotherapy were resected in 39 patients (31%), showing undifferentiated tumour in only 6 (15%). 23 of the 127 patients (18%) failed to respond or developed recurrent disease after BEP; only 5 were successfully salvaged. Myelotoxicity of treatment was mild with grade 4 toxicity in 2% of chemotherapy courses and 3 episodes of neutropenic sepsis. Mean glomerular filtration rates fell by 15.6% between courses 1 and 4 of BEP. Bleomycin pneumonitis developed in 13% of cases with 1 fatality. So far 21 men have had children following chemotherapy, but semen analysis 12 months or more (median 36 months) after treatment showed azoospermia in 11 out of 54 (20%) men tested. BEP chemotherapy can be regarded as standard treatment for patients with metastatic NSGCT in low-risk categories, but more intensive therapy is required for advanced presentations. Strategies to develop “risk related” treatment are under investigation.

In a Japanese randomized trial, treatment with irinotecan+cisplatin in patients with SCLC-ED was associated with prolonged survival as compared to etoposide+cisplatin. The present trial was undertaken to evaluate the effects of irinotecan+carboplatin compared to etoposide+carboplatin. Patients with SCLC-ED were randomized to receive either etoposide, 120 mg/m2/day, orally, on days 1-5, plus carboplatin, AUC=4 (Chatelut formula) on day 1 (EC), or irinotecan, 175 mg/m2, plus carboplatin (Chatelut AUC=4), both on day 1 (IC). Treatments were repeated every 3 weeks, with 4 cycles planned. Primary endpoint was overall survival (OS), secondary were quality of life (QoL) evaluated by EORTC-QLQ-C30/LC13, and frequency of complete remissions (CR). No upper age nor performance status limits were applied. Between November, 2001 and July, 2005, 220 patients were randomized. 210 were eligible (EC 105, IC 105), while 10 were excluded due to wrong diagnosis (8), limited disease (1) or elevated liver enzymes (1). WHO performance status was: PS0: 20, PS1: 91, PS2: 62, PS3: 29, and PS4: 8 patients. Median age was 67 years (range 39-82). By 1st August, 2006, 192 patients had died (EC 100, IC 92). Median OS was 214 days in the EC group vs. 255 days in the IC group (P=0.04; HR 1.34, 95% CI 1.01-1.79). 1-year survival was 28% vs. 35%. CR was reported in 7 (EC) vs. 18 (IC) patients (P=0.02). There were no significant differences with respect to haematological grade III-IV toxicity, and no severe diarrhea was observed. Minor group differences were seen with regard to patient reported symptom palliation (i.e. sleep disturbance and dyspnea) and hair loss in favour of the IC group, while functioning and global QoL ratings over time were similar in both groups. Irinotecan+carboplatin is superior to oral etoposide+carboplatin with respect to overall survival in SCLC-ED, without compromising QoL.

7523 Background: A Japanese randomized trial has shown superior survival for SCLC-ED patients receiving irinotecan+cisplatin as compared to etoposide+cisplatin. Our trial was performed to evaluate the effect of irinotecan+carboplatin compared to oral etoposide+carboplatin. Patients and Methods: In a phase III trial, patients with SCLC-ED were randomly assigned to receive carboplatin, AUC=4 (Chatelut formula) and irinotecan, 175 mg/m2, both on day 1 (IC) or carboplatin (Chatelut AUC=4) on day 1 and etoposide 120 mg/m2/day, orally, on days 1–5 (EC). In both arms, courses were repeated on day 21 with 4 cycles planned. Primary endpoint was overall survival (OS), secondary endpoints were quality of life, evaluated by EORTC-QLQ-C30 and QLQ-LC 13, and complete response rate. There were neither upper limits for age or performance status. Results: Between November, 2001 and July, 2005, 220 patients were randomized. 210 patients were eligible for analysis (other type of cancer, 8 pts., limited disease, 1 pt., elevated liver function tests, 1 pt.). Performance status (PS) 0: 20 patients, PS 1: 91, PS 2: 62, PS 3: 29, PS 4: 8. Median age IC was 67 years (46–81), EC 67 years (39–82). OS was 255 days (IC) versus 214 days (EC) (P=0.04, log rank test). HR for overall survival was 1.34, 95% CI: 1.01–1.79. 1-year survival was 35% vs 28%. CR was observed in 18 patients in the IC arm and 7 patients in the EC arm (P=0.02, chi-square test). There were no statistically significant differences with respect to haematological grade III-IV toxicity. No severe diarrhea was observed in the IC group. There were no significant differences regarding quality of life. Conclusion: Irinotecan + carboplatin is superior to oral etoposide + carboplatin with respect to overall survival in SCLC-ED. No significant financial relationships to disclose.

BACKGROUND:The aim of this study was to examine satisfaction with the quality of the doctor-patient relationship (QCD) and the information (INF) made available, as well as the influence of different treatment modalities and psychosocial variables in testicular cancer survivors (TCSs).MATERIALS AND METHODS:Two-hundred and 6 TCSs, seen at 2 Norwegian university hospitals, were studied retrospectively and currently in a cross-sectional follow-up design. Questionnaires were filled in prior to and at the patients' follow-up examination. The mean length of time since their management period had ended was 6.5 years (range 0-17 years).RESULTS:The QCD was rated higher than the INF. The QCD was also the strongest contributor to the variance in the INF. The patients in the surveillance group had the lowest QCD.CONCLUSION:The relatively high QCD scores may reflect the fact that the patients had been cured from a life-threatening disease. The low INF scores may indicate that the TCSs were poorly informed about the potential health problems related to their treatment. Thus, it is suggested that more attention should be focused on the education of the patients.

To examine the effects of combined blockade of DNA-dependent protein kinase (DNA-PK) and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) on accelerated senescence in irradiated H460 and A549 non-small cell lung cancer cells.The effects of KU5788 and AG014699 (inhibitors of DNA-PK and PARP-1, respectively) on clonogenic survival, DNA double-strand breaks (DSBs), apoptosis, mitotic catastrophe, and accelerated senescence in irradiated cells were examined in vitro. For in vivo experiments, H460 xenografts established in athymic nude mice were treated with BEZ235 (a DNA-PK, ATM, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor) and AG014699 to determine effects on proliferation, DNA DSBs, and accelerated senescence after radiation.Compared with either inhibitor alone, combination treatment with KU57788 and AG014699 reduced postradiation clonogenic survival and significantly increased persistence of Gamma-H2AX (γH2AX) foci in irradiated H460 and A549 cells. Notably, these effects coincided with the induction of accelerated senescence in irradiated cells as reflected by positive β-galactosidase staining, G2-M cell-cycle arrest, enlarged and flattened cellular morphology, increased p21 expression, and senescence-associated cytokine secretion. In irradiated H460 xenografts, concurrent therapy with BEZ235 and AG014699 resulted in sustained Gamma-H2AX (γH2AX) staining and prominent β-galactosidase activity.Combined DNA-PK and PARP-1 blockade increased tumor cell radiosensitivity and enhanced the prosenescent properties of ionizing radiation in vitro and in vivo. These data provide a rationale for further preclinical and clinical testing of this therapeutic combination.

Background and purpose To compare the course of symptoms and health-related quality-of-life (HRQOL) after immediate thoracic radiotherapy (TRT) between symptomatic (S) and non-symptomatic (NS) patients with advanced NSCLC. Patients and methods 407 stage III/IV patients were initially treated with immediate TRT within a randomised phase III trial comparing different fractionation schedules. At inclusion, patients were prospectively stratified according to presence (S) or absence (NS) of tumour-related chest/airway symptoms to facilitate comparison between these groups. The EORTC QLQ-C30 and LC-13 were used for symptom and HRQOL assessments at baseline and at regular intervals up to 1 year (N=395). Results NS patients had significantly more favourable baseline characteristics when compared to S patients with a median survival of 11.8 versus 6.0 months (P<0.0001), respectively. At baseline, S patients demonstrated HRQOL scores inferior to those of NS patients (P<0.01) for most scales. Until week 14, NS patients developed more symptoms while S patients experienced symptom relief in most scales. After week 14, no significant differences could be observed between the groups. Conclusion This study indicates that immediate TRT, given to patients with minimal/none chest symptoms, does not prevent development of disease-related symptoms and diminished HRQOL. A wait-and-see policy appears to be acceptable.